DAIDS Safety Workshop: Part IClinical Trial Safety and Safety Monitoring

DAIDS Safety Workshop: Part IClinical Trial Safety and Safety Monitoring

Albert Yoyin, M.D. and Anuradha Jasti, M.D.DAIDS Regulatory Support Center (RSC) Safety Office

Johannesburg, South Africa

29 Aug 2012

Albert Yoyin, M.D. and Anuradha Jasti, M.D.DAIDS Regulatory Support Center (RSC) Safety Office

Johannesburg, South Africa

29 Aug 2012

ObjectivesObjectives

Participants will be able to demonstrate an understanding of:

Human Subject Protections and Safety Monitoring Current context regarding safety in clinical trials Key roles and responsibilities related to safety Protocol requirements pertaining to safety Safety and adverse event terminology Expedited reporting of adverse events What makes a well-documented adverse event,

including a comprehensive narrative

2

History of Research Involving HumansHistory of Research Involving Humans

3

History of Research Involving HumansHistory of Research Involving Humans

4

Regulations: Federally Supported Research Involving Human SubjectsRegulations: Federally Supported Research Involving Human Subjects

45 CFR 46: Protection of Human Research Subjects

Applies to all research involving human subjects

Institution must provide assurance of compliance, such as a Federal Wide Assurance (FWA) on file with the Office for Human Research Protection (OHRP)

FWA provides assurance that research is conducted in accordance with the regulations

• Research reviewed and approved by IRB• Subject to continuing review by IRB

5

Regulations: Non-Federally Supported Studies Involving Human SubjectsRegulations: Non-Federally Supported Studies Involving Human Subjects

21 CFR 50: Protection of Human Subjects

Requirement for informed consent

• Elements of informed consent• Documentation of informed consent

21 CFR 56: Institutional Review Boards

Requirements for IRB review

• Membership, functions, review procedures, etc.• Criteria for IRB approval

Applies to all clinical investigators regulated by FDA

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NIH ResearchNIH Research

Must comply with regulations pertaining to research involving human subjects, investigations of new drugs, biologics, or devices, or new indications, or use in new populations

• HHS, OHRP

• FDA

Must adhere to NIH and Institute Policies for clinical research and conduct of clinical trials

Additional monitoring bodies: Network-specific clinical safety monitors/groups, IRBs, DSMBs

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Institutional Review Board (IRB)Institutional Review Board (IRB)

At least 5 members:

• At least 1 in scientific area, 1 in non-scientific area• At least 1 not affiliated with institution nor family member• Individual knowledgeable/experienced in working with vulnerable

populations of such research• No member with conflict of interest (COI), except to provide information at

IRB request• May invite individuals to assist in review of special areas requiring expertise

beyond that available on the IRB; non-voting Be able to ascertain the acceptability of proposed research in terms of

institutional commitments and regulations, applicable law, and standards or professional conduct and practice

• Authority to approve, require modifications, or disapprove all research activities

• Written notification to include a statement of the reasons for disapproval; investigator has opportunity to respond in person or in writing

8

IRB ReviewIRB Review

Initial and continuing review:

• At convened meetings (at intervals appropriate to level of risk; not less than 1/year)

• Majority of members must be present; Approval by majority

• Approval of Informed Consent Form• Unanticipated problems involving risks to human

subjects or others• Any instance of serious or continuing non-compliance

with regulations, requirements, or determinations of the IRB

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IRB Review: Approval CriteriaIRB Review: Approval Criteria

Risks to subjects are minimized:

• By using procedures consistent with sound research design which do not unnecessarily expose subjects to risk

• Whenever appropriate, by using procedures already being performed for diagnostic or treatment purposes

Risks to subjects are reasonable in relation to anticipated benefits, and the importance of the knowledge that may reasonably be expected to result

Other criteria 45 CFR 46.111 or 21 CFR 56.111

10

Data Safety and Monitoring Board (DSMBs)/ Data Monitoring Committees (DMCs)Data Safety and Monitoring Board (DSMBs)/ Data Monitoring Committees (DMCs)

Government agencies, e.g., NIH and the VA, have required the use of DSMBs in certain trials

Current FDA regulations impose no such requirements except under 21 CFR 50.24 (Exception from Informed Consent Requirements for Emergency Research)

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Data Safety and Monitoring Board (DSMBs)/ Data Monitoring Committees (DMCs)Data Safety and Monitoring Board (DSMBs)/ Data Monitoring Committees (DMCs)

Group of individuals with pertinent expertise; reviews accumulating data from one or more ongoing clinical trials: • Clinicians with expertise in relevant clinical specialties• At least one biostatistician knowledgeable about statistical

methods for clinical trials and sequential analysis of trial data• A medical ethicist, and/or patient advocate• Other scientific areas: toxicologist, clinical pharmacologist,

epidemiologist Advises the sponsor:

• Continuing safety of trial subjects and those to be recruited• Continuing validity and scientific merit of the trial

Two important considerations: Confidentiality and COI• Knowledge of interim results could influence conduct of the trial

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PerspectivePerspective

Differing viewpoints on safety requirements:

Imposes a burden on investigators

• Cumbersome bureaucratic hindrance

• Holds back pace of science

• Delays availability of new or much needed treatments

Represent only a minimal standard

• What is at least reasonable, practical

• Not what would be most ideal

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PerspectivePerspective

Subject participation in research is voluntary

• Placed their faith in the investigators

• Participation is a gift in the service of the public interest

Investigators must not betray the public trust

• Must conduct trials with ethical and scientific integrity

• Must implement high standards for human subject protections

• Must assure subject well-being and safety at all times

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Current Safety EnvironmentCurrent Safety Environment

Increasing public demands for safety data

• Fast track approvals • Post-market events leading to changes in labeling e.g., additional

precautions, black box warnings

Global reporting to EMA and other countries throughout the world

Food and Drug Administration Amendments Act of 2007 (FDAAA): Provides FDA with additional requirements, authorities, and resources with regard to both pre- and post-market drug safety

Final Rule 21 CFR 312.32 (Sep 2010): focus on signal detection (only submit evidence-based Serious Suspected Unexpected AEs), encourage noise reduction (less submission)

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Clinical Trial Continuum: From Drug Development to Optimal Regimens to Treatment Strategies

Clinical Trial Continuum: From Drug Development to Optimal Regimens to Treatment Strategies

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SCHARPSCHARP

MTNMTN HPTNHPTNHVTNHVTN

FSTRFFSTRF U MNU MN

IMPAACTIMPAACT ACTGACTG INSIGHTINSIGHT

PHASE I PHASE II PHASE III PHASE IV POST PHASE III/IVPHASE I PHASE II PHASE III PHASE IV POST PHASE III/IV

NME FIH TREATMENT STRATEGY

NME FIH TREATMENT STRATEGY

CONTROLLED SETTING REAL-WORLD SETTINGCONTROLLED SETTING REAL-WORLD SETTING

PRE-MARKET POSTMARKETPRE-MARKET POSTMARKET

Safety MonitoringSafety Monitoring

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Why is safety monitoringrequired in all clinical trials?

Why is safety monitoringrequired in all clinical trials?

To Ensure Subject Safety and Study Integrity

Investigator assures Subject Safety and Study

Integrity by:

Investigator assures Subject Safety and Study

Integrity by:

Implementing the protocol “as written” Implementing the protocol “as written”

Strict adherence to inclusionand exclusion criteria

Strict adherence to inclusionand exclusion criteria

Monitoring subject status, e.g., subject wellbeing, minimization of risk, toxicity

management, etc.

Monitoring subject status, e.g., subject wellbeing, minimization of risk, toxicity

management, etc.

Continued adherence to the protocolthroughout study duration

Continued adherence to the protocolthroughout study duration

Monitoring safety data collection:• Study database• Safety database

Monitoring safety data collection:• Study database• Safety database

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Roles and Responsibilities: Site InvestigatorRoles and Responsibilities: Site Investigator

Roles and Responsibilities:Research StaffRoles and Responsibilities:Research Staff

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• Record AE and/or SAE per protocol specifications

• Follow protocol toxicity management section

• Record AE and/or SAE per protocol specifications

• Follow protocol toxicity management section

• Follow site SOP for emergencies

• Follow site SOP to notify study clinician/physician

• Record the AE/SAE

• Follow site SOP for emergencies

• Follow site SOP to notify study clinician/physician

• Record the AE/SAE

Is immediate/emergency intervention needed?Is immediate/emergency intervention needed?

YesYes NoNo

Roles and Responsibilities: Study Clinician/PhysicianRoles and Responsibilities: Study Clinician/Physician

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Subject reports AESubject reports AE

Documentation • Follow until AE resolution

or condition stabilizes

Documentation • Follow until AE resolution

or condition stabilizes

Study clinician/physician will assess and managethe AE; Decide if SAE

Study clinician/physician will assess and managethe AE; Decide if SAE

Emergency intervention vs. Non-emergency care

Emergency intervention vs. Non-emergency care

Research provisions vs.

Clinical care

Research provisions vs.

Clinical care

Assurance of Safety and Well-Being:Research vs. Medical RolesAssurance of Safety and Well-Being:Research vs. Medical Roles

Emergency intervention vs. Non-emergency care

• Acute on-site management, as necessary, and per site SOP

• Referral to care when stable

Research provisions vs. Clinical care

• Provide interventions permitted by the protocol• Follow protocol specifications for toxicity management • Beyond protocol specifications, refer out for clinical

care

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Clinical Role vs. Research RoleClinical Role vs. Research Role

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Therapeutic MisconceptionTherapeutic Misconception

Subjects think they are receiving proven interventions, per their usual clinical care, despite participating in a research study

• Informed Consent Process must not be trivialized or relegated to administrative status

• Check for understanding• Time for questions, making decision

Physicians think they can provide interventions, per usual practice

• Strict adherence to protocol provisions for care, toxicity management

• Decide if subject can continue in study

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Roles and Responsibilities: Study Clinician/PhysicianRoles and Responsibilities: Study Clinician/Physician

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Study product: Per site, per study?

Study status: Safety pause, clinical hold, early termination?

Study product: Per site, per study?

Study status: Safety pause, clinical hold, early termination?

Study product:

Dose held, changed,

or discontinued?

Study participation:

Continue, withdraw?

Study product:

Dose held, changed,

or discontinued?

Study participation:

Continue, withdraw?

Action taken with Study product

after AE

Action taken with Study product

after AE

SubjectSubject StudyStudy

Roles and Responsibilities:Study TeamRoles and Responsibilities:Study Team

Safety: Ensure safety and well-being of subjects at all times

Monitor safety across all study sites

Review all safety data at specified intervals

Discuss need for change(s) driven by safety

Data: Ensure data integrity to assess the risks/safety profile of the study intervention

Data capture; especially safety data

Be cognizant of expedited reporting requirements for safety data

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Roles and Responsibilities:Study Team vs. Sponsor/RSCRoles and Responsibilities:Study Team vs. Sponsor/RSC

Safety monitoring by study team

• Acute on-site management and discussion with study team

• Periodic review by study team and monitoring committees– Data generated by Data Management Centers (DMCs)

Expedited reporting to sponsor/RSC

• SAE sent to RSC• RSC processes event and sends queries to site to obtain additional

information• All follow-up information should be provided to RSC• RSC is not part of discussions that occur within study/safety monitoring

teams regarding the event• The RSC only has information about the event from the SAE Form; site

should include relevant information from study team discussions

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Mental Break

Mental Break

Drug Development Model:Safety Data Flow in DAIDS Clinical TrialsDrug Development Model:Safety Data Flow in DAIDS Clinical Trials

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Subject EnrolledSubject Enrolled

AE ReportedAE Reported

Record AE*Record AE*YesYes

SAE?SAE?

To SponsorTo Sponsor

Record SAE**Record SAE**

To IRBTo IRB

To FDATo FDA

To otherTo other

Follow until Resolutionor Stability

Follow until Resolutionor Stability

Outcome: Resolved/

Stable?

Outcome: Resolved/

Stable?

Update SAEUpdate SAE

NoNo

Adverse Event FlowchartAdverse Event Flowchart

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Subject EnrolledSubject Enrolled

AE ReportedAE Reported

Record AE*Record AE*YesYes

SAE?SAE?

To SponsorTo Sponsor

Record SAE**Record SAE**

To IRBTo IRB

To FDATo FDA

To otherTo other

Follow until Resolutionor Stability

Follow until Resolutionor Stability

Outcome: Resolved/

Stable?

Outcome: Resolved/

Stable?

Update SAEUpdate SAE

NoNo

Adverse EventAdverse Event

*Protocol specifications for AE When to collect, e.g., study visit Method of collection, e.g., in person, telephone call Duration of collection, e.g., from enrollment to completion What to collect, e.g., all AEs, only certain AEs by body

system, only certain AEs by severity What forms to use, e.g., AE CRF, study CRFs

**Protocol specifications for SAE Criteria Expedited timeframes Reporting form, e.g., SAE

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Documentation Differences Between AE CRF and SAE FormDocumentation Differences Between AE CRF and SAE Form

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Record in source document

Record in source document

Record on AE case report form

Record on AE case report form

YesYes

Attach additional documentation

Attach additional documentation

Does AE meet SAE criteria?

Does AE meet SAE criteria?

Record on SAE Form (includes narrative)

Record on SAE Form (includes narrative)

Documentation Differences Between AE CRF and SAE Form: Data ElementsDocumentation Differences Between AE CRF and SAE Form: Data Elements

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Stretch Break

Stretch Break

Adverse EventAdverse Event

ICH E2A:Any untoward medical occurrence in a patient or

clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.

21 CFR 312.32 (Sep 2010)Any untoward medical occurrence associated with

the use of a drug in humans, whether or not considered drug related.

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Adverse Event TermAdverse Event Term

The AE term should best describe what the subject says (i.e., verbatim description)

Can use medical records, assessment, autopsy, and medical diagnosis to select primary AE term

Can use other events section (clinically significant events) to submit associated events

Accurate AE term is required to establish accurate safety database. At Safety Office all AE terms will be coded using a standard dictionary, MedDRA

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MedDRA® Coding of Primary AE Terms

MedDRA® Coding of Primary AE Terms

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Importance of AE Term in PharmacovigilanceImportance of AE Term in Pharmacovigilance

All AE terms submitted by sites are:

• part of the safety database• coded using ICH recognized global terminology tool

called MedDRA• reported to Regulatory agencies [Individual Case Safety

Report(ICSR)/Annual Reports]

These terms become part of the regulatory/safety databases like AERS, VAERS, and WHO VIGIBASE

Inaccurate AE term submission by sites puts subject and sponsor at risk

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MedDRA DefinitionMedDRA Definition

Medical Dictionary for Regulatory Activities MedDRA is a medical terminology used to classify

adverse event information associated with the use of biopharmaceuticals and other medical products (e.g., medical devices and vaccines)

MedDRA was developed by ICH Expert working group Maintained by MSSO (Maintenance Support Service

Organization) and is updated twice a year Each MedDRA term is assigned an 8-digit numeric code

(using universal 8 digit code, for example headache is coded to LLT headache with LLT code of 10019211)

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Current MedDRA Hierarchical StructureCurrent MedDRA Hierarchical Structure

Lowest Level Term (LLT) (70,177)

Preferred Term (PT) (19,550)

High Level Term (HLT) (1,713)

High Level Group Term (HLGT) (335)

System Organ Class (SOC) (26)

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Current MedDRA Hierarchical Structure: Example for JaundiceCurrent MedDRA Hierarchical Structure: Example for Jaundice

LLT: Jaundice

PT: Jaundice

HLT: Cholestasis and jaundice

HLGT: Hepatic hepatobiliary disorders

SOC: Hepatobiliary disorders

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Why Do We Code?Why Do We Code?

ICH approved global regulatory language

Ease of the data exchange and reconciliation between the parties

Enables data mining and signal detection (FDA AERS, WHO VIGIBASE)

Most of the regulatory authorities require electronic submissions using MedDRA

Less paper submissions, environmental care (“go green”)

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DAIDS MedDRA PoliciesDAIDS MedDRA Policies

MSSO MedDRA Term Selection: Points to Consider

• http://www.meddramsso.com/subscriber_library_ptc.asp

DAIDS MedDRA Implementation Working Group (MIWG)

• Comprised of DAIDS, DMCs and RSC representatives. Include staff that performs MedDRA coding; co-chaired by DAIDS and RSC

• Reviews ongoing MedDRA coding issues• Maintains the DAIDS MedDRA Term Selection Guidelines• Collect non-codable new AE terms• Submits change requests to MSSO

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Applications of MedDRAApplications of MedDRA

Clinical trial databases (adverse events, medical & social history, investigations, etc.)

Investigator’s Brochures, Core Safety Information, Safety summaries

Clinical Study Reports

Individual Case Safety Reports

Periodic Safety Update Reports

Product Labeling

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AE Term Selection:Points for ConsiderationAE Term Selection:Points for Consideration

Though coding is NOT the site’s responsibility, accurate AE term submission is required for coding and regulatory submissions (FDA)

No additions or omissions to AE term are recommended which would lead to inaccurate coding and data analysis

Provide applicable identifiers and available diagnosis

Multiple medical concepts: • select only one as Primary AE • report only one medical concept per report

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AE Term Selection:Points for ConsiderationAE Term Selection:Points for Consideration

Avoid using acronyms – spell out the AE term

• “Herpes zoster virus” rather than “HZV”

Provide details: site/location

• “Right leg pain” rather than “Pain”• “Ocular pain” rather than “Pain”

Do not add or remove medical concepts

• “Candida vulvovaginitis” rather than “Vulvovaginitis”• “Gastrointestinal infection” rather than “Gastrointestinal

illness” (which need not be of infectious etiology)

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AE Term Selection:Points for ConsiderationAE Term Selection:Points for Consideration

Provide applicable identifiers for abnormal test results. Only test name is not accurate

• “Decreased hemoglobin” rather than “Hemoglobin”• “Elevated glucose” rather than “Glucose”

Provide diagnosis, if available, rather than just signs/symptoms

• “Myocardial infarction” rather than “Chest pain,” “Shortness of breath,” “Diaphoresis”

• “Anaphylactic reaction” rather than “Rash,” “Dyspnea,” “Hypotension,” “Laryngospasm”

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AE Term Selection:Points for ConsiderationAE Term Selection:Points for Consideration

Multiple medical concepts; select only one as primary AE and report only one medical concept per report

• “Peptic ulcer disease” and “Cerebrovascular accident”

– Report as two separate events

• “Hyperemesis” and “Antepartum hemorrhage”

– Report as two separate events

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AE Term Selection:Points for ConsiderationAE Term Selection:Points for Consideration

Multiple medical concepts that are associated; Review and select one Primary AE and report others as associated events

• “Prematurity,” “Low birth weight,” and “Respiratory distress syndrome”

• “Rash,” “Jaundice,” and “Hepatitis B”

– If multiple events occurred at the same time period and all were clearly associated with each other:

• select one as Primary AE

• report the rest as associated events

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Mental Break

Mental Break

Serious Adverse Event (SAE)Serious Adverse Event (SAE)

A serious adverse event (experience) or reaction is any untoward medical occurrence that at any dose:

Results in deathIs life-threatening Requires inpatient hospitalization or prolongation of existing hospitalizationIs a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or A congenital anomaly/birth defectImportant 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

50(ICH E2A, Final Rule)

Suspected Adverse ReactionAdverse ReactionSuspected Adverse ReactionAdverse Reaction

21 CFR 312.32 (Sep 2010)

Suspected Adverse Reaction: Any adverse event for which there is a reasonable possibility that the drug caused the adverse event

Adverse Reaction: Any adverse event caused by a drug

Suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction

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The Universe of Adverse EventsThe Universe of Adverse Events

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Adverse Events

Suspected Adverse Suspected Adverse ReactionsReactions

Adverse Reactions

Adverse Event vs. Event OutcomeAdverse Event vs. Event Outcome

Hospitalization

Hospitalization is a consequence and is not usually considered an AE

• e.g., If the subject was hospitalized due to congestive heart failure, “congestive heart failure” is the primary AE and hospitalization is the outcome

If the only information available is that the study subject was hospitalized, “hospitalization” can be reported

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HospitalizationHospitalization

Hospitalization in the absence of a medical AE is not in itself an AE and does not need to be reported in an expedited timeframe, such as:

• Admission for treatment of a pre-existing condition (can include target disease) not associated with the development of a new AE or with a worsening of the pre-existing condition

• Diagnostic admission (e.g., for work-up of persistent existing condition such as pre-treatment lab abnormality)

• Protocol-specified admission (e.g., procedure required by study protocol)

• Administrative admission (e.g., for yearly physical exam)• Social admission (e.g., study subject has no place to sleep)• Elective admission (e.g., elective surgery)

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SeveritySeverity

Describes the intensity of the event

Events are graded on a severity scale

• Mild, Moderate, Severe• Numeric Scale, e.g., 1 to 5

Severity grading must match the clinical picture

• Presenting AE is Grade 1• AE progressed to SAE (hospitalization)• The expedited report should have the grade of the

SAE, not the AE

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Seriousness is NOT the same as SeveritySeriousness is NOT the same as Severity

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Based on the intensity of the AE and is not a factor in determining reportability (clinical description)

Based on the intensity of the AE and is not a factor in determining reportability (clinical description)

Based on outcome of the AE and is a factor in determining reportability (regulatory definition)

Based on outcome of the AE and is a factor in determining reportability (regulatory definition)

SeriousnessSeriousness SeveritySeverity

Determined using the SAE criteriaDetermined using the SAE criteria

Determined using the DAIDS AE grading tableDetermined using the DAIDS AE grading table

≠

Action Taken with DrugAction Taken with Drug

Action Taken with Drug

• Withdrawn• Dose reduced• Dose increased• Dose not changed• Unknown• Not applicable > ICH E2B

(R3)

Refer to protocol

Refer to DAERS

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OutcomeOutcome

Outcome of reaction/event at the time of last observation

• Recovered/Resolved• Recovering/Resolving• Not recovered/not resolved• Recovered/resolved with sequelae• Fatal• Unknown > ICH E2B (R3)

Outcome of subject in study

• Remains in Study• Withdrawn• Lost to follow-up• Death

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Unexpected Adverse EventUnexpected Adverse Event

21 CFR 312.32 (Sep 2010)

Considered unexpected if not listed in the IB or is not listed in the specificity or severity that has been observed; … or is not consistent with the risk information described in the general investigational plan…

• Hepatic necrosis vs. Elevated hepatic enzymes (↑ severity)• Cerebral thromboembolism vs. Cerebral vascular accidents

(specificity)

Also… mentioned as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned with the particular drug under investigation

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CausalityCausality

21 CFR 312.32 (Sep 2010) For the purposes of IND safety reporting, “reasonable possibility”

means that there is evidence to suggest a causal relationship between the drug and the adverse event

ICH E2A Conveys that a “causal relationship” between the study product

and the adverse event is “at least a reasonable possibility” • Facts (evidence) exist to suggest the relationship• Information on SAEs generally incomplete when first received• Follow-up information actively pursued

Assessed by:• Reporting health professional• Sponsor

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Examples of Reasonable PossibilityExamples of Reasonable Possibility

Individual occurrence

a single occurrence of an event that is uncommon and known to be strongly associated with drug exposure

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Angiodema Anaphylaxis

Hepatic Injury Blood Dyscrasias

Stevens-Johnson Syndrome Rhabdomyolysis

Examples of Reasonable PossibilityExamples of Reasonable Possibility

One or more occurrences

a single occurrence, or a small number of occurrences, of an event that is not commonly associated with drug exposure, but is otherwise uncommon in the population exposed to the drug; esp. if the event occurs in association with other factors strongly suggesting causation (e.g., strong temporal association, event recurs on rechallenge)

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Tendon Rupture

Heart Valve Lesions in young adults

Intussusception in healthy infants

Examples of Reasonable PossibilityExamples of Reasonable Possibility

Aggregate analysis or specific events

an analysis of events, observed in a clinical trial that indicates those events occur more frequently in the drug treatment group than in a control group, e.g.i. known consequences of underlying diseaseii. events common in study pop independent of drug therapy

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i. non-acute death in a cancer trial

ii. acute MI in a long-duration trial with an elderly population with cancer

Determination of CausalityDetermination of Causality

Standard determinations include:

• Is there [Drug Exposure] and [Temporal Association]?

• Is there [Dechallenge/Rechallenge] or [Dose Adjustments]?

• Any known association per [Investigator’s Brochure] or [Package Insert]?

• Is there [Biological Plausibility]?

• Any other possible [Etiology]?

[More on this during case discussion on causality]

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NarrativeNarrative

Comprehensive, stand-alone “medical story”

• Written in logical time sequence• Include key information from supplementary records• Include relevant autopsy or post-mortem findings

Summarize all relevant clinical and related information including:

• Study subject characteristics• Medical history• Clinical course of the event and therapy details• Diagnosis (workup, relevant tests/procedures, lab results)• Other information that supports or refutes an AE

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Narrative TemplateNarrative Template

This is a [Age] year old [Race] [Male/Female] in [Study] who reported [Primary AE] on [Date of AE]. Enrolled into study on [Date Enrolled], Study medication was started on [Date], which is [Study Day _/Week _], taken for [Duration]. The event occurred during the [Treatment/Follow-up Phase].

If fetus/nursing infant: provide [Gestational Age], (or mother’s LMP), at time of event. Also, [Gestational Age/Trimester] at first drug exposure and duration of exposure. If birth, provide details of [Infant Status] at birth. If hospital stay is complicated, provide details of hospital stay.

Provide details of the [AE] in chronological order, along with other [Signs/Symptoms]. Provide details of [Physical Exam], along with all relevant [Procedures] and [Lab Results].

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Narrative TemplateNarrative Template

Provide details of [Treatment] and [Treatment Rationale] on basis of [Findings/Test Result(s)]. Describe [Treatment Response].

If hospitalization, provide [Dates Hospitalization], describe relevant [Hospital Course], [Diagnostic Work-up], [Procedures/Tests and Results], [Treatment], [Treatment Response].

Provide [Discharge Diagnosis], and any [Follow-up Information]. List [Discharge Meds].

Provide pertinent [Past Medical Hx], [Family Hx], [Concomitant Meds], [Alcohol/Tobacco/Substance Use] and any previous similar [AEs].

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Review and Assessment of SAEReview and Assessment of SAE

Assemble all information available and use medical judgment

Standards for each AE:

• Select [Seriousness Criteria]

• Grade [Severity] per DAIDS Toxicity Table

• Specify [Actions Taken on Study Product]

• Specify [Outcome of SAE]. If Outcome is not resolved at time of evaluation, follow until resolution or stability at each study visit

• Is it [Expected]?

• Is it [Related]?

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Clinical Case EvaluationClinical Case Evaluation

Sponsor role: (ICH E2D)

• Information about the case should be collected from the healthcare professionals who are directly involved in the study subject’s case

• Clearly identified evaluations by the sponsor are considered appropriate and are required by some regulatory authorities

• Opportunity to render another opinion; may be in disagreement with; and/or provide another alternative to the diagnosis/assessment given by initial reporter

• Sponsor makes an assessment of causality (attribution) just as the PI makes an assessment of causality (attribution)

• If causality (attribution) is different between the sponsor and the investigator, both assessments are reported

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Site vs. Sponsor AssessmentSite vs. Sponsor Assessment

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Questions?

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Appendix

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1947: Nuremberg Code: Ten Directives for Human Experimentation1947: Nuremberg Code: Ten Directives for Human Experimentation

1. Voluntary consent of the human subject is absolutely essential:2. The experiment must yield generalizable knowledge that could not be

obtained in any other way and is not random and unnecessary in nature 3. Animal experimentation should precede human experimentation 4. All unnecessary physical and mental suffering and injury should be

avoided 5. No experiment should be conducted if there is reason to believe that

death or disabling injury will occur6. The degree of risk to subjects should never exceed the humanitarian

importance of the problem 7. Risks … should be minimized through proper preparations 8. Experiments … conducted by scientifically qualified investigators 9. Subjects … at liberty to withdraw from experiments 10. Investigators must be ready to end the experiment at any stage if there

is cause to believe that continuing the experiment is likely to result in injury, disability or death to the subject

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1948: Universal Declaration of Human Rights 1948: Universal Declaration of Human Rights

The UN General Assembly proclaims THIS UNIVERSAL DECLARATION OF HUMAN RIGHTS as a common standard of achievement for all peoples and all nations

•All human beings are born free and equal in dignity and rights

•Everyone has the right to life, liberty and security of person

•No one shall be subjected to torture or to cruel, inhuman or degrading treatment or punishment

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• Statement of ethical principles to provide guidance to physicians and other participants in medical research involving human subjects

• Considerations related to the well-being of the human subject should take precedence over the interests of science and society

• Medical research subject to ethical standards that promote respect for all human beings and protect their health and rights• Vulnerable populations need special protection

• Research Investigators should be aware of the ethical, legal and regulatory requirements for research on human subjects in their own countries as well as applicable international requirements

• Risks involved have been adequately assessed and can be satisfactorily managed• Cease any investigation if risks found to outweigh potential benefits or if conclusive

proof of positive and beneficial results

1964: Declaration of Helsinki:INTRODUCTION1964: Declaration of Helsinki:INTRODUCTION

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• Must conform to generally accepted scientific principles … thorough knowledge of the scientific literature, other relevant sources of information, adequate laboratory and … animal experimentation

• Design … experimental procedure should be clearly formulated in an experimental protocol. … submitted for consideration, approval to a specially appointed ethical review committee, … independent of the investigator, sponsor or any other kind of undue influence. The committee has the right to monitor ongoing trials

• Should be conducted only by scientifically qualified persons …. under supervision of a clinically competent medical person

• Participation by competent individuals as subjects must be voluntary

1964: Declaration of Helsinki:PRINCIPLES FOR ALL MEDICAL RESEARCH 1964: Declaration of Helsinki:PRINCIPLES FOR ALL MEDICAL RESEARCH

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• Every precaution to protect privacy … and confidentiality of personal information … and to minimize the impact of the study on their physical, mental and social integrity

• Right to abstain from participation or to withdraw consent … at any time without reprisal. … obtain the subject's freely-given informed consent … in writing

• Both authors and publishers have ethical obligations. … preserve the accuracy of the results. Reports of experimentation not in accordance with principles of DoH should not be accepted for publication

1964: Declaration of Helsinki:PRINCIPLES FOR ALL MEDICAL RESEARCH 1964: Declaration of Helsinki:PRINCIPLES FOR ALL MEDICAL RESEARCH

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• May combine medical research with medical care only to extent justified by its potential preventive, diagnostic or therapeutic value and … participation will not adversely affect the health of the patients who serve as research subjects.

• Benefits, risks, burdens and effectiveness of a new intervention must be tested against best current proven intervention, except in the following circumstances:

• Use of placebo, or no treatment, is acceptable where no current proven intervention exists; or

• For compelling and scientifically sound methodological reasons, placebo is necessary to determine efficacy or safety of an intervention

– patients who receive placebo/no treatment will not be subject to any risk of serious or irreversible harm

– extreme care to avoid abuse of this option

1964: Declaration of Helsinki:MEDICAL RESEARCH and MEDICAL CARE1964: Declaration of Helsinki:MEDICAL RESEARCH and MEDICAL CARE

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1964: Declaration of Helsinki: MEDICAL RESEARCH and MEDICAL CARE1964: Declaration of Helsinki: MEDICAL RESEARCH and MEDICAL CARE

• At conclusion, patients are entitled to be informed about outcome of the study and to share any benefits that result from it, for example, access to interventions identified as beneficial in the study

• Refusal of a patient to participate or to withdraw from the study must never interfere with the patient-physician relationship

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1966: International Covenant on Civil and Political Rights1966: International Covenant on Civil and Political Rights

• Adopted by UN General Assembly

• Article 7:

No one shall be subjected to torture or to cruel, inhuman or degrading treatment or punishment. In particular, no one shall be subjected without his free consent to medical or scientific experimentation

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1979: The Belmont Report1979: The Belmont Report

• Issued by National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research

• Boundaries between research and practice

• 3 ethical principles for research:• Respect for Persons• Beneficence• Justice• Interests other than those of the subject may on some

occasions be sufficient by themselves to justify the risks involved in the research, so long as the subjects’ rights have been protected

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• Respect for Persons• Individuals should be treated as autonomous agents (capable of self

determination)• Persons with diminished autonomy deserve protection• Application: Informed consent

• Beneficence• Two general complementary rules:

– Do not harm– Maximize possible benefits and minimize possible harms

• Application: Risk/Benefit assessment

• Justice• Fairness in the distribution of the benefits and burdens of research• Application: Fair procedures and outcomes in the selection of subjects

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1979: The Belmont Report1979: The Belmont Report

1982: International Ethical Guidelines For Biomedical Research Involving Human Subjects1982: International Ethical Guidelines For Biomedical Research Involving Human Subjects

• Prepared by the Council for International Organizations of Medical Sciences (CIOMS)

• Responsiveness to the health needs and priorities of the community

• Biomedical research with human subjects is to be distinguished from the practice of medicine, public health and other forms of health care, which is designed to contribute directly to the health of individuals or communities

• 2002 Revision:• Ethical justification & scientific validity (#1), Ethical review (#2-3)

• Informed consent (#4-6), Inducement to Participate (#7)

• Benefits and Risks (#8) Choice of control (#10)

• Equitable distribution of burdens and benefits (#12)

• Special pops: vulnerable, children, incapable of consent, women, pregnant women (#13-17)

• Right of injured subjects to treatment and compensation (#19)

• Obligation of external sponsors to provide health care services (#21)

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1995: Guidelines for Good Clinical Practice (GCP) for Trials on Pharmaceutical Products1995: Guidelines for Good Clinical Practice (GCP) for Trials on Pharmaceutical Products

• GCP Definition: • (globally applicable) standard for clinical studies• encompasses the design, conduct, monitoring, termination, audit,

analyses, reporting and documentation of the studies• ensures studies are scientifically and ethically sound• clinical properties of the pharmaceutical product (diagnostic,

therapeutic or prophylactic) under investigation are properly documented

• Guidelines developed by WHO in consultation with national drug regulatory authorities within WHO’s Member States

• Handbook for Good Clinical Research Practice (GCP) as an adjunct to Guidelines

• Adopted by International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use

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• 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

• Clinical data are credible

• Facilitates mutual acceptance of clinical data internationally among regulatory authorities in participating regions

• Defines specific responsibilities: • Institutional Review Boards/Independent Ethics Committees• Investigators• Sponsors• Monitors

1995: Guidelines for Good Clinical Practice (GCP) for Trials on Pharmaceutical Products1995: Guidelines for Good Clinical Practice (GCP) for Trials on Pharmaceutical Products

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Safety Monitoring EnvironmentSafety Monitoring Environment

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ICH: E Documents on SafetyICH: E Documents on Safety

Clinical Safety

• ICH E1 – The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life Threatening Conditions

• ICH E2A – Clinical Safety Data Management: Definitions and Standards for Expedited Reporting

• ICH E2B – Clinical Safety Data Management: Data Elements for Transmission of Individual Case Safety Reports

• ICH E2C – Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs

• ICH E2D – Post-Approval Safety Data Management: Definitions and Standards for Expedited Reporting

• ICH E2E – Pharmacovigilance Planning

• ICH E2F – Development Safety Update Report

Good Clinical Practice

• ICH E6 – Good Clinical Practice

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