20170910 History The International Council for Harmonisation (ICH), formerly the International Conference on Harmonisation (ICH) held the inaugural Assembly meetings on 23 October 2015 establishing ICH as an international association, a legal entity under Swiss law. This step built upon a 25-year track record of successful delivery of harmonised guidelines for global pharmaceutical development as well as their regulation, and a longer standing recognition of the need to harmonise. The Need to Harmonise The realisation that it was important to have an independent evaluation of medicinal products before they are allowed on the market was reached at different times in different regions. However in many cases the realisation was driven by tragedies, such as that with thalidomide in Europe in the 1960s. For most countries, whether or not they had initiated product registration controls earlier, the 1960s and 1970s saw a rapid increase in laws, regulations and guidelines for reporting and evaluating the data on safety, quality and efficacy of new medicinal products. The industry, at the time, was becoming more international and seeking new global markets; however the divergence in technical requirements from country to country was such that industry found it necessary to duplicate many time-consuming and expensive test procedures, in order to market new products, internationally. The urgent need to rationalise and harmonise regulation was impelled by concerns over rising costs of health care, escalation of the cost of R&D and the need to meet the public expectation that there should be a minimum of delay in making safe and efficacious new treatments available to patients in need. Initiation of ICH Harmonisation of regulatory requirements was pioneered by the European Community (EC), in the 1980s, as the EC (now the European Union) moved towards the development of a single market for pharmaceuticals. The success achieved in Europe demonstrated that harmonisation was feasible. At the same time there were discussions between Europe, Japan and the US on possibilities for harmonisation. It was, however, at the WHO Conference of Drug Regulatory Authorities (ICDRA), in Paris, in 1989, that specific plans for action began to materialise. Soon afterwards, the authorities approached International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) to discuss a joint regulatory-industry initiative on international harmonisation, and ICH was conceived. The birth of ICH took place at a meeting in April 1990, hosted by European Federation of Pharmaceutical Industries and Associations (EFPIA) in Brussels. Representatives of the regulatory agencies and industry associations of Europe, Japan and the US met, primarily, to plan an International Conference but the meeting also discussed the wider implications and terms of reference of ICH. At the first ICH Steering Committee meeting of ICH the Terms of Reference were agreed and it was decided that the Topics selected for harmonisation would be divided into Safety, Quality and Efficacy to reflect the three criteria which are the basis for approving and authorising new medicinal products.
Transcript
20170910
History The International Council for Harmonisation (ICH), formerly the International Conference on Harmonisation(ICH) held the inaugural Assembly meetings on 23 October 2015 establishing ICH as an international association, a legal entity under Swiss law.
This step built upon a 25-year track record of successful delivery of harmonised guidelines for global pharmaceutical development as well as theirregulation, and a longer standing recognition of the need to harmonise.
The Need to Harmonise
The realisation that it was important to have an independent evaluation of medicinal products before they areallowed on the market was reached at different times in different regions. However in many cases the realisationwas driven by tragedies, such as that with thalidomide in Europe in the 1960s.
For most countries, whether or not they had initiated product registration controls earlier, the 1960s and 1970ssaw a rapid increase in laws, regulations and guidelines for reporting and evaluating the data on safety, qualityand efficacy of new medicinal products. The industry, at the time, was becoming more international and seekingnew global markets; however the divergence in technical requirements from country to country was such thatindustry found it necessary to duplicate many time-consuming and expensive test procedures, in order to marketnew products, internationally.
The urgent need to rationalise and harmonise regulation was impelled by concerns over rising costs of healthcare, escalation of the cost of R&D and the need to meet the public expectation that there should be a minimumof delay in making safe and efficacious new treatments available to patients in need.
Initiation of ICH
Harmonisation of regulatory requirements was pioneered by the European Community (EC), in the 1980s, as theEC (now the European Union) moved towards the development of a single market for pharmaceuticals. Thesuccess achieved in Europe demonstrated that harmonisation was feasible. At the same time there werediscussions between Europe, Japan and the US on possibilities for harmonisation. It was, however, at the WHOConference of Drug Regulatory Authorities (ICDRA), in Paris, in 1989, that specific plans for action began tomaterialise. Soon afterwards, the authorities approached International Federation of PharmaceuticalManufacturers and Associations (IFPMA) to discuss a joint regulatory-industry initiative on internationalharmonisation, and ICH was conceived.
The birth of ICH took place at a meeting in April 1990, hosted by European Federation of PharmaceuticalIndustries and Associations (EFPIA) in Brussels. Representatives of the regulatory agencies and industryassociations of Europe, Japan and the US met, primarily, to plan an International Conference but the meetingalso discussed the wider implications and terms of reference of ICH.
At the first ICH Steering Committee meeting of ICH the Terms of Reference were agreed and it was decided thatthe Topics selected for harmonisation would be divided into Safety, Quality and Efficacy to reflect the threecriteria which are the basis for approving and authorising new medicinal products.
Since ICH's inception in 1990, the ICH process has gradually evolved. ICH's first decade saw significantprogress in the development of ICH Guidelines on Safety, Quality and Efficacy topics. Work was alsoundertaken on a number of important multidisciplinary topics, which included MedDRA (Medical Dictionary forRegulatory Activities) and the CTD (Common Technical Document). As ICH started into a new millennium, theneed to expand communication and dissemination of information on ICH Guidelines with non-ICH regionsbecame a key focus. Attention was also directed throughout the second decade towards facilitating theimplementation of ICH Guidelines in ICH's own regions and maintaining already existing ICH Guidelines asscience and technology continued to evolve.
Now in its third decade of activity, ICH's attention is directed towards extending the benefits of harmonisationbeyond the founding ICH regions. A significant step was taken in 2015 to facilitate this which saw ICHundergoing a series of organisational changes. These changes constituted a number of reforms including:increasing international outreach; changing ICH’s governance structure; disseminating more information on ICHprocesses to a wider number of stakeholders; and establishing ICH as a legal entity to provide for a more stableoperating structure.
The resulting ICH association establishes an Assembly as the over-arching governing body with the aim offocusing global pharmaceutical regulatory harmonisation work in one venue that allows pharmaceuticalregulatory authorities and notably concerned industry organisations to be more actively involved in ICH’sharmonisation work.
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INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE
ICH HARMONISED GUIDELINE
INTEGRATED ADDENDUM TO ICH E6(R1): GUIDELINE FOR GOOD CLINICAL PRACTICE
E6(R2)
Current Step 2 version
dated 11 June 2015
At Step 2 of the ICH Process, a consensus draft text or guideline, agreed by the appropriate ICH Expert Working Group, is transmitted by the ICH Steering Committee to the regulatory authorities of the ICH regions (the European Union, Japan, the USA, Health Canada and Switzerland) for internal and external consultation, according to national or regional procedures.
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E6(R1) Document History
First Codification
History Date
New Codification
November 2005
E6 Approval by the Steering Committee under Step 2 and release for public consultation.
27 April 1995
E6
E6 Approval by the Steering Committee under Step 4 and recommended for adoption to the three ICH regulatory bodies.
1 May 1996
E6
E6(R1) Step 4 version
E6 Approval by the Steering Committee of Post-Step 4 10 E6(R1) editorial corrections. June
1996
Current E6(R2) Addendum Step 2 version
Code History Date E6(R2) Approval by the Steering Committee under Step 2 and release for
public consultation.
Integrated Addendum to ICH E6(R1) document. Changes are integrated directly into the following sections of the parental Guideline: Introduction, 1.11.1, 1.38.1, 1.39, 1.60.1, 2.10, 4.2.5, 4.2.6, 4.9.0, 5.0, 5.0.1, 5.0.2, 5.0.3, 5.0.4, 5.0.5, 5.0.6, 5.0.7, 5.2.1, 5.2.2, 5.5.3 (b), 5.5.3 (h), 5.18.3, 5.18.6 (e), 5.18.7, 5.20.1, 8.1
11 June 2015
Legal notice: This document is protected by copyright and may be used, reproduced, incorporated into other works, adapted, modified, translated or distributed under a public license provided that ICH's copyright in the document is acknowledged at all times. In case of any adaption, modification or translation of the document, reasonable steps must be taken to clearly label, demarcate or otherwise identify that changes were made to or based on the original document. Any impression that the adaption, modification or translation of the original document is endorsed or sponsored by the ICH must be avoided. The document is provided "as is" without warranty of any kind. In no event shall the ICH or the authors of the original document be liable for any claim, damages or other liability arising from the use of the document. The above-mentioned permissions do not apply to content supplied by third parties. Therefore, for documents where the copyright vests in a third party, permission for reproduction must be obtained from this copyright holder.
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ICH HARMONISED GUIDELINE
INTEGRATED ADDENDUM TO ICH E6(R1): GUIDELINE FOR GOOD CLINICAL PRACTICE ICH
E6(R2)
Draft ICH Consensus Guideline Released for Consultation on 11 June 2015, at Step 2 of the ICH Process
8.2 Before the Clinical Phase of the Trial Commences .......................................................47
8.3 During the Clinical Conduct of the Trial .....................................................................53
8.4 After Completion or Termination of the Trial ..............................................................59
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INTEGRATED ADDENDUM TO ICH E6(R1): GUIDELINE FOR GOOD CLINICAL PRACTICE ICH
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INTRODUCTION
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.
The objective of this ICH GCP Guideline is to provide a unified standard for the European Union (EU), Japan and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions.
The guideline was developed with consideration of the current good clinical practices of the European Union, Japan, and the United States, as well as those of Australia, Canada, the Nordic countries and the World Health Organization (WHO).
This guideline should be followed when generating clinical trial data that are intended to be submitted to regulatory authorities.
The principles established in this guideline may also be applied to other clinical investigations that may have an impact on the safety and well-being of human subjects.
ADDENDUM
Since the development of the ICH GCP Guideline, the scale, complexity, and cost of clinical trials have increased. Evolutions in technology and risk management processes offer new opportunities to increase efficiency and focus on relevant activities. This guideline has been amended to encourage implementation of improved and more efficient approaches to clinical trial design, conduct, oversight, recording and reporting while continuing to ensure human subject protection and data integrity. Standards regarding electronic records and essential documents intended to increase clinical trial quality and efficiency have also been updated.
This ICH GCP Guideline integrated Addendum provides a unified standard for the European Union (EU), Japan, the United States, Canada and Switzerland to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions.
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31 1. GLOSSARY
32 1.1 Adverse Drug Reaction (ADR)
33 In the pre-approval clinical experience with a new medicinal product or its new usages, 34 particularly as the therapeutic dose(s) may not be established: all noxious and unintended
responses to a medicinal product related to any dose should be considered adverse drug 36 reactions. The phrase responses to a medicinal product means that a causal relationship 37 between a medicinal product and an adverse event is at least a reasonable possibility, i.e., the 38 relationship cannot be ruled out.
39 Regarding marketed medicinal products: a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or
41 therapy of diseases or for modification of physiological function (see the ICH Guideline for 42 Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).
43 1.2 Adverse Event (AE)
44 Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this
46 treatment. An adverse event (AE) can therefore be any unfavourable and unintended sign 47 (including an abnormal laboratory finding), symptom, or disease temporally associated with 48 the use of a medicinal (investigational) product, whether or not related to the medicinal 49 (investigational) product (see the ICH Guideline for Clinical Safety Data Management:
Definitions and Standards for Expedited Reporting).
51 1.3 Amendment (to the protocol)
52 See Protocol Amendment.
53 1.4 Applicable Regulatory Requirement(s)
54 Any law(s) and regulation(s) addressing the conduct of clinical trials of investigational products.
56 1.5 Approval (in relation to Institutional Review Boards)
57 The affirmative decision of the IRB that the clinical trial has been reviewed and may be 58 conducted at the institution site within the constraints set forth by the IRB, the institution, 59 Good Clinical Practice (GCP), and the applicable regulatory requirements.
1.6 Audit
61 A systematic and independent examination of trial related activities and documents to 62 determine whether the evaluated trial related activities were conducted, and the data were 63 recorded, analyzed and accurately reported according to the protocol, sponsor's standard 64 operating procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory
requirement(s).
66 1.7 Audit Certificate
67 A declaration of confirmation by the auditor that an audit has taken place.
68 1.8 Audit Report
69 A written evaluation by the sponsor's auditor of the results of the audit.
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1.9 Audit Trail
Documentation that allows reconstruction of the course of events.
1.10 Blinding/Masking
A procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s). Single-blinding usually refers to the subject(s) being unaware, and double-blinding usually refers to the subject(s), investigator(s), monitor, and, in some cases, data analyst(s) being unaware of the treatment assignment(s).
1.11 Case Report Form (CRF)
A printed, optical, or electronic document designed to record all of the protocol required information to be reported to the sponsor on each trial subject.
ADDENDUM
1.11.1 Certified Copy
A paper or electronic copy of the original record that has been verified (e.g., by a dated signature) or has been generated through a validated process to produce an exact copy having all of the same attributes and information as the original.
1.12 Clinical Trial/Study
Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy. The terms clinical trial and clinical study are synonymous.
1.13 Clinical Trial/Study Report
A written description of a trial/study of any therapeutic, prophylactic, or diagnostic agent conducted in human subjects, in which the clinical and statistical description, presentations, and analyses are fully integrated into a single report (see the ICH Guideline for Structure and Content of Clinical Study Reports).
1.14 Comparator (Product)
An investigational or marketed product (i.e., active control), or placebo, used as a reference in a clinical trial.
1.15 Compliance (in relation to trials)
Adherence to all the trial-related requirements, Good Clinical Practice (GCP) requirements, and the applicable regulatory requirements.
1.16 Confidentiality
Prevention of disclosure, to other than authorized individuals, of a sponsor's proprietary information or of a subject's identity.
1.17 Contract
A written, dated, and signed agreement between two or more involved parties that sets out any arrangements on delegation and distribution of tasks and obligations and, if appropriate, on financial matters. The protocol may serve as the basis of a contract.
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1.18 Coordinating Committee
A committee that a sponsor may organize to coordinate the conduct of a multicentre trial.
1.19 Coordinating Investigator
An investigator assigned the responsibility for the coordination of investigators at different centres participating in a multicentre trial.
1.20 Contract Research Organization (CRO)
A person or an organization (commercial, academic, or other) contracted by the sponsor to perform one or more of a sponsor's trial-related duties and functions.
1.21 Direct Access
Permission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a clinical trial. Any party (e.g., domestic and foreign regulatory authorities, sponsor's monitors and auditors) with direct access should take all reasonable precautions within the constraints of the applicable regulatory requirement(s) to maintain the confidentiality of subjects' identities and sponsor’s proprietary information.
1.22 Documentation
All records, in any form (including, but not limited to, written, electronic, magnetic, and optical records, and scans, x-rays, and electrocardiograms) that describe or record the methods, conduct, and/or results of a trial, the factors affecting a trial, and the actions taken.
1.23 Essential Documents
Documents which individually and collectively permit evaluation of the conduct of a study and the quality of the data produced (see 8. Essential Documents for the Conduct of a Clinical Trial).
1.24 Good Clinical Practice (GCP)
A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected.
1.25 Independent Data-Monitoring Committee (IDMC) (Data and Safety Monitoring Board, Monitoring Committee, Data Monitoring Committee)
An independent data-monitoring committee that may be established by the sponsor to assess at intervals the progress of a clinical trial, the safety data, and the critical efficacy endpoints, and to recommend to the sponsor whether to continue, modify, or stop a trial.
1.26 Impartial Witness
A person, who is independent of the trial, who cannot be unfairly influenced by people involved with the trial, who attends the informed consent process if the subject or the subject’s legally acceptable representative cannot read, and who reads the informed consent form and any other written information supplied to the subject.
1.27 Independent Ethics Committee (IEC)
An independent body (a review board or a committee, institutional, regional, national, or supranational), constituted of medical professionals and non-medical members, whose responsibility it is to ensure the protection of the rights, safety and well-being of human
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subjects involved in a trial and to provide public assurance of that protection, by, among other things, reviewing and approving/providing favourable opinion on, the trial protocol, the suitability of the investigator(s), facilities, and the methods and material to be used in obtaining and documenting informed consent of the trial subjects.
The legal status, composition, function, operations and regulatory requirements pertaining to Independent Ethics Committees may differ among countries, but should allow the Independent Ethics Committee to act in agreement with GCP as described in this guideline.
1.28 Informed Consent
A process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject's decision to participate. Informed consent is documented by means of a written, signed and dated informed consent form.
1.29 Inspection
The act by a regulatory authority(ies) of conducting an official review of documents, facilities, records, and any other resources that are deemed by the authority(ies) to be related to the clinical trial and that may be located at the site of the trial, at the sponsor's and/or contract research organization’s (CRO’s) facilities, or at other establishments deemed appropriate by the regulatory authority(ies).
1.30 Institution (medical)
Any public or private entity or agency or medical or dental facility where clinical trials are conducted.
1.31 Institutional Review Board (IRB)
An independent body constituted of medical, scientific, and non-scientific members, whose responsibility is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial by, among other things, reviewing, approving, and providing continuing review of trial protocol and amendments and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects.
1.32 Interim Clinical Trial/Study Report
A report of intermediate results and their evaluation based on analyses performed during the course of a trial.
1.33 Investigational Product
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use.
1.34 Investigator
A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator. See also Subinvestigator.
1.35 Investigator/Institution
An expression meaning "the investigator and/or institution, where required by the applicable regulatory requirements".
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1.36 Investigator's Brochure
A compilation of the clinical and nonclinical data on the investigational product(s) which is relevant to the study of the investigational product(s) in human subjects (see 7. Investigator’s Brochure).
1.37 Legally Acceptable Representative
An individual or juridical or other body authorized under applicable law to consent, on behalf of a prospective subject, to the subject's participation in the clinical trial.
1.38 Monitoring
The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).
ADDENDUM
1.38.1 Monitoring Plan
A description of the methods, responsibilities and requirements for monitoring the trial.
1.39 Monitoring Report
A written report from the monitor to the sponsor after each site visit and/or other trial-related communication according to the sponsor’s SOPs.
ADDENDUM
Outcomes of any centralized monitoring should also be reported.
1.40 Multicentre Trial
A clinical trial conducted according to a single protocol but at more than one site, and therefore, carried out by more than one investigator.
1.41 Nonclinical Study
Biomedical studies not performed on human subjects.
1.42 Opinion (in relation to Independent Ethics Committee)
The judgement and/or the advice provided by an Independent Ethics Committee (IEC).
1.43 Original Medical Record
See Source Documents.
1.44 Protocol
A document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial. The protocol usually also gives the background and rationale for the trial, but these could be provided in other protocol referenced documents. Throughout the ICH GCP Guideline the term protocol refers to protocol and protocol amendments.
1.45 Protocol Amendment
A written description of a change(s) to or formal clarification of a protocol.
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1.46 Quality Assurance (QA)
All those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented (recorded), and reported in compliance with Good Clinical Practice (GCP) and the applicable regulatory requirement(s).
1.47 Quality Control (QC)
The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled.
1.48 Randomization
The process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce bias.
1.49 Regulatory Authorities
Bodies having the power to regulate. In the ICH GCP Guideline the expression Regulatory Authorities includes the authorities that review submitted clinical data and those that conduct inspections (see 1.29). These bodies are sometimes referred to as competent authorities.
1.50 Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR)
Any untoward medical occurrence that at any dose:
- results in death,
- is life-threatening,
- requires inpatient hospitalization or prolongation of existing hospitalization,
- results in persistent or significant disability/incapacity,
or
- is a congenital anomaly/birth defect
(see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).
1.51 Source Data
All information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies).
1.52 Source Documents
Original documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects' diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical trial).
1.53 Sponsor
An individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial.
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1.54 Sponsor-Investigator
An individual who both initiates and conducts, alone or with others, a clinical trial, and under whose immediate direction the investigational product is administered to, dispensed to, or used by a subject. The term does not include any person other than an individual (e.g., it does not include a corporation or an agency). The obligations of a sponsor-investigator include both those of a sponsor and those of an investigator.
1.55 Standard Operating Procedures (SOPs)
Detailed, written instructions to achieve uniformity of the performance of a specific function.
1.56 Subinvestigator
Any individual member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial-related procedures and/or to make important trial-related decisions (e.g., associates, residents, research fellows). See also Investigator.
1.57 Subject/Trial Subject
An individual who participates in a clinical trial, either as a recipient of the investigational product(s) or as a control.
1.58 Subject Identification Code
A unique identifier assigned by the investigator to each trial subject to protect the subject's identity and used in lieu of the subject's name when the investigator reports adverse events and/or other trial related data.
1.59 Trial Site
The location(s) where trial-related activities are actually conducted.
1.60 Unexpected Adverse Drug Reaction
An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator's Brochure for an unapproved investigational product or package insert/summary of product characteristics for an approved product) (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).
ADDENDUM
1.60.1 Validation of computerized systems
A process of establishing and documenting that the specified requirements of a computerized system can be consistently fulfilled. Validation should ensure accuracy, reliability and consistent intended performance, from design until decommissioning of the system or transition to a new system.
1.61 Vulnerable Subjects
Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects include patients with incurable diseases, persons in nursing homes,
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311 unemployed or impoverished persons, patients in emergency situations, ethnic minority 312 groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.
313 1.62 Well-being (of the trial subjects)
314 The physical and mental integrity of the subjects participating in a clinical trial.
2. THE PRINCIPLES OF ICH GCP
316 2.1 Clinical trials should be conducted in accordance with the ethical principles that have 317 their origin in the Declaration of Helsinki, and that are consistent with GCP and the 318 applicable regulatory requirement(s).
319 2.2 Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial
321 should be initiated and continued only if the anticipated benefits justify the risks.
322 2.3 The rights, safety, and well-being of the trial subjects are the most important 323 considerations and should prevail over interests of science and society.
324 2.4 The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial.
326 2.5 Clinical trials should be scientifically sound, and described in a clear, detailed 327 protocol.
328 2.6 A trial should be conducted in compliance with the protocol that has received prior 329 institutional review board (IRB)/independent ethics committee (IEC)
approval/favourable opinion.
331 2.7 The medical care given to, and medical decisions made on behalf of, subjects should 332 always be the responsibility of a qualified physician or, when appropriate, of a 333 qualified dentist.
334 2.8 Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s).
336 2.9 Freely given informed consent should be obtained from every subject prior to clinical 337 trial participation.
338 2.10 All clinical trial information should be recorded, handled, and stored in a way that 339 allows its accurate reporting, interpretation and verification.
ADDENDUM
341 This principle applies to all records (paper or electronic) referenced in this guideline.
342 2.11 The confidentiality of records that could identify subjects should be protected, 343 respecting the privacy and confidentiality rules in accordance with the applicable 344 regulatory requirement(s).
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2.12 Investigational products should be manufactured, handled, and stored in accordance 346 with applicable good manufacturing practice (GMP). They should be used in 347 accordance with the approved protocol.
348 2.13 Systems with procedures that assure the quality of every aspect of the trial should be 349 implemented.
353 3.1.1 An IRB/IEC should safeguard the rights, safety, and well-being of all trial subjects. 354 Special attention should be paid to trials that may include vulnerable subjects.
3.1.2 The IRB/IEC should obtain the following documents:
356 trial protocol(s)/amendment(s), written informed consent form(s) and consent form 357 updates that the investigator proposes for use in the trial, subject recruitment 358 procedures (e.g., advertisements), written information to be provided to subjects, 359 Investigator's Brochure (IB), available safety information, information about payments
and compensation available to subjects, the investigator’s current curriculum vitae 361 and/or other documentation evidencing qualifications, and any other documents that 362 the IRB/IEC may need to fulfil its responsibilities.
363 The IRB/IEC should review a proposed clinical trial within a reasonable time and 364 document its views in writing, clearly identifying the trial, the documents reviewed
and the dates for the following:
366 - approval/favourable opinion;
367 - modifications required prior to its approval/favourable opinion;
368 - disapproval / negative opinion; and
369 - termination/suspension of any prior approval/favourable opinion.
3.1.3 The IRB/IEC should consider the qualifications of the investigator for the proposed 371 trial, as documented by a current curriculum vitae and/or by any other relevant 372 documentation the IRB/IEC requests.
373 3.1.4 The IRB/IEC should conduct continuing review of each ongoing trial at intervals 374 appropriate to the degree of risk to human subjects, but at least once per year.
3.1.5 The IRB/IEC may request more information than is outlined in paragraph 4.8.10 be 376 given to subjects when, in the judgement of the IRB/IEC, the additional information 377 would add meaningfully to the protection of the rights, safety and/or well-being of the 378 subjects.
379 3.1.6 When a non-therapeutic trial is to be carried out with the consent of the subject’s legally acceptable representative (see 4.8.12, 4.8.14), the IRB/IEC should determine
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that the proposed protocol and/or other document(s) adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such trials.
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3.1.7 Where the protocol indicates that prior consent of the trial subject or the subject’s legally acceptable representative is not possible (see 4.8.15), the IRB/IEC should
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determine that the proposed protocol and/or other document(s) adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such trials (i.e., in emergency situations).
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3.1.8 The IRB/IEC should review both the amount and method of payment to subjects to assure that neither presents problems of coercion or undue influence on the trial
391 subjects. Payments to a subject should be prorated and not wholly contingent on completion of the trial by the subject.
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3.1.9 The IRB/IEC should ensure that information regarding payment to subjects, including the methods, amounts, and schedule of payment to trial subjects, is set forth in the written informed consent form and any other written information to be provided to subjects. The way payment will be prorated should be specified.
396 3.2 Composition, Functions and Operations
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3.2.1 The IRB/IEC should consist of a reasonable number of members, who collectively have the qualifications and experience to review and evaluate the science, medical aspects, and ethics of the proposed trial. It is recommended that the IRB/IEC should include:
401 (a) At least five members.
402 (b) At least one member whose primary area of interest is in a nonscientific area.
403 (c) At least one member who is independent of the institution/trial site.
404 Only those IRB/IEC members who are independent of the investigator and the sponsor of the trial should vote/provide opinion on a trial-related matter.
406 A list of IRB/IEC members and their qualifications should be maintained.
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3.2.2 The IRB/IEC should perform its functions according to written operating procedures, should maintain written records of its activities and minutes of its meetings, and should comply with GCP and with the applicable regulatory requirement(s).
411 3.2.3 An IRB/IEC should make its decisions at announced meetings at which at least a
quorum, as stipulated in its written operating procedures, is present.
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3.2.4 Only members who participate in the vote/provide their opinion and/or advise.
IRB/IEC review and discussion should
414 3.2.5 The investigator may provide information on any aspect of the trial, but should not participate in the deliberations of the IRB/IEC or in the vote/opinion of the IRB/IEC.
416 3.2.6 An IRB/IEC may invite nonmembers with expertise in special areas for assistance.
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3.3 Procedures
The IRB/IEC should establish, document in writing, and follow its procedures, which should include:
3.3.1 Determining its composition (names and qualifications of the members) and the authority under which it is established.
3.3.2 Scheduling, notifying its members of, and conducting its meetings.
3.3.3 Conducting initial and continuing review of trials.
3.3.4 Determining the frequency of continuing review, as appropriate.
3.3.5 Providing, according to the applicable regulatory requirements, expedited review and approval/favourable opinion of minor change(s) in ongoing trials that have the approval/favourable opinion of the IRB/IEC.
3.3.6 Specifying that no subject should be admitted to a trial before the IRB/IEC issues its written approval/favourable opinion of the trial.
3.3.7 Specifying that no deviations from, or changes of, the protocol should be initiated without prior written IRB/IEC approval/favourable opinion of an appropriate amendment, except when necessary to eliminate immediate hazards to the subjects or when the change(s) involves only logistical or administrative aspects of the trial (e.g., change of monitor(s), telephone number(s)) (see 4.5.2).
3.3.8 Specifying that the investigator should promptly report to the IRB/IEC:
(a) Deviations from, or changes of, the protocol to eliminate immediate hazards to the trial subjects (see 3.3.7, 4.5.2, 4.5.4).
(b) Changes increasing the risk to subjects and/or affecting significantly the conduct of the trial (see 4.10.2).
(c) All adverse drug reactions (ADRs) that are both serious and unexpected.
(d) New information that may affect adversely the safety of the subjects or the conduct of the trial.
3.3.9 Ensuring that the IRB/IEC promptly notify in writing the investigator/institution concerning:
(a) Its trial-related decisions/opinions.
(b) The reasons for its decisions/opinions.
(c) Procedures for appeal of its decisions/opinions.
3.4 Records
The IRB/IEC should retain all relevant records (e.g., written procedures, membership lists, lists of occupations/affiliations of members, submitted documents, minutes of meetings, and correspondence) for a period of at least 3-years after completion of the trial and make them available upon request from the regulatory authority(ies).
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453 The IRB/IEC may be asked by investigators, sponsors or regulatory authorities to provide its 454 written procedures and membership lists.
4. INVESTIGATOR
456 4.1 Investigator's Qualifications and Agreements
457 4.1.1 The investigator(s) should be qualified by education, training, and experience to 458 assume responsibility for the proper conduct of the trial, should meet all the 459 qualifications specified by the applicable regulatory requirement(s), and should
provide evidence of such qualifications through up-to-date curriculum vitae and/or 461 other relevant documentation requested by the sponsor, the IRB/IEC, and/or the 462 regulatory authority(ies).
463 4.1.2 The investigator should be thoroughly familiar with the appropriate use of the 464 investigational product(s), as described in the protocol, in the current Investigator's
Brochure, in the product information and in other information sources provided by the 466 sponsor.
467 4.1.3 The investigator should be aware of, and should comply with, GCP and the applicable 468 regulatory requirements.
469 4.1.4 The investigator/institution should permit monitoring and auditing by the sponsor, and inspection by the appropriate regulatory authority(ies).
471 4.1.5 The investigator should maintain a list of appropriately qualified persons to whom the 472 investigator has delegated significant trial-related duties.
473 4.2 Adequate Resources
474 4.2.1 The investigator should be able to demonstrate (e.g., based on retrospective data) a potential for recruiting the required number of suitable subjects within the agreed
476 recruitment period.
477 4.2.2 The investigator should have sufficient time to properly conduct and complete the trial 478 within the agreed trial period.
479 4.2.3 The investigator should have available an adequate number of qualified staff and adequate facilities for the foreseen duration of the trial to conduct the trial properly and
481 safely.
482 4.2.4 The investigator should ensure that all persons assisting with the trial are adequately 483 informed about the protocol, the investigational product(s), and their trial-related 484 duties and functions.
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ADDENDUM
4.2.5 The investigator is responsible for supervising any individual or party to whom the investigator delegates study tasks conducted at the trial site.
4.2.6 If the investigator/institution retains the services of any party to perform study tasks they should ensure this party is qualified to perform those study tasks and should implement procedures to ensure the integrity of the study tasks performed and any data generated.
4.3 Medical Care of Trial Subjects
4.3.1 A qualified physician (or dentist, when appropriate), who is an investigator or a sub-investigator for the trial, should be responsible for all trial-related medical (or dental) decisions.
4.3.2 During and following a subject's participation in a trial, the investigator/institution should ensure that adequate medical care is provided to a subject for any adverse events, including clinically significant laboratory values, related to the trial. The investigator/institution should inform a subject when medical care is needed for intercurrent illness(es) of which the investigator becomes aware.
4.3.3 It is recommended that the investigator inform the subject's primary physician about the subject's participation in the trial if the subject has a primary physician and if the subject agrees to the primary physician being informed.
4.3.4 Although a subject is not obliged to give his/her reason(s) for withdrawing prematurely from a trial, the investigator should make a reasonable effort to ascertain the reason(s), while fully respecting the subject's rights.
4.4 Communication with IRB/IEC
4.4.1 Before initiating a trial, the investigator/institution should have written and dated approval/favourable opinion from the IRB/IEC for the trial protocol, written informed consent form, consent form updates, subject recruitment procedures (e.g., advertisements), and any other written information to be provided to subjects.
4.4.2 As part of the investigator's/institution’s written application to the IRB/IEC, the investigator/institution should provide the IRB/IEC with a current copy of the Investigator's Brochure. If the Investigator's Brochure is updated during the trial, the investigator/institution should supply a copy of the updated Investigator’s Brochure to the IRB/IEC.
4.4.3 During the trial the investigator/institution should provide to the IRB/IEC all documents subject to review.
4.5 Compliance with Protocol
4.5.1 The investigator/institution should conduct the trial in compliance with the protocol agreed to by the sponsor and, if required, by the regulatory authority(ies) and which was given approval/favourable opinion by the IRB/IEC. The investigator/institution
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524 and the sponsor should sign the protocol, or an alternative contract, to confirm agreement.
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4.5.2 The investigator should not implement any deviation from, or changes of the protocol without agreement by the sponsor and prior review and documented approval/favourable opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to trial subjects, or when the change(s)
531 involves only logistical or administrative monitor(s), change of telephone number(s)).
aspects of the trial (e.g., change in
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4.5.3 The investigator, or person designated by the investigator, should document and explain any deviation from the approved protocol.
534 4.5.4 The investigator may implement a deviation from, or a change of, the protocol to
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eliminate an immediate hazard(s) to trial subjects without prior IRB/IEC approval/favourable opinion. As soon as possible, the implemented deviation or change, the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be submitted:
539 (a) to the IRB/IEC for review and approval/favourable opinion,
(b) to the sponsor for agreement and, if required,
541 (c) to the regulatory authority(ies).
542 4.6 Investigational Product(s)
543 544
4.6.1 Responsibility for investigational product(s) accountability at the trial site(s) rests with the investigator/institution.
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4.6.2 Where allowed/required, the investigator/institution may/should assign some or all of the investigator's/institution’s duties for investigational product(s) accountability at the trial site(s) to an appropriate pharmacist or another appropriate individual who is under the supervision of the investigator/institution..
549 4.6.3 The investigator/institution and/or a pharmacist or other appropriate individual, who is
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designated by the investigator/institution, should maintain records of the product's delivery to the trial site, the inventory at the site, the use by each subject, and the return to the sponsor or alternative disposition of unused product(s). These records should include dates, quantities, batch/serial numbers, expiration dates (if applicable), and the unique code numbers assigned to the investigational product(s) and trial
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subjects. Investigators should maintain records that document adequately that the subjects were provided the doses specified by the protocol and reconcile all investigational product(s) received from the sponsor.
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4.6.4 The investigational product(s) should be stored as specified by the sponsor (see 5.13.2 and 5.14.3) and in accordance with applicable regulatory requirement(s).
561 4.6.5 The investigator should ensure that the investigational product(s) are used only in
accordance with the approved protocol.
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4.6.6 The investigator, or a person designated by the investigator/institution, should explain the correct use of the investigational product(s) to each subject and should check, at intervals appropriate for the trial, that each subject is following the instructions properly.
566 4.7 Randomization Procedures and Unblinding
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The investigator should follow the trial's randomization procedures, if any, and should ensure that the code is broken only in accordance with the protocol. If the trial is blinded, the investigator should promptly document and explain to the sponsor any premature unblinding
571 (e.g., accidental unblinding, unblinding due to a serious adverse event) of the investigational product(s).
572 4.8 Informed Consent of Trial Subjects
573 574
4.8.1 In obtaining and documenting informed consent, the investigator should comply with the applicable regulatory requirement(s), and should adhere to GCP and to the ethical
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principles that have their origin in the Declaration of Helsinki. Prior to the beginning of the trial, the investigator should have the IRB/IEC's written approval/favourable opinion of the written informed consent form and any other written information to be provided to subjects.
579 4.8.2 The written informed consent form and any other written information to be provided to
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subjects should be revised whenever important new information becomes available that may be relevant to the subject’s consent. Any revised written informed consent form, and written information should receive the IRB/IEC's approval/favourable opinion in advance of use. The subject or the subject’s legally acceptable representative should be informed in a timely manner if new information becomes
586 available that may be relevant to the subject’s willingness to continue participation in the trial. The communication of this information should be documented.
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4.8.3 Neither the investigator, nor the trial staff, should coerce or unduly influence a subject to participate or to continue to participate in a trial.
589 4.8.4 None of the oral and written information concerning the trial, including the written
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informed consent form, should contain any language that causes the subject or the subject's legally acceptable representative to waive or to appear to waive any legal rights, or that releases or appears to release the investigator, the institution, the sponsor, or their agents from liability for negligence.
594 4.8.5 The investigator, or a person designated by the investigator, should fully inform the
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subject or, if the subject is unable to provide informed consent, the subject's legally acceptable representative, of all pertinent aspects of the trial including the written information and the approval/ favourable opinion by the IRB/IEC.
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4.8.6 The language used in the oral and written information about the trial, including the written informed consent form, should be as non-technical as practical and should be
601 understandable to the subject or the subject's legally acceptable representative and the impartial witness, where applicable.
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4.8.7 Before informed consent may be obtained, the investigator, or a person designated by the investigator, should provide the subject or the subject's legally acceptable representative ample time and opportunity to inquire about details of the trial and to
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decide whether or not to participate in the trial. All questions about the trial should be answered to the satisfaction of the subject or the subject's legally acceptable representative.
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4.8.8 Prior to a subject’s participation in the trial, the written informed consent form should be signed and personally dated by the subject or by the subject's legally acceptable representative, and by the person who conducted the informed consent discussion.
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4.8.9 If a subject is unable to read or if a legally acceptable representative is unable to read, an impartial witness should be present during the entire informed consent discussion. After the written informed consent form and any other written information to be provided to subjects, is read and explained to the subject or the subject’s legally
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acceptable representative, and after the subject or the subject’s legally acceptable representative has orally consented to the subject’s participation in the trial and, if capable of doing so, has signed and personally dated the informed consent form, the witness should sign and personally date the consent form. By signing the consent form, the witness attests that the information in the consent form and any other written
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information was accurately explained to, and apparently understood by, the subject or the subject's legally acceptable representative, and that informed consent was freely given by the subject or the subject’s legally acceptable representative.
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4.8.10 Both the informed consent discussion and the written informed consent form and any other written information to be provided to subjects should include explanations of the following:
626 (a) That the trial involves research.
627 (b) The purpose of the trial.
628 (c) The trial treatment(s) and the probability for random assignment to each treatment.
629 (d) The trial procedures to be followed, including all invasive procedures.
(e) The subject's responsibilities.
631 (f) Those aspects of the trial that are experimental.
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(g) The reasonably foreseeable risks or inconveniences to the subject and, when applicable, to an embryo, fetus, or nursing infant.
634 (h) The reasonably expected benefits. When there is no intended clinical benefit to the subject, the subject should be made aware of this.
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(i) The alternative procedure(s) or course(s) of treatment that may be available to the subject, and their important potential benefits and risks.
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(j) The compensation and/or treatment available to the subject in the event of trial-related injury.
641 (k) The anticipated prorated payment, if any, to the subject for participating in the
trial.
642 (l) The anticipated expenses, if any, to the subject for participating in the trial.
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(m) That the subject's participation in the trial is voluntary and that the subject may refuse to participate or withdraw from the trial, at any time, without penalty or loss of benefits to which the subject is otherwise entitled.
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(n) That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be granted direct access to the subject's original medical records for verification of clinical trial procedures and/or data, without violating the confidentiality of the subject, to the extent permitted by the applicable laws and
651 regulations and that, by signing a written informed consent form, the subject or the subject's legally acceptable representative is authorizing such access.
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(o) That records identifying the subject will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly available. If the results of the trial are published, the subject’s identity will remain confidential.
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(p) That the subject or the subject's legally acceptable representative will be informed in a timely manner if information becomes available that may be relevant to the subject's willingness to continue participation in the trial.
659 (q) The person(s) to contact for further information regarding the trial and the rights of trial subjects, and whom to contact in the event of trial-related injury.
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(r) The foreseeable circumstances and/or reasons participation in the trial may be terminated.
under which the subject's
663 (s) The expected duration of the subject's participation in the trial.
664 (t) The approximate number of subjects involved in the trial.
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4.8.11 Prior to participation in the trial, the subject or the subject's legally acceptable representative should receive a copy of the signed and dated written informed consent form and any other written information provided to the subjects. During a subject’s participation in the trial, the subject or the subject’s legally acceptable representative should receive a copy of the signed and dated consent form updates and a copy of any amendments to the written information provided to subjects.
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4.8.12 When a clinical trial (therapeutic or non-therapeutic) includes subjects who can only be enrolled in the trial with the consent of the subject’s legally acceptable representative (e.g., minors, or patients with severe dementia), the subject should be informed about the trial to the extent compatible with the subject’s understanding and, if capable, the subject should sign and personally date the written informed consent.
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4.8.13 Except as described in 4.8.14, a non-therapeutic trial (i.e., a trial in which there is no anticipated direct clinical benefit to the subject), should be conducted in subjects who personally give consent and who sign and date the written informed consent form.
679 4.8.14 Non-therapeutic trials may be conducted in subjects with consent of a legally acceptable representative provided the following conditions are fulfilled:
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(a) The objectives of the trial can not be met by means of a trial in subjects who can give informed consent personally.
683 (b) The foreseeable risks to the subjects are low.
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(c) The negative impact on the subject’s well-being is minimized and low.
(d) The trial is not prohibited by law.
(e) The approval/favourable opinion of the IRB/IEC is expressly sought on the inclusion of such subjects, and the written approval/ favourable opinion covers this aspect.
Such trials, unless an exception is justified, should be conducted in patients having a disease or condition for which the investigational product is intended. Subjects in these trials should be particularly closely monitored and should be withdrawn if they appear to be unduly distressed.
4.8.15 In emergency situations, when prior consent of the subject is not possible, the consent of the subject's legally acceptable representative, if present, should be requested. When prior consent of the subject is not possible, and the subject’s legally acceptable representative is not available, enrolment of the subject should require measures described in the protocol and/or elsewhere, with documented approval/favourable opinion by the IRB/IEC, to protect the rights, safety and well-being of the subject and to ensure compliance with applicable regulatory requirements. The subject or the subject's legally acceptable representative should be informed about the trial as soon as possible and consent to continue and other consent as appropriate (see 4.8.10) should be requested.
4.9 Records and Reports
ADDENDUM
4.9.0 The investigator should maintain adequate and accurate source documents and trial records that include all pertinent observations on each of the site’s trial subjects. Source data should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to source data should be traceable, should not obscure the original entry and should be explained if necessary (e.g., via an audit trail).
4.9.1 The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data reported to the sponsor in the CRFs and in all required reports.
4.9.2 Data reported on the CRF, that are derived from source documents, should be consistent with the source documents or the discrepancies should be explained.
4.9.3 Any change or correction to a CRF should be dated, initialed, and explained (if necessary) and should not obscure the original entry (i.e., an audit trail should be maintained); this applies to both written and electronic changes or corrections (see 5.18.4 (n)). Sponsors should provide guidance to investigators and/or the investigators' designated representatives on making such corrections. Sponsors should have written procedures to assure that changes or corrections in CRFs made by sponsor's designated representatives are documented, are necessary, and are endorsed by the investigator. The investigator should retain records of the changes and corrections.
4.9.4 The investigator/institution should maintain the trial documents as specified in Essential Documents for the Conduct of a Clinical Trial (see 8.) and as required by the applicable regulatory requirement(s). The investigator/institution should take measures to prevent accidental or premature destruction of these documents.
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726 4.9.5 Essential documents should be retained until at least 2-years after the last approval of a 727 marketing application in an ICH region and until there are no pending or contemplated 728 marketing applications in an ICH region or at least 2-years have elapsed since the 729 formal discontinuation of clinical development of the investigational product. These
documents should be retained for a longer period however if required by the applicable 731 regulatory requirements or by an agreement with the sponsor. It is the responsibility of 732 the sponsor to inform the investigator/institution as to when these documents no 733 longer need to be retained (see 5.5.12).
734 4.9.6 The financial aspects of the trial should be documented in an agreement between the sponsor and the investigator/institution.
736 4.9.7 Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the 737 investigator/institution should make available for direct access all requested trial-738 related records.
739 4.10 Progress Reports
4.10.1 The investigator should submit written summaries of the trial status to the IRB/IEC 741 annually, or more frequently, if requested by the IRB/IEC.
742 4.10.2 The investigator should promptly provide written reports to the sponsor, the IRB/IEC 743 (see 3.3.8) and, where applicable, the institution on any changes significantly affecting 744 the conduct of the trial, and/or increasing the risk to subjects.
4.11 Safety Reporting
746 4.11.1 All serious adverse events (SAEs) should be reported immediately to the sponsor 747 except for those SAEs that the protocol or other document (e.g., Investigator's 748 Brochure) identifies as not needing immediate reporting. The immediate reports 749 should be followed promptly by detailed, written reports. The immediate and follow-
up reports should identify subjects by unique code numbers assigned to the trial 751 subjects rather than by the subjects' names, personal identification numbers, and/or 752 addresses. The investigator should also comply with the applicable regulatory 753 requirement(s) related to the reporting of unexpected serious adverse drug reactions to 754 the regulatory authority(ies) and the IRB/IEC.
4.11.2 Adverse events and/or laboratory abnormalities identified in the protocol as critical to 756 safety evaluations should be reported to the sponsor according to the reporting 757 requirements and within the time periods specified by the sponsor in the protocol.
758 4.11.3 For reported deaths, the investigator should supply the sponsor and the IRB/IEC with 759 any additional requested information (e.g., autopsy reports and terminal medical
reports).
761 4.12 Premature Termination or Suspension of a Trial
762 If the trial is prematurely terminated or suspended for any reason, the investigator/institution 763 should promptly inform the trial subjects, should assure appropriate therapy and follow-up for 764 the subjects, and, where required by the applicable regulatory requirement(s), should inform
the regulatory authority(ies). In addition:
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806
4.12.1 If the investigator terminates or suspends a trial without prior agreement of the sponsor, the investigator should inform the institution where applicable, and the investigator/institution should promptly inform the sponsor and the IRB/IEC, and should provide the sponsor and the IRB/IEC a detailed written explanation of the termination or suspension.
4.12.2 If the sponsor terminates or suspends a trial (see 5.21), the investigator should promptly inform the institution where applicable and the investigator/institution should promptly inform the IRB/IEC and provide the IRB/IEC a detailed written explanation of the termination or suspension.
4.12.3 If the IRB/IEC terminates or suspends its approval/favourable opinion of a trial (see 3.1.2 and 3.3.9), the investigator should inform the institution where applicable and the investigator/institution should promptly notify the sponsor and provide the sponsor with a detailed written explanation of the termination or suspension.
4.13 Final Report(s) by Investigator
Upon completion of the trial, the investigator, where applicable, should inform the institution; the investigator/institution should provide the IRB/IEC with a summary of the trial’s outcome, and the regulatory authority(ies) with any reports required.
5. SPONSOR
ADDENDUM
5.0 Quality Management
The sponsor should implement a system to manage quality throughout the design, conduct, recording, evaluation, reporting and archiving of clinical trials.
Sponsors should focus on trial activities essential to ensuring human subject protection and the reliability of trial results. Quality management includes the efficient design of clinical trial protocols, data collection tools and procedures, and the collection of information that is essential to decision making.
The methods used to assure and control the quality of the trial should be proportionate to the risks inherent in the trial and the importance of the information collected. The sponsor should ensure that all aspects of the trial are operationally feasible and should avoid unnecessary complexity, procedures and data collection. Protocols, case report forms, and other operational documents should be clear, concise and consistent.
The quality management system should use a risk-based approach as described below.
5.0.1 Critical Process and Data Identification During protocol development, the sponsor should identify those processes and data that are critical to assure human subject protection and the reliability of study results.
5.0.2 Risk Identification Risks to critical study processes and data should be identified. Risks should be considered at both the system level (e.g., facilities, standard operating procedures, computerized systems, personnel, vendors) and clinical trial level (e.g., investigational product, trial design, data collection and recording).
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811
812 813 814
816 817
818 819
821 822
823 824
826
827 828 829
831 832 833 834
836 837 838 839
841 842 843
844
846 847 848
5.0.3 Risk Evaluation The identified risks should be evaluated by considering: (a) The likelihood of errors occurring, given existing risk controls. (b) The impact of such errors on human subject protection and data integrity. (c) The extent to which such errors would be detectable.
5.0.4 Risk Control The sponsor should identify those risks that should be reduced (through mitigating actions) and/or can be accepted. Risk mitigation activities may be incorporated in protocol design and implementation, monitoring plans, agreements between parties defining roles and responsibilities, systematic safeguards to ensure adherence to standard operating procedures, and training in processes and procedures.
Predefined quality tolerance limits should be established, taking into consideration the medical and statistical characteristics of the variables as well as the statistical design of the trial, to identify systematic issues that can impact subject safety or data integrity. Detection of deviations from the predefined quality tolerance limits should trigger an evaluation to determine if action is needed.
5.0.5 Risk Communication The quality management activities should be documented and communicated to stakeholders to facilitate risk review and continual improvement during clinical trial execution.
5.0.6 Risk Review The sponsor should periodically review risk control measures to ascertain whether the implemented quality management activities remain effective and relevant, taking into account emerging knowledge and experience.
5.0.7 Risk Reporting The sponsor should describe the quality management approach implemented in the trial and summarize important deviations from the predefined quality tolerance limits in the clinical study report (ICH E3, Section 9.6 Data Quality Assurance).
5.1 Quality Assurance and Quality Control
5.1.1 The sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s).
5.1.2 The sponsor is responsible for securing agreement from all involved parties to ensure direct access (see 1.21) to all trial related sites, source data/documents , and reports for the purpose of monitoring and auditing by the sponsor, and inspection by domestic and foreign regulatory authorities.
5.1.3 Quality control should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly.
5.1.4 Agreements, made by the sponsor with the investigator/institution and any other parties involved with the clinical trial, should be in writing, as part of the protocol or in a separate agreement.
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851 852 853
854
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857 858
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861
862 863
864
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867 868 869
871 872 873 874
876 877
878
5.2 Contract Research Organization (CRO)
5.2.1 A sponsor may transfer any or all of the sponsor's trial-related duties and functions to a CRO, but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor. The CRO should implement quality assurance and quality control.
ADDENDUM
The sponsor should ensure oversight of any trial-related duties and functions carried out on its behalf.
5.2.2 Any trial-related duty and function that is transferred to and assumed by a CRO should be specified in writing.
ADDENDUM
The sponsor should document approval of any subcontracting of trial-related duties and functions by a CRO.
5.2.3 Any trial-related duties and functions not specifically transferred to and assumed by a CRO are retained by the sponsor.
5.2.4 All references to a sponsor in this guideline also apply to a CRO to the extent that a CRO has assumed the trial related duties and functions of a sponsor.
5.3 Medical Expertise
The sponsor should designate appropriately qualified medical personnel who will be readily available to advise on trial related medical questions or problems. If necessary, outside consultant(s) may be appointed for this purpose.
5.4 Trial Design
5.4.1 The sponsor should utilize qualified individuals (e.g., biostatisticians, clinical pharmacologists, and physicians) as appropriate, throughout all stages of the trial process, from designing the protocol and CRFs and planning the analyses to analyzing and preparing interim and final clinical trial reports.
5.4.2 For further guidance: Clinical Trial Protocol and Protocol Amendment(s) (see 6.), the ICH Guideline for Structure and Content of Clinical Study Reports, and other appropriate ICH guidance on trial design, protocol and conduct.
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881 882
883 884
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888 889
891 892
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896 897 898 899
901 902 903 904
906
907 908
909
911
912
913 914
916
917 918
5.5 Trial Management, Data Handling, and Record Keeping
5.5.1 The sponsor should utilize appropriately qualified individuals to supervise the overall conduct of the trial, to handle the data, to verify the data, to conduct the statistical analyses, and to prepare the trial reports.
5.5.2 The sponsor may consider establishing an independent data-monitoring committee (IDMC) to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial. The IDMC should have written operating procedures and maintain written records of all its meetings.
5.5.3 When using electronic trial data handling and/or remote electronic trial data systems, the sponsor should:
(a) Ensure and document that the electronic data processing system(s) conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistent intended performance (i.e., validation).
(b) Maintains SOPs for using these systems.
ADDENDUM
The SOPs should cover system setup, installation and use. The SOPs should describe system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning and decommissioning. The responsibilities of the sponsor, investigator and other parties with respect to the use of these computerized systems should be clear, and the users should be provided with training in the use of the systems.
(c) Ensure that the systems are designed to permit data changes in such a way that the data changes are documented and that there is no deletion of entered data (i.e., maintain an audit trail, data trail, edit trail).
(d) Maintain a security system that prevents unauthorized access to the data.
(e) Maintain a list of the individuals who are authorized to make data changes (see 4.1.5 and 4.9.3).
(f) Maintain adequate backup of the data.
(g) Safeguard the blinding, if any (e.g., maintain the blinding during data entry and processing).
ADDENDUM
(h) Ensure the integrity of the data including any data that describe the context, content and structure of the data. This is particularly important when making changes to the computerized systems, such as software upgrades or migration of data.
5.5.4 If data are transformed during processing, it should always be possible to compare the original data and observations with the processed data.
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919 5.5.5 The sponsor should use an unambiguous subject identification code (see 1.58) that allows identification of all the data reported for each subject.
921 5.5.6 The sponsor, or other owners of the data, should retain all of the sponsor-specific 922 essential documents pertaining to the trial (see 8. Essential Documents for the Conduct 923 of a Clinical Trial).
924 5.5.7 The sponsor should retain all sponsor-specific essential documents in conformance with the applicable regulatory requirement(s) of the country(ies) where the product is
926 approved, and/or where the sponsor intends to apply for approval(s).
927 5.5.8 If the sponsor discontinues the clinical development of an investigational product (i.e., 928 for any or all indications, routes of administration, or dosage forms), the sponsor 929 should maintain all sponsor-specific essential documents for at least 2-years after
formal discontinuation or in conformance with the applicable regulatory 931 requirement(s).
932 5.5.9 If the sponsor discontinues the clinical development of an investigational product, the 933 sponsor should notify all the trial investigators/institutions and all the regulatory 934 authorities.
5.5.10 Any transfer of ownership of the data should be reported to the appropriate 936 authority(ies), as required by the applicable regulatory requirement(s).
937 5.5.11 The sponsor specific essential documents should be retained until at least 2-years after 938 the last approval of a marketing application in an ICH region and until there are no 939 pending or contemplated marketing applications in an ICH region or at least 2-years
have elapsed since the formal discontinuation of clinical development of the 941 investigational product. These documents should be retained for a longer period 942 however if required by the applicable regulatory requirement(s) or if needed by the 943 sponsor.
944 5.5.12 The sponsor should inform the investigator(s)/institution(s) in writing of the need for record retention and should notify the investigator(s)/institution(s) in writing when the
946 trial related records are no longer needed.
947 5.6 Investigator Selection
948 5.6.1 The sponsor is responsible for selecting the investigator(s)/institution(s). Each 949 investigator should be qualified by training and experience and should have adequate
resources (see 4.1, 4.2) to properly conduct the trial for which the investigator is 951 selected. If organization of a coordinating committee and/or selection of coordinating 952 investigator(s) are to be utilized in multicentre trials, their organization and/or 953 selection are the sponsor's responsibility.
954 5.6.2 Before entering an agreement with an investigator/institution to conduct a trial, the sponsor should provide the investigator(s)/institution(s) with the protocol and an up-
956 to-date Investigator's Brochure, and should provide sufficient time for the 957 investigator/institution to review the protocol and the information provided.
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958 5.6.3 The sponsor should obtain the investigator's/institution's agreement:
959 (a) to conduct the trial in compliance with GCP, with the applicable regulatory requirement(s) (see 4.1.3), and with the protocol agreed to by the sponsor and
961 given approval/favourable opinion by the IRB/IEC (see 4.5.1);
962 (b) to comply with procedures for data recording/reporting;
963 (c) to permit monitoring, auditing and inspection (see 4.1.4) and
964 (d) to retain the trial related essential documents until the sponsor informs the investigator/institution these documents are no longer needed (see 4.9.4 and
966 5.5.12).
967 The sponsor and the investigator/institution should sign the protocol, or an alternative 968 document, to confirm this agreement.
969 5.7 Allocation of Responsibilities
Prior to initiating a trial, the sponsor should define, establish, and allocate all trial-related 971 duties and functions.
972 5.8 Compensation to Subjects and Investigators
973 5.8.1 If required by the applicable regulatory requirement(s), the sponsor should provide 974 insurance or should indemnify (legal and financial coverage) the investigator/the
institution against claims arising from the trial, except for claims that arise from 976 malpractice and/or negligence.
977 5.8.2 The sponsor's policies and procedures should address the costs of treatment of trial 978 subjects in the event of trial-related injuries in accordance with the applicable 979 regulatory requirement(s).
5.8.3 When trial subjects receive compensation, the method and manner of compensation 981 should comply with applicable regulatory requirement(s).
982 5.9 Financing
983 The financial aspects of the trial should be documented in an agreement between the sponsor 984 and the investigator/institution.
5.10 Notification/Submission to Regulatory Authority(ies)
986 Before initiating the clinical trial(s), the sponsor (or the sponsor and the investigator, if 987 required by the applicable regulatory requirement(s)) should submit any required 988 application(s) to the appropriate authority(ies) for review, acceptance, and/or permission (as 989 required by the applicable regulatory requirement(s)) to begin the trial(s). Any
notification/submission should be dated and contain sufficient information to identify the 991 protocol.
992 5.11 Confirmation of Review by IRB/IEC
993 5.11.1 The sponsor should obtain from the investigator/institution:
994 (a) The name and address of the investigator's/institution’s IRB/IEC.
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(b) A statement obtained from the IRB/IEC that it is organized and operates according 996 to GCP and the applicable laws and regulations.
997 (c) Documented IRB/IEC approval/favourable opinion and, if requested by the 998 sponsor, a current copy of protocol, written informed consent form(s) and any 999 other written information to be provided to subjects, subject recruiting procedures,
and documents related to payments and compensation available to the subjects, 1001 and any other documents that the IRB/IEC may have requested.
1002 5.11.2 If the IRB/IEC conditions its approval/favourable opinion upon change(s) in any 1003 aspect of the trial, such as modification(s) of the protocol, written informed consent 1004 form and any other written information to be provided to subjects, and/or other
procedures, the sponsor should obtain from the investigator/institution a copy of the 1006 modification(s) made and the date approval/favourable opinion was given by the 1007 IRB/IEC.
1008 5.11.3 The sponsor should obtain from the investigator/institution documentation and dates 1009 of any IRB/IEC reapprovals/re-evaluations with favourable opinion, and of any
withdrawals or suspensions of approval/favourable opinion.
1011 5.12 Information on Investigational Product(s)
1012 5.12.1 When planning trials, the sponsor should ensure that sufficient safety and efficacy data 1013 from nonclinical studies and/or clinical trials are available to support human exposure 1014 by the route, at the dosages, for the duration, and in the trial population to be studied.
5.12.2 The sponsor should update the Investigator's Brochure as significant new information 1016 becomes available (see 7. Investigator's Brochure).
1017 5.13 Manufacturing, Packaging, Labelling, and Coding Investigational Product(s)
1018 5.13.1 The sponsor should ensure that the investigational product(s) (including active 1019 comparator(s) and placebo, if applicable) is characterized as appropriate to the stage of
development of the product(s), is manufactured in accordance with any applicable 1021 GMP, and is coded and labelled in a manner that protects the blinding, if applicable. In 1022 addition, the labelling should comply with applicable regulatory requirement(s).
1023 5.13.2 The sponsor should determine, for the investigational product(s), acceptable storage 1024 temperatures, storage conditions (e.g., protection from light), storage times,
reconstitution fluids and procedures, and devices for product infusion, if any. The 1026 sponsor should inform all involved parties (e.g., monitors, investigators, pharmacists, 1027 storage managers) of these determinations.
1028 5.13.3 The investigational product(s) should be packaged to prevent contamination and 1029 unacceptable deterioration during transport and storage.
5.13.4 In blinded trials, the coding system for the investigational product(s) should include a 1031 mechanism that permits rapid identification of the product(s) in case of a medical 1032 emergency, but does not permit undetectable breaks of the blinding.
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1033 5.13.5 If significant formulation changes are made in the investigational or comparator 1034 product(s) during the course of clinical development, the results of any additional
studies of the formulated product(s) (e.g., stability, dissolution rate, bioavailability) 1036 needed to assess whether these changes would significantly alter the pharmacokinetic 1037 profile of the product should be available prior to the use of the new formulation in 1038 clinical trials.
1039 5.14 Supplying and Handling Investigational Product(s)
5.14.1 The sponsor is responsible for supplying the investigator(s)/institution(s) with the 1041 investigational product(s).
1042 5.14.2 The sponsor should not supply an investigator/institution with the investigational 1043 product(s) until the sponsor obtains all required documentation (e.g., 1044 approval/favourable opinion from IRB/IEC and regulatory authority(ies)).
5.14.3 The sponsor should ensure that written procedures include instructions that the 1046 investigator/institution should follow for the handling and storage of investigational 1047 product(s) for the trial and documentation thereof. The procedures should address 1048 adequate and safe receipt, handling, storage, dispensing, retrieval of unused product 1049 from subjects, and return of unused investigational product(s) to the sponsor (or
alternative disposition if authorized by the sponsor and in compliance with the 1051 applicable regulatory requirement(s)).
1052 5.14.4 The sponsor should:
1053 (a) Ensure timely delivery of investigational product(s) to the investigator(s).
1054 (b) Maintain records that document shipment, receipt, disposition, return, and destruction of the investigational product(s) (see 8. Essential Documents for the
1056 Conduct of a Clinical Trial).
1057 (c) Maintain a system for retrieving investigational products and documenting this 1058 retrieval (e.g., for deficient product recall, reclaim after trial completion, expired 1059 product reclaim).
(d) Maintain a system for the disposition of unused investigational product(s) and for 1061 the documentation of this disposition.
1062 5.14.5 The sponsor should:
1063 (a) Take steps to ensure that the investigational product(s) are stable over the period 1064 of use.
(b) Maintain sufficient quantities of the investigational product(s) used in the trials to 1066 reconfirm specifications, should this become necessary, and maintain records of 1067 batch sample analyses and characteristics. To the extent stability permits, samples 1068 should be retained either until the analyses of the trial data are complete or as 1069 required by the applicable regulatory requirement(s), whichever represents the
longer retention period.
1071
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1072 5.15 Record Access
1073 5.15.1 The sponsor should ensure that it is specified in the protocol or other written 1074 agreement that the investigator(s)/institution(s) provide direct access to source
data/documents for trial-related monitoring, audits, IRB/IEC review, and regulatory 1076 inspection.
1077 5.15.2 The sponsor should verify that each subject has consented, in writing, to direct access 1078 to his/her original medical records for trial-related monitoring, audit, IRB/IEC review, 1079 and regulatory inspection.
5.16 Safety Information
1081 5.16.1 The sponsor is responsible for the ongoing safety evaluation of the investigational 1082 product(s).
1083 5.16.2 The sponsor should promptly notify all concerned investigator(s)/institution(s) and the 1084 regulatory authority(ies) of findings that could affect adversely the safety of subjects,
impact the conduct of the trial, or alter the IRB/IEC's approval/favourable opinion to 1086 continue the trial.
1087 5.17 Adverse Drug Reaction Reporting
1088 5.17.1 The sponsor should expedite the reporting to all concerned 1089 investigator(s)/institutions(s), to the IRB(s)/IEC(s), where required, and to the
regulatory authority(ies) of all adverse drug reactions (ADRs) that are both serious and 1091 unexpected.
1092 5.17.2 Such expedited reports should comply with the applicable regulatory requirement(s) 1093 and with the ICH Guideline for Clinical Safety Data Management: Definitions and 1094 Standards for Expedited Reporting.
5.17.3 The sponsor should submit to the regulatory authority(ies) all safety updates and 1096 periodic reports, as required by applicable regulatory requirement(s).
1097 5.18 Monitoring
1098 5.18.1 Purpose
1099 The purposes of trial monitoring are to verify that:
(a) The rights and well-being of human subjects are protected.
1101 (b) The reported trial data are accurate, complete, and verifiable from source 1102 documents.
1103 (c) The conduct of the trial is in compliance with the currently approved 1104 protocol/amendment(s), with GCP, and with the applicable regulatory
requirement(s).
1106 5.18.2 Selection and Qualifications of Monitors
1107 (a) Monitors should be appointed by the sponsor.
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1108 1109
1111 1112 1113 1114
1116 1117 1118 1119
1121 1122 1123 1124
1126
1127 1128 1129
1131 1132
1133 1134
1136 1137 1138 1139
1141 1142 1143
1144
1146
1147
1148
(b) Monitors should be appropriately trained, and should have the scientific and/or clinical knowledge needed to monitor the trial adequately. A monitor’s qualifications should be documented.
(c) Monitors should be thoroughly familiar with the investigational product(s), the protocol, written informed consent form and any other written information to be provided to subjects, the sponsor’s SOPs, GCP, and the applicable regulatory requirement(s).
5.18.3 Extent and Nature of Monitoring
The sponsor should ensure that the trials are adequately monitored. The sponsor should determine the appropriate extent and nature of monitoring. The determination of the extent and nature of monitoring should be based on considerations such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial. In general there is a need for on-site monitoring, before, during, and after the trial; however in exceptional circumstances the sponsor may determine that central monitoring in conjunction with procedures such as investigators’ training and meetings, and extensive written guidance can assure appropriate conduct of the trial in accordance with GCP. Statistically controlled sampling may be an acceptable method for selecting the data to be verified.
ADDENDUM
The sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials. The flexibility in the extent and nature of monitoring described in this section is intended to permit varied approaches that improve the effectiveness and efficiency of monitoring. A combination of on-site and centralized monitoring activities may be appropriate. The sponsor should document the rationale for the chosen monitoring strategy (e.g., in the monitoring plan).
On-site monitoring is performed at the sites at which the clinical trial is being conducted.
Centralized monitoring is a remote evaluation of ongoing and/or cumulative data collected from trial sites, in a timely manner. Centralized monitoring processes provide additional monitoring capabilities that can complement and reduce the extent and/or frequency of on-site monitoring by such methods as: (a) Routine review of submitted data.
(b) Identification of missing data, inconsistent data, data outliers or unexpected lack of variability and protocol deviations that may be indicative of systematic or significant errors in data collection and reporting at a site or across sites, or may be indicative of potential data manipulation or data integrity problems.
(c) Using statistical analyses to identify data consistency of data within and across sites.
trends such as the range and
(d) Analyzing site characteristics and performance metrics.
(e) Selection of sites and/or processes for targeted on-site monitoring.
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5.18.4 Monitor's Responsibilities
The monitor(s) in accordance with the sponsor’s requirements should ensure that the trial is conducted and documented properly by carrying out the following activities when relevant and necessary to the trial and the trial site:
(a) Acting as the main line of communication between the sponsor and the investigator.
(b) Verifying that the investigator has adequate qualifications and resources (see 4.1, 4.2, 5.6) and remain adequate throughout the trial period, that facilities, including laboratories, equipment, and staff, are adequate to safely and properly conduct the trial and remain adequate throughout the trial period.
(c) Verifying, for the investigational product(s):
(i) That storage times and conditions are acceptable, and that supplies are sufficient throughout the trial.
(ii) That the investigational product(s) are supplied only to subjects who are eligible to receive it and at the protocol specified dose(s).
(iii) That subjects are provided with necessary instruction on properly using, handling, storing, and returning the investigational product(s).
(iv) That the receipt, use, and return of the investigational product(s) at the trial sites are controlled and documented adequately.
(v) That the disposition of unused investigational product(s) at the trial sites complies with applicable regulatory requirement(s) and is in accordance with the sponsor.
(d) Verifying that the investigator follows the approved protocol and all approved amendment(s), if any.
(e) Verifying that written informed consent was obtained before each subject's participation in the trial.
(f) Ensuring that the investigator receives the current Investigator's Brochure, all documents, and all trial supplies needed to conduct the trial properly and to comply with the applicable regulatory requirement(s).
(g) Ensuring that the investigator and the investigator's trial staff are adequately informed about the trial.
(h) Verifying that the investigator and the investigator's trial staff are performing the specified trial functions, in accordance with the protocol and any other written agreement between the sponsor and the investigator/institution, and have not delegated these functions to unauthorized individuals.
(i) Verifying that the investigator is enroling only eligible subjects.
(j) Reporting the subject recruitment rate.
(k) Verifying that source documents and other trial records are accurate, complete, kept up-to-date and maintained.
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1188 (l) Verifying that the investigator provides all the required reports, notifications, 1189 applications, and submissions, and that these documents are accurate, complete,
timely, legible, dated, and identify the trial.
1191 (m) Checking the accuracy and completeness of the CRF entries, source documents 1192 and other trial-related records against each other. The monitor specifically should 1193 verify that:
1194 (i) The data required by the protocol are reported accurately on the CRFs and are consistent with the source documents.
1196 (ii) Any dose and/or therapy modifications are well documented for each of the 1197 trial subjects.
1198 (iii) Adverse events, concomitant medications and intercurrent illnesses are 1199 reported in accordance with the protocol on the CRFs.
(iv) Visits that the subjects fail to make, tests that are not conducted, and 1201 examinations that are not performed are clearly reported as such on the 1202 CRFs.
1203 (v) All withdrawals and dropouts of enrolled subjects from the trial are reported 1204 and explained on the CRFs.
(n) Informing the investigator of any CRF entry error, omission, or illegibility. The 1206 monitor should ensure that appropriate corrections, additions, or deletions are 1207 made, dated, explained (if necessary), and initialled by the investigator or by a 1208 member of the investigator's trial staff who is authorized to initial CRF changes 1209 for the investigator. This authorization should be documented.
(o) Determining whether all adverse events (AEs) are appropriately reported within 1211 the time periods required by GCP, the protocol, the IRB/IEC, the sponsor, and the 1212 applicable regulatory requirement(s).
1213 (p) Determining whether the investigator is maintaining the essential documents (see 1214 8. Essential Documents for the Conduct of a Clinical Trial).
(q) Communicating deviations from the protocol, SOPs, GCP, and the applicable 1216 regulatory requirements to the investigator and taking appropriate action designed 1217 to prevent recurrence of the detected deviations.
1218 5.18.5 Monitoring Procedures
1219 The monitor(s) should follow the sponsor’s established written SOPs as well as those procedures that are specified by the sponsor for monitoring a specific trial.
1221 5.18.6 Monitoring Report
1222 (a) The monitor should submit a written report to the sponsor after each trial-site visit 1223 or trial-related communication.
1224 (b) Reports should include the date, site, name of the monitor, and name of the investigator or other individual(s) contacted.
1226 (c) Reports should include a summary of what the monitor reviewed and the monitor's 1227 statements concerning the significant findings/facts, deviations and deficiencies,
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1231
1232
1233 1234
1236 1237
1238 1239
1241 1242 1243 1244
1246 1247 1248
1249
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1252
1253 1254
1256
1257 1258
1259
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conclusions, actions taken or to be taken and/or actions recommended to secure compliance.
(d) The review and follow-up of the monitoring report with the sponsor should be documented by the sponsor’s designated representative.
ADDENDUM
(e) Monitoring results should be provided to the sponsor (including appropriate management and staff responsible for trial and site oversight) in a timely manner for review and follow up as indicated. Results of monitoring activities should be documented in sufficient detail to allow verification of compliance with the monitoring plan.
ADDENDUM
5.18.7 Monitoring Plan
The sponsor should develop a monitoring plan that is tailored to the specific human subject protection and data integrity risks of the trial. The plan should describe the monitoring strategy, the monitoring responsibilities of all the parties involved, the various monitoring methods to be used and the rationale for their use. The plan should also emphasize the monitoring of critical data and processes. Particular attention should be given to those aspects that are not routine clinical practice and that require additional training. The monitoring plan should reference the applicable policies and procedures.
5.19 Audit
If or when sponsors perform audits, as part of implementing quality assurance, they should consider:
5.19.1 Purpose
The purpose of a sponsor's audit, which is independent of and separate from routine monitoring or quality control functions, should be to evaluate trial conduct and compliance with the protocol, SOPs, GCP, and the applicable regulatory requirements.
5.19.2 Selection and Qualification of Auditors
(a) The sponsor should appoint individuals, who are independent of the clinical trials/systems, to conduct audits.
(b) The sponsor should ensure that the auditors are qualified by training and experience to conduct audits properly. An auditor’s qualifications should be documented.
5.19.3 Auditing Procedures
(a) The sponsor should ensure that the auditing of clinical trials/systems is conducted in accordance with the sponsor's written procedures on what to audit, how to audit, the frequency of audits, and the form and content of audit reports.
(b) The sponsor's audit plan and procedures for a trial audit should be guided by the importance of the trial to submissions to regulatory authorities, the number of
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subjects in the trial, the type and complexity of the trial, the level of risks to the trial subjects, and any identified problem(s).
(c) The observations and findings of the auditor(s) should be documented.
(d) To preserve the independence and value of the audit function, the regulatory authority(ies) should not routinely request the audit reports. Regulatory authority(ies) may seek access to an audit report on a case by case basis when evidence of serious GCP non-compliance exists, or in the course of legal proceedings.
(e) When required by applicable law or regulation, the sponsor should provide an audit certificate.
5.20 Noncompliance
5.20.1 Noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory requirement(s) by an investigator/institution, or by member(s) of the sponsor's staff should lead to prompt action by the sponsor to secure compliance.
ADDENDUM
When significant noncompliance is discovered, the sponsor should perform a root cause analysis and implement appropriate corrective and preventive actions. If required by applicable law or regulation the sponsor should inform the regulatory authority(ies) when the noncompliance is a serious breach of the trial protocol or GCP.
5.20.2 If the monitoring and/or auditing identifies serious and/or persistent noncompliance on the part of an investigator/institution, the sponsor should terminate the investigator's/institution’s participation in the trial. When an investigator's/institution’s participation is terminated because of noncompliance, the sponsor should notify promptly the regulatory authority(ies).
5.21 Premature Termination or Suspension of a Trial
If a trial is prematurely terminated or suspended, the sponsor should promptly inform the investigators/institutions, and the regulatory authority(ies) of the termination or suspension and the reason(s) for the termination or suspension. The IRB/IEC should also be informed promptly and provided the reason(s) for the termination or suspension by the sponsor or by the investigator/institution, as specified by the applicable regulatory requirement(s).
5.22 Clinical Trial/Study Reports
Whether the trial is completed or prematurely terminated, the sponsor should ensure that the clinical trial reports are prepared and provided to the regulatory agency(ies) as required by the applicable regulatory requirement(s). The sponsor should also ensure that the clinical trial reports in marketing applications meet the standards of the ICH Guideline for Structure and Content of Clinical Study Reports. (NOTE: The ICH Guideline for Structure and Content of Clinical Study Reports specifies that abbreviated study reports may be acceptable in certain cases.)
5.23 Multicentre Trials
For multicentre trials, the sponsor should ensure that:
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1308 5.23.1 All investigators conduct the trial in strict compliance with the protocol agreed to by 1309 the sponsor and, if required, by the regulatory authority(ies), and given
approval/favourable opinion by the IRB/IEC.
1311 5.23.2 The CRFs are designed to capture the required data at all multicentre trial sites. For 1312 those investigators who are collecting additional data, supplemental CRFs should also 1313 be provided that are designed to capture the additional data.
1314 5.23.3 The responsibilities of coordinating investigator(s) and the other participating investigators are documented prior to the start of the trial.
1316 5.23.4 All investigators are given instructions on following the protocol, on complying with a 1317 uniform set of standards for the assessment of clinical and laboratory findings, and on 1318 completing the CRFs.
1319 5.23.5 Communication between investigators is facilitated.
6. CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S)
1321 The contents of a trial protocol should generally include the following topics. However, site 1322 specific information may be provided on separate protocol page(s), or addressed in a separate 1323 agreement, and some of the information listed below may be contained in other protocol 1324 referenced documents, such as an Investigator’s Brochure.
6.1 General Information
1326 6.1.1 Protocol title, protocol identifying number, and date. Any amendment(s) should also 1327 bear the amendment number(s) and date(s).
1328 6.1.2 Name and address of the sponsor and monitor (if other than the sponsor).
1329 6.1.3 Name and title of the person(s) authorized to sign the protocol and the protocol amendment(s) for the sponsor.
1331 6.1.4 Name, title, address, and telephone number(s) of the sponsor's medical expert (or 1332 dentist when appropriate) for the trial.
1333 6.1.5 Name and title of the investigator(s) who is (are) responsible for conducting the trial, 1334 and the address and telephone number(s) of the trial site(s).
6.1.6 Name, title, address, and telephone number(s) of the qualified physician (or dentist, if 1336 applicable), who is responsible for all trial-site related medical (or dental) decisions (if 1337 other than investigator).
1338 6.1.7 Name(s) and address(es) of the clinical laboratory(ies) and other medical and/or 1339 technical department(s) and/or institutions involved in the trial.
6.2 Background Information
1341 6.2.1 Name and description of the investigational product(s).
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1342 6.2.2 A summary of findings from nonclinical studies that potentially have clinical 1343 significance and from clinical trials that are relevant to the trial.
1344 6.2.3 Summary of the known and potential risks and benefits, if any, to human subjects.
6.2.4 Description of and justification for the route of administration, dosage, dosage 1346 regimen, and treatment period(s).
1347 6.2.5 A statement that the trial will be conducted in compliance with the protocol, GCP and 1348 the applicable regulatory requirement(s).
1349 6.2.6 Description of the population to be studied.
6.2.7 References to literature and data that are relevant to the trial, and that provide 1351 background for the trial.
1352 6.3 Trial Objectives and Purpose
1353 A detailed description of the objectives and the purpose of the trial.
1354 6.4 Trial Design
The scientific integrity of the trial and the credibility of the data from the trial depend 1356 substantially on the trial design. A description of the trial design, should include:
1357 6.4.1 A specific statement of the primary endpoints and the secondary endpoints, if any, to 1358 be measured during the trial.
1359 6.4.2 A description of the type/design of trial to be conducted (e.g., double-blind, placebo-controlled, parallel design) and a schematic diagram of trial design, procedures and
1361 stages.
1362 6.4.3 A description of the measures taken to minimize/avoid bias, including:
1363 (a) Randomization.
1364 (b) Blinding.
6.4.4 A description of the trial treatment(s) and the dosage and dosage regimen of the 1366 investigational product(s). Also include a description of the dosage form, packaging, 1367 and labelling of the investigational product(s).
1368 6.4.5 The expected duration of subject participation, and a description of the sequence and 1369 duration of all trial periods, including follow-up, if any.
6.4.6 A description of the "stopping rules" or "discontinuation criteria" for individual 1371 subjects, parts of trial and entire trial.
1372 6.4.7 Accountability procedures for the investigational product(s), including the placebo(s) 1373 and comparator(s), if any.
1374 6.4.8 Maintenance of trial treatment randomization codes and procedures for breaking codes.
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1376 6.4.9 The identification of any data to be recorded directly on the CRFs (i.e., no prior 1377 written or electronic record of data), and to be considered to be source data.
1383 (a) When and how to withdraw subjects from the trial/ investigational product 1384 treatment.
(b) The type and timing of the data to be collected for withdrawn subjects.
1386 (c) Whether and how subjects are to be replaced.
1387 (d) The follow-up for subjects withdrawn from investigational product treatment/trial 1388 treatment.
1389 6.6 Treatment of Subjects
6.6.1 The treatment(s) to be administered, including the name(s) of all the product(s), the 1391 dose(s), the dosing schedule(s), the route/mode(s) of administration, and the treatment 1392 period(s), including the follow-up period(s) for subjects for each investigational 1393 product treatment/trial treatment group/arm of the trial.
1394 6.6.2 Medication(s)/treatment(s) permitted (including rescue medication) and not permitted before and/or during the trial.
1396 6.6.3 Procedures for monitoring subject compliance.
1397 6.7 Assessment of Efficacy
1398 6.7.1 Specification of the efficacy parameters.
1399 6.7.2 Methods and timing for assessing, recording, and analysing of efficacy parameters.
6.8 Assessment of Safety
1401 6.8.1 Specification of safety parameters.
1402 6.8.2 The methods and timing for assessing, recording, and analysing safety parameters.
1403 6.8.3 Procedures for eliciting reports of and for recording and reporting adverse event and 1404 intercurrent illnesses.
6.8.4 The type and duration of the follow-up of subjects after adverse events.
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1407 6.9 Statistics
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6.9.1 A description of the statistical methods to be employed, including timing of any planned interim analysis(ses).
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6.9.2 The number of subjects planned to be enrolled. In multicentre trials, the numbers of enrolled subjects projected for each trial site should be specified. Reason for choice of sample size, including reflections on (or calculations of) the power of the trial and clinical justification.
1414 6.9.3 The level of significance to be used.
6.9.4 Criteria for the termination of the trial.
1416 6.9.5 Procedure for accounting for missing, unused, and spurious data.
1417 1418 1419
6.9.6 Procedures for reporting any deviation(s) from the original statistical plan (any deviation(s) from the original statistical plan should be described and justified in protocol and/or in the final report, as appropriate).
1421 6.9.7 The selection of subjects to be included in the analyses (e.g., all randomized subjects,
all dosed subjects, all eligible subjects, evaluable subjects).
1422 6.10 Direct Access to Source Data/Documents
1423 1424
The sponsor should ensure that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, and regulatory inspection(s), providing direct access to source data/documents.
1426 6.11 Quality Control and Quality Assurance
1427 6.12 Ethics
1428 Description of ethical considerations relating to the trial.
1429 6.13 Data Handling and Record Keeping
6.14 Financing and Insurance
1431 Financing and insurance if not addressed in a separate agreement.
1432 6.15 Publication Policy
1433 Publication policy, if not addressed in a separate agreement.
1434 6.16 Supplements
1436 (NOTE: Since the protocol and the clinical trial/study report are closely related, further relevant information can be found in the ICH Guideline for Structure and Content of Clinical
1437 Study Reports.)
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1439 7. INVESTIGATOR’S BROCHURE
7.1 Introduction
1441 The Investigator's Brochure (IB) is a compilation of the clinical and nonclinical data on the 1442 investigational product(s) that are relevant to the study of the product(s) in human subjects. Its 1443 purpose is to provide the investigators and others involved in the trial with the information to 1444 facilitate their understanding of the rationale for, and their compliance with, many key features
of the protocol, such as the dose, dose frequency/interval, methods of administration: and 1446 safety monitoring procedures. The IB also provides insight to support the clinical management 1447 of the study subjects during the course of the clinical trial. The information should be 1448 presented in a concise, simple, objective, balanced, and non-promotional form that enables a 1449 clinician, or potential investigator, to understand it and make his/her own unbiased risk-
benefit assessment of the appropriateness of the proposed trial. For this reason, a medically 1451 qualified person should generally participate in the editing of an IB, but the contents of the IB 1452 should be approved by the disciplines that generated the described data.
1453 This guideline delineates the minimum information that should be included in an IB and 1454 provides suggestions for its layout. It is expected that the type and extent of information
available will vary with the stage of development of the investigational product. If the 1456 investigational product is marketed and its pharmacology is widely understood by medical 1457 practitioners, an extensive IB may not be necessary. Where permitted by regulatory 1458 authorities, a basic product information brochure, package leaflet, or labelling may be an 1459 appropriate alternative, provided that it includes current, comprehensive, and detailed
information on all aspects of the investigational product that might be of importance to the 1461 investigator. If a marketed product is being studied for a new use (i.e., a new indication), an IB 1462 specific to that new use should be prepared. The IB should be reviewed at least annually and 1463 revised as necessary in compliance with a sponsor's written procedures. More frequent 1464 revision may be appropriate depending on the stage of development and the generation of
relevant new information. However, in accordance with Good Clinical Practice, relevant new 1466 information may be so important that it should be communicated to the investigators, and 1467 possibly to the Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs) 1468 and/or regulatory authorities before it is included in a revised IB.
1469 Generally, the sponsor is responsible for ensuring that an up-to-date IB is made available to the investigator(s) and the investigators are responsible for providing the up-to-date IB to the
1471 responsible IRBs/IECs. In the case of an investigator sponsored trial, the sponsor-investigator 1472 should determine whether a brochure is available from the commercial manufacturer. If the 1473 investigational product is provided by the sponsor-investigator, then he or she should provide 1474 the necessary information to the trial personnel. In cases where preparation of a formal IB is
impractical, the sponsor-investigator should provide, as a substitute, an expanded background 1476 information section in the trial protocol that contains the minimum current information 1477 described in this guideline.
1478 7.2 General Considerations
1479 The IB should include:
7.2.1 Title Page
1481 This should provide the sponsor's name, the identity of each investigational product 1482 (i.e., research number, chemical or approved generic name, and trade name(s) where
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legally permissible and desired by the sponsor), and the release date. It is also suggested that an edition number, and a reference to the number and date of the edition it supersedes, be provided. An example is given in Appendix 1.
1486 7.2.2 Confidentiality Statement
1487 1488
The sponsor may wish to include a statement instructing the investigator/recipients to treat the IB as a confidential document for the sole information and use of the
1489 investigator's team and the IRB/IEC.
7.3 Contents of the Investigator’s Brochure
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The IB should appropriate:
contain the following sections, each with literature references where
1493 7.3.1 Table of Contents
1494 An example of the Table of Contents is given in Appendix 2
7.3.2 Summary
1496 1497 1498 1499
A brief summary (preferably not exceeding two pages) should be given, highlighting the significant physical, chemical, pharmaceutical, pharmacological, toxicological, pharmacokinetic, metabolic, and clinical information available that is relevant to the stage of clinical development of the investigational product.
7.3.3 Introduction
1501 1502 1503 1504
A brief introductory statement should be provided that contains the chemical name (and generic and trade name(s) when approved) of the investigational product(s), all active ingredients, the investigational product (s ) pharmacological class and its expected position within this class (e.g., advantages), the rationale for performing
1506 1507
research with the investigational product(s), and the anticipated prophylactic, therapeutic, or diagnostic indication(s). Finally, the introductory statement should provide the general approach to be followed in evaluating the investigational product.
1508 7.3.4 Physical, Chemical, and Pharmaceutical Properties and Formulation
1509 A description should be provided of the investigational product substance(s) (including
1511 the chemical and/or structural formula(e)), and a brief summary should be given of the relevant physical, chemical, and pharmaceutical properties.
1512 1513 1514
To permit appropriate safety measures to be taken in the course of the trial, a description of the formulation(s) to be used, including excipients, should be provided and justified if clinically relevant. Instructions for the storage and handling of the dosage form(s) should also be given.
1516 Any structural similarities to other known compounds should be mentioned.
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7.3.5 Nonclinical Studies
Introduction:
The results of all relevant nonclinical pharmacology, toxicology, pharmacokinetic, and investigational product metabolism studies should be provided in summary form. This summary should address the methodology used, the results, and a discussion of the relevance of the findings to the investigated therapeutic and the possible unfavourable and unintended effects in humans.
The information provided may include the following, as appropriate, if known/available:
Species tested
Number and sex of animals in each group
Unit dose (e.g., milligram/kilogram (mg/kg))
Dose interval
Route of administration
Duration of dosing
Information on systemic distribution
Duration of post-exposure follow-up
Results, including the following aspects:
Nature and frequency of pharmacological or toxic effects Severity or intensity of pharmacological or toxic effects Time to onset of effects Reversibility of effects Duration of effects Dose response
Tabular format/listings should be used whenever possible to enhance the clarity of the presentation.
The following sections should discuss the most important findings from the studies, including the dose response of observed effects, the relevance to humans, and any aspects to be studied in humans. If applicable, the effective and nontoxic dose findings in the same animal species should be compared (i.e., the therapeutic index should be discussed). The relevance of this information to the proposed human dosing should be addressed. Whenever possible, comparisons should be made in terms of blood/tissue levels rather than on a mg/kg basis.
(a) Nonclinical Pharmacology
A summary of the pharmacological aspects of the investigational product and, where appropriate, its significant metabolites studied in animals, should be included. Such a summary should incorporate studies that assess potential therapeutic activity (e.g., efficacy models, receptor binding, and specificity) as well as those that assess safety (e.g., special studies to assess pharmacological actions other than the intended therapeutic effect(s)).
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(b) Pharmacokinetics and Product Metabolism in Animals
A summary of the pharmacokinetics and biological transformation and disposition of the investigational product in all species studied should be given. The discussion of the findings should address the absorption and the local and systemic bioavailability of the investigational product and its metabolites, and their relationship to the pharmacological and toxicological findings in animal species.
(c) Toxicology
A summary of the toxicological effects found in relevant studies conducted in different animal species should be described under the following headings where appropriate:
Single dose Repeated dose Carcinogenicity Special studies (e.g., irritancy and sensitisation) Reproductive toxicity Genotoxicity (mutagenicity)
7.3.6 Effects in Humans
Introduction:
A thorough discussion of the known effects of the investigational product(s) in humans should be provided, including information on pharmacokinetics, metabolism, pharmacodynamics, dose response, safety, efficacy, and other pharmacological activities. Where possible, a summary of each completed clinical trial should be provided. Information should also be provided regarding results of any use of the investigational product(s) other than from in clinical trials, such as from experience during marketing.
(a) Pharmacokinetics and Product Metabolism in Humans
A summary of information on the pharmacokinetics of the investigational product(s) should be presented, including the following, if available:
Pharmacokinetics (including metabolism, as appropriate, and absorption, plasma protein binding, distribution, and elimination).
Bioavailability of the investigational product (absolute, where possible, and/or relative) using a reference dosage form.
Population subgroups (e.g., gender, age, and impaired organ function). Interactions (e.g., product-product interactions and effects of food). Other pharmacokinetic data (e.g., results of population studies performed
within clinical trial(s).
(b) Safety and Efficacy
A summary of information should be provided about the investigational product's/products' (including metabolites, where appropriate) safety, pharmacodynamics, efficacy, and dose response that were obtained from preceding trials in humans (healthy volunteers and/or patients). The implications of this information should be discussed. In cases where a number of clinical trials have been completed, the use of summaries of safety and efficacy across multiple trials by indications in subgroups may provide a clear presentation of the data. Tabular summaries of adverse drug reactions for all the clinical trials (including those for all
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1603 the studied indications) would be useful. Important differences in adverse drug reaction 1604 patterns/incidences across indications or subgroups should be discussed.
The IB should provide a description of the possible risks and adverse drug reactions to 1606 be anticipated on the basis of prior experiences with the product under investigation 1607 and with related products. A description should also be provided of the precautions or 1608 special monitoring to be done as part of the investigational use of the product(s).
1609 (c) Marketing Experience
The IB should identify countries where the investigational product has been marketed 1611 or approved. Any significant information arising from the marketed use should be 1612 summarised (e.g., formulations, dosages, routes of administration, and adverse product 1613 reactions). The IB should also identify all the countries where the investigational 1614 product did not receive approval/registration for marketing or was withdrawn from
marketing/registration.
1616 7.3.7 Summary of Data and Guidance for the Investigator
1617 This section should provide an overall discussion of the nonclinical and clinical data, 1618 and should summarise the information from various sources on different aspects of the 1619 investigational product(s), wherever possible. In this way, the investigator can be
provided with the most informative interpretation of the available data and with an 1621 assessment of the implications of the information for future clinical trials.
1622 Where appropriate, the published reports on related products should be discussed. This 1623 could help the investigator to anticipate adverse drug reactions or other problems in 1624 clinical trials.
The overall aim of this section is to provide the investigator with a clear understanding 1626 of the possible risks and adverse reactions, and of the specific tests, observations, and 1627 precautions that may be needed for a clinical trial. This understanding should be based 1628 on the available physical, chemical, pharmaceutical, pharmacological, toxicological, and 1629 clinical information on the investigational product(s). Guidance should also be provided
to the clinical investigator on the recognition and treatment of possible overdose and 1631 adverse drug reactions that is based on previous human experience and on the 1632 pharmacology of the investigational product.
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7.4 APPENDIX 1:
TITLE PAGE (Example)
SPONSOR'S NAME
Product:
Research Number:
Name(s): Chemical, Generic (if approved)
Trade Name(s) (if legally permissible and desired by the sponsor)
INVESTIGATOR'S BROCHURE
Edition Number:
Release Date:
Replaces Previous Edition Number:
Date:
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7.5 APPENDIX 2:
TABLE OF CONTENTS OF INVESTIGATOR'S BROCHURE (Example)
7 Summary of Data and Guidance for the Investigator ......................................................
NB:References on 1. Publications
2. Reports
These references should be found at the end of each chapter
Appendices (if any)
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8. ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL
8.1 Introduction
Essential Documents are those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor and monitor with the standards of Good Clinical Practice and with all applicable regulatory requirements.
Essential Documents also serve a number of other important purposes. Filing essential documents at the investigator/institution and sponsor sites in a timely manner can greatly assist in the successful management of a trial by the investigator, sponsor and monitor. These documents are also the ones which are usually audited by the sponsor's independent audit function and inspected by the regulatory authority(ies) as part of the process to confirm the validity of the trial conduct and the integrity of data collected.
The minimum list of essential documents which has been developed follows. The various documents are grouped in three sections according to the stage of the trial during which they will normally be generated: 1) before the clinical phase of the trial commences, 2) during the clinical conduct of the trial, and 3) after completion or termination of the trial. A description is given of the purpose of each document, and whether it should be filed in either the investigator/institution or sponsor files, or both. It is acceptable to combine some of the documents, provided the individual elements are readily identifiable.
Trial master files should be established at the beginning of the trial, both at the investigator/institution’s site and at the sponsor's office. A final close-out of a trial can only be done when the monitor has reviewed both investigator/institution and sponsor files and confirmed that all necessary documents are in the appropriate files.
Any or all of the documents addressed in this guideline may be subject to, and should be available for, audit by the sponsor’s auditor and inspection by the regulatory authority(ies).
ADDENDUM
The sponsor and investigator/institution should maintain a record of the location(s) of their respective essential documents. The storage system (irrespective of the media used) should provide for document identification, search and retrieval.
Depending on the activities being carried out, individual trials may require additional documents not specifically mentioned in the essential document list. The sponsor and/or investigator/institution should include these as part of the trial master file.
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The sponsor should ensure that the investigator has control of and continuous access to the CRF data reported to the sponsor. The sponsor should not have exclusive control of those data.
When a copy is used to replace an original document, the copy should fulfill the requirements for certified copies.
The investigator/institution should have control of all essential documents and records generated by the investigator/institution before, during and after the trial.
8.2 Before the Clinical Phase of the Trial Commences
During this planning stage the following documents should be generated and should be on file before the trial formally starts
Title of Document Purpose Located in Files of
Investigator/ Sponsor Institution
8.2.1 INVESTIGATOR’S BROCHURE To document that relevant and current scientific X X information about the investigational product has been provided to the investigator
8.2.2 SIGNED PROTOCOL AND AMENDMENTS, IF ANY, AND SAMPLE CASE REPORT FORM (CRF)
To document investigator and sponsor agreement to the protocol/amendment(s) and CRF
X X
8.2.3 INFORMATION GIVEN TO TRIAL X X SUBJECT
- INFORMED CONSENT FORM To document the informed consent (including all applicable translations)
- ANY OTHER WRITTEN INFORMATION To document that subjects will be given appropriate written information (content and wording) to support their ability to give fully informed consent
X X
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- ADVERTISEMENT FOR SUBJECT RECRUITMENT (if used)
To document that recruitment appropriate and not coercive
measures are X
8.2.4 FINANCIAL ASPECTS OF THE TRIAL To document the financial agreement between the investigator/institution and the sponsor for the trial
X X
Title of Document Purpose Located in Files of
Investigator/ Sponsor Institution
8.2.5 INSURANCE STATEMENT (where required)
To document that compensation to subject(s) for trial-related injury will be available
X X
8.2.6 SIGNED AGREEMENT BETWEEN INVOLVED PARTIES, e.g.: - investigator/institution and sponsor - investigator/institution and CRO
- sponsor and CRO - investigator/institution and authority(ies)
(where required)
To document agreements
X X
X
X X
(where required)
X X
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8.2.7 DATED, DOCUMENTED APPROVAL/FAVOURABLE OPINION OF INSTITUTIONAL REVIEW BOARD (IRB) /INDEPENDENT ETHICS COMMITTEE (IEC) OF THE FOLLOWING: - protocol and any amendments - CRF (if applicable) - informed consent form(s) - any other written information to be provided to
the subject(s) - advertisement for subject recruitment
(if used) - subject compensation (if any) - any other documents given approval/
favourable opinion
1709
To document that the trial has been subject to X X IRB/IEC review and given approval/favourable opinion. To identify the version number and date of the document(s)
REGULATORY AUTHORITY(IES) AUTHORISATION/APPROVAL/ NOTIFICATION OF PROTOCOL (where required)
CURRICULUM VITAE AND/OR OTHER RELEVANT DOCUMENTS EVIDENCING QUALIFICATIONS OF INVESTIGATOR(S) AND SUB-INVESTIGATOR(S)
NORMAL VALUE(S)/RANGE(S) FOR MEDICAL/ LABORATORY/TECHNICAL PROCEDURE(S) AND/OR TEST(S) INCLUDED IN THE PROTOCOL
Purpose Located in Files of
Investigator/ Sponsor Institution
To document that the IRB/IEC is constituted in X X agreement with GCP (where
required)
To document appropriate X X authorisation/approval/notification by the regulatory authority(ies) has been obtained prior to initiation of the trial in compliance with the
(where (where required) required)
applicable regulatory requirement(s)
To document qualifications and eligibility to X X conduct trial and/or provide medical supervision of subjects
To document normal values and/or ranges of the X X
tests
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8.2.12 MEDICAL/LABORATORY/TECHNICAL PROCEDURES /TESTS - certification or - accreditation or - established quality control and/or external
quality assessment or - other validation (where required)
Title of Document
8.2.13 SAMPLE OF LABEL(S) ATTACHED TO INVESTIGATIONAL PRODUCT CONTAINER(S)
8.2.14 INSTRUCTIONS FOR HANDLING OF INVESTIGATIONAL PRODUCT(S) AND TRIAL-RELATED MATERIALS (if not included in protocol or Investigator’s Brochure)
8.2.15 SHIPPING RECORDS FOR INVESTIGATIONAL PRODUCT(S) AND TRIAL-RELATED MATERIALS
To document competence of facility to perform required test(s), and support reliability of results
Purpose
To document compliance with applicable labelling regulations and appropriateness of instructions provided to the subjects
To document instructions needed to ensure proper storage, packaging, dispensing and disposition of investigational products and trial-related materials
To document shipment dates, batch numbers and method of shipment of investigational product(s) and trial-related materials. Allows tracking of product batch, review of shipping conditions, and accountability
X X
(where required)
Located in Files of
Investigator/ Sponsor Institution
X
X X
X X
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Guideline for Good Clinical Practice
8.2.16 CERTIFICATE(S) OF ANALYSIS OF To document identity, purity, and strength of INVESTIGATIONAL PRODUCT(S) SHIPPED investigational product(s) to be used in the trial
8.2.17 DECODING PROCEDURES FOR BLINDED To document how, in case of an emergency, X X TRIALS identity of blinded investigational product can be
revealed without breaking the blind for the remaining subjects' treatment
(third party if applicable)
1711
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1712
Title of Document Purpose Located in Files of
Investigator/ Sponsor Institution
8.2.18 MASTER RANDOMISATION LIST To document method for randomisation of trial X population (third party if
applicable)
8.2.19 PRE-TRIAL MONITORING REPORT To document that the site is suitable for the trial X (may be combined with 8.2.20)
8.2.20 TRIAL INITIATION MONITORING To document that trial procedures were reviewed X X REPORT with the investigator and the investigator’s trial
staff ( may be combined with 8.2.19)
1713 8.3 During the Clinical Conduct of the Trial
1714 In addition to having on file the above documents, the following should be added to the files during the trial as evidence that all new relevant 1715 information is documented as it becomes available
8.3.1 INVESTIGATOR’S BROCHURE UPDATES To document that investigator is informed in a X X timely manner of relevant information as it becomes available
1716
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1717
Title of Document Purpose Located in Files of
Investigator/ Sponsor Institution
8.3.2 ANY REVISION TO: To document revisions of these trial related X X - protocol/amendment(s) and CRF documents that take effect during trial - informed consent form - any other written information provided to
subjects - advertisement for subject recruitment
(if used)
8.3.3 DATED, DOCUMENTED To document that the amendment(s) and/or X X APPROVAL/FAVOURABLE OPINION OF revision(s) have been subject to IRB/IEC review INSTITUTIONAL REVIEW BOARD (IRB) and were given approval/favourable opinion. To /INDEPENDENT ETHICS COMMITTEE identify the version number and date of the (IEC) OF THE FOLLOWING: document(s).
- protocol amendment(s) - revision(s) of:
- informed consent form - any other written information to be
provided to the subject - advertisement for subject recruitment
(if used) - any other documents given
approval/favourable opinion - continuing review of trial (where required)
1718
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1719
Title of Document
8.3.4 REGULATORY AUTHORITY(IES) AUTHORISATIONS/APPROVALS/NOTIFIC ATIONS WHERE REQUIRED FOR: - protocol amendment(s) and other documents
8.3.5 CURRICULUM VITAE FOR NEW INVESTIGATOR(S) AND/OR SUB-INVESTIGATOR(S)
8.3.6 UPDATES TO NORMAL VALUE(S)/RANGE(S) FOR MEDICAL/ LABORATORY/ TECHNICAL PROCEDURE(S)/TEST(S) INCLUDED IN THE PROTOCOL
8.3.7 UPDATES OF MEDICAL/LABORATORY/ TECHNICAL PROCEDURES/TESTS
- certification or - accreditation or - established quality control and/or external
quality assessment or - other validation (where required)
8.3.8 DOCUMENTATION OF INVESTIGATIONAL PRODUCT(S) AND TRIAL-RELATED MATERIALS SHIPMENT
1720
Purpose Located in
Investigator/ Institution
Files of
Sponsor
To document compliance with applicable regulatory requirements
X (where
required)
X
(see 8.2.10) X X
To document normal values and ranges that are revised during the trial (see 8.2.11)
X X
To document that tests remain adequate throughout the trial period (see 8.2.12)
X (where
required)
X
(see 8.2.15.) X X
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1721
Title of Document Purpose
8.3.9 CERTIFICATE(S) OF ANALYSIS FOR NEW BATCHES OF INVESTIGATIONAL
(see 8.2.16)
PRODUCTS
8.3.10 MONITORING VISIT REPORTS To document site visits by, and findings of, the monitor
8.3.11 RELEVANT COMMUNICATIONS OTHER THAN SITE VISITS
- letters - meeting notes - notes of telephone calls
To document any agreements or significant discussions regarding trial administration, protocol violations, trial conduct, adverse event (AE) reporting
8.3.12 SIGNED INFORMED CONSENT FORMS To document that consent is obtained in accordance with GCP and protocol and dated prior to participation of each subject in trial. Also to document direct access permission (see 8.2.3)
8.3.13 SOURCE DOCUMENTS To document the existence of the subject and substantiate integrity of trial data collected. To include original documents related to the trial, to medical treatment, and history of subject
1722
Located in Files of
Investigator/ Sponsor Institution
X
X
X X
X
X
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1723
Title of Document
8.3.14
8.3.15
8.3.16
8.3.17
8.3.18
8.3.19
SIGNED, DATED AND COMPLETED CASE REPORT FORMS (CRF)
DOCUMENTATION OF CRF CORRECTIONS
NOTIFICATION BY ORIGINATING INVESTIGATOR TO SPONSOR OF SERIOUS ADVERSE EVENTS AND RELATED REPORTS
NOTIFICATION BY SPONSOR AND/OR INVESTIGATOR, WHERE APPLICABLE, TO REGULATORY AUTHORITY(IES) AND IRB(S)/IEC(S) OF UNEXPECTED SERIOUS ADVERSE DRUG REACTIONS AND OF OTHER SAFETY INFORMATION
NOTIFICATION BY SPONSOR TO INVESTIGATORS OF SAFETY INFORMATION
INTERIM OR ANNUAL REPORTS TO IRB/IEC AND AUTHORITY(IES)
Title of Document
Purpose
To document that the investigator or authorised member of the investigator’s staff confirms the observations recorded
To document all changes/additions or corrections made to CRF after initial data were recorded
Notification by originating investigator to sponsor of serious adverse events and related reports in accordance with 4.11
Notification by sponsor and/or investigator, where applicable, to regulatory authorities and IRB(s)/IEC(s) of unexpected serious adverse drug reactions in accordance with 5.17 and 4.11.1 and of other safety information in accordance with 5.16.2 and 4.11.2
Notification by sponsor to investigators of safety information in accordance with 5.16.2
Interim or annual reports provided to IRB/IEC in accordance with 4.10 and to authority(ies) in accordance with 5.17.3
Purpose
Located in Files of
Investigator/ Sponsor Institution
X X (copy) (original)
X X (copy) (original)
X X
X X (where
required)
X X
X X (where
required)
Located in Files of
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8.3.20 SUBJECT SCREENING LOG To document identification of subjects who entered pre-trial screening
8.3.21 SUBJECT IDENTIFICATION CODE LIST To document that investigator/institution keeps a confidential list of names of all subjects allocated to trial numbers on enrolling in the trial. Allows investigator/institution to reveal identity of any subject
8.3.22 SUBJECT ENROLMENT LOG To document chronological enrolment of subjects by trial number
8.3.23 INVESTIGATIONAL PRODUCTS ACCOUNTABILITY AT THE SITE
To document that investigational product(s) have been used according to the protocol
8.3.24 SIGNATURE SHEET To document signatures and initials of all persons authorised to make entries and/or corrections on CRFs
8.3.25 RECORD OF RETAINED BODY FLUIDS/ TISSUE SAMPLES (IF ANY)
To document location and identification of retained samples if assays need to be repeated
1724
Investigator/ Institution
X
X
Sponsor
X (where
required)
X
X X
X X
X X
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1725 8.4 After Completion or Termination of the Trial
1726 After completion or termination of the trial, all of the documents identified in Sections 8.2 and 8.3 should be in the file together with the 1727 following
Title of Document Purpose
8.4.1 INVESTIGATIONAL PRODUCT(S) ACCOUNTABILITY AT SITE
To document that the investigational product(s) have been used according to the protocol. To documents the final accounting of investigational product(s) received at the site, dispensed to subjects, returned by the subjects, and returned to sponsor
8.4.2 DOCUMENTATION OF INVESTIGATIONAL PRODUCT DESTRUCTION
To document destruction of unused investigational products by sponsor or at site
8.4.3 COMPLETED SUBJECT IDENTIFICATION CODE LIST
To permit identification of all subjects enrolled in the trial in case follow-up is required. List should be kept in a confidential manner and for agreed upon time
8.4.4 AUDIT CERTIFICATE (if available) To document that audit was performed
8.4.5 FINAL TRIAL CLOSE-OUT MONITORING REPORT
To document that all activities required for trial close-out are completed, and copies of essential documents are held in the appropriate files
Located in Files of
Investigator/ Sponsor Institution
X X
X X (if destroyed at
site)
X
X
X
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8.4.6 TREATMENT ALLOCATION AND Returned to sponsor to document any decoding that X DECODING DOCUMENTATION may have occurred
Title of Document Purpose Located in Files of
Investigator/ Sponsor Institution
8.4.7 FINAL REPORT BY INVESTIGATOR TO To document completion of the trial X IRB/IEC WHERE REQUIRED, AND WHERE APPLICABLE, TO THE REGULATORY AUTHORITY(IES)
8.4.8 CLINICAL STUDY REPORT To document results and interpretation of trial X X (if applicable)
1728
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Guidance for Industry
Oversight of Clinical Investigations —
A Risk-Based Approach to Monitoring
U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Devices and Radiological Health (CDRH)
Office of Good Clinical Practice (OGCP) Office of Regulatory Affairs (ORA)
August 2013 Procedural
OMB Control No. 0910-0733 Expiration Date: 06/30/2019 (Note: Expiration date updated 07/15/2016)
See additional PRA statement in section VII of this guidance.
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Guidance for Industry Oversight of Clinical Investigations — A
Risk-Based Approach to Monitoring Additional copies are available from:
Office of Communications Division of Drug Information, WO51, Room 2201
Center for Drug Evaluation and Research Food and Drug Administration
10903 New Hampshire Ave. Silver Spring, MD 20993-0002
I. INTRODUCTION............................................................................................................. 1
II. BACKGROUND ............................................................................................................... 2
A. Current Monitoring Practices and FDA Guidance .................................................................... 3
B. FDA’s Rationale for Risk-Based Monitoring .............................................................................. 5
III. OVERVIEW OF MONITORING METHODS ............................................................. 6
A. On-Site and Centralized Monitoring ........................................................................................... 6 1. On-Site Monitoring.......................................................................................................................... 6 2. Centralized Monitoring.................................................................................................................... 7
B. Examples of Alternative Monitoring Techniques ....................................................................... 7 1. Communication with Study Site Staff ............................................................................................. 9 2. Review of Site’s Processes, Procedures, and Records..................................................................... 9 3. Source Data Verification and Corroboration ................................................................................. 10
IV. RISK-BASED MONITORING...................................................................................... 10
A. Identify Critical Data and Processes to be Monitored.............................................................. 11
B. Risk Assessment ........................................................................................................................... 12
C. Factors to Consider when Developing a Monitoring Plan ....................................................... 13
D. Monitoring Plan ........................................................................................................................... 14 1. Description of Monitoring Approaches.......................................................................................... 15 2. Communication of Monitoring Results.......................................................................................... 15 3. Management of Noncompliance .................................................................................................... 16 4. Ensuring Quality Monitoring ......................................................................................................... 16 5. Monitoring Plan Amendments....................................................................................................... 17
V. DOCUMENTING MONITORING ACTIVITIES ...................................................... 17
VI. ADDITIONAL STRATEGIES TO ENSURE STUDY QUALITY............................ 17
A. Protocol and Case Report Form Design .................................................................................... 17
B. Clinical Investigator Training and Communication................................................................. 18
C. Delegation of Monitoring Responsibilities to a CRO................................................................ 18
D. Clinical Investigator and Site Selection and Initiation............................................................. 19
VII. PAPERWORK REDUCTION ACT OF 1995.............................................................. 19
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Guidance for Industry1
Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring
This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.
I. INTRODUCTION
This guidance assists sponsors of clinical investigations in developing risk-based monitoring strategies and plans for investigational studies of medical products, including human drug and biological products, medical devices, and combinations thereof. The overarching goal of this guidance is to enhance human subject protection and the quality of clinical trial data by focusing sponsor oversight on the most important aspects of study conduct and reporting.
This guidance makes clear that sponsors can use a variety of approaches to fulfill their responsibilities for monitoring clinical investigator (CI) conduct and performance in investigational new drug (IND) studies conducted under 21 CFR part 312 or investigational device exemption (IDE) studies conducted under 21 CFR part 812. The guidance describes strategies for monitoring activities that reflect a modern, risk-based approach that focuses on critical study parameters and relies on a combination of monitoring activities to oversee a study effectively. For example, the guidance specifically encourages greater use of centralized monitoring methods where appropriate.
FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Rather, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.
1 This guidance has been prepared by the Office of Medical Policy in the Center for Drug Evaluation and Research (CDER) in cooperation with CDER’s Office of Scientific Investigations in the Office of Compliance, CBER’s Office of Compliance and Biologics Quality, CDRH’s Office of Compliance, Office of the Commissioner’s Office of Good Clinical Practice, and the Office of Regulatory Affairs (ORA).
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II. BACKGROUND
Effective monitoring of clinical investigations by sponsors is critical to the protection of human subjects and the conduct of high-quality studies. Sponsors of clinical investigations involving human drugs, biological products, medical devices, and combinations thereof are required to provide oversight to ensure adequate protection of the rights, welfare, and safety of human subjects and the quality of the clinical trial data submitted to FDA.2 FDA’s regulations require sponsors to monitor the conduct and progress of their clinical investigations.3,4 The regulations are not specific about how sponsors are to conduct such monitoring and are therefore compatible with a range of approaches to monitoring (see section III) that will vary depending on multiple factors (see section IV.C).
During the past two decades, the number and complexity of clinical trials have grown dramatically. These changes create new challenges to clinical trial oversight, particularly increased variability in clinical investigator experience, site infrastructure, treatment choices, and standards of health care,5 as well as challenges related to geographic dispersion. At the same time, increasing use of electronic systems and records and improvements in statistical assessments, present opportunities for alternative monitoring approaches (e.g., centralized monitoring) that can improve the quality and efficiency of sponsor oversight of clinical investigations. FDA encourages sponsors to develop monitoring plans that manage important risks to human subjects and data quality and address the challenges of oversight in part by taking advantage of the innovations in modern clinical trials. A risk-based approach to monitoring does not suggest any less vigilance in oversight of clinical investigations. Rather, it focuses sponsor oversight activities on preventing or mitigating important and likely risks to data quality and to processes critical to human subject protection and trial integrity. Moreover, a risk-based approach is dynamic, more readily facilitating continual improvement in trial conduct and oversight. For example, monitoring findings should be evaluated to determine whether additional actions (e.g., training of clinical investigator and site staff, clarification of protocol requirements) are necessary to ensure human subject protection and data quality across sites.
This guidance focuses principally on monitoring, which is one aspect of the processes and procedures needed to ensure clinical trial quality and subject safety. Monitoring is a quality control tool for determining whether study activities are being carried out as planned, so that deficiencies can be identified and corrected. Monitoring, or oversight, alone cannot ensure quality. Rather, quality is an overarching objective that must be built into the clinical trial enterprise. FDA recommends a quality risk management approach to clinical trials and is considering the need for additional guidance describing this approach.
2 21 CFR part 312, subpart D generally (Responsibilities of Sponsors and Investigators) and 21 CFR part 812, subpart C generally (Responsibilities of Sponsors).3 21 CFR 312.50 requires a sponsor to, among other things, ensure “proper monitoring of the investigation(s)” and “that the investigation(s) is conducted in accordance with the general investigational plan and protocols contained in the IND.” 21 CFR 812.40 states that sponsors are responsible for, among other things, “ensuring proper monitoring of the investigation, …” 4 See also 21 CFR 312.53(d), 312.56(a), 812.43(d), and 812.46. 5 Glickman et al. Ethical and Scientific Implications of the Globalization of Clinical Research. NEJM. 360: 816-823 (2009).
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We are aware that the term monitoring is used in different ways in the clinical trial context. It can refer to the assessment of CI conduct, oversight, and reporting of findings of a clinical trial; to the ongoing evaluation of safety data and the emerging benefit-risk profile of an investigational product; and to the monitoring of internal sponsor and contract research organization (CRO) processes and systems integral to proposing, designing, performing, recording, supervising, reviewing, or reporting clinical investigations.
For purposes of this guidance, monitoring refers to the methods used by sponsors of investigational studies, or CROs delegated responsibilities for the conduct of IND studies, to oversee the conduct of, and reporting of data from, clinical investigations, including appropriate CI supervision of study site staff and third party contractors. Monitoring activities include communication with the CI and study site staff; review of the study site’s processes, procedures, and records; and verification of the accuracy of data submitted to the sponsor.
A. Current Monitoring Practices and FDA Guidance
A survey conducted through the Clinical Trials Transformation Initiative (CTTI)6 indicated that a range of practices has been used to monitor the conduct of clinical trials. These practices vary in intensity, focus, and methodology and include centralized monitoring of clinical data by statistical and data management personnel; targeted on-site visits to higher risk CIs (e.g., where centralized monitoring suggests problems at a site); and frequent, comprehensive on-site visits to all CI sites by sponsor personnel or representatives (e.g., clinical monitors or clinical research associates).7 See definitions of on-site and centralized monitoring in section III.A.
Although survey participants reported a range of monitoring methods, periodic, frequent visits to each CI site to evaluate study conduct and review data for each enrolled subject remain the predominant mechanism by which pharmaceutical, biotechnology, and medical device companies monitor the progress of clinical investigations. For major efficacy trials, companies typically conduct on-site monitoring visits at approximately 4- to 8-week intervals,8 at least partly because of the perception that the frequent on-site monitoring visit model, with 100% verification of all data, historically has been FDA’s preferred way for sponsors to meet their monitoring obligations. In contrast, academic coordinating centers, cooperative groups, and government organizations use on-site monitoring less extensively. For example, some government agencies and oncology cooperative groups typically visit sites only once every 2 or 3 years to qualify or certify clinical study sites9 to ensure they have the resources, training, and safeguards to conduct clinical trials. FDA also recognizes that regulators and practitioners have relied on data from critical outcome studies (e.g., many National Institutes of Health-sponsored trials, Medical Research Council-sponsored trials in the United Kingdom, ISIS (International
6 CTTI is a public-private partnership involving FDA, academia, industry representatives, patient and consumer representatives, professional societies, investigator groups, and other government agencies, initiated in 2008. CTTI’s mission is to identify practices that will increase the quality and efficiency of clinical trials.7 Morrison et al. Monitoring the Quality of Conduct of Clinical Trials: A Survey of Current Practices. Clin Trials. 8: 342-349 (2011).8 Usher, R. PhRMA BioResearch Monitoring Committee Perspective on Acceptable Approaches for Clinical Trial Monitoring. Drug Inf J. 44: 477-483 (2010). 9 Id.
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Study of Infarct Survival) trials,10 and GISSI11), which had no regular on-site monitoring and used primarily centralized and other alternative monitoring methods.12 These examples suggest that use of alternative monitoring approaches should be considered by all sponsors, including commercial sponsors, when developing risk-based monitoring strategies and plans.
The 1996 International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidance on good clinical practice (ICH E6) and the 2011 International Standards Organization (ISO) Clinical investigation of medical devices for human subjects – good clinical practice (ISO 14155:2011) address monitoring. Both ICH E6 and ISO 14155:2011 specifically provide for flexibility in how trials are monitored. ICH E6 and ISO 14155:2011 advise sponsors to consider the objective, design, complexity, size, and endpoints of a trial in determining the extent and nature of monitoring for a given trial.13,14 The ISO standard further states that a sponsor’s assessment of these factors should be used to develop a monitoring plan, a recommendation consistent with FDA’s recommendation for monitoring plan development in this guidance. Although the ICH guidance and ISO standard specifically provide for the possibility of reduced, or even no, on-site monitoring, they also make clear that it would be appropriate to rely entirely on centralized monitoring only in exceptional circumstances.
FDA has communicated the goals of, and recommendations for, risk-based monitoring to FDA staff in review, inspection, and compliance functions. FDA’s bioresearch monitoring compliance program guidance manuals (CPGMs) for sponsors, CROs, and monitors (CPGM 7348.810)15 and for CIs and sponsor-investigators (CPGM 7348.811)16 are compatible with the approaches described in this guidance. For example, CPGM 7348.810 informs FDA field staff that the regulations do not prescribe a specific monitoring technique. While CPGM 7348.810 refers to site visits and does not discuss centralized monitoring, the focus is on the review of monitoring activities through documentation and whether these activities were carried out in accordance with the sponsor’s (or CRO’s) monitoring procedures.
10 Califf et al. Developing Systems for Cost-Effective Auditing of Clinical Trials. Controlled Clinical Trials. 18: 651-660 (1997).11 Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Italian group for the study of the survival of myocardial infarction.12 Temple, R. Policy Developments in Regulatory Approval. Statistics in Medicine. 21: 2939-2948 (2002). 13 Guidance for industry, E6 Good Clinical Practice: Consolidated Guidance, 1996, section 5.18.3. We update guidances periodically. To make sure you have the most recent version of a guidance, check the guidance Web site. CDER guidance documents can be found at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. CBER guidance documents can be found at http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. CDRH guidance documents can be found at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm. 14 ISO 14155:2011, Clinical investigation of medical devices for human subjects – Good clinical practice, sections 5.7 and 6.3. 15 CPGM 7348.810: Sponsors, Contract Research Organizations and Monitors (March 11, 2011), available at: http://www.fda.gov/ICECI/EnforcementActions/BioresearchMonitoring/ucm133777.htm. 16 CPGM 7348.811: Clinical Investigators and Sponsor-Investigators (December 8, 2008), available at: http://www.fda.gov/ICECI/EnforcementActions/BioresearchMonitoring/ucm133562.htm.
FDA is issuing this guidance to provide FDA’s current recommendations regarding monitoring practices and to encourage sponsors to consider a change in approach to monitoring. FDA believes that risk-based monitoring could improve sponsor oversight of clinical investigations. This guidance is therefore intended to make it clear that risk-based monitoring, including the appropriate use of centralized monitoring (see section III.A.2 for discussion of centralized monitoring) and reliance on technological advances (e.g., e-mail, webcasts, online training modules), can meet statutory and regulatory requirements under appropriate circumstances.
There is a growing consensus that risk-based approaches to monitoring, focused on risks to the most critical data elements and processes necessary to achieve study objectives, are more likely than routine visits to all clinical sites and 100% data verification to ensure subject protection and overall study quality.17,18,19,20 For example, incorporation of centralized monitoring practices, where appropriate, should improve a sponsor’s ability to ensure the quality of clinical trial data. Several publications suggest that certain data anomalies (e.g., fraud, including fabrication of data, and other non-random data distributions) may be more readily detected by centralized monitoring techniques than by on-site monitoring.21, 22, 23 It has been suggested that a statistical approach to central monitoring can “help improve the effectiveness of on-site monitoring by prioritizing site visits and by guiding site visits with central statistical data checks,” an approach that is supported by illustrative examples using actual trial datasets.24 A recent review of on-site monitoring findings collected during a multi-center international trial also suggests that centralized monitoring can identify the great majority of on-site monitoring findings. The review determined that centralized monitoring activities could have identified more than 90% of the findings identified during on-site monitoring visits.25
FDA encourages sponsors to tailor monitoring plans to the needs of the trial (see section IV). FDA recognizes that this guidance places greater emphasis on centralized monitoring than appeared feasible at the time ICH E6 was finalized. However, FDA considers the approach to monitoring described in this guidance to be consistent with ICH E6 and ISO 14155:2011. FDA
17 Usher, R. PhRMA BioResearch Monitoring Committee Perspective on Acceptable Approaches for Clinical Trial Monitoring. Drug Inf J. 44: 477-483 (2010). 18 FDA, Concept Paper: Quality in FDA-Regulated Clinical Research; Background to HSP/BIMO Workshop 5/10-5/11/07, (4/26/07).19 Brosteanu et al. Risk Analysis and Risk Adapted On-Site Monitoring in Noncommercial Clinical Trials. Clin Trials. 6: 585-595 (2009). 20 Tantsyura et al. Risk-Based Source Data Verification Approaches: Pros and Cons. Drug Inf J. 44: 745-756 (2010). 21 Usher, R. PhRMA BioResearch Monitoring Committee Perspective on Acceptable Approaches for Clinical Trial Monitoring. Drug Inf J. 44: 477-483 (2010). 22 Baigent et al. Ensuring Trial Validity by Data Quality Assurance and Diversification of Monitoring Methods. Clin Trials. 5: 49-55 (2008). 23 Buyse et al. The Role of Biostatistics in the Prevention, Detection and Treatment of Fraud in Clinical Trials. Statistics in Medicine. 18: 3435-51 (1999). 24 Venet et al. A Statistical Approach to Central Monitoring of Data Quality in Clinical Trials. Clin Trials. 0: 1-9 (2012).25 Bakobaki et al. The Potential for Central Monitoring Techniques to Replace On-Site Monitoring: Findings from an International Multi-Centre Clinical Trial. Clin Trials. 9: 257-264 (2012).
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believes it is reasonable to conclude that the flexibility described in ICH E6 and ISO 14155:2011 was intended to permit innovative approaches to improve the effectiveness of monitoring. Notably, the advancement in electronic systems and increasing use of electronic records (i.e., electronic data capture (EDC) systems) facilitate remote access to electronic data and, increasingly, to some source data (see section III.B.2.b for further discussion of access to electronic source data). Additionally, statistical assessments using data submitted on paper CRFs or via EDC may permit timely identification of clinical sites that require additional training, monitoring, or both. We expect that the pharmaceutical and device industries will, for the foreseeable future, continue to use some amount of on-site monitoring, but we anticipate decreased use of on-site monitoring with evolving monitoring methods and technological capabilities.
The following sections reflect FDA’s current thinking on monitoring and include recommendations on how to develop and implement a study-specific monitoring plan as well as how to document monitoring activities. FDA acknowledges that there are limited empirical data to support the utility of the various methods employed to monitor clinical investigations (e.g., superiority of one method versus another), including data to support on-site monitoring.26 As a result, the recommendations are based, in part, on FDA’s experience from the review of protocols during the IND or IDE phase, data submitted in pre-approval applications, results of inspections conducted to ensure human subject protection and data integrity, and information obtained from public outreach efforts conducted under the auspices of the CTTI.
III. OVERVIEW OF MONITORING METHODS
A. On-Site and Centralized Monitoring
This section is intended to assist sponsors in identifying and designing monitoring practices appropriate to a given clinical trial. It describes some of the capabilities of on-site and centralized monitoring processes and factors to consider in determining which monitoring practices may be appropriate for a given clinical trial. See section IV.C for a discussion of factors to consider when determining the types, frequency, and extent of monitoring activities and section IV.D.1 for examples of events or results that would trigger a change in planned monitoring activities.
1. On-Site Monitoring
On-site monitoring is an in-person evaluation carried out by sponsor personnel or representatives at the sites at which the clinical investigation is being conducted. On-site monitoring can identify data entry errors (e.g., discrepancies between source records and case report forms (CRFs)) and missing data in source records or CRFs; provide assurance that study documentation exists; assess the familiarity of the site’s study staff with the protocol and required procedures; and assess compliance with the protocol and investigational product
26 Two studies are on-going as of June 2013 that compare the effectiveness of on-site to alternative (e.g., centralized) monitoring methods (OPTIMON study (https://ssl2.isped.u-bordeaux2.fr/optimon/Default.aspx) and ADAMON study (http://ctj.sagepub.com/content/6/6/585.full.pdf+html)).
accountability. On-site monitoring can also provide a sense of the quality of the overall conduct of the trial at a site (e.g., attention to detail, thoroughness of study documentation, appropriate delegation of study tasks, appropriate CI supervision of site staff performing critical study functions). On-site monitoring can therefore be particularly helpful early in a study, especially if the protocol is complex and includes novel procedures with which CIs may be unfamiliar. Findings at the site may lead to training efforts at both the site visited and elsewhere (see section VI.B).
2. Centralized Monitoring
Centralized monitoring is a remote evaluation carried out by sponsor personnel or representatives (e.g., clinical monitors, data management personnel, or statisticians) at a location other than the sites at which the clinical investigation is being conducted. Centralized monitoring processes can provide many of the capabilities of on-site monitoring as well as additional capabilities.
FDA encourages greater use of centralized monitoring practices, where appropriate, than has been the case historically, with correspondingly less emphasis on on-site monitoring. The types of monitoring activities and the extent to which centralized monitoring practices can be employed depend on various factors, including the sponsor’s use of electronic systems; the sponsor’s access to subjects’ electronic records, if applicable; the timeliness of data entry from paper CRF, if applicable; and communication tools available to the sponsor and study site. These may vary by study and by site. Sponsors who plan to use centralized monitoring processes should ensure that the processes and expectations for site record keeping, data entry, and reporting are well-defined and ensure timely access to clinical trial data and supporting documentation.27 If sponsors intend to rely heavily on centralized monitoring practices, they should identify, in the monitoring plan, when one or more on-site monitoring visits would be indicated.
B. Examples of Alternative Monitoring Techniques
As discussed in section II, monitoring activities broadly include communication with the CI and study site staff; review of the study site’s processes, procedures, and records; and verification of the accuracy of data submitted to the sponsor. This section highlights areas for which centralized monitoring techniques could be considered. For certain monitoring activities, centralized monitoring techniques can be considered in place of, or to complement, traditional monitoring techniques. Specific techniques used should be prospectively included in the monitoring plan and should be informed by the risk assessment (see section IV.B for discussion of risk assessment).
Centralized monitoring techniques should be used to the extent appropriate and feasible to:
27 See guidances for industry: Part 11, Electronic Records; Electronic Signatures – Scope and Application and Computerized Systems Used in Clinical Investigations.
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• Supplement or reduce the frequency and extent of on-site monitoring with monitoring activities that can be done as well or better remotely or with monitoring activities that can be accomplished using centralized processes only. Examples include:
o Monitor data quality through routine review of submitted data to identify and follow-up on missing data, inconsistent data, data outliers, and potential protocol deviations that may be indicative of systemic or significant errors in data collection and reporting at a site
o Conduct statistical analyses to identify data trends not easily detected by on-site monitoring, such as
Standard checks of range, consistency, and completeness of data
Checks for unusual distribution of data within and between study sites, such as too little variance28
o Analyze site characteristics, performance metrics (e.g., high screen failure or withdrawal rates, high frequency of eligibility violations, delays in reporting data), and clinical data to identify trial sites with characteristics correlated with poor performance or noncompliance
o Verify critical source data remotely as described in the monitoring plan, in cases where such source data are accessible, or where CRF data are, according to the protocol, source data
o Complete administrative and regulatory tasks. Such tasks include, for example, verifying continuous institutional review board (IRB) approval by reviewing electronic IRB correspondence, if available; performing portions of investigational product accountability, such as comparison of randomization and CRF data, to preliminarily assess whether the subject was administered or dispensed the assigned product and to evaluate consistency between investigational product receipt, use, and disposition records; and verifying whether previously requested CRF corrections were made.
Centralized techniques, including routine review of submitted data and statistical and other analyses, may also be used to identify significant concerns (e.g., need for clarification of a protocol procedure, indications of data fabrication) with non-critical data that may not have otherwise been a focus of monitoring (e.g., source document verification).
• Target on-site monitoring by identifying higher risk clinical sites (e.g., sites with data anomalies or a higher frequency of errors, protocol violations, or dropouts relative to other sites), through the activities described above. Such findings, whether related to critical or non-critical data, may warrant more intensive and consideration of on-site monitoring.
The following sections provide additional descriptions of alternative monitoring techniques.
28 Collins, Rory. (2010, October) Quality Design of Clinical Trials. Presentation at CTTI work stream 3 expert meeting. Available at: https://www.ctti-clinicaltrials.org/website-administration/documents/COLLINS%20FDA%20trial%20quality%200811%20FINAL_no%20animation.pdf/view
Communication between the monitor and the study site staff is an essential component of monitoring. Various modes of communication (e.g., teleconferences, videoconferencing, email) could be considered for specific study time points (e.g., study initiation) and activities (e.g., to discuss findings of a monitor’s eCRF review, training of new site staff).
2. Review of Site’s Processes, Procedures, and Records
Techniques for monitoring informed consent and site records are included here as examples of approaches to monitoring site’s processes, procedures, and records.
a. Informed Consent
Verification of subjects’ informed consent is a critical activity that should be monitored (see section IV.A). Alternatives to the traditional approach (monitors verifying the original signature on the consent form for each subject at the site) may be more effective in identifying inadequacies in the consent process and may be more efficient. For example, the study site electronically sends (e.g., fax, e-mail) the signed page(s) of consent forms to the monitor, or the monitor performs remote comparison of dates of study procedures and documentation of informed consent on CRFs. An internet portal that enables the site staff to upload signed consent forms and enables access by designated monitors is a tool that can be considered. Use of electronic informed consent may also facilitate sponsor oversight of human subject protection. We recognize that sponsors must attend to privacy and confidentiality concerns when considering techniques for monitoring informed consent remotely.
b. Site’s Records
A growing portion of source documents (e.g., laboratory and radiology reports, source documents submitted by the CI for other purposes such as health records documenting serious adverse events or adjudicated events) are electronic and may be available to the sponsor remotely. Furthermore, consistent with ICH E6 and ISO 14155:2011, original observations can be entered directly into the eCRF or transmitted to the eCRF from various locations, devices, or instruments.29 We recognize that sponsors may not have remote access to electronic health records maintained by hospitals, universities, and other institutions because of data privacy and security concerns as well as technological challenges. Sponsors should consider risk-based approaches to monitoring using the format of study information (i.e., electronic, paper, or combination of electronic and paper), tools, and other resources available to them.
As discussed in this guidance, a variety of centralized monitoring techniques can be used to replace, supplement, and target on-site monitoring activities. The majority of these techniques
29 Section 6.4.9 of ICH E6 provides that the trial design description should include “The identification of any data to be recorded directly on the CRFs (i.e., no prior written or electronic record of data), and to be considered to be source data.” ISO 14155:2011, section 6.8.2, provides that the clinical investigation plan “shall specify which data can be recorded directly in the CRFs.”
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(e.g., checks for completeness of data, sites with a higher frequency of protocol violations relative to other sites, sites with high screen failure rates) can be performed regardless of the extent of use of electronic records in the study. For example, the majority of these techniques can be performed using CRF data collected either using electronic data capture systems or entered into a database from a paper CRF collected by the sponsor. A recent publication discusses statistical techniques for identifying various types of data errors.30 We recognize that the statistical techniques described in this guidance may not be routinely used by all sponsors and may not be appropriate for every trial, but they are included in this guidance as examples of monitoring techniques that may be considered by sponsors.
Additional monitoring techniques, such as routine review of data as they are submitted, are possible for studies that use electronic CRFs. Although not a monitoring technique, another method of ensuring data quality routinely implemented in eCRFs is the use of electronic prompts in the eCRF to minimize errors and omissions at the time of data entry, particularly if data are entered directly into the eCRF.
3. Source Data Verification and Corroboration
The sponsor should consider the quantity and types of source data that need to be verified against CRFs or corroborated against other records (e.g., review of medical record to corroborate a subject’s response of “no hospitalizations” since the previous visit on a CRF) during the sponsor’s identification of critical data and processes or in the risk assessment, or both. The sponsor should include a description of the quantity and types of source records to verify or corroborate in the monitoring plan. The sponsor should consider which source records are likely to provide the most meaningful information about a subject’s participation and the CI’s conduct and oversight. For example, for a particular study, there may be minimal benefit in comparing 100% of the source data for each subject to the CRFs for each study visit. Rather, it may be sufficient to compare the most critical data points for a sample of subjects and study visits as an indicator of data accuracy. Similarly, for a particular study, although collection of all concomitant medications, body temperature, and body weight are required by the protocol and are documented in the medical record and transcribed to a CRF, they may not be identified by the sponsor as critical data, because a small error rate in those variables would not affect the outcome of the trial. In the absence of information indicating potential concerns with the data (e.g., sites with data anomalies, inconsistent data), source document verification or corroboration of these non-critical data may not provide significantly useful information to the sponsor.
IV. RISK-BASED MONITORING
No single approach to monitoring is appropriate or necessary for every clinical trial. FDA recommends that each sponsor design a monitoring plan that is tailored to the specific human subject protection and data integrity risks of the trial. Ordinarily, such a risk-based plan would
30 Venet et al. A Statistical Approach to Central Monitoring of Data Quality in Clinical Trials. Clin Trials. 0: 1-9 (2012).
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include a mix of centralized and on-site monitoring practices. The monitoring plan should identify the various methods intended to be used and the rationale for their use (see section IV.D for recommendations on the components of a monitoring plan).
Monitoring activities should focus on preventing or mitigating important and likely sources of error in the conduct, collection, and reporting of critical data and processes necessary for human subject protection and trial integrity. Sponsors should prospectively identify critical data and processes, then perform a risk assessment to identify and understand the risks that could affect the collection of critical data or the performance of critical processes, and then develop a monitoring plan that focuses on the important and likely risks to critical data and processes.
A. Identify Critical Data and Processes to be Monitored
Sponsors should prospectively identify critical data and processes that if inaccurate, not performed, or performed incorrectly, would threaten the protection of human subjects or the integrity of the study results. As examples, the following types of data and processes should ordinarily be identified as critical:
• Verification that informed consent was obtained appropriately
• Adherence to protocol eligibility criteria designed to exclude individuals for whom the investigational product may be less safe than the protocol intended and to include only subjects from the targeted study population for whom the test article is most appropriate
• Procedures for documenting appropriate accountability and administration of the investigational product (e.g., ensuring the integrity of randomization at the site level, where appropriate)
• Conduct and documentation of procedures and assessments related to – study endpoints
– protocol-required safety assessments
– evaluating, documenting, and reporting serious adverse events and unanticipated adverse device effects, subject deaths, and withdrawals, especially when a withdrawal may be related to an adverse event
• Conduct and documentation of procedures essential to trial integrity, such as ensuring the study blind is maintained, both at the site level and at the sponsor level, as appropriate, referring specified events for adjudication, and allocation concealment
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Other types of data (e.g., covariates such as concomitant treatments or demographic characteristics, routine laboratory tests performed as part of subject monitoring that do not address protocol specified safety or efficacy endpoints) and processes (e.g., a hospital pharmacy’s storage of an investigational product with no specific critical handling instructions) identified by the sponsor as non-critical often may be monitored less intensively.
There is increasing recognition that some types of errors in a clinical trial are more important than others.31 For example, a low, but non-zero rate of errors in capturing certain baseline characteristics of enrolled subjects (e.g., age, concomitant treatment, or concomitant illness) will not, in general, have a significant effect on study results if the errors are distributed randomly. In contrast, a small number of errors related to study endpoints (e.g., not following protocol-specified definitions) can profoundly affect study results, as could failure to report rare but important adverse events. Based on FDA’s inspection and review experience, infrequent errors in non-critical data are unlikely to alter FDA’s conclusions about whether a product is safe and effective and whether participants’ safety was appropriately monitored.
B. Risk Assessment
This guidance discusses the risk assessment, a component of risk management, as applied in the context of clinical monitoring. Risk assessment generally involves identifying risks, analyzing risks, and then determining whether risks need to be modified by implementing controls (e.g., processes, policies, or practices). The risk assessment recommended in this guidance to inform development of a monitoring plan may also support efforts to manage risks across a clinical trial (e.g., through modifying the protocol design or implementation) or development program. This guidance does not provide comprehensive detail on how to perform a risk assessment. There are many risk assessment methodologies and tools from a variety of industries that can be applied to clinical trials. 32,33
Following the identification of critical data and processes (section IV.A), sponsors should perform a risk assessment to identify and understand the nature, sources, and potential causes of risks that could affect the collection of critical data or the performance of critical processes. Risks to critical data and processes most merit consideration during risk assessment, to ensure that monitoring efforts are focused on preventing or mitigating important and likely sources of error in their conduct, collection and reporting.
Risk identification for monitoring purposes should generally consider the types of data to be collected, the specific activities required to collect these data, and the range of potential safety and other human subject protection concerns that are inherent to the clinical investigation (e.g., based on trial design or investigational product).
31 Baigent et al. Ensuring Trial Validity by Data Quality Assurance and Diversification of Monitoring Methods. Clin Trials. 5: 49-55 (2008). 32 Guidance for industry, Q9 Quality Risk Management, June 2006. 33 ISO 31010:2009 Risk Management – Risk Assessment Techniques.
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The identified risks should be assessed and prioritized by considering the following:
• the likelihood of errors occurring • the impact of such errors on human subject protection and trial integrity • the extent to which such errors would be detectable
Sponsors should use the results of the risk assessment in developing the monitoring plan (e.g., determining which risks may be addressed through monitoring, determining the types and intensity of monitoring activities best suited to addressing these risks). Sponsors may also determine that some risks are better managed through activities other than monitoring, for example, modifying the protocol to remove the source of the risk. Sponsors should periodically evaluate emerging risks and whether monitoring activities require modification to effectively oversee the risks.
C. Factors to Consider when Developing a Monitoring Plan
A monitoring plan ordinarily should focus on preventing or mitigating important and likely risks, identified by the risk assessment, to critical data and processes. The types (e.g., on-site, centralized), frequency (e.g., early, for initial assessment and training versus throughout the study), and extent (e.g., comprehensive (100% data verification) versus targeted or random review of certain data (less than 100% data verification)) of monitoring activities will depend to some degree on a range of factors, considered during the risk assessment, including the following:
• Complexity of the study design More intensive monitoring (e.g., increased frequency and extent of review) may be necessary as study design complexity increases. Examples may include studies with adaptive designs, stratified designs, complex dose titrations, or multiple device placement studies.
• Types of study endpoints
Endpoints that are more interpretative or subjective may require on-site visits to assess the totality of subject records and to review application of protocol definitions with the CI. More objective endpoints (e.g., death, hospitalization, or clinical laboratory values and standard measurements) may be more suitable for remote verification. Endpoints for which inappropriate subject withdrawal or lack of follow-up may impede study evaluation are likely to need more intensive monitoring to identify the reason(s) subjects are withdrawing and to determine whether follow-up can be improved.
• Clinical complexity of the study population A study that involves a population that is seriously ill or vulnerable may require more intensive monitoring and consideration of on-site monitoring visits to be sure appropriate protection is being provided.
• Geography Sites in geographic areas where there are differences in standards of medical practice or subject demographics, or where there is a less established clinical trial infrastructure may require more intensive monitoring and consideration of on-site monitoring visits.
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• Relative experience of the CI and of the sponsor with the CI CIs who lack significant experience in conducting and overseeing investigations, using a novel or innovative medical device, or with the surgical procedure associated with medical device use may benefit from more intensive monitoring and frequent communication to ensure CI understanding of responsibilities. In addition, the relative experience of a sponsor with the CI may be a factor in determining an appropriate monitoring plan.
• Electronic data capture Use of EDC systems with the capability to assess quality metrics (e.g., missing data, data error rates, protocol violations) in real-time could help identify potentially higher risk sites for the purpose of targeting sites in need of more intensive monitoring.
• Relative safety of the investigational product A study of a product that has significant safety concerns or for which there is no prior experience in human clinical trials (e.g., a phase 1 pharmaceutical investigation or a device feasibility study) may require more intensive monitoring and consideration of on-site monitoring visits to ensure appropriate CI oversight of subject safety.
• Stage of the study
A tapered approach to monitoring may be used where appropriate, with more intensive monitoring at initiation and during early stages of a trial. For example, a tapered approach could be used for a complex study where more intensive and on-site monitoring might be required early, but where, once procedures are established, less intensive monitoring might suffice. Similarly, a tapered approach could be used for relatively inexperienced CIs.
• Quantity of data Some centralized monitoring tools may be more useful as the quantity of data (e.g., size or duration of trial, number of sites) collected increases.
D. Monitoring Plan
For each clinical trial, the sponsor should develop a monitoring plan that describes the monitoring methods, responsibilities, and requirements for the trial. The monitoring plan should include a brief description of the study, its objectives, and the critical data and study procedures, with particular attention to data and procedures that are unusual in relation to clinical routine and require training of study site staff. The plan should also communicate the specific risks to be addressed by monitoring and should provide those involved in monitoring with adequate information to effectively carry out their duties. A monitoring plan may reference existing policies and procedures (e.g., standard operating procedure describing general monitoring processes or issue investigation and resolution). All sponsor and CRO personnel involved with monitoring, including those who review or determine appropriate action regarding potential issues identified through monitoring, should review the monitoring plan and associated documents (e.g., standard operating procedures or other documents referenced in the monitoring plan).
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Sponsors of device studies wishing to solicit feedback on their monitoring procedures prior to the submission of the application may either submit a Pre-Submission,34 or contact CDRH’s Division of Bioresearch Monitoring.35
Sponsors of drug studies may include specific questions about a monitoring plan in a request for a formal meeting with FDA (e.g., end of phase 2 meeting).
The components of a monitoring plan might include the following:
1. Description of Monitoring Approaches
• A description of each monitoring method to be employed during the study and how it will be used to address important risks and ensure the validity of critical data
• Criteria for determining the timing, frequency, and extent of planned monitoring activities
• Specific activities required for each monitoring method employed during the study, including reference to required tools, logs, or templates
• Definitions of events or results (e.g., findings from central monitoring activities) that would trigger changes in planned monitoring activities for a particular CI
For example, if it is determined that a CI differs markedly from other CIs in making safety-related findings or other key safety metrics, in rate of enrollment, in the number of protocol deviations, or in the rate of missing CRFs, the CI’s site should be considered for targeted on-site visits. The establishment of acceptable variation for particular critical data and processes would facilitate identification of significant deviations.
• Identification of possible deviations or failures that would be critical to study integrity and how these are to be recorded and reported
For example, sponsors may wish to establish a specific mechanism for tracking and notifying key study personnel of deviations related to collection or reporting of data necessary to interpret the primary endpoint, regardless of which monitoring method identified a concern.
The study monitoring plan should also describe how various monitoring activities will be documented, regardless of whether they are conducted on-site or centrally (see section V).
2. Communication of Monitoring Results
• Format, content, timing, and archiving requirements for reports and other documentation of monitoring activities (see section V)
• Process for appropriate communication
34 For more information, see FDA’s draft guidance Medical Devices: The Pre-Submission Program and Meetings with FDA Staff. When final, this guidance will represent the FDA’s current thinking on this topic. 35 IDE regulations (21 CFR 812.25(e)) require that written monitoring procedures be submitted as part of the IDE application.
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– of routine monitoring results to management and other stakeholders (e.g., CRO, data management)
– of immediate reporting of significant monitoring issues to appropriate parties (e.g., sponsor management, CI and site staff, IRB, FDA), as necessary
– from study management and other stakeholders to monitors
For example, data management personnel may provide monitors with routine reports of outstanding CRFs or of common data queries at or across sites that may enable effective targeting of monitoring activities.
3. Management of Noncompliance
• Processes for addressing unresolved or significant issues (e.g., significant non-compliance with the investigational plan, suspected or confirmed data falsification) identified by monitoring, whether at a particular site or across study sites
• Processes to ensure that root cause analyses are conducted where important deviations are discovered and that appropriate corrective and preventive actions (e.g., additional training on a study or site level) are implemented to address issues identified by monitoring
• Other quality management practices applicable to the clinical investigation (e.g., reference to any other written documents describing appropriate actions regarding non-compliance)
4. Ensuring Quality Monitoring
• Description of any specific training required for personnel carrying out monitoring activities, including personnel conducting internal data monitoring, statistical monitoring, or other centralized review activities. Training should include principles of clinical investigations and human subject protection. In addition, study-specific training should include discussion of the trial design, protocol requirements, the study monitoring plan, applicable standard operating procedures, appropriate monitoring techniques, and applicable electronic systems.
• Planned audits of monitoring to ensure that sponsor and CRO staff conduct monitoring activities in accordance with the monitoring plan, applicable regulations, guidance, and sponsor policies, procedures, templates, and other study plans. Auditing is a quality assurance tool that can be used to evaluate the effectiveness of monitoring to ensure human subject protection and data integrity.36
• Many sponsors have successfully implemented on-site co-monitoring visits (i.e., monitoring visits performed by both a study monitor and the monitor’s supervisor or another evaluator designated by the sponsor or CRO) to evaluate whether monitors are effectively carrying out visit activities, in compliance with the study monitoring plan. These visits may be conducted either for randomly selected monitors or may be targeted to specific monitors, based upon questions arising from review of monitoring visit documentation.
36 See ICH E6, section 5.19 and ISO 14155:2011, section 6.11 for additional information on audits.
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5. Monitoring Plan Amendments
Sponsors should consider what events would indicate a need for review and revision of the monitoring plan and establish processes to permit timely updates where necessary. For example, a protocol amendment, change in the definition of significant protocol deviations, or identification of new risks to study integrity could result in a change to the monitoring plan.
V. DOCUMENTING MONITORING ACTIVITIES
Documentation of monitoring activities should generally include the following:
• The date of the activity and the individual(s) conducting and participating in it
• A summary of the data or activities reviewed
• A description of any noncompliance, potential noncompliance, data irregularities, or other deficiencies identified
• A description of any actions taken, to be taken, or recommended, including the person responsible for completing actions and the anticipated date of completion
Documentation of monitoring should include sufficient detail to allow verification that the monitoring plan was followed.
Monitoring documentation should be provided to appropriate management in a timely manner for review and follow-up, as indicated.
VI. ADDITIONAL STRATEGIES TO ENSURE STUDY QUALITY
Although the focus of this guidance is on monitoring the oversight and conduct of, and reporting of data from, clinical investigations, FDA considers monitoring to be just one component of a multi-factor approach to ensuring the quality of clinical investigations. Many other factors contribute to the quality of a clinical investigation. This section highlights additional areas that complement monitoring and can affect study quality.
A fundamental component of ensuring quality monitoring is a sponsor’s compliance with monitoring plans and any accompanying procedures.
A. Protocol and Case Report Form Design
The most important tool for ensuring human subject protection and high-quality data is a well-designed and articulated protocol. A poorly designed or ambiguous protocol may introduce systemic errors that can render a clinical investigation unreliable despite rigorous monitoring. Additionally, the complexity of the trial design and the type and amount of data collected may influence data quality.37 The CRF, which captures the data required by the protocol, is another
37 Sponsors are encouraged to consult the appropriate review division within FDA's medical product centers with questions about quality aspects of clinical trial design.
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critical tool for which design directly affects the quality of trial data. Care should be taken to ensure that the CRF captures data accurately (e.g., as required by the protocol) and that the CRF design and instructions facilitate consistent data collection across CI sites.
B. Clinical Investigator Training and Communication
Clinical trial monitors conducting on-site visits have historically played an important role in training the CI and site staff during a study. On-site visits also have served as a primary means of providing feedback to CIs and study personnel on study conduct. Without meaningful training prior to the conduct of a study and of appropriate instruction during the study (e.g., when changes are made to the protocol), CIs and their staff may have difficulty carrying out a trial correctly. Sponsors who plan less frequent or limited on-site monitoring should consider the following:
• Monitoring activities should include sufficient time for discussion of CI’s and site staff’s responsibilities, feedback, and additional training, if needed, during the conduct of the study.
• It may be necessary to implement alternative training (e.g., teleconferences, webcasts, online training modules) and communication methods (see section III.B.1) for providing and documenting ongoing, timely training and feedback, as well as to provide notification of significant changes to study conduct or other important information.
C. Delegation of Monitoring Responsibilities to a CRO
If a sponsor of an IND study delegates the responsibility for ensuring proper monitoring to a CRO, FDA regulations (21 CFR 312.52) require the written transfer of any obligations from a sponsor to a CRO and require the CRO to comply with the regulations.38 Although sponsors can transfer responsibilities for monitoring to a CRO(s), they retain responsibility for oversight of the work completed by the CRO(s) that assume this responsibility. Sponsors should evaluate CRO compliance with regulatory requirements and contractual obligations in an ongoing manner. For example, sponsor oversight of monitoring performed by a CRO may include the sponsor’s periodic review of monitoring reports and vendor performance or quality metrics and documented communication between the sponsor and CRO regarding monitoring progress and findings.
Sponsors and CROs should consider additional factors when a sponsor transfers responsibilities for monitoring to a CRO. Sponsors and CROs should prospectively establish a clear understanding of both parties’ responsibilities and of the expectations for the conduct of the transferred obligations. Sponsors should share information with a CRO that may inform decisions a CRO may make regarding the monitoring practices for a trial (e.g., findings of a risk assessment). Sponsors should prospectively evaluate monitoring procedures and monitoring plans developed by a CRO to ensure the monitoring approach is consistent with applicable aspects of the trial. In addition, sponsors and CROs should have processes in place for timely
38 The regulations for investigational device exemptions (21 CFR part 812) do not contain a provision for delegation to a contract research organization.
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exchange of relevant information (e.g., significant monitoring findings, significant changes in risk for a trial).
D. Clinical Investigator and Site Selection and Initiation
In addition to regulatory requirements for CI selection, sponsors should consider factors such as sponsor’s previous experience with the CI or site, workload of the CI and study staff, and resource availability at the study site during CI and site selection.
Site initiation is a critical study activity that often involves sponsor personnel from a range of disciplines, including monitors. Key components of site initiation include ensuring the CIs and site staff understand their responsibilities, including applicable regulatory requirements as well as study processes and procedures, including the sponsor’s processes for monitoring the investigation. Communication and documentation tools for monitoring discussed in this guidance can also be used for site selection and initiation activities.
VII. PAPERWORK REDUCTION ACT OF 1995
This guidance contains information collection provisions that are subject to review by the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520).
The time required to complete this information collection is estimated to average 4 hours per response, including the time to review instructions, search existing data resources, gather the data needed, and complete and review the information collection. Send comments regarding this burden estimate or suggestions for reducing this burden to:
Food and Drug Administration Center for Drug Evaluation and Research Office of Medical Policy 10903 New Hampshire Avenue, Bldg. 51, rm. 6337 Silver Spring, MD 20993-0002
This guidance also refers to previously approved collections of information found in FDA regulations. The collections of information in part 312, including certain provisions under subpart D, and part 812 have been approved under OMB control numbers 0910-0014 and 0910-0078.
An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB control number. The OMB control number for this information collection is 0910-0733 (expires 06/30/2019) (Note: Expiration date updated 07/15/2016).
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Guidance for Industry and Investigators
Safety Reporting Requirements for INDs and BA/BE Studies
U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER)
December 2012 Drug Safety
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Guidance for Industry and Investigators
Safety Reporting Requirements for INDs and BA/BE Studies
Additional copies are available from:
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I. INTRODUCTION..............................................................................................................................................1
II. BACKGROUND AND BRIEF OVERVIEW OF THE REQUIREMENTS.................................................1
A. IND SAFETY REPORTING REQUIREMENTS .......................................................................................................2 B. SAFETY REPORTING REQUIREMENTS FOR BA AND BE STUDIES (21 CFR 320.31(d)(3)) .................................3
III. DEFINITIONS (21 CFR 312.32(a))..................................................................................................................3
A. ADVERSE EVENT (21 CFR 312.32(a)) ..............................................................................................................3 B. SUSPECTED ADVERSE REACTION (21 CFR 312.32(a)) .....................................................................................4 C. ADVERSE REACTION .......................................................................................................................................5 D. UNEXPECTED (21 CFR 312.32(a)) ...................................................................................................................5 E. SERIOUS (21 CFR 312.32(a)) ...........................................................................................................................6 F. LIFE-THREATENING (21 CFR 312.32(a)) .........................................................................................................7
IV. REVIEW OF SAFETY INFORMATION (21 CFR 312.32(b))......................................................................7
V. MONITORING THE SAFETY DATABASE AND SUBMITTING IND SAFETY REPORTS .................7
A. SERIOUS AND UNEXPECTED SUSPECTED ADVERSE REACTION (21 CFR 312.32(c)(1)(i)).................................8 B. FINDINGS FROM OTHER SOURCES (21 CFR 312.32(c)(1)(ii) AND (iii)) ..........................................................13 C. INCREASED OCCURRENCE OF SERIOUS SUSPECTED ADVERSE REACTIONS (21 CFR 312.32(c)(1)(iv)) ..........14
VI. OTHER SAFETY REPORTING ISSUES.....................................................................................................14
A. ALTERNATIVE REPORTING ARRANGEMENTS (21 CFR 312.32(c)(3)) .............................................................14 B. INVESTIGATOR BROCHURE.............................................................................................................................15 C. UNBLINDING ..................................................................................................................................................16 D. INVESTIGATOR REPORTING (21 CFR 312.64(b)) ............................................................................................17 E. INVESTIGATIONS OF MARKETED DRUGS (21 CFR 312.32(c)(4))....................................................................19 F. ADVERSE EVENT REPORTING TO INSTITUTIONAL REVIEW BOARDS (IRBS)...................................................20 G. DURATION OF SAFETY REPORTING ................................................................................................................20 H. IND ANNUAL REPORTS AND LABELING.........................................................................................................21
VII. SUBMITTING AN IND SAFETY REPORT (21 CFR 312.32(c)(1)(v))......................................................21
A. REPORT IDENTIFICATION AND FORMAT .........................................................................................................21 B. WHERE AND HOW TO SUBMIT........................................................................................................................23 C. REPORTING TIME FRAME ...............................................................................................................................23
VIII. FOLLOWUP INFORMATION (21 CFR 312.32(d)) ..................................................................................24
IX. SAFETY REPORTING REQUIREMENTS FOR BA AND BE STUDIES..............................................25
A. BA/BE STUDY SAFETY REPORTING REQUIREMENTS (21 CFR 320.31(d)(3)) ................................................25 B. BA/BE STUDIES CONDUCTED AT NON-U.S. SITES ........................................................................................26 C. HOW AND WHERE TO SUBMIT A REPORT (21 CFR 320.31(d)(3))...................................................................26
APPENDIX A: THE UNIVERSE OF ADVERSE EVENTS ................................................................................28
APPENDIX B: INVESTIGATOR AND SPONSOR REPORTING RESPONSIBILITIES..............................29
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Guidance for Industry and Investigators1
Safety Reporting Requirements for INDs and BA/BE Studies
This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.
I. INTRODUCTION
This guidance is intended to help sponsors and investigators comply with the requirements for investigational new drug (IND) safety reporting and safety reporting for bioavailability (BA) and bioequivalence (BE) studies under 21 CFR 312.32, 312.64(b), and 320.31(d)(3). This document provides guidance to sponsors and investigators on expedited safety reporting requirements for human drug and biological products2 that are being investigated under an IND and for drugs that are the subjects of BA and BE studies that are exempt from the IND requirements. This guidance defines terms used for safety reporting, makes recommendations on when and how to submit a safety report, and provides advice on other safety reporting issues that have arisen from sponsors and investigators.
FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.
II. BACKGROUND AND BRIEF OVERVIEW OF THE REQUIREMENTS
On September 29, 2010, FDA published a final rule amending the IND safety reporting requirements under 21 CFR part 312 and adding safety reporting requirements for persons conducting BA and BE studies under 21 CFR part 320.
1 This guidance has been prepared by the Office of Medical Policy in the Center for Drug Evaluation and Research (CDER) in conjunction with the Center for Biologics Evaluation and Research (CBER) at FDA. 2 For the purposes of this document, unless otherwise specified, all references to “drugs” or “drug products” include human drug products and biological products that are also drugs.
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A. IND Safety Reporting Requirements
Under the former 21 CFR 312.32(c)(1)(i)(A) and (B), sponsors investigating a drug under an IND were required to notify FDA and all participating investigators, in a written IND safety report, of any adverse experience associated with the use of the drug that was both serious and unexpected, and any finding from tests in laboratory animals that suggested a significant risk for human subjects. The phrase associated with the use of the drug was defined as “there is a reasonable possibility that the experience may have been caused by the drug” (former 21 CFR 312.32(a)). Notwithstanding this definition, sponsors frequently reported, as individual cases, serious adverse experiences for which there was little reason to believe that the drug caused the event. For example, sponsors often reported:
Serious adverse experiences (e.g., mortality or major morbidity) that were likely to have been manifestations of the underlying disease
Serious adverse experiences that commonly occurred in the study population independent of drug exposure (e.g., strokes or acute myocardial infarctions in an elderly population)
Serious adverse experiences that were study endpoints (i.e., the study was evaluating whether the drug reduced the rate of these events)
These types of reports are generally uninformative when reported as single events (i.e., without a comparison of the incidence of the event in treated and untreated subjects), and they do not contribute meaningfully to the developing safety profile of an investigational drug or to human subject protection. Attempting to review and evaluate these reports without the necessary context was also a drain on resources for FDA, investigators, and institutional review boards (IRBs),3 diverting them from other activities.
The tendency for sponsors to report such uninformative individual cases seems to have been primarily related to interpretation of the reasonable possibility standard in the definition of associated with the use of the drug. For an individual case of the types of adverse events described above, there would generally not be enough evidence to suggest that there was a reasonable possibility that the drug caused the adverse event. Such events would therefore not meet the definition of “associated with the use of the drug” and should not have been reported as IND safety reports.
Under 21 CFR 312.32, the amended requirements revise the definitions used for safety reporting and make clear when to submit expedited safety reports. The requirements distinguish circumstances in which it is appropriate to submit individual cases and circumstances in which cases should be aggregated and compared to cases in a control group and submitted only if the event occurs more frequently in the drug treatment group. Compliance with these requirements will increase the likelihood that submitted information will be interpretable and will meaningfully contribute to the developing safety profile of the investigational drug and improve the overall quality of safety reporting. In addition, reducing the number of uninformative individual reports will enhance the ability of sponsors, FDA, investigators, and IRBs to focus on safety issues that affect public health.
See section VI.F of this guidance for more information on safety reporting to IRBs. 3
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Because the regulations require reporting certain adverse events in the aggregate rather than as individual cases, it is important for sponsors to collect and evaluate safety data systematically during product development, including accumulating safety data (see section V.A.3).
B. Safety Reporting Requirements for BA and BE Studies (21 CFR 320.31(d)(3))
Under former 21 CFR 320.31(d), certain in vivo BA and BE studies in humans were exempted from the IND requirements under part 312 if specific conditions were satisfied (i.e., samples of any test article and reference standard were reserved by the persons conducting the study and released to FDA upon request, studies were conducted in compliance with the requirements for institutional review set forth in 21 CFR part 56 and informed consent set forth in 21 CFR part 50). Although these studies were not subject to the IND safety reporting requirements under 21 CFR 312.32, FDA received safety information from these studies that provided important information about drugs under investigation. For this reason, the final rule contains safety reporting requirements under 21 CFR 320.31(d)(3) for persons conducting BA or BE studies that are exempt from the IND requirements. These requirements will help FDA monitor the safety of these drugs and better protect human subjects enrolled in BA or BE studies.
III. DEFINITIONS (21 CFR 312.32(a))
The IND safety reporting rule introduces terms and definitions that are meant to be clear and consistent. New definitions replace the definition of the phrase associated with the use of the drug in former 21 CFR 312.32(a), which, as previously discussed, has been a source of confusion. The definitions, followed by further explanation and examples, are provided in this section, and Appendix A provides a visual representation of the relationship between three of the terms.
A. Adverse Event (21 CFR 312.32(a))
Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.
An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, and does not imply any judgment about causality. An adverse event can arise with any use of the drug (e.g., off-label use, use in combination with another drug) and with any route of administration, formulation, or dose, including an overdose.
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B. Suspected Adverse Reaction (21 CFR 312.32(a))
Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable possibility’ means there is evidence to suggest a causal relationship between the drug and the adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug.
Within the reporting requirement under 21 CFR 312.32(c)(1)(i), FDA makes clear the meaning of reasonable possibility by providing the following examples of types of evidence that would suggest a causal relationship between the drug and the adverse event.
A single occurrence of an event that is uncommon and known to be strongly associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome)
One or more occurrences of an event that is not commonly associated with drug exposure, but is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture)
An aggregate analysis of specific events observed in a clinical trial (such as known consequences of the underlying disease or condition under investigation or other events that commonly occur in the study population independent of drug therapy) that indicates those events occur more frequently in the drug treatment group than in a concurrent or historical control group
Suspected adverse reactions are the subset of all adverse events for which there is a reasonable possibility that the drug caused the event. Inherent in this definition, and in the requirement to report suspected adverse reactions, is the need for the sponsor to evaluate the available evidence and make a judgment about the likelihood that the drug actually caused the adverse event. We consider the application of the reasonable possibility causality standard to be consistent with the discussion about causality in the International Conference on Harmonization (ICH) E2A Guideline (“ICH E2A guidance”).4 However, the Agency notes there is a difference between this rule and the ICH E2A guidance with respect to who is responsible for making the causality judgment. The sponsor is responsible for making the causality judgment for this rule, whereas the ICH E2A guidance recommends that the judgment be based on either the investigator’s or the sponsor’s opinion. This is explained further in sections V.A and VI.D.1 of this document.
4 ICH E2A Guideline for Industry, Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, March 1995, pages 6-7. CDER guidance documents can be found on the Internet at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER guidance Web site. CBER guidance documents can be found at http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
An adverse reaction means any adverse event caused by a drug. Adverse reactions are a subset of all suspected adverse reactions where there is reason to conclude that the drug caused the event.
D. Unexpected (21 CFR 312.32(a))
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed; or, if an investigator brochure is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current application, as amended. For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the investigator brochure referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the investigator brochure listed only cerebral vascular accidents. "Unexpected," as used in this definition, also refers to adverse events or suspected adverse reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned as occurring with the particular drug under investigation.
This definition relies entirely on the adverse events or suspected adverse reactions listed in the investigator brochure for the particular drug under investigation (or elsewhere in the general investigational plan if an investigator brochure is not required or available) as the basis for determining whether newly acquired information generated from clinical trials or reported from other sources is unexpected.6 This means that events not listed for the particular drug under investigation in the investigator brochure are considered “unexpected” and those listed are considered “expected.” When new adverse event information is received, it is the sponsor’s responsibility to determine whether the event is “unexpected” for IND safety reporting purposes. In the clinical trial setting, there has been some confusion with the term “expected” as it has been used to mean “anticipated” for the disease being treated or population being studied rather than “listed in the investigator brochure.” For example, some adverse events can be anticipated to occur as a result of a disease or in an older population (e.g., cancer-related deaths in a cancer trial, strokes or acute myocardial infarctions in an older population). However, for reporting purposes, these anticipated events are not “expected” because they are not listed in the investigator brochure (i.e., the test drug is not suspected or known to cause them). Monitoring and reporting these types of anticipated events are further discussed in section V.A.3 of this document.
5 For the purposes of prescription drug labeling, the term adverse reaction is defined to mean “an undesirable effect, reasonably associated with use of a drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. This definition does not include all adverse events observed during use of a drug, only those adverse events for which there is some basis to believe there is a causal relationship between the drug and the occurrence of the adverse event” (see 21 CFR 201.57(c)(7) and 201.80(g)). 6 For drugs marketed or approved in the United States, ordinarily FDA-approved prescription drug labeling is used as the basis for determining whether an event is unexpected for reporting purposes.
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Adverse events listed in the investigator brochure as occurring with members of the same class of drugs, or as anticipated from the pharmacological properties of the drug, would be considered unexpected until they have been observed with the drug under investigation. For example, although angioedema is anticipated to occur in some patients exposed to drugs in the angiotensin-converting enzyme (ACE) inhibitor class and angioedema would be described in the investigator brochure as a class effect, a case of angioedema observed with the drug under investigation should be considered unexpected for reporting purposes until it is included in the investigator brochure as occurring with the drug under investigation.
E. Serious (21 CFR 312.32(a))
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the investigator or sponsor, it results in any of the following outcomes: Death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.
This definition permits either the sponsor or the investigator to decide whether an event is serious. The investigator’s perspective may be informed by having actually observed the event, while the sponsor is likely to have broader knowledge of the drug and its effects to inform its evaluation of the significance of the event. Because serious adverse events are critically important for the identification of significant safety problems, FDA believes taking into account both the investigator’s and the sponsor’s assessment is important. Therefore, if either the sponsor or investigator believes that the event is serious, the event must be considered serious and evaluated by the sponsor for expedited reporting (21 CFR 312.32(a) and 312.32(c)(1)).
We note that the definition of “serious” differs slightly from the ICH E2A guidance7 (i.e., FDA definition uses “and” rather than “or” in the sentence “Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition”). We will accept application of either the FDA definition (i.e., “and”) or the ICH E2A guidance criteria (i.e., “or”) in determining the seriousness of an event.
7 ICH E2A, pages 4-5.
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F. Life-Threatening (21 CFR 312.32(a))
An adverse event or suspected adverse reaction is considered “life-threatening” if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have caused death.
As with the definition of serious, the determination of whether an adverse event is life-threatening can be based on the opinion of either the investigator or sponsor. Thus, if either believes that it meets the definition of life-threatening, it must be considered life-threatening for reporting purposes (21 CFR 312.32(a)).
IV. REVIEW OF SAFETY INFORMATION (21 CFR 312.32(b))
The sponsor is required to review promptly all information relevant to the safety of the drug (21 CFR 312.32(b)). During the course of drug development, adverse event information is generally reported to a sponsor by investigators conducting clinical trials; however, a sponsor may become aware of new safety information from a variety of sources, both domestic and foreign. Some examples of sources are listed as follows, but safety information from any other source would also need to be reviewed and evaluated by the sponsor.
Animal studies or in vitro studies Clinical or epidemiological investigations Reports in the scientific literature Unpublished scientific papers Information presented at scientific meetings Reports from foreign regulatory authorities Reports from commercial marketing experience Safety information presented at a professional meeting Foreign spontaneous reports
The sponsor’s review should include examining data from all sources and deciding whether the information meets the criteria for expedited reporting (see section V), as well as evaluating all accumulating data at regular intervals to update safety information and to identify new safety signals. Some types of information should be sought by the sponsor as part of its continuous pharmacovigilance on the safety of the drug. For example, the sponsor should conduct literature searches regularly with a frequency appropriate to the drug or study design to seek safety information and report that information if necessary.
V. MONITORING THE SAFETY DATABASE AND SUBMITTING IND SAFETY REPORTS
Under 21 CFR 312.32(c), the sponsor is required to notify FDA and all participating investigators in an IND safety report (i.e., 7- or 15-day expedited report) of potentially serious risks from clinical trials or any other source as soon as possible, but no later than 15 calendar days after the sponsor receives the safety information and determines that the information
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qualifies for reporting (see VII.C for a discussion of IND safety reporting time frames). Participating investigators include all investigators to whom the sponsor is providing drug under any of its INDs or under any investigator’s IND (21 CFR 312.32(c)(1)). This includes, for example, all investigators participating in clinical trials under an IND, at U.S. and non-U.S. sites, for the investigational drug, and any investigators conducting a study under their own IND for whom the sponsor provides investigational drug.
In addition, the sponsor must identify in each IND safety report all IND safety reports previously submitted to FDA concerning a similar suspected adverse reaction and must analyze the significance of the suspected adverse reaction in light of previous, similar reports or any other relevant information (21 CFR 312.32(c)(1)). The analysis must include similar reports from all INDs held by the sponsor and any other relevant information known to the sponsor (21 CFR 312.32(c)(1)). Sponsors should evaluate a suspected adverse reaction in the context of other related reports or adverse events, including those that occurred in the placebo or active comparator group and those that occurred in pre- and postmarketing studies.
Sponsors should conduct ongoing safety evaluations, including periodic review and analyses of their entire safety database, not only for IND safety reporting purposes, but also to update investigator brochures, protocols, and consent forms with new safety information (see section VI.B.2 for information about updating investigator brochures).
Sponsor-investigators, as defined in 21 CFR 312.3(b), are required to comply with both the sponsor and the investigator responsibilities under 21 CFR part 312. With respect to safety reporting under 21 CFR 312.32, this includes examining data from reports in the scientific literature and reports from foreign commercial marketing experience. The Agency recognizes that a sponsor-investigator may not have access to complete safety data maintained by a commercial sponsor or other sponsor-investigators, but sponsor-investigators are responsible for evaluating all safety information available to them. To protect human subjects, we recommend that entities that provide drug to or receive drug from other entities share safety information with each other.
The sponsor must submit an IND safety report when any of the following criteria are met:
A. Serious and Unexpected Suspected Adverse Reaction (21 CFR 312.32(c)(1)(i))
The sponsor must report in an IND safety report any suspected adverse reaction to study treatment (i.e., including active comparators) that is both serious and unexpected (21 CFR 312.32(c)(1)(i)). Before submitting an IND safety report, the sponsor needs to ensure that the event meets all three of the definitions:
Suspected adverse reaction Serious Unexpected
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If the adverse event does not meet all three of the definitions, it should not be submitted as an IND safety report.8
Deciding whether the adverse event meets the definition of a suspected adverse reaction is usually the most difficult determination, but this decision is critical to avoid the submission of uninformative IND safety reports. The sponsor should evaluate the available information and decide whether there is a reasonable possibility that the drug caused the adverse event and, therefore, that the event meets the definition of a suspected adverse reaction. The suspected adverse reaction must then be reported expeditiously in an IND safety report if it also meets the definitions of serious and unexpected (21 CFR 312.32(c)(1)(i)).
Under 21 CFR 312.64, investigators are required to provide a causality assessment for each serious adverse event reported to the sponsor. For serious events that are unexpected, the sponsor considers the investigator’s causality assessment but submits an IND safety report only for those events for which the sponsor determines there is a reasonable possibility that the drug caused the event, regardless of the investigator’s causality assessment. (See Appendix B for a chart that clarifies sponsor and investigator responsibilities for reporting.)
For example:
Sponsor would not report events for which the investigator’s assessment is positive for causality, but where the sponsor’s evaluation did not find evidence to suggest a causal relationship between the drug and the event.
Sponsor would report events for which the investigator’s assessment is negative for causality, but where the sponsor’s evaluation found evidence to suggest a causal relationship between the drug and the event.
The investigator’s assessment of causality should be included in the report submitted to the sponsor. If the investigator fails to provide a causality assessment and the sponsor is unable to obtain it, or if the investigator assesses the causality as unknown, the sponsor should evaluate the event without the investigator’s assessment.
To assist sponsors with determining whether an adverse event meets the definition of suspected adverse reaction, the requirement under 21 CFR 312.32(c)(1)(i) specifies that sponsors are to report to FDA only if there is evidence to suggest a causal relationship between the drug and the adverse event and it provides examples of such evidence, described below.
Certain serious adverse events are informative as single cases because they are uncommon and are known to be strongly associated with drug exposure. Some examples include angioedema, blood dyscrasias, rhabdomyolysis, hepatic injury, anaphylaxis, and Stevens-Johnson Syndrome. The occurrence of even one case of such adverse events
8 Adverse events that do not meet the criteria for reporting in an IND safety report must still be reported in accordance with the periodic reporting regulations, when applicable (e.g., 21 CFR 312.33 IND annual report).
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would meet the definition of suspected adverse reaction (i.e., there is a reasonable possibility that the drug caused the event).
2. One or More Occurrences (21 CFR 312.32(c)(1)(i)(B))
A single occurrence, or a small number of occurrences, of a serious adverse event that is uncommon in the study population, but not commonly associated with drug exposure may also be informative. If the event occurs in association with other factors strongly suggesting causation (e.g., strong temporal association, event recurs on rechallenge), a single case may be sufficiently persuasive to report in an IND safety report. Often, more than one occurrence from one or multiple studies would be needed before the sponsor could determine that there is a reasonable possibility that the drug caused the event. Examples include tendon rupture or heart valve lesions in young adults, or intussusception in healthy infants.
3. Aggregate Analysis of Specific Events (21 CFR 312.32(c)(1)(i)(C))
Certain serious adverse events can be anticipated to occur in the study population independent of drug exposure. Such events include known consequences of the underlying disease or condition under investigation (e.g., symptoms, disease progression) and events unlikely to be related to the underlying disease or condition under investigation but common in the study population independent of drug therapy (e.g., cardiovascular events in an elderly population). An example of the former would be a non-acute death observed in a trial in cancer patients. An example of the latter would be an acute myocardial infarction observed in a long-duration trial in an elderly population with cancer. Although these serious adverse events meet the definition of unexpected at 21 CFR 312.32(a), as they are not listed in the investigator brochure (see sections III.D and VI.B), these events do not warrant expedited reporting as individual cases because it is not possible, based on a single case, to determine that there is a reasonable possibility that the drug caused the event. As a result, they do not meet the definition of a suspected adverse reaction.
Section 312.32(c)(1)(i)(C) requires reporting in an IND safety report when an aggregate analysis of specific events observed in a clinical trial indicates those events occur more frequently in the drug treatment group than in a concurrent control group. In cases where a randomized comparison is not available, the estimate of whether the rate is greater than in a control population would have to be based on some other group not receiving the drug, such as the general population or populations similar to the drug population with respect to demographics and disease state but not receiving the test drug (e.g., a historical control). An aggregate analysis of specific events should reflect information from all relevant studies. Therefore, it should be performed both for individual studies (if there are enough events to be informative) and across all studies, including across INDs of the drug, to determine whether they meet the criteria for expedited reporting.
The following recommendations are intended to assist sponsors with protocol development and monitoring the safety database.
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a. Reporting Study Endpoints (21 CFR 312.32(c)(5))
Generally, study endpoints refer to outcomes that sponsors are measuring to evaluate efficacy. For trials designed to evaluate the effect of a drug on disease-related mortality or major morbidity, endpoint information should be collected, tracked, and monitored, usually by a Data Monitoring Committee (DMC), during the course of the study. The protocol would prespecify a monitoring plan for determining whether subjects receiving the drug treatment are at higher risk for the outcome (e.g., all-cause mortality), and such results would be reported according to the protocol. The study endpoints must be reported to FDA by the sponsor according to the protocol, and ordinarily would not be reported as IND safety reports, except when there is evidence suggesting a causal relationship between the drug and the event (21 CFR 312.32(c)(5)). For example, a death ordinarily would not be reported as an individual case in an expedited report from a trial designed to compare all-cause mortality in subjects receiving either drug treatment or a placebo. On the other hand, in the same trial with an all-cause mortality endpoint, if the death occurred as a result of an anaphylactic reaction that coincided with initial exposure to the drug, or as a result of fatal hepatic necrosis, the death must be reported as an individual case in an IND safety report because there would then be evidence suggesting a causal relationship between the drug and the event (21 CFR 312.32(c)(5)).
In addition to the study endpoints described above, some studies also evaluate the effect of the drug on several other specific adverse events, often called “safety endpoints” or “secondary endpoints.” These safety endpoints or secondary endpoints should be identified in the protocol and monitored and reported by the sponsor as described in section V.A.3.b.
b. Serious Adverse Events That Are Not Study Endpoints
Other serious adverse events that are not study endpoints and are not “expected” (e.g., because they are not in the investigator’s brochure), can be anticipated to occur with some frequency during the course of the trial, regardless of drug exposure, depending on the patient population and disease under study. Examples of such “anticipated” events include known consequences of the underlying disease or condition under investigation, events anticipated from any background regimen, events common in the study population, or re-emergence or worsening of a condition relative to pretreatment baseline. In general, a limited number of occurrences of such an adverse event in a study population in which occurrences of the event are anticipated is not an adequate basis to conclude that the event is a suspected adverse reaction (i.e., that there is a reasonable possibility that the drug caused the event). Such events should not be reported individually as they occur because they are uninformative as single cases. Such anticipated adverse events should nonetheless be monitored at appropriate intervals, and the numbers of events in each arm of a controlled study should be compared. The adverse event must be reported to FDA expeditiously as an IND safety report if there is an imbalance between arms suggesting there is a reasonable possibility that the drug
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caused the adverse event (21 CFR 312.32(c)(1)(i)(C)). It is important to consider the entire clinical trial database in such analyses.
i. Identifying and monitoring protocol-specified serious adverse events
At the time of protocol development, the sponsor should identify in the protocol the serious adverse events that it does not plan to report individually in an expedited manner because they are anticipated to occur in the study population at some frequency independent of drug exposure. It is not possible or desirable to list in the protocol every adverse event that may occur in the study population. Factors to consider when deciding which adverse events to identify include, for example, characteristics of the study population, natural progression of the disease, background event rates, background regimens, co-morbid conditions, and past experience with similar populations. The list of the more common serious adverse events, based on past experience, could be used for all protocols (taking into account population differences) because the analyses of these adverse events should consider the entire safety database. Therefore, the sponsor should limit the list to those events that are common enough to make an overall analysis useful. For example, in a long-term osteoporosis trial in an elderly population, it would be reasonable to list myocardial infarction, but unreasonable to list acute narrow angle glaucoma, an event that can occur in this elderly population, but is relatively rare. The protocol should also describe how the protocol-specified serious adverse events will be monitored. The sponsor or an independent group should monitor the identified events during the conduct of the trial and submit an IND safety report if an aggregate analysis indicates that the events are occurring more frequently in the drug treatment group (see section V.A.3.c).
ii. Reporting serious adverse events that are not protocol-specified
The fact that an event is not identified in the protocol does not mean that the sponsor must report a single occurrence of the event expeditiously. The sponsor should use judgment in determining whether there is a reasonable possibility that the drug caused the event. Often, a single case will be unpersuasive. For example, in the osteoporosis trial previously described, a single case of acute narrow angle glaucoma would generally not be reported in an IND safety report because such cases are seen in an untreated elderly population, but if monitoring for subsequent cases revealed additional cases in the drug treatment group, the sponsor would consider the events to meet the definition of suspected adverse reactions at 21 CFR 312.32(a) and would report them expeditiously. However, FDA will accept expedited reports for individual cases of unexpected serious adverse events that are not study endpoints and are not specified in the protocol as “anticipated” (e.g., they are known consequences of the disease being treated or common in the study population) to address concerns expressed by sponsors about not expeditiously reporting such cases.
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c. Safety Surveillance for Ongoing Clinical Trials9
Because it is critical that a drug product’s risks be adequately assessed during development, sponsors should ensure that they have in place a systematic approach for safety surveillance. Such an approach should include a process for reviewing, evaluating, and managing accumulating safety data from the entire clinical trial database at appropriate intervals. In some cases, a specific independent committee with substantial external representation could be created to perform this function. In others, the sponsor may choose to create a safety team within the sponsor’s organization. In either case, this independent group would oversee the evolving safety profile of the investigational drug and evaluate, at appropriate intervals, the accumulating data from individual and multiple clinical trials, as well as other available information.
B. Findings From Other Sources (21 CFR 312.32(c)(1)(ii) and (iii))
The sponsor must also report expeditiously any findings from clinical, epidemiological, or pooled analysis of multiple studies or any findings from animal or in vitro testing that suggest a significant risk in humans exposed to the drug (21 CFR 312.32(c)(1)(ii) and (iii)). These reports are required for studies from any source, regardless of whether they are conducted under the IND or by the sponsor (21 CFR 312.32(c)(1)(ii) and (iii)). A finding that suggests a significant risk would ordinarily result in a safety-related change in the protocol, informed consent, investigator brochure (excluding routine updates of these documents), or other aspects of the overall conduct of the clinical investigation. For example, actions often taken in response to a significant risk finding include immediate revision of the informed consent, intensification of subject monitoring, revised eligibility criteria or screening procedures, enrollment hold, or consideration of discontinuation of the trial. The sponsor is also required to submit protocol amendments that describe changes to the protocol or other documents (21 CFR 312.30(b)) in addition to the IND safety report.
1. Findings From Other Studies (21 CFR 312.32(c)(1)(ii))
Findings that suggest a significant risk generally arise from ongoing or completed clinical studies, pooled data from multiple studies, epidemiological studies, and published and unpublished scientific papers. Findings from clinical studies that are subject to this requirement are those that have not already been reported under 21 CFR 312.32(c)(1)(i). For example, any clinically important finding from a drug interaction study, from a study evaluating the QT interval, or from a study of a marketed drug would be reported under this provision. An example of such a finding would be a prolongation of the QT interval in subjects receiving the investigational product.
9 For more discussion of this subject, see FDA’s guidances on Establishment and Operation of Clinical Trial Data Monitoring Committees and Premarketing Risk Assessment (see footnote 4 for location), and references 1-3.
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2. Findings From Animal or In Vitro Testing (21 CFR 312.32(c)(1)(iii))
Findings from animal studies, such as carcinogenicity, mutagenicity, teratogenicity, or reports of significant organ toxicity at or near the expected human exposure are examples of the types of findings that could suggest a significant risk. Before reporting a finding to FDA, the sponsor should use judgment to decide whether the finding suggests a significant risk in humans or is too preliminary to interpret without replication or further investigation.
C. Increased Occurrence of Serious Suspected Adverse Reactions (21 CFR 312.32(c)(1)(iv))
The sponsor must report any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure (21 CFR 312.32(c)(1)(iv)). A baseline incidence rate may not always be available, but when one is available or can be inferred from data or analyses in the investigator brochure (e.g., from a table), a clinically important increase from that rate must be reported (21 CFR 312.32(c)(1)(iv)). The decision about when to report is a matter of judgment based on a variety of factors including the study population, the nature and seriousness of the reaction, and the magnitude of the observed increase in the rate. For example, rhabdomyolysis is a recognized, infrequent adverse reaction that is known to occur in the HMG-CoA reductase inhibitor class of drugs (i.e., statins). A higher than expected rate would merit reporting.
VI. OTHER SAFETY REPORTING ISSUES
A. Alternative Reporting Arrangements (21 CFR 312.32(c)(3))
Title 21 of the CFR §§ 312.32(c)(1) and 312.32(c)(1)(v) specify the format and time frame for reporting suspected adverse reactions in an IND safety report (see section VII). Sponsors may request and adopt different reporting formats or frequencies if agreed to in advance by the director of the FDA review division that has responsibility for review of the IND (21 CFR 312.32(c)(3)). In addition, FDA may require a sponsor to submit IND safety reports in a different format or at a different frequency than required under 21 CFR 312.32(c)(1) and 312.32(c)(1)(v) (see 21 CFR 312.32(c)(3)). FDA may require a sponsor to continue to report expeditiously a medically significant suspected adverse reaction that is listed in the investigator brochure as observed with the drug (i.e., expected) so that its rate can be carefully monitored (21 CFR 312.32(c)(3)). For example, if a single occurrence of Stevens-Johnson Syndrome was observed in a subject receiving the investigational drug, FDA may require expedited reporting of additional cases of rash of a lesser severity. FDA may also require an alternative format or frequency for reporting suspected adverse reactions from clinical trials once a study or design has been identified as posing a potential or previously unforeseen risk to participants. See sections VI.D and VI.D.3 for information on investigator reporting arrangements.
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B. Investigator Brochure
The purpose of the investigator brochure is to provide the investigator with information (clinical and nonclinical) about the investigational drug that is relevant to the study of the drug in human subjects. The investigator brochure should include the information that is important for the investigator, who is administering the drug to human subjects, to know and understand. The investigator brochure is required to include information about the following (see 21 CFR 312.23(a)(5)):
Drug substance and formulation Pharmacological and toxicological effects of the drug in animals (and in humans, if
known) Pharmacokinetics and biological disposition of the drug in animals (and in humans, if
known) Information relating to safety and effectiveness in humans obtained from prior clinical
studies Information about possible risks and side effects to be anticipated on the basis of prior
experience with the drug under investigation or with related drugs Precautions or special monitoring to be done as part of the investigational use of the drug
The Agency accepts a variety of formats for the investigator brochure. Although the most important purpose of the investigator brochure is to provide the investigator with information about the investigational product, the investigator brochure is also used by the sponsor as the basis for determining whether a suspected adverse reaction is unexpected for purposes of IND safety reporting (see section III.D).
1. Clinical Risk Information
With respect to clinical risk information, the investigator brochure should specifically and accurately list those adverse events that have been observed with an investigational drug and for which a causal relationship with the drug is suspected or confirmed. In addition, the investigator brochure should list adverse events that commonly occur with the class of drugs or may be predicted to occur based on the pharmacological properties of the drug, even if not yet observed with the drug under investigation, to alert the investigator to the possibility of their occurrence. Sponsors should use judgment in determining which terms accurately reflect a particular adverse event, including syndrome names if applicable. The investigator brochure should not list adverse events that are unlikely to have been caused by the drug because such lists could dilute the importance of clinically meaningful risk information.
2. Updating the Investigator Brochure
During the course of the clinical trial, the sponsor must update the investigator brochure on an ongoing basis with new important safety information (21 CFR 312.55). Some updates to the investigator brochure should be made as soon as possible while others can be made on a routine basis. For example, a new safety finding that represents a
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significant risk to study subjects (e.g., a finding that patients with renal impairment are likely to experience a serious adverse reaction) should be communicated to investigators immediately, along with an update to the investigator brochure and possibly to the protocol (e.g., a change in screening procedures and eligibility criteria). On the other hand, an update to reflect a minor change in a suspected adverse reaction rate could be done on an annual basis.
The sponsor should exercise judgment when deciding whether the threshold has been reached for adding a newly observed adverse event to the investigator brochure. Criteria to consider usually include the strength of the evidence from individual or multiple cases and previous knowledge about the drug or drug class.
Until the investigator brochure is updated to include a new serious, suspected adverse reaction, subsequent occurrences of similar serious, suspected adverse reactions must be submitted expeditiously in IND safety reports (21 CFR 312.32(c)(1)(i)) to FDA and all participating investigators.
There is more than one acceptable approach for updating the investigator brochure with new safety information. For example, adding a new serious and unexpected suspected adverse reaction to the investigator brochure as an addendum, rather than reissuing the entire brochure, is an acceptable approach for keeping investigators informed of new observations. Sponsors should ensure that any addenda are incorporated into the next full revision of the investigator brochure.
C. Unblinding
The blind should ordinarily be broken for IND safety reports submitted to FDA and all participating investigators. Knowledge of the treatment received is necessary for interpreting the event, may be essential for the medical management of the subject, and may provide critical safety information about a drug that could have implications for the ongoing conduct of the trial (e.g., monitoring, informed consent). The Agency does not believe that unblinding single or small numbers of serious and unexpected adverse event cases will compromise the integrity of the study, in part because such unblinding should be infrequent. For example, because the requirement under § 312.32(c)(5) specifically describes different reporting requirements for study endpoints, in a trial evaluating death, myocardial infarctions, and strokes as endpoints, a case of liver injury, if unblinded, would have no effect on overall study integrity.
In general, if the blind is broken and a subject with an adverse event that would meet the criteria for reporting as a single event was receiving placebo, the event should not be reported in an IND safety report because there is not a reasonable possibility that the drug caused the adverse event. If the blind is broken and this subject was receiving drug treatment (test drug or active comparator), it must be reported in an IND safety report (21 CFR 312.32(c)(1)(i)(A)). For those adverse events that would not be reported unless an aggregate analysis indicated that they are occurring more frequently in the drug treatment group than in the placebo group, a determination that the adverse event is a suspected adverse reaction would require analysis and reporting of the event rates in both the drug-treatment and placebo groups.
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To comply with the requirements for IND safety reports based on data in the aggregate, the sponsor should have in place a systematic approach for evaluating the accumulating safety data. A Data Monitoring Committee (DMC) or an independent sponsor safety team could perform this function (see sections V and V.A.3.c).
As described in section V.A.3.a, there should generally be no need to report unblinded study endpoints in an IND safety report. In many cases, an independent DMC would monitor the serious events that are study endpoints (see FDA’s guidance document on Establishment and Operation of Clinical Trial Data Monitoring Committees).10 If a sponsor has concerns that unblinding of adverse events will compromise the integrity of the study, the sponsor can propose in advance an alternative reporting format or frequency to maintain the blind that must be agreed to by the director of the review division in FDA with responsibility for review of the IND (21 CFR 312.32(c)(3)) (see section VI.A).
D. Investigator Reporting (21 CFR 312.64(b))
Most of the information about the safety of a drug prior to marketing comes from clinical trials. Therefore, adverse event reports from investigators are critically important, as they observe subjects’ responses to the drug. Except for study endpoints, the investigator must immediately report to the sponsor all serious adverse events, regardless of whether the investigator believes that they are drug related, including those events listed in the protocol as anticipated to occur in the study population independent of drug exposure or in the investigator brochure as predicted to occur with the drug (21 CFR 312.64(b)). The Agency recognizes that it may take the investigator a short period of time (i.e., a day) to compile information about the event, but then expects the information to be immediately reported to the sponsor. Investigators are not required to determine whether an event is “unexpected,” as defined in 312.32(a). This is a sponsor responsibility (see Appendix B).
Although it is the exception, immediate reporting of all serious adverse events to the sponsor may not be necessary in certain trials if the events are expected and well-defined. For example, many oncologic clinical trials use drugs with known serious hematologic adverse reactions and immediate reporting of each serious adverse event may not be useful. In these cases, the sponsor may propose an alternative reporting arrangement by identifying and describing the alternative reporting arrangement in the protocol or by requesting a waiver. The review division that has responsibility for the IND must agree to any alternative reporting arrangements (21 CFR 312.32(c)(3) and 312.10). Sponsor monitoring and reporting of these types of serious adverse events is discussed in section V.A.3.b.
10 See footnote 4 for location.
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1. Assessment of Causality
FDA believes that the sponsor is better positioned than the individual investigator to assess the overall safety of the investigational drug because the sponsor has access to serious adverse event reports from multiple study sites and multiple studies and is able to aggregate and analyze these reports (see section V.A). Moreover, the sponsor is more familiar with the drug’s mechanism of action, class effects, and other information. For these reasons, investigators must immediately report any serious adverse event to the sponsor, whether or not the investigator considers the event to be drug related (21 CFR 312.64(b)).
In the report to the sponsor, the investigator must include an assessment of causality (i.e., whether there is a reasonable possibility that the drug caused the event) (21 CFR 312.64(b)). The investigator’s view is important for the sponsor to consider when assessing the safety of the drug and determining whether to report an event expeditiously to FDA, because the investigator, who monitors the subject’s response to the drug, is knowledgeable about the subject’s clinical state (e.g., medical history, concomitant medications) and thus may be sensitive to distinctions between events that may be related to the drug versus those due to the underlying disease process and/or concomitant therapies. The sponsor should decide how to capture the investigator’s causality assessment (e.g., rating scale, yes/no response to a question such as, “Was there a reasonable possibility that the drug caused the adverse event?”).
2. Study Endpoints
The investigator must report study endpoints that are serious adverse events in accordance with the protocol (21 CFR 312.64(b)). Because endpoints are specifically defined in the protocol, they are often not collected on the adverse event pages of the case report form. The exception to this reporting requirement is when there is evidence suggesting a causal relationship between a drug and an event (e.g., death from anaphylaxis). In this case, the investigator must immediately report the event to the sponsor, even if the event is a component of the endpoint (e.g., all-cause mortality) (21 CFR 312.64(b)). “Safety endpoints” or “secondary endpoints,” as described in section V.A.3.a, are not considered “study endpoints” and, therefore, must be reported to the sponsor immediately (21 CFR 312.64(b)).
3. Nonserious Adverse Events
The investigator must record nonserious adverse events and report them to the sponsor according to the timetable for reporting specified in the protocol (21 CFR 312.64(b)). Generally, nonserious events are recorded on the case report forms and are submitted to the sponsor and reviewed at regular intervals during the course of the investigation. The
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investigator’s assessment of causality is not required for nonserious adverse events by the regulations, although many sponsors may require it in the protocol.11
For certain trials, such as a postmarketing outcome trial for a drug that has a well-established safety profile, it may be necessary for investigators to record only a subset of nonserious adverse events, or none at all. The sponsor can arrange that only specific types of adverse events be reported to the sponsor (e.g., those that resulted in withdrawal from the study or cessation of therapy, modification of dose, or addition of another drug) provided the director of the FDA review division that has responsibility for review of the IND has agreed to that arrangement in advance (21 CFR 312.32(c)(3)). Other nonserious adverse events would not need to be recorded by the investigator on the case report form.
E. Investigations of Marketed Drugs (21 CFR 312.32(c)(4))
According to 21 CFR 312.32(c)(4), a sponsor of a clinical study of a drug marketed or approved in the United States that is conducted under an IND must submit IND safety reports for suspected adverse reactions that are observed in the study, at either domestic or foreign sites. The sponsor must also submit safety information from the clinical study as prescribed by the relevant postmarketing safety reporting requirements (e.g., under 21 CFR 310.305, 314.80, 600.80, 606.170, or under the Dietary Supplement and Nonprescription Drug Consumer Protection Act (Public Law 109-462)). Note that § 312.32(c)(1)(ii) requires the sponsor to report findings from other studies that suggest a significant risk in humans, whether or not conducted under an IND and whether or not conducted by the sponsor. Therefore, as long as the sponsor maintains an open IND for a drug marketed or approved in the United States, safety information from foreign and domestic studies, including non-IND studies, must be reported to the IND and in accordance with the postmarketing requirements, if it meets the criteria for reporting.
For example, if an applicant of a drug marketed or approved in the United States sponsors a multicenter, multinational clinical trial for a new indication, where the domestic sites are included in an IND, adverse events from the clinical trial, whether or not the foreign sites are also conducted under the IND, must be promptly evaluated and reported if they qualify for reporting under § 312.32 and the postmarketing requirements.
If the same applicant or sponsor receives a spontaneous report of an adverse event from U.S. or foreign commercial marketing experience for a drug that is also under investigation, the report would not need to be reported to the IND because it is not a suspected adverse reaction observed in a study, but would need to be reported in accordance with the postmarketing reporting requirements, if it meets the criteria for reporting.
11 CIOMS VI recommends that collection of investigator’s causality assessments are not needed for routine regulatory reporting, but “there may be circumstances when such assessments are useful and important, such as for non-serious adverse events of special interest” (CIOMS 2005, at 85).
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F. Adverse Event Reporting to Institutional Review Boards (IRBs)
Investigators are required to promptly report “to the IRB … all unanticipated problems involving risk to human subjects or others,” including adverse events that should be considered unanticipated problems (21 CFR 312.66). In 2009, FDA issued a guidance on Adverse Event Reporting to IRBs – Improving Human Subject Protection that makes recommendations on the types of adverse event information that should be reported to an IRB.12 The term unanticipated problem used in the Adverse Event Reporting to IRBs guidance describes adverse events and other types of problems (i.e., adverse events are a subset of unanticipated problems) that investigators are required to report to IRBs.
Although the rule on IND safety reporting does not directly address safety reporting by investigators to IRBs, questions have arisen about its impact on adverse event reports to IRBs, particularly with respect to the specific adverse events considered to be “unanticipated problems” that must be reported to the IRB. In general, a report that meets the criteria for reporting in an IND safety report should also be considered an “unanticipated problem” and reported to the IRB by the investigator.
It is important to note that some events that would not meet the criteria for reporting in an IND safety report would be considered unanticipated problems involving risk to human subjects (e.g., informed consent or privacy issues, certain adverse events that could not be caused by the investigational drug, such as events that occur prior to test article administration as a result of a washout period or due to a screening procedure). As part of their clinical trial monitoring responsibility, sponsors generally require that investigators report such unanticipated problems to them. Sponsors should discuss any significant unanticipated problem with the applicable FDA review division, as the problem may affect trial conduct and subject monitoring.
G. Duration of Safety Reporting
The purpose of sending IND safety reports to investigators is to provide investigators with information they need to protect their patients participating in clinical trials. Once they are no longer enrolling or monitoring patients, this information is no longer necessary. Cutoff dates for sending IND safety reports to investigators may be described in the protocol. If no cutoff dates are specified, once a site has been officially closed out, the sponsor usually does not need to continue sending IND safety reports to that site, and an investigator does not need to receive or review them. If the sponsor continues to send IND safety reports to the investigator and the investigator does not wish to continue receiving them, the investigator should contact the sponsor and request that the sponsor stop sending them.
In unusual cases, safety information related to delayed toxicity may be reported after a site is officially closed out. For example, if a late toxicity is discovered that would affect subjects who received the investigational drug, the investigator should be notified so that patients could be followed up if necessary.
12 See footnote 4 for location.
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H. IND Annual Reports and Labeling
The IND safety reporting requirements did not make any changes to the requirements for IND annual reports (21 CFR 312.33). FDA recently adopted the guidance for industry E2F Development Safety Update Report,13 which describes a common standard for periodic reporting on drugs under development among the ICH regions and is intended to meet the IND annual reporting requirements. Questions have arisen about whether the Agency will accept the Development Safety Update Report (DSUR) because of the difference in the party responsible for making the causality judgment (see section III.C of this document). To promote global harmonization, FDA will accept the DSUR, as described in the E2F Development Safety Update Report guidance, to meet the IND annual report requirements.
The Agency does not expect the IND safety reporting requirements to have any impact on the adverse reaction information presented in prescription drug labeling.14
VII. SUBMITTING AN IND SAFETY REPORT (21 CFR 312.32(c)(1)(v))
A. Report Identification and Format
Each report must prominently identify its contents (21 CFR 312.32(c)(1)(v)).
“IND safety report” for 15-day reports “Followup IND safety report” for followup information “7-day IND safety report” for unexpected fatal or life threatening adverse reaction
reports
The type of report should be checked in box G7 on the FDA Form 3500A. The report can also be identified in box B5 and/or on a cover letter submitted with the FDA Form 3500A.
The format for IND safety reports is based on the type of expedited report.
1. Individual Cases
For reports of individual cases, a sponsor would ordinarily use FDA Form 3500A.15
FDA will accept foreign suspected adverse reaction reports on a CIOMS I Form instead of FDA Form 3500A (21 CFR 312.32(c)(1)(v)). These forms should be completed with all available information, including a brief narrative describing the suspected adverse reaction and any other relevant information. If applicable, the narrative must also include identification of similar reports and an analysis of the significance of the suspected adverse reaction (21 CFR 312.32(c)(1)).
13 See footnote 4 for location. 14 For more information, see 21 CFR 201.57(c)(7), 201.80(g) and the guidance for industry on Adverse Reactions Section of Labeling for Human Prescription Drug and Biological Products – Content and Format. See footnote 4 for location. 15 FDA Form 3500A can be found on the Internet at http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm.
An IND safety report based on data in the aggregate must be in a narrative format (§ 312.32(c)(1)(v)). Sponsors should use judgment in deciding what to include in the narrative report. The report should include a description of the suspected adverse reaction, along with all relevant information, such as summary information about symptoms, concomitant medications, demographics, comorbid conditions, past history, pertinent laboratory test results, timing of events (onset and duration), and duration of treatment. Data from previously submitted individual case IND safety reports should be included, if applicable. Finally, the narrative report should describe the characteristics and results of the analysis, including a description of the databases, how the conclusion was reached, who reviewed the analysis, any planned changes in monitoring or to study documents (e.g., informed consent, investigator brochure), and any planned further analyses.
To evaluate the aggregated data in narrative format, FDA and participating investigators need the information on the individual cases that are summarized in the report. Therefore, at the same time that the narrative format IND safety report is submitted, the individual cases that were analyzed should also be submitted (e.g., a completed FDA Form 3500A for each case). If some individual cases were previously submitted as IND safety reports, they should be resubmitted and clearly identified as duplicates. Before submission, each individual case report should generally be unblinded. If a sponsor has concerns that unblinding will compromise the integrity of the study, the sponsor should discuss this in advance with the review division (see section VI.C).
If a sponsor is monitoring and evaluating the occurrence of a serious event in the aggregate (rather than submitting each case individually), FDA expects that records of each case will be complete (e.g., a completed FDA Form 3500A for each case), including a description of the suspected adverse reaction and any other relevant information, and that each case will be followed up for additional information, if necessary.
The sponsor should determine an appropriate approach for reporting subsequent occurrences of the same event to FDA and all participating investigators, and the sponsor should include a description of this approach in the initial expedited narrative IND safety report. For example, each subsequent occurrence of an infrequent event with immediate health implications or an event that is uncommon in a specific study population (e.g., stroke in young adults) should be reported in an expedited report. For an event that is known to occur independent of drug exposure in the study population, the sponsor may specifically describe an approach for reporting to FDA and all participating investigators (e.g., an updated aggregate narrative once a certain number of additional cases are identified or after a specified period of time, as appropriate).
3. Other Reports
For reports of overall findings or pooled analyses from published and unpublished in vitro, animal, epidemiological, or clinical studies, a narrative format must be used (21
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CFR 312.32(c)(1)(v)). If the findings are published, in full or in abstract form, the sponsor should include a copy of the publication.
B. Where and How to Submit
The report must be transmitted to the CDER or CBER review division that has responsibility for review of the IND (21 CFR 312.32(c)(1)(v)). IND safety reports should be submitted to all of the sponsor’s INDs under which the drug is being administered. For example, if a drug is found to cause drug induced liver injury, that should be reported to any IND under which the drug is being administered. The sponsor should reference all INDs to which the IND safety report is being submitted in the subject line of the cover letter. If applicable, the sponsor should also identify (e.g., with use of an underline) the specific IND under which the suspected adverse reaction occurred (e.g., “Suspected adverse reaction occurred under IND XXXX1, reference to INDs XXXX2, XXXX3”).
FDA accepts electronic submission of 15-day IND safety reports in eCTD format to the IND application if the IND is in eCTD format or if the sponsor intends to convert the IND to eCTD format. Complete information on eCTD specifications and guidance can be found on the FDA eCTD Web site, and assistance may be obtained by contacting [email protected].
We recommend that sponsors submit 7-day IND safety reports electronically in eCTD format. If the IND is not in eCTD format, other means of rapid communication (e.g., telephone, facsimile transmission, email) may be used. If the IND is not in eCTD format and the sponsor intends to submit 7-day IND safety reports by facsimile transmission or email, the sponsor should address the submissions to the Regulatory Project Manager and the Chief, Project Management Staff in the FDA review division that has responsibility for review of the IND. In addition, if the sponsor intends to submit 7-day IND safety reports by email, we recommend the sponsor obtain a secure email account with FDA.16
C. Reporting Time Frame
The time frame for submitting an IND safety report to FDA and all participating investigators is no later than 15 calendar days after the sponsor determines that the suspected adverse reaction or other information qualifies for reporting (21 CFR 312.32(c)(1)). The language in the IND safety reporting regulations was modified to describe the reporting time frame applicable to aggregate reports (§ 312.32(c)(1)(i)(B) and (C)) and increases in rates of occurrence of serious suspected adverse reactions (§ 312.32(c)(1)(iv)), which generally require more than one occurrence to make the determination that the event meets the criteria for reporting. Thus, the date of initial receipt of the first event could be well before it was determined that the event must be reported.
Sponsors should have a predefined safety monitoring plan that includes processes and procedures for the review of safety information, including the frequency of review (see section V). FDA
16 Refer to the following link for details on obtaining a secure email account with FDA: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/de fault.htm.
expects that events that are interpretable as single cases (i.e., uncommon and known to be strongly associated with drug exposure) should be reported to FDA within 15 days from initial receipt. For events that require more than one occurrence to assess causality and events evaluated in the aggregate, the time clock starts when the sponsor determines that the events qualify for expedited reporting. This means that, for example, incomplete cases should be immediately followed up for additional information so that a determination can be made about whether the event is reportable as an IND safety report.
Unexpected fatal or life-threatening suspected adverse reactions represent especially important safety information and, therefore, must be reported more rapidly to FDA (21 CFR 312.32(c)(2)). The requirement for reporting any unexpected fatal or life-threatening suspected adverse reaction to FDA is no later than 7 calendar days after the sponsor’s initial receipt of the information (21 CFR 312.32(c)(2)). If the safety report submitted within 7 calendar days is complete, an additional submission within 15 days from day zero is not required.
The day of initial receipt for cases that are interpretable as single cases and the day the sponsor determines that multiple cases qualify for expedited reporting are considered day zero.
If FDA requests any additional data or information, the sponsor must submit it to FDA as soon as possible, but no later than 15 calendar days after receiving the request (21 CFR 312.32(c)(1)(v)). See section VIII for reporting time frames for followup information.
VIII. FOLLOWUP INFORMATION (21 CFR 312.32(d))
Most IND safety reports are derived from observations from clinical trials. In the setting of a clinical trial, information is collected in a controlled environment so that the information needed to evaluate the suspected adverse reaction (e.g., information that would be contained in a narrative report or on FDA Form 3500A) is generally readily available. If any information necessary to evaluate the suspected adverse reaction is missing or unknown, the sponsor should actively seek such information from the source of the report. Any relevant additional information that the sponsor obtains that pertains to a previously submitted IND safety report must be submitted as a Followup IND Safety Report without delay, as soon as the information is available (21 CFR 312.32(d)(2)), but should be submitted no later than 15 calendar days after the sponsor receives the information. The sponsor should maintain records of its efforts to obtain additional information.
For example, if information on concomitant medications is obtained after the initial IND safety report is submitted, and such information is relevant to evaluating the suspected adverse reaction, a sponsor must submit a Followup IND Safety Report immediately (21 CFR 312.32(d)(2)). However, if the sponsor obtains other information that is not relevant to evaluating the suspected adverse reaction, records of such information should be maintained by the sponsor and, if applicable, submitted in an information amendment (21 CFR 312.31) or in an IND annual report (21 CFR 312.33).
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IX. SAFETY REPORTING REQUIREMENTS FOR BA AND BE STUDIES
The IND safety reporting requirements under 21 CFR 312.32 apply to BA and BE studies that are conducted under an IND. However, BA and BE studies that meet the conditions for exemption under 21 CFR 320.31 are not conducted under an IND and are not subject to the IND safety reporting requirements. The rule contains safety reporting requirements under 21 CFR 320.31(d)(3) that apply to persons conducting BA or BE studies that are exempt from the IND requirements. The following information addresses these requirements.
FDA believes that BA and BE studies that meet the requirements for exemption are generally safe. The occurrence of a serious adverse event is very unusual because the number of subjects enrolled in such a study is small, subjects are usually healthy volunteers, and drug exposure is typically brief. However, FDA occasionally receives safety-related information associated with these types of studies, which could reflect either a problem with the drug product being evaluated or with the study design being used. For these reasons, the occurrence of any serious adverse event, whether or not it is considered drug related, is of interest. Timely review of this safety information is critical to ensuring the safety of study subjects.
A. BA/BE Study Safety Reporting Requirements (21 CFR 320.31(d)(3))
The person conducting a BA or BE study, including any contract research organization, must notify FDA and all participating investigators of any serious adverse event observed during conduct of the study, regardless of whether the event is considered drug related, as soon as possible but in no case later than 15 calendar days after becoming aware of its occurrence (21 CFR 320.31(d)(3)). This includes, for example, serious adverse events listed in the reference listed product’s approved labeling, the investigator brochure, and protocol. Serious adverse events, whether observed in the investigational drug group or in the approved drug group (e.g., reference listed drug), must be reported (21 CFR 320.31(d)(3)).
If any information necessary to evaluate the serious adverse event is missing or unknown, the person conducting the study should actively seek such information and maintain records of efforts made to obtain additional information. Any relevant additional information that is obtained that pertains to a previously submitted safety report must be submitted as a Followup Bioavailability/Bioequivalence Safety Report as soon as the information is available (21 CFR 320.31(d)(3)), but should be submitted no later than 15 calendar days after the sponsor receives the information. In addition, upon request from FDA, the person conducting the study must submit to FDA any additional data or information that FDA deems necessary as soon as possible, but in no case later than 15 calendar days after receiving the request (e.g., hospital record, autopsy report) (21 CFR 320.31(d)(3)).
If the adverse event is fatal or life-threatening, the person conducting the study must also notify the Clinical Safety Coordinator in CDER’s Office of Generic Drugs as soon as possible but in no case later than 7 calendar days after becoming aware of its occurrence (21 CFR 320.31(d)(3)). We recommend that these notifications be made by telephone, email, or facsimile transmission.
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B. BA/BE Studies Conducted at Non-U.S. Sites
Under 21 CFR 320.31(d)(3), persons conducting human BA and BE studies in the United States that are exempt from the IND requirements under part 312 must report any serious adverse events from the study to FDA and to all participating investigators. The requirements under 21 CFR 320.31(d)(3) do not apply to human BA and BE studies that are exempt from the IND requirements and conducted outside of the United States. However, as part of the information required to establish that the proposed drug product can be expected to have the same therapeutic effect as the reference listed product, adverse event information from foreign clinical studies must be included in the abbreviated new drug application (ANDA) submission (see 21 CFR 314.94(a)(7)).
C. How and Where to Submit a Report (21 CFR 320.31(d)(3))
Each report must be submitted on FDA Form 3500A (21 CFR 320.31(d)(3)). The form should be completed with all the available information, including a brief narrative describing the serious adverse event, an assessment of causality, and any other relevant information. If applicable, the narrative should also include identification of other similar reports and an analysis of the significance of the serious adverse event. A summary of the study protocol should be submitted with the report.
Each report must prominently identify its contents (21 CFR 320.31(d)(3)).
“Bioavailability/Bioequivalence safety report” for 15-day reports “Followup Bioavailability/Bioequivalence safety report” for followup information “7-day Bioavailability/Bioequivalence safety report” for unexpected fatal or life
threatening adverse reaction reports
The type of report should be checked in box G7 on FDA Form 3500A. The report can also be identified in box B5 and/or in a cover letter submitted with the FDA Form 3500A.
The drug product should be listed in box C1 of FDA Form 3500A, and if the serious adverse event occurs in a subject receiving the investigational drug product, the drug administered during the BA/BE study should be identified as investigational and the established name of the reference listed drug should be identified.
Fifteen-day reports should be sent by email to [email protected]. Paper reports may be sent to the Clinical Safety Coordinator, Office of Generic Drugs, in the Center for Drug Evaluation and Research at FDA.17
We recommend that 7-day notifications be made by telephone, email, or facsimile transmission. If the safety report submitted within 7 calendar days is complete, an additional submission within 15 days from day zero is not required.
17 The address for the Office of Generic Drugs is available at http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm119100.htm. The phone and fax numbers (for fatal or life-threatening adverse event reports) are also available at this site.
1. Crowe BJ, Xia HA, Berlin JA, et al. Recommendations for safety planning, data collection, evaluation and reporting during drug, biologic and vaccine development: a report of the Safety Planning, Evaluation and Reporting Team (SPERT). Clin Trials 2009: 6: 430-40.
2. Report of the Council for International Organizations of Medical Sciences (CIOMS) Working Group VI, 2005, Management of Safety Information from Clinical Trials. Report of CIOMS Working Group VI.
3. Xia HA, Crowe BJ, Schriver RC, et al. Planning and core analyses for periodic aggregate safety data reviews. Clin Trials 2011: 8: 175-182.
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APPENDIX A: The Universe of Adverse Events
The diagram below depicts the relationship between adverse events, suspected adverse reactions, and adverse reactions.
Adverse Events
Suspected Adverse Reactions
Adverse Reactions
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APPENDIX B: Investigator and Sponsor Reporting Responsibilities
Reporting Responsibilities of Investigators under 21 CFR 312.64(b) and Sponsors under 21 CFR 312.32(c)(1)(i) for Serious and Unexpected Suspected Adverse Reactions
Term Investigator Responsibility
Sponsor Responsibility
Final Determination Responsibility
Serious Yes Yes An event is considered (or life- (Investigator must serious or life-threatening, threatening) report all serious
adverse events to the sponsor immediately)
based on either the investigator’s or sponsor’s opinion.
Unexpected No (No requirement to assess “expectedness”)
Yes The sponsor is responsible for determining whether event meets the definition of “unexpected,” based on whether the event is listed in the investigator brochure; or if an investigator brochure is not required or available, is not consistent with the risk information described elsewhere in the general investigational plan or elsewhere in the current application.
Suspected Yes Yes The sponsor is responsible Adverse (Investigator must (Sponsor’s for determining whether Reaction – provide sponsor with assessment there is a reasonable (causality an assessment of determines possibility that the drug assessment causality) reportability, caused the adverse event, standard - regardless of taking into consideration the “reasonable investigator’s investigator’s assessment. possibility”) assessment)
↓ The sponsor reports serious and unexpected suspected adverse reaction to the FDA and all participating investigators.
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Commu-nication
Gover-
nance Measure-
ment
ARZNEIMITTELPRÜFUNG
Vendor Oversight Management as a Professional Skill and Function
Successful CRO Oversight: Mission Impossible? With the biopharmaceutical industry outsourcing more than ever, Contract Research Organization (CRO) oversight has become increasingly important for the industry in recent years. As the ultimate accounta-bility stays with the sponsor in outsourcing situations, companies are obligated to establish and execute effective CRO oversight strategies. At the same time, study oversight has come under scrutiny by regu-latory agencies. Overall, there is a lot of frustration and disappointment at all ends. Sponsors are unhappy about what they receive from their vendors, CROs complain about the constant pressure, unrealistic ex-pectations and change requests they receive from their clients, and regulatory agencies are concerned about the deficiencies in CRO oversight or the lack thereof. This article addresses the questions of why this is such a dilemma, what are the real issues, and what can be done to mitigate them?
| Detlef Nehrdich, Waife & Associates, Freinsheim
Outsourcing Modalities and the are quite a few mixed forms of these agencies mandate sufficient sponsor Regulatory Perspective modalities and often sponsors apply oversight of clinical trials. They have
more than one at a time. The issues also been very clear with their expec-There is a broad range of different discussed below are not substantially tations in an outsourced environment:
outsourcing strategies. It starts with different between these modalities. “Although sponsors can transfer re-the occasional need for “a little help However, the extent to which they sponsibilities for monitoring to a this quarter” and ends with so-called are visible may vary depending on the CRO(s), they retain responsibility for “Partnerships”. And in between one specific way a certain model is being oversight of the work completed by can find “full” outsourcing, program applied. the CRO(s) that assume this responsi-outsourcing, project outsourcing, skill US American Food and Drug Ad- bility” [1]. outsourcing, functional outsourcing ministration (FDA), European Medicines However, it seems this is not always and low priority outsourcing. There Agency (EMA), and other regulatory working this way. The example below
from an FDA Warning Letter sent to a pharmaceutical company demonstrate the implications of lacking oversight:
“Although SPONSOR contracted with CRO to conduct monitoring […] did not ensure that the clinical investigators were properly monitored to fully assess and ensure site compliance […]. As sponsor of Studies […] conducted un-
der Investigational New Drug Appli-cation […], you were responsible for ensuring that these studies were ade-quately monitored for compliance with regulatory requirements […]” [2].
EMA does not publish their inspec-tion reports but the quote below is from a presentation provided by an EMA official about inspection find-ings:
“No clear communication lines be-tween investigator, CROs and sponsor, lack of communication; audits insuffi-cient, no documentation which tasks are delegated from the sponsor to the CRO (the only documentation is an e-mail: ‘...trial is out-sourced to …‘)” [3].
These examples show that inappro-priate CRO oversight is not only an in-convenience for the people involved but it also bears a considerable regu-latory risk.
Issue Patterns
In our work with sponsor clients over many years we see issue patterns, which will be shown in this section. Instead of CRO oversight the term “Vendor Oversight Management” will be used here. Vendor oversight includes
not only traditional CROs but providers of technology, e.g., Interactive X Re-sponse Systems (IXRS), Electronic Data Capture (EDC), electronic Clinical Out-come Assessment (eCOA), electronic Trial Master File (eTMF), and similar vendors where the issues are not any different, as well as other third-party service providers such as central labs, biomarker assay processors, imaging reviewers and so on.
A typical outsourcing situation in-volves a strong or even rapidly in-creasing pipeline. At the same time there is insufficient internal staff size, or the staff's experience level might not be sufficient. This combination, along with disappointing vendor per-formance, leads to a difficult discussion. Many times there is a debate about professional vs. service contributions of a certain function, while internal resources are constrained and under-prepared.
One Size for All? Frequently outsourcing decisions are
made at a high management level. This may affect the outsourcing modal-ity, scope and vendor selection. From a management perspective there are good reasons to keep this straight, consistent and simplistic. However, if
this translates into a “one size fits all” approach across clinical development functions, for some of the functions this might become rather difficult. For example, to ensure sufficient site access from a clinical operations perspective, “global presence” may be an important CRO attribute for studies with investi-gational sites on all continents. For functions like biostatistics or medical writing, “global” may mean that their vendor counterparts are located many time zones away from where they are, which simply makes their work somewhat harder, with no strategic, economic or operational advantage.
It is not only in companies with a rather new outsourcing approach where you can find internal staff not skilled, not trained, or underprepared to manage vendors correctly. Staff may be qualified and experienced in certain roles and jobs for many years, and they may have performed great in those jobs. But now they are ex-pected to supervise someone else's work – the work, which they used to do. Now their primary job becomes project management and people man-agement – skills quite different from their previous job.
There is a high degree of uncertainty on how to check vendor deliverables
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in general. This affects those individuals mentioned above who are inexperi-enced or not sufficiently trained in handling third party vendors, but is not limited to them. Without corre-sponding guidance, individual practice may be quite different. One extreme is the complete “hands off” approach, which basically lets the vendor do the work and mostly trusts in their proper execution. On the opposite side we have been in sponsor situations where every deliverable has been checked in detail – for instance, every single analysis table was re-programmed. Of course neither of these two approaches is demonstrating reasonable vendor oversight or efficient vendor man-agement.
Internal Dysfunction Some outsourcing collaborations suf-
fer from inefficient processes and com-plicated communication paths. How-ever, there are many cases where the root cause for this does not lie in the interaction itself or on the CRO side. Instead it might be that the sponsor’s internal study team collaboration is suboptimal. We have observed conflicts about who is doing what in an out-sourcing environment. Who manages a data manager when data manage-ment is done outside? Who is endorsed to interact with the external medical writer or the Interactive Voice Response System (IVRS) provider? In other words:
the definition and execution of sponsor internal roles in an outsourcing envi-ronment can be the issue.
As already described above, it is pretty common for sponsors to handle multiple outsourcing approaches in parallel. This may appear to increase flexibility, but for the people who are doing the day-to-day interaction with vendors this increases complexity. The share of responsibilities between spon-sor and vendor may be different de-pending on the model, and even within the same model but with different vendors.
Vendor oversight management is further complicated and obstructed by the contract. Nowadays the legal or procurement department mostly de-termines the content of contracts. On the one hand people working in these groups usually are not experts in the work they are contracting out. On the other hand, even if the experts’ input is requested, it is hard for the opera-tional staff to have the time or under-standing to review a contract properly. So neither the professional researcher nor the professional contractor should be left alone to the task.
In consequence this increases the risk of suboptimal contract issues, which does not get noticed until execution. This may include some administrative overkill, such as a high degree of doc-umentation needs on the sponsor side. We also noticed contracts, which have
been very specific about “bonus” but very unspecific about “penalties”. If the experts have not been asked for their advice on payments triggers (or did not looked at them), you can fre-quently find payments per the wrong items (e.g. query resolution, per check, per table, …) and high costs for rather repetitive tasks (e.g. programming of tables, listings, and figures – TLF pro-gramming). Overall it seems that there is a pretty high tolerance for failed milestones anyway, as eventually the sponsors just “want to get things done”. Many of our clients who have experi-ence with contracts containing bonuses and penalties report that they do not find them very effective either, but even counterproductive, depending on how they are actually implemented.
The Operational Mismatch The most fundamental and overar-
ching issue is the operational mismatch between service providers and their customers. Figure 1 illustrates the dif-ferences in operating models between pharmaceutical companies and CROs – which do not quite fit together. There is (big) pharma on one side – a complex organization with its multi-million dollar projects and with the target to bring their medical innova-tions as quickly as possible to the mar-ket. And on the other side there are the CROs, which are more organized like a “Unit of Work” factory, for which quarterly cash flow goals are most important.
This is no argument about the size as we already have some CROs being bigger than some pharma companies. It is more about the incompatibilities of company cultures. Changes of pri-orities, project success and project fail-ures are common when working for a sponsor. Biopharmas have worked hard over the last 15 years to tear down in-tra-company silos and to attract and develop broadly qualified people. Ven-dors tend to lag behind in this regard. In practice this leads to significant ex-pectation mismatches. Where the spon-sor expects flexibility and a solution-focused approach, CROs often have a more formalistic, “one step after the other” approach, and silo thinking is much more pronounced than on the sponsor side.
This description of issues may be overly simplistic and exaggerated. It is not complete either. And of course you will not find all of this at one place or in one specific sponsor/vendor situation. However, none of the above is theoretical, these are all concrete examples of client situations. And it is important to understand what can and what does happen before looking into potential improvements of the vendor oversight situations.
Leverage Categories
Conceptually there are four cate-gories to be considered when vendor oversight is under review: – Governance– Communication– Measurement– Sustained Effort.
All of these play their role and are equally important. The sustained effort needed has a prominent position though, as it makes this change man-agement effort so challenging. With-out sustained effort the change will not “stick”. There is no quick solution and no immediate healing.
Governance It may sound contradictory to read-
ers who live and work under “Part-nership” agreements with their vendor counterparts, but our experience is that to assert control over vendor counterparts is essential in developing a successful vendor oversight strategy. There is a sponsor at one end of the equation who takes the risk and the costs for the clinical trial endeavor. At the other end there is the service provider who does certain things for the sponsor and gets paid for it. This sponsor/service provider relationship should be named what it is. Any at-tempts to blur these lines are mis-leading and have not helped to im-prove clinical trial execution. The sponsor needs to lead this collabora-tion from the basis of authority no matter what label the sponsor/service provider collaboration has. Ronald Waife, a colleague of the author, wrote an extended column about this topic a couple of years ago [4].
The basis of a successful sponsor/ven-dor relationship is an ongoing, thor-ough and strong vendor performance review on the study level. This is where the experts from both parties talk to each other, discuss issues and track study progress. Further up, committees are usually used to govern sponsor/ven-dor collaboration. Typically there are too many of them. Two committees are usually enough. One higher-level committee should be focusing on long-term review, planning, and busi-ness strategies. Another committee, which discusses status and escalated issues from the operational level, can complement the governance struc-ture.
Meetings are the No. 1 time con-sumer in today's business. This is true across industries, including the phar-maceutical industry. Particular atten-tion needs to be paid to the frequency of meetings. With good intentions, regular meetings are used as the gov-ernance means of many sponsor/ven-dor relationships – the quarterly steer-ing committee, monthly project and weekly study team meetings. However, we found it much more efficient to adapt meeting frequency to project needs rather than to the calendar. Sometimes there is no need to meet on a monthly basis if there is not any-thing to talk about. On the other hand a weekly study team meeting may not be often enough during a critical phase of a study.
Governance structure, meeting phi-losophy, and any other aspect of the collaboration should be described in detail in one internal document, which could be called the “Vendor Oversight Plan”. This fundamental repository serves as the basis of proper vendor oversight. It is the reference for every-one, the basis for training, and the foundation for healthy sponsor/vendor relationship.
Communication A primary factor of success in vendor
oversight and collaboration is effective communication. Table 1 summarizes some recommendations for the spon-sor side.
It is essential people on both sides understand and use each kind of com-munication mode appropriately. The
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Table 1: Suggestions for Effective Sponsor/Vendor Communication
Insist on a single point of contact at the operational level.
A single point of contact for each functional group is an important enabler of proper expert-to-expert communication. This helps to ensure that interactions between sponsor and vendor are consistent, transparent and establish accountability on both sides of the relationship.
Have frequent face-to-face contacts with service provider personnel.
This solidifies the personal relationship by reinforcing the fact that on both sides there are real people with a common goal, and that counterparts are not just another voice on the phone or teleconference, or just an e-mail correspondent. The project budget should factor in these face-to-face meetings. E-mail should be used as a last resort or when it is important to have a record for documentation purposes.
Avoid passive-aggressive behavior and request vendors to do the same.
An example of this is copying everyone on e-mail when a simple direct one-to-one communication is sufficient (which is nearly always). This is especially important when the e-mails discuss something contentious in nature. Passive-aggressive behavior only serves to drive a wedge in the relationship, as each party feels threatened by the other and is less apt to trust and work well together.
Select vendor with counterparts co-located whenever possible.
Distance drives a wedge into relationships just by the fact that it takes more work and effort to get in touch with someone who is multiple time zones or thousands of kilometers away, notwithstanding the other inherent difficulties of managing from afar.
Request that status reports, for the most part, have the form of exception reports.
Exception reports should show only outliers on both ends of the spectrum to be addressed. This will help make the oversight more efficient and focus specifically on the items that need to be recognized.
Self determine the content of meetings with your service providers.
The vendor is more than welcome to bring up topics to be discussed and suggestions for agenda items are also appreciated. However, in general the sponsor sets the agenda.
Lead and facilitate meetings with your service providers.
Leading and facilitating reaffirms the governance and ensures that the required topics are addressed and that the meetings are productive and efficient.
Provide frequent, open and honest feedback to your service providers.
Feedback focuses on facts and not on subjective information.
Feedback provided should be positive and negative.
In particular recognizing achievements as well as exceptional performance. You should assume that most people at both sides come to work wanting to do a good job; positive feedback boosts morale and the recognition goes a long way in promoting a healthy working relationship.
Encourage proactive engagement on both side of the vendor and sponsor relationship.
If something important needs to be discussed, the topic should be brought up immediately and nobody should wait until the next scheduled meeting to do it.
Motivate your internal team members to be role models for your service provider counterparts.
Transparent, fair expectations not only allow for effective relationship building but also provide solid objective data on performance measurements that can be discussed frankly and professionally.
Establish proper internal communication about vendor performance.
Have issues solved at the lowest level possible and set the expectation that internal leaders are on top of things and are knowledgeable of all current issues. This allows management to escalate and focus on the most critical issues.
importance of effective communica-tion for the collaboration cannot be overstressed.
Measurement The definition and application of
some vital and objective metrics is key to assess vendor performance based on facts. It does not help to have many Key Performance Indicators (KPIs) or metrics, as the volume is not important. In the worst case too many metrics may even mean that nobody is paying attention to any of them. So the art is to identify those few items which are important and which may make a difference to the organ-ization. If these few numbers are
monitored regularly, issues can be identified right after they occurred. The review of vendor output on an ongoing basis is also important since process compliance and quality of de-liverables are interrelated and require permanent attention and not at the study end only.
In some situations it is difficult to operationalize the review of deliver-ables, which are less quantitative (e.g., statistical analysis plan, clinical study report). Therefore certain criteria need to be defined which allow a systematic and consistent assessment.
To take the example of the clinical study report, the following categories might be used:
– Content – Accuracy – Compliance
(with formats and standards) – Completeness – Timing.
Of course content and accuracy are most important, but having the doc-ument in the wrong version or the vendor template incomplete or much too late – this impacts the overall sponsor satisfaction with the report. There are different approaches to further operationalize these or similar categories, starting with simply count-ing errors or using a certain score (in-cluding weights) for each category. Most important, however, it is to de-
velop a consolidated and consistent approach for the assessment.
Sustained Effort What makes change management
projects in vendor oversight so chal-lenging for sponsors is the fact that substantial efforts are needed after the initial definition and implemen-tation. Essentially, implementation al-most never stops, as the new way of vendor management needs to be ap-plied repeatedly for each project and every study.
All of the efforts necessary for gov-ernance, communication and meas-urement have to be sustained throughout the life of the trial or program.
This requires appropriate training and mentoring and the soft skills fac-tor must not be under-estimated. Consistent and repeated messages, and actual support from management, need to go along with this, in partic-ular when it comes to issues or dis-agreements with the vendor.
First Steps
Depending on the status and pre-paredness of an organization, it can take a while and some effort to de-velop and implement a new vendor oversight strategy. So where to start? What to do first?
The obvious answer is to start with some homework, i.e. identify areas for internal process optimization. If for instance your study start-up processes are inefficient or not work-ing well, this may become a roadblock for better vendor management. If a company’s electronic Case Report Form (eCRF) design is not up-to-date this may lead to site dissatisfaction, many queries and a lot of work (= costs!) for the monitoring vendor. This is also an example where the CRO could well be “ahead” of the sponsor. A re-view of standards to be developed and to be used by vendors will help to streamline the corresponding in-teractions. The definition of those “vital few” objective metrics/KPI’s, corresponding information sources, reporting methods, and their appli-cation serve as the foundation of ob-
jective assessment of vendor deliver-ables. Collect all fundamental aspects of the collaboration and develop the vendor oversight plan. This plan will be the guidance for everyone to apply proper risk-based vendor oversight.
It is also important to align with key stakeholders on functional needs at an early stage. Although very much desirable, not all departments may follow the same vendor oversight strategy and approaches. Therefore the relationship and responsibilities of in-house managers need to be clear. As part of interdepartmental alignment it should also be clarified who is in charge of overall vendor control and who does functional over-sight. This begs the question as to whether staff is qualified for the over-sight, and may lead to soft-skill train-ing requirements.
The Way Forward
The guiding principle for a healthy sponsor/vendor relationship is that the sponsor (big or small, experienced or naïve) should govern the relation-ship with service providers. Although some vendors are still suggesting to strive for the “we are one team spirit” [5], in fact managing sponsor/provider communication and control from a position of accepted authority is key to establish appropriate vendor over-sight. Collaboration should never mean abdication: the authority needs to be natural and fact-based. Some further points to be considered: – A team cannot be the responsible
party – only a single individual is responsible.
– Meet only when there is a good reason to do so.
– Nobody is perfect, including you. – Learn and communicate reasonable
expectations. – Model good behavior to your
providers. – Manage through facts and your
eyes. In our experience clinical develop-
ment organizations are typically not prepared and not staffed to set up a successful vendor oversight manage-ment strategy. Instead sponsors jump to another vendor or another out-
sourcing model. There is never time or money to set up something sus-tainable from scratch. In consequence the learning effect of bad experiences is negligible.
This may sound pessimistic but it need not be; there is no “one-size-fits-all” solution for vendor oversight management any more than there is only one approach to managing ven-dors. Although issues might be similar, sponsors are different. They are as different as their key business drivers are different. And those key business drivers should drive the solution. Things like an increasing or downsiz-ing pipeline, in-licensing or integration efforts, cost-containment, community labor commitments, absorbing entirely new therapeutic areas, or any other high-level company targets may lead to very different solutions for a given set of sponsors. What is common to all sponsor situations however, is to approach vendor oversight manage-ment as a professional skill and func-tion requiring professional develop-ment and a robust function-driven strategy. Not an impossible mission, but a challenging and unavoidable one. |
Detlef Nehrdich, Diplom-Statistiker, ist Senior Associate bei Waife & Associates und berät in dieser Funktion biophar-mazeutische Unternehmen im Bereich der klinischen Entwicklung. Beratungs-schwerpunkte sind Change Manage-ment, Auswahl und Implementierung von eClinical Systemen,Vendor Oversight Management sowie Biostatistik.
