DAIDS Safety Workshop: Part I
Clinical 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
Objectives
Participants will be able to demonstrate an
understanding of:
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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
Humans
1747
1897
1898
1901
1939
• Lind: first recorded clinical trial: Navy surgeon, evaluated 6 different interventions on 12 sailors for
the treatment of scurvy
• Sanarelli: discovered bacillus of yellow fever, produced yellow fever in 5 patients
• Osler: “To deliberately inject a poison of known high degree of virulency into a human being, unless
you obtain that man’s sanction, is not ridiculous, it is criminal”
• Walter Reed: yellow fever research that included: self-experimentation, written agreements with
other subjects, payment in gold, restriction to adult subjects, using the phrase “with his full consent”
• Nazi medical war experiments (1939 – 1945)
3
History of Research Involving
Humans
• Nuremberg Code: Basic Principles for research-first international standard. Judgment by war crimes
1947 tribunal at Nuremberg – The Doctor’s Trial
• Universal Declaration of Human Rights: As common standard for human rights. By UN General
1948 Assembly
1964
• Declaration of Helsinki: Ethical Principles to guide physicians. By World Medical Association
• International Covenant on Civil and Political Rights: Article on human experimentation. Codified
1966 and adopted by UN General Assembly
• Belmont Report: 3 Ethical Principles of Respect, Beneficence, Justice. National Commission for the
1979 Protection of Human Subjects of Biomedical and Behavioral Research
• International Ethical Guidelines for Biomedical Research Involving Human Subjects: By Council
1982 for International Organizations of Medical Sciences
• Guidelines for Good Clinical Practice (GCP) for Trials on Pharmaceutical Products: Standard for
1995 design, conduct, monitoring of clinical studies. By WHO with Member States Adopted by ICH
4
Regulations: 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 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
6
NIH 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
7
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 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
9
IRB 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)
 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)
11
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
12
Perspective
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
13
Perspective
 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
14
Current 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 postmarket 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)
15
Clinical Trial Continuum: From Drug
Development to Optimal Regimens to
Treatment Strategies
SCHARP
HVTN
MTN
PHASE I
PHASE II
NME FIH
HPTN
PHASE III
IMPAACT
FSTRF
U MN
ACTG
INSIGHT
PHASE IV
POST PHASE III/IV
TREATMENT STRATEGY
PRE-MARKET
CONTROLLED SETTING
POSTMARKET
REAL-WORLD SETTING
16
Safety Monitoring
Why is safety monitoring
required in all clinical trials?
To Ensure Subject Safety
and Study Integrity
17
Roles and Responsibilities:
Site Investigator
Implementing the protocol “as written”
Strict adherence to inclusion
and exclusion criteria
Investigator
assures Subject
Safety and Study
Integrity by:
Continued adherence to the protocol
throughout study duration
Monitoring subject status, e.g., subject
wellbeing, minimization of risk, toxicity
management, etc.
Monitoring safety data collection:
• Study database
• Safety database
18
Roles and Responsibilities:
Research Staff
Is immediate/emergency intervention needed?
Yes
• Follow site SOP for
emergencies
• Follow site SOP to notify
study clinician/physician
No
• Record AE and/or SAE per
protocol specifications
• Follow protocol toxicity
management section
• Record the AE/SAE
19
Roles and Responsibilities:
Study Clinician/Physician
Subject reports AE
Study clinician/physician
will assess and manage
the AE; Decide if SAE
Emergency intervention vs.
Non-emergency care
Research provisions
vs.
Clinical care
Documentation
• Follow until AE resolution
or condition stabilizes
20
Assurance 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
21
Clinical Role vs. Research Role
Balancing Both Roles
Clinical Role: Subject OK
• Is subject in imminent jeopardy?
• Provide appropriate management
commensurate with clinical
situation, e.g. toxicity
management
• Provide appropriate referral:
emergent care or back to regular
care
• Follow up with subject status
Not Subject’s Primary Clinician
Research Role: Study/Data OK
• Identification of adverse event
• Immediate notification necessary?
•
•
•
•
•
To whom? [per protocol and safety
monitoring plans]
Complete documentation of adverse
event. Follow until resolution/stability
including updating records
Determine if AE meets criteria for
SAE
Adhere to reporting requirements
Adhere to toxicity management as
specified
22
Adhere to stopping rules as specified
Therapeutic 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
23
Roles and Responsibilities:
Study Clinician/Physician
Action taken with Study product
after AE
Subject
Study product:
Dose held, changed,
or discontinued?
Study participation:
Study
Study product:
Per site, per study?
Study status:
Safety pause, clinical hold,
early termination?
Continue, withdraw?
24
Roles 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
25
Roles 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
26
Mental
Break
Drug Development Model:
Safety Data Flow in DAIDS Clinical Trials
28
Adverse Event Flowchart
To other
Subject Enrolled
To IRB
AE Reported
To Sponsor
Yes
Record AE*
Follow until
Resolution
or Stability
SAE?
No
Record
SAE**
To FDA
Outcome:
Resolved/
Stable?
Update SAE
29
Adverse 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
30
Documentation Differences Between
AE CRF and SAE Form
Record in source
document
Attach additional
documentation
Record on AE
case report form
Record on SAE Form
(includes narrative)
Does AE
meet SAE
criteria?
Yes
31
Documentation Differences Between
AE CRF and SAE Form: Data Elements
AE CRF
Data Elements
•
•
•
•
•
•
•
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AE
Start Date
Stop Date / Continuing
Is it SAE?
Severity
Relatedness
Action taken with Study Agent
Outcome (study participation)
SAE Form
Data Elements
•
•
•
•
•
•
•
•
Participant Identifiers
Study Agent details
Narrative
Past medical history
Relevant labs, tests, procedures
Concomitant meds
Outcome of SAE
Other supporting information
32
Stretch
Break
Adverse 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.
34
Adverse 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
35
MedDRA® Coding of Primary AE
Terms
36
Importance 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
37
MedDRA 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)
38
Current 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)
39
Current MedDRA Hierarchical Structure:
Example for Jaundice
LLT: Jaundice
PT: Jaundice
HLT: Cholestasis and jaundice
HLGT: Hepatic hepatobiliary disorders
SOC: Hepatobiliary disorders
40
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”)
41
DAIDS 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
42
Applications of MedDRA
 Clinical trial databases (adverse events, medical
& social history, investigations, etc.)
 Investigator’s Brochures, Core Safety
Information, Safety summaries

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Clinical Study Reports
Individual Case Safety Reports
Periodic Safety Update Reports
Product Labeling
43
AE 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
44
AE 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)
45
AE 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”
46
AE 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
47
AE 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
48
Mental
Break
Serious Adverse Event (SAE)
A serious adverse event (experience) or reaction is any
untoward medical occurrence that at any dose:
 Results in death
 Is life-threatening
 Requires inpatient hospitalization or prolongation of existing



hospitalization
Is 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 lifethreatening, 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
(ICH E2A, Final Rule)
50
Suspected Adverse Reaction
Adverse 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
51
The Universe of Adverse Events
Adverse
Events
Suspected Adverse
Reactions
Adverse
Reactions
52
Adverse 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
53
Hospitalization
 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)
54
Severity
 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
55
Seriousness is NOT the same as
Severity
Seriousness
≠
Severity
Based on outcome of the
AE and is a factor in
determining reportability
(regulatory definition)
Based on the intensity of the
AE and is not a factor in
determining reportability
(clinical description)
Determined using the SAE
criteria
Determined using the DAIDS
AE grading table
56
Action 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
57
Outcome
 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
58
Unexpected 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
59
Causality
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
60
Examples of Reasonable Possibility
Individual occurrence
 a single occurrence of an event that is
uncommon and known to be strongly associated
with drug exposure
Angiodema
Anaphylaxis
Hepatic Injury
Blood Dyscrasias
Stevens-Johnson Syndrome
Rhabdomyolysis
61
Examples 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)
Tendon Rupture
Heart Valve Lesions in young adults
Intussusception in healthy infants
62
Examples 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.
ii.
known consequences of underlying disease
events common in study pop independent of drug therapy
i. non-acute death in a cancer trial
ii. acute MI in a long-duration trial with an
elderly population with cancer
63
Determination 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]
64
Narrative
 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
65
Narrative 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].
66
Narrative 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].
67
Review 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]?
68
Clinical 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 Assessment
Site Assessment
Sponsor Assessment
• Site advantage: has access to subject;
may elicit further info, perform PE,
obtain tests, labs, records
• Information limited to what was submitted
• Information from self-report (may lack
validation)
• Know subject best
• Judgment stands
• Open to dialog with sponsor
from site
• May initiate queries to site: incur time and
delay
• Constraint: Must adhere to reporting
timelines to FDA
• MO level: Serious? Unexpected?
Related?
• Open to dialog with Site PI, DAIDS MO
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Questions?
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Appendix
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1947: 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 occur
6. 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
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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1964: Declaration of Helsinki:
INTRODUCTION
•
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
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1964: Declaration of Helsinki:
PRINCIPLES FOR ALL MEDICAL RESEARCH
• 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
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1964: Declaration of Helsinki:
PRINCIPLES FOR ALL MEDICAL RESEARCH
• 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
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1964: Declaration of Helsinki:
MEDICAL RESEARCH and MEDICAL CARE
• 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
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1964: 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 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 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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1979: The Belmont Report
• 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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1982: 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 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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1995: Guidelines for Good Clinical Practice
(GCP) for Trials on Pharmaceutical Products
• 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
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Safety Monitoring Environment
IND Trials: Pre-market
OHRP 45 CFR 46
Postmarket
OHRP 45 CFR 46
FDA
21 CFR Part 312 – IND
21 CFR 312.32 (IND Safety Reports)
21 CFR 312.33 (Annual Reports)
21 CFR 812.150 (IDE Reports)
21 CFR Part 314 - NDA
21 CFR 314.80 (Postmarketing)
21 CFR 314.98 (Generics)
21 CFR 600.80 (Biologics)
21 CFR 803 (Medical Devices)
ICH E2A (Oct 1994)
ICH E2D (Nov 2003)
NIH Policy
NIH Policy
Country/State Regulations
Country/State Regulations
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ICH: 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
http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html
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