ICH-GCP AND THEIR DIFFIRENCES TO INDIAN CLINICAL TRIAL GUIDELINES

Good Clinical Practices (GCP)

DR. RANJEET PRASAD(MPH,MBA,CCRP,BDS)

Agenda

• Evolution of GCP.

• ICH-GCP.

• Differences and Similarities between ICH-GCP , Indian GCP and Schedule-Y

• Key Players in Clinical Research and their checklists

Evolution

• Nuremberg Code, 1947

• Declaration of Helsinki, 1964 → 2001

• ICH GCP guidelines, 1996

• Ethical Guidelines for Biomedical Research in Human Subjects (ICMR), 2000

• GCP Guidelines, CDSCO, New Delhi, 2001

ICH-GCP-Introduction

• Good Clinical Practices (GCP) is an international ethical & scientific quality standard for designing, conducting, recording & reporting trials that involve the participation of human subjects.

• Compliance with this standard provides public assurance that rights, safety & 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

ICH GCP- Objective

• To provide a unified standard for the EU, Japan & the US to facilitate the mutual acceptance of clinical data by regulatory authorities in these jurisdictions

• Should be followed when generating data that are intended to be submitted to regulatory authorities (only then??)

ICH GCP-Section 1

Section 1- Glossary of various terms, eg...

• Adverse drug reaction & Adverse Event

• Case report form & Clinical Study Report

• Coordinating Committee & Contract Research Organization

• Independent Ethics Committee & Institutional Review Board

• Investigator & Investigator’s Brochure

ICH GCP-Section 1 Cont…

• Monitoring & Monitoring report

• Protocol & Protocol Amendment

• Serious Adverse Event

• Source data & Source documents

• Sponsor & Sponsor investigator

• Standard Operating Procedures

• Vulnerable subjects

ICH GCP-Section 2

Section 2- Principles of ICH-GCP.2.1 Clinical Trials should be conducted in accordance with the

ethical principles consistent with GCP and applicable regulatory requirements

2.2 Before a trial is initiated, forseeable risks & inconveniences should be weighed against anticipated benefit for the trial subject & society.

2.3 The rights, safety, and well being of the trial subjects are the most important considerations & should prevail over interests of science and society

2.4 The available nonclinical & clinical information on an investigational product should be adequate support the proposed clinical trial.

2.5Clinical trials should be scientifically sound, and described in a clear, detailed protocol.

ICH GCP-Section 2 Cont..

2.6 Trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/ independent ethics committee (IEC) approval/favourable opinion.

2.7 The medical care and medical decisions for subjects should be the responsibility of a qualified physician

2.8 Each individual involved in conducting a trial should be qualified by education, training & experience to perform his respective task


2.9 Freely given informed consent should be obtained from every subject prior to clinical trial participation

2.10 All clinical information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification

2.11 The confidentiality of records that could identify patients should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirements


2.12 Investigational products should be manufactured, handled and stored in accordance with applicable GMP, and used in accordance with the protocol

2.13 Systems with procedures that assure the quality of every aspect of the trial should be implemented


ICH-GCP-Section 3

Institutional Review Boards/ Independent Ethics Committee

Section 3.1: IRB/IEC Responsibilities

• Should safeguard the rights, safety & well being of all trial subjects.

• Should obtains following Documents: Protocol & their amendments, Patient Information sheet & consent form, subject recruitment procedures (e.g. advertisements), Investigator's Brochure (IB), available safety information, information about payments and compensation available to subjects, the investigator’s current curriculum vitae and/or other documentation evidencing qualifications, and any other documents that the IRB/IEC may need to fulfil its responsibilities

• should conduct continuing review of each ongoing trial at intervals appropriate to the degree of risk

to human subjects, but at least once per year. • Review Protocol/ ICD/ recruitment procedures/ IB/payments

• Continuing review for Ongoing Progress/Adverse events

Section 3.1: IRB/IEC Responsibilities Cont..

Section 3.2: IRB/IEC Composition

• At least 5 members

• At least one non scientific member

• At least one independent member

• Maintain list of members and qualifications

• Only independent members to vote

• Quorum to be present

Section 3.3: Procedures

The IRB/IEC should establish, document in writing, and

follow its procedures, which should include – Composition

– Meeting Scheduling & conduct

– Specify that trial starts only after IRB review

– Specify regarding changes in protocol

– Specify prompt reporting of adverse events

Section 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).

• The IRB/IEC may be asked by investigators, sponsors or regulatory authorities to provide its written procedures and membership lists.

ICH-GCP: Section 4

Investigator

Section 4.1Investigator qualifications & Agreements

• Qualified (documented) by education, training & experience to assume responsibility for proper trial conduct

• Should be familiar with the appropriate use of the investigational product, IB, and other information provided by sponsor

• Should be aware of, & should comply with, GCP and the applicable regulatory requirements

• Should permit monitoring, auditing and inspection

• Delegation of duties to appropriately qualified persons

Section 4.2: Adequate Resources

• Potential for recruitment

• Sufficient time for trial conduct and completion

• Staff, facilities

• Ensure training to staff

Section 4.3: Medical care of trial subjects

• Qualified physician investigator/sub investigator for the trial, should be responsible for all trial related medical decisions

• Adequate medical care during and after trail participation• Make reasonable efforts ascertaining for premature

withdrawal from trial

Section 4.4: Communication with IRB

• Written & dated approval for trial protocol, ICD, recruitment procedures etc prior to trial initiation

• Should provide latest copies of IB to IRB

• Should provide all relevant documents for review during trial

Section 4.5: Compliance with Protocol

• Should conduct trial in accordance with the protocol version agreed & documented by the sponsor, IRB and regulatory authority

• No changes allowed in the protocol except in case of immediate hazard to the patient; which should be submitted to all immediately

Section 4.6: Investigational Product

• Responsible for accountability at site

• May be assigned to pharmacist/individual

• Stored as specified by sponsor or regulatory authority

• Used only in accordance with the protocol

Section 4.7: Randomization Procedures and unblinding

• Should follow the trial’s randomization procedure

• Any premature unblinding to be explained to sponsor

Section 4.8: Informed Consent

• Comply with regulatory requirement, GCP and ethical principles

• Documented Communication of revised ICD to IRB and patient

• No influence or coercion to participate

• Subject or their legal representative should be fully informed in their own language

• Non technical language

• Ample time for consent and opportunity for questions

• Impartial witness for illiterate patients

• Subject should receive a copy of the signed and dated ICD/ amendment

Section 4.8: Informed Consent cont..

Section 4.9 :Records and reports

• Should ensure accuracy, completeness, legibility and timeliness of data to sponsor in CRF

• Correction in CRF should be signed, dated• Maintain trial related documents• Financial agreements in place• Access to records by monitor, regulatory agency or auditors• Progress reports to IRB

• The investigator should submit written summaries of the trial status to the IRB/IEC annually, or more frequently, if requested by the IRB/IEC.

• The investigator should promptly provide written reports to the sponsor, the IRB/IEC (see 3.3.8) and, where applicable, the institution on any changes significantly affecting the

conduct of the trial, and/or increasing the risk to subjects

Section 4.10 :Progress reports

Section 4.11:Safety Reporting

• SAE should be reported immediately to sponsor, and timely as required to IRB/regulatory agency

• Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety evaluations should be reported to the sponsor according to the reporting requirements and within the time periods specified by the sponsor in the protocol.

• For reported deaths, the investigator should supply the sponsor and the IRB/IEC with any additional requested information (e.g., autopsy reports and terminal medical reports).

Section 4.12: Premature termination of trial

If the trial is prematurely terminated or suspended for any

reason , Investigator :

• Should inform subjects

• Should assure therapy and follow up

• Should inform regulatory authorities

• Should inform sponsor/IRB with explanation

Section 4.13: Final Report

• Upon completion, should inform institution, IRB, and regulatory authorities with a summary of the trial’s outcome

ICH-GCP: Section 5

Sponsor Responsibilities

Sponsor

• An individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial

Section 5.1: Quality Assurance & Quality Control

• Implementing & maintaining QA and QC systems with written SOPs to ensure GCP compliance

• Securing agreements from all sites for monitoring, auditing, and inspections

• QC of data handling

• Payment agreements

Section 5.2: 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

• Sponsor may transfer all or some duties to CRO

• Ultimate responsibility for quality lies with the sponsor

• Document of all duty delegation required

Sponsor Responsibilities

• Designate Medical Expertise :who will be readily available to advise on trial related medical questions or problems. (Section 5.3)

• Trial design (Section.5.4), Trial management, Data handling and Record Keeping (Section 5.5) and Investigator selection (Section 5.6), Allocation of Responsibilities (Section 5.7)

• Compensation to Subjects and Investigators (Section 5.8), Financing (Section 5.9)

• Submission to regulatory authorities (Section 5.10)

• Confirmation of review by IRBs (Section5.11)

Sponsor ResponsibilitiesCont….

• Information on investigational product (Section 5.12)

• Manufacturing, labeling, packaging & coding of product (Section 5.13)

• Supplying and Handling Investigational Product(s) (Section 5.14) and Record Assess (Section 5.15)

• Safety Evaluation (Section 5.16) and Adverse Drug Reaction Reporting (Section 5.17)

• Monitoring (Section 5.18)

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, SOPs, GCP, and the applicable regulatory requirements

Sponsor ResponsibilitiesCont….

• Audit (Section 5.19)

• Noncompliance (Section 5.20)

• Premature Termination or Suspension of a Trial (Section5.21)

• Multicentre Trials (Section 5.22)

ICH-GCP: Section 6

CLINICAL TRIAL PROTOCOL

AND

PROTOCOL AMENDMENT(S)

Protocol

• Document describing all aspects of the study

• Well designed and thoroughly considered

• Well structured

• Complete

Protocol- Relevant components

• General Information (Section 6.1)

• Background Information (Section 6.2)

• Trial Objectives and Purpose (Section 6.3)

• Trial Design (Section 6.4)

• Selection and Withdrawal of Subjects (Section 6.5)

• Treatment of Subjects (Section 6.6)

• Assessment of Efficacy (Section 6.7)

• Assessment of safety (Section 6.8)

Protocol- Relevant componentsCont…

• Statistics (Section 6.9)

• Direct Access to Source Data/Documents (Section 6.10)

• Quality Control and Quality Assurance (section 6.11)

• Ethics (section 6.12)

• Data handling & management (Section 6.13)

• Financing and Insurance (Section 6.14)

• Publication Policy (Section 6.15)

• Supplements (Section 6.16)

Sec 6.1: Protocol- General Information

• Protocol Title, identifying number & date. Amendment number

• Contact names, addresses• Name and title of Authorized signatory• Contact medical expert• Contact investigator(s)• Institution(s), Laboratories, department contact

Sec. 6.2:Protocol- Objective & Justification

• Aims & objectives, phase of study• Name & description of Inv product• Summary of non clinical & clinical studies• Summary of risks & benefits• Description of route of administration, dosage• Statement of GCP compliance

Sec 6.4: Protocol- Trial Design• Primary & secondary endpoints• Randomized/comparator/blinded/open, placebo controlled• Blinding technique(double blind/single blind)• Randomization(method & procedure)• Diagram of design, procedure & stages• Medications permitted & not permitted during study• Description of study treatments, dose, route during study

conduct• Packing/labeling description• Duration of subject participation & sequence of all study

periods, including follow up

Sec 6.4: Protocol- Trial DesignCont….

• Proposed date of initiation of study• Discontinuation criteria for subjects• Instructions on suspending or terminating the

study• Procedures for monitoring compliance

Sec 6.5: Selection and Withdrawal of Subjects Inclusion/ Exclusion criteria:• Specifications of the subjects to be included (age, gender,

ethnic groups, prognostic factors, diagnostic criteria)

• Specify exclusion criteria

• Subject withdrawal criteria & procedures

Sec 6.7: Protocol-Assessment of Efficacy • Specifications of efficacy parameters• Descriptions of how these are measured and recorded• Time & periodicity of recording• Description of special analysis/ tests (PK, clinical, lab,

radiology)• Specifications of safety parameters• Procedures for eliciting reports of and reporting ADR• Time &method of recording• Type, duration of follow up after adverse events)

Sec 6.9: Protocol- Statistics

• Description of statistical methods employed

• Timing of interim analysis, if any

• Details of enrollment plan

• Significance level, power

• Procedures for reporting any deviations from the original statistical plan

• Selection of subjects to be included in final analysis

Sec 6.10: Direct Access to Source Data/Documents

• 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

Sec 6.11: Protocol- QC & QA

• Steps & procedures for monitoring study

• Instructions for protocol deviations

• Allocation of duties & responsibilities within research teams

• Quality control of methods & evaluation procedures

Sec 6.12:Protocol- Ethical considerations

• Description of how patients/volunteers would be informed

Sec 6.13:

Protocol-Data Handling and Record Keeping • Procedures for handling & processing records of

effects and adverse events• Handling of Products:

– Safe handling and storage measures

– System to be followed for labelling

– Labeling specifications

Sec. 6.14: Protocol- Finance & insurance

• Budget, financial aspects

• Sources of economic support

• Subject payments

• Reimbursement to team members

• Insurance details of study subjects

ICH-GCP: Section 7

Informed Consent

Section 7: Investigator Brochure-Introduction

• Compilation of the clinical and nonclinical data on the investigational product that are relevant to the study of the products in human subjects

Sec 7: Investigator Brochure: Contents• Introduction

DefinitionPurpose Information formEditionType & extentReview & reviseUp-date

• General consideration• Contents of the IB• Conclusion

ICH-GCP: Section 8

ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A

CLINICAL TRIAL

Sec 8: Essential Documents -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 to be Kept before Trial Commences

Investigators Brochure Signed protocols, amendments (if any) and sample CRF Information given to the trial subjects

Informed Consent Applicable translations of informed consent (if any) Any other written information Advertisements for subject recruitment Subject compensation

Financial aspects of the trial Compensation document for trial-related injury Signed agreements of all involved parties

Investigator and sponsor Investigator and CRO (if any) Investigator/institution and regulatory authorities (if any)

Approval letter from the IRB IRB Composition Authorization or notification from the regulatory agencies (where required)

Essential Documents to be Kept before Trial Commences

CV of investigator and sub-investigators evidencing qualifications Normal values of labs /technical procedures included in the protocol Medical/laboratory and technical procedures of tests

Certification Accreditation Established Quality control (QC assessments) Other validations

Sample labels attached to investigational product containers Instructions for handling investigational products and trial-related materials

(sometimes this information is included in the investigator’s brochure) Shipping records of investigational products and trial-related materials Certificates of analysis of investigational products shipped Decoding procedures for blinded trials Master randomization list Pretrial monitoring report Trail initiation monitoring report

Essential Documents to be Kept During the Trial

Investigator’s brochure updates Any revisions to:

Protocol, amendments and CRF Informed consent form Written information provided to subjects/LAR Advertisement

Dated, IRB approved documents of: Protocol amendments Revisions of informed consent, information to subjects/LAR Advertisements and any other documents given Continuing review of trial

Dated Regulatory approved documents of: Authorizations and notifications Protocol amendments and other documents

Curriculum Vitae of new investigators and sub-investigators Updates to normal value(s) range(s) for medical lab technical procedure(s), test(s)

included in the protocol Updates on medical/laboratory/technical procedure tests

Certificates Accreditation Established quality control/external quality assessment Other validations

Documentation of investigational products and trial-related materials shipment Certificate(s) of analysis for new batches of investigational products Monitoring visit reports Relevant communications other than site visits (Letters, meeting notes and notes of

telephone calls) Signed informed consent forms Source documents Signed, dated and completed CRF Documentation of CRF Corrections


Notification by the originating investigator to sponsor of serious adverse evens and related reports

Notification by investigator (if applicable) to regulatory authorities and IRB of unexpected serious adverse reactions and of other safety information

Notification by sponsor to investigators of safety information Subject screening log Subject identification code list Subject enrolling log Investigational product(s) accountability at the sire Signature sheet Record of retained body fluids/tissue samples (if any)


Essential Documents to be Kept After Completion or Termination of the Trial

Investigational product(s) accountability at sire Documentation of investigational product(s) destruction Completed subject identification code list (to permit identification of all

subjects enrolled in the trial in case of follow up is required – this information should be kept in a confidential manner and for agreed period of time)

Audit certificate (if required) Final trial close-out monitoring report Treatment allocation and decoding documentation returned to sponsor

to document any decoding that may have occurred Final report by investigator to IRB where required Final report by investigator to regulatory authorities where applicable

to document completion of the trial Clinical study report to document results and interpretation

Differences and similarities between ICH-GCP and Indian GCP

Expert Committee set up by Central Drugs Standard Control Organization (CDSCO) in consultation with clinical expert has formulated this GCP guideline

• Drug Technical Advisory Board (DTAB), the highest technical body under D&C, Act, has endorsed adoption of this GCP guideline for streamlining the clinical studies in India

• These guidelines have been evolved with consideration of WHO, ICH, USFDA and European GCP guidelines as well as the Ethical Guidelines for Biomedical research on Human Subjects issued by the Indian Council of Medical Research. 70

Indian GCP :Dec 2001

STRUCTURE

• Glossary

• Principles

• IRB/IEC

• Investigator

• Sponsor

• Protocol

• Investigators’ Brochure

• Essential Documents

• Definitions

• Pre-requisites

• Responsibilities

• Records & Data

• Quality Assurance

• Statistics

• Special Concerns

• Appendices

ICH E6 Indian GCP

71

GCP - A Shared Responsibility

Sponsor

Investigator

Regulatory Authority

Ethics Committee72

Performance

SkillsKnowledge

What toWhy to

73

Want to

How to

GCP IMPLEMENTATION

• Amendment to Drugs and Cosmetics Act, 1940

• Enacted by Parliament in the Fifty-sixth year of Republic of India

•Published in the Gazette of India Part-II, section 3, sub-section (i) vide G.S.R. 32(E), dated 20th January, 2005

74

Schedule Y DRUGS AND COSMETICS (IIND AMENDMENT)

RULES, 2005 NOTIFICATION the 20th January, 2005

Regulation and guidelines for permission to import and / or manufacture of new drugs for sale or to undertake clinical trials

It has outlined extensive study criteria in line with the globally accepted formats such as ICH and US FDA guidelines

REFER TO RULES 122A, 122B, 122D, 122DA, 122DAA and 122E

75

Schedule Y

122-A : Application for permission to import new drug

122-B : Application for approval to manufacture new drug

122-D: Permission to import or manufacture FDC

122-DA : Permission to conduct clinical trials for New Drug / Investigational New Drug

122-DAA : Clinical trial

122-E:New drug 76

List of Appendices For Schedule Y

Appendix XContents Of The Proposed Protocol

For Conducting Clinical Trials

Appendix IXStability Testing Of New Drugs

Appendix VIIIEthics Committee

Appendix VIIUndertaking by the Investigator

Appendix VIFixed Dose Combinations (Fdcs)

Appendix VInformed Consent

Appendix IVAnimal pharmacology

Appendix IIIAnimal toxicology (non-clinical toxicity studies)

Appendix IIStructure, contents & format for clinical

study reports

Appendix I-AData required to be submitted by an

applicant for grant of permission to import &/or manufacture a new drug already approved

in the country.

Appendix I Data to be submitted along with the application to conduct clinical trials / import / manufacture

of new drugs for marketing in the country.

Appendix XI Data Elements For Reporting Serious Adverse Events Occurring In A Clinical Trial.

78

Appendix IIIAnimal toxicology (non-clinical toxicity studies)

Appendix IIStructure, contents & format for clinical

study reports

79

INFORMED CONSENT PROCESS

ICH GCP Indian GCP Schedule-Y

•Any one designated by the investigator to conduct and to sign the consent form.(4.8.8)

•Investigator should sign the form. (2.4.3.1)

•Investigator should sign the form.(Appendix V)


•Not Explained •cover issues of biological samples. (2.4.3.2)

•Not Detailed

ESSENTIAL ITEMS FOR INFORMED CONSENT

ETHICS COMMITTEE COMPOSITION


• At least 5 members. •At least 1 member -nonscientific area. •Quorum members number not detailed.

•Maximum number is not detailed.

•Not recommended.

•Fairly small (5-7 members).•Not Explained

•The quorum should have a minimum of 5 members.

•12 to 15 is the maximum recommended number.

•Member Secretary belongs to the same Institution.

•At least 7 members. •Not Explained.•The quorum should have at least 5 members. •Maximum number is not detailed.

•Not recommended.


•Not Explained •Should include name and contact numbers of investigator and name of institution. (2.3.1.6)

•Not Explained

DRUG LABEL

DOCUMENT RETENTION


•The records are linked to marketing approval

•Study related documents/materials should be safe guarded by the sponsor for 3 years. (3.1.5)

•Not Explained

POWERS OF IEC


•It is the responsibility of independent data-monitoring committee (IDMC)

•IEC has power to order discontinuation of a trial if goals of the trial have already been achieved or unequivocal results obtained. (2.4.2.6)

•Not Explained

STANDARD OPERATING PROCEDURES


•Expects the investigator to comply with the protocol and leaves the task of monitoring compliance to SOPs to monitors and auditors.

•Mandates that the sponsor and the investigator should sign a copy of the Standard Operating Procedures (SOPs). (3.1.3)

•Not Explained

INVESTIGATOR’S QUALIFICATION


•Not Recommended

•Should be qualified as per the requirement of the Medical Council of India (MCI). (3.3.1)

•Not Explained

Key Players in Clinical Research and their checklists

Players in Clinical Research

• Investigators• Sponsors• Regulatory agency• Ethics Committee

Investigator’s checklist - 1

• Interest, expertise, time and facilities

• Interaction with sponsor– Protocol, CRF, PIS and ICF

– Financial grant

– Publication policy

• Interaction with ethics committee– Presentation and defense of protocol

– Compliance with conditions of approval

Investigator’s checklist - 2

• Implementation– Organizing, briefing and supervising the team– Facilitating informed consent process– Completing and signing CRFs– Reporting SAE– Interacting with monitor– Reviewing and approving final report– Archiving source documents– Preparing for audit and/or inspection

Sponsor’s checklist - 1

• Scientific, regulatory and ethical basis of the protocol, PIS and ICF

• Investigator’s qualifications, training and experience

• Regulatory and ethical approvals

• Publication policy

• Quality of trial supplies

• Initiation, monitoring and audit

Sponsor’s checklist - 2

• Data management and analysis

• Drafting of study report

• Preparation for inspection

• Archives of source documents

Regulator’s checklist

• Periodic review of current regulations from scientific and ethical angles

• Advance consultation to sponsors on protocols– Efficacy and safety criteria– Comparator product

• Advisory panels for review of applications and decision making

• Inspection of investigational centers

Ethics Committee’s checklist - 1

• Need for trial

• Scientific aspects of protocol with ethical implications

– Participants

• Number

• Healthy volunteers or patients

• Vulnerable persons


– Treatment

• Withdrawal of current treatment

• Assignment of placebo

• Dosage and route

– Assessment of response

• Nature and frequency

• Invasive or non-invasive

• Total blood drawn


• Ethical aspects of protocol

– Information and consent form

• Content and language

• Risks and benefits

• Compensation or other payments

• Insurance for study-related injury

• Treatment after study

• Regulatory approval

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ICH-GCP AND THEIR DIFFIRENCES TO INDIAN CLINICAL TRIAL GUIDELINES

Health & Medicine