Safety Workshop: Part I
Clinical Trial Safety and Safety Monitoring
August 18, 2010
Albert Yoyin, M.D.
DAIDS Regulatory Support Center (RSC)
Objectives
At the conclusion of this workshop, participants will
be able to demonstrate an understanding of:
• Current context regarding safety in clinical trials
• The concept of safety and safety monitoring and how it
relates to clinical trials research
• Protocol requirements pertaining to areas relevant to
safety
• Key roles and responsibilities related to safety
• Safety and adverse event terminology
• Expedited reporting of adverse events
2
Objectives
At the conclusion of this workshop, participants will
be able to demonstrate an understanding of:
• Ensuring safety in clinical trials
• The adverse event life cycle
• What makes a well-documented adverse event, including
a comprehensive narrative
• How to assess an adverse event case, including causality
assessment
3
Regulations: Federally Supported Research
Involving Human Subjects
45 CFR 46: Protection of Human Research Subjects
•
•
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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
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Regulations: Non-Federally Supported Studies
Involving Human Subjects
21 CFR 50: Protection of Human Subjects
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Clinical investigations regulated by FDA
Requirements for informed consent
• Elements of informed consent
• Documentation of informed consent
• Form approved by IRB
21 CFR 56: Institutional Review Boards
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•
Clinical investigations regulated by FDA
Requirements for IRB review
• Membership, functions, review procedures, etc
• Criteria for IRB approval
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Current Safety Environment
 Increasing demands for safety data:
• All Serious Adverse Events (SAEs); Follow all AEs/SAEs till
resolved or stable
• Additional adverse events of interest (e.g. cancers, MIs,
hepatic events)
• Pregnancy outcomes
• 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
• Global reporting to EMEA and regulatory agencies of
European Union (EU) member states
– Use of CIOMS form
– Country of origin of AE
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Clinical Trial Continuum: From Drug Development
to Optimal Regimens to Treatment Strategies
SCHARP
HVTN
MTN
PHASE I
PHASE II
PRE-MARKET
CONTROLLED SETTING
HPTN
PHASE III
IMPAACT
PHASE IV
FSTRF
U MN
ACTG
INSIGHT
POST PHASE III/IV
POSTMARKET
REAL-WORLD SETTING
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Safety Monitoring
Why is safety monitoring
required in all clinical trials?
To Ensure Subject Safety and
Study Integrity
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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
throughout study duration
Monitoring subject status, i.e. subject wellbeing,
minimization of risk, toxicity management, etc.
Monitoring safety data collection:
• Study database
• Safety database
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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
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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
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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
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Clinical Role vs. Research Role
Balancing Both Roles
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
• Adhere to stopping rules as specified
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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
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Roles and Responsibilities –
Study Clinician/Physician
Action taken with Study product
after AE
Study
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?
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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
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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 (DMC)
• Expedited reporting to sponsor/RSC
• SAE sent 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
• RSC processes event and sends queries to site to obtain additional
information
• All follow-up information should be provided to RSC
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Mental
Break
Land’s End at Cabo San Lucas
The majestic stone arch at the southern tip of Baja,
where the Sea of Cortez meets the Pacific Ocean
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
IRBs/ECs
IRBs/ECs
Sponsor
Sponsor
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ICH: E Documents on Safety
Clinical Safety
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ICH E1 – The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for
Long-Term Treatment of Non-Life Threatening Conditions
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ICH E2A – Clinical Safety Data Management: Definitions and Standards for Expedited Reporting
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ICH E2C – Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs
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ICH E2E – Pharmacovigilance Planning
ICH E2B – Clinical Safety Data Management: Data Elements for Transmission of Individual Case
Safety Reports
ICH E2D – Post-Approval Safety Data Management: Definitions and Standards for Expedited
Reporting
ICH E2F – Development Safety Update Report
Good Clinical Practice
•
ICH E6 – Good Clinical Practice
http://www.ich.org/cache/compo/276-254-1.html
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Drug Development Model:
Safety Data Flow in Clinical Trials
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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
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Adverse Event
* Protocol specifications for AE
• When to collect e.g., study visit
• Method of collection e.g., in person, telephone call
• 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 time frames
• Reporting form (e.g. SAE)
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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
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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
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Participant Identifiers
Study Agent details
Narrative
Past medical history
Relevant labs, tests, procedures
Concomitant meds
Outcome of SAE
Other supporting information
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Safety Data from Clinical Trials
Obligations to report safety data (IND or Non-IND studies):
• Data for non-expedited reporting:
• Recorded on AE CRF, goes to clinical trial database
• Data for expedited reporting:
• Recorded on AE CRF and linked to an SAE type form
• Goes to safety database
• IND timelines: 24o to sponsor, 7/15 days to FDA, EMEA
• Post-marketing timelines: depends on sponsor, 15 days to FDA, EMEA
• Annual/Periodic Reports :
• Need safety data from clinical and safety database
• Must be reconciled
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Stretch
Break
Adverse Event
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.
(ICH E2A)
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Adverse Event Term
• The AE should best describe what the subject says (i.e.
verbatim description)
• Can be extracted from medical records
• Can incorporate medical assessment (including a
diagnosis if available)
• The more accurate the AE term, the more accurate the
safety database. The AE terms will be coded using a
standard dictionary, e.g. Medical Dictionary for
Regulatory Activities (MedDRA); this is NOT site
responsibility
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AE Term - Examples
• If “anaphylactic reaction” is associated with “rash,
dyspnea, hypotension, and laryngospasm,” report
primary AE as “anaphylactic reaction.”
• If “myocardial infarction” is associated with “chest
pain, dyspnea, diaphoresis, ECG changes and
jaundice,” report “myocardial infarction” and
“jaundice” as separate primary AEs.
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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
• Results in persistent or significant disability/incapacity
• Is a congenital anomaly/birth defect
• In addition, “…important medical events that may not be immediately lifethreatening or result in death or hospitalization but may jeopardize the
patient or may require intervention to prevent one of the other outcomes
listed in the definition above…should also usually be considered serious.”
(ICH E2A)
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Adverse Event vs. Event Outcome
Hospitalization
• Hospitalization is a consequence and is not usually
considered an AE.
• Example: 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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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 time frame, 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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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
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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 descriptor)
Determined using the SAE
criteria
Determined using the DAIDS
grading table
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Action Taken with Drug
• Action Taken with Drug:
• Withdrawn
• Dose reduced
• Dose increased
• Dose not changed
• Unknown
• Not applicable
• Refer to protocol
• Refer to DAERS
> ICH E2B (R3)
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Outcome
• Outcome of reaction/event at the time of last observation
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Recovered/resolved
Recovering/resolving
Not recovered/not resolved
Recovered/resolved with sequelae
Fatal
Unknown
> ICH E2B (R3)
• Outcome of subject in study
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•
•
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Remains in Study
Withdrawn
Lost to follow-up
Death
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Expectedness
• Pertains to whether an event is expected or
unexpected (on the basis of previous
observation, not what might be anticipated from
the pharmacological properties of the product)
• Unexpected: the nature or severity of the
adverse event is not consistent with the
applicable product information (e.g.
Investigator’s Brochure for unapproved product,
Package Insert for approved product)
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Relatedness (Causality)
• No standard international nomenclature
• Conveys that a “causal relationship” between the study
product and the adverse event is “at least a reasonable
possibility” [ICH E2A]
• Facts (evidence) exist to suggest the relationship
• Information on SAEs generally incomplete when first received
• Follow-up information actively pursued
• Judged by:
• Reporting health professional
• Sponsor
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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]?
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Determination of Causality
• ‘May be more art than science’
• NR: evidence for alternate etiology and/or low or no biologic
plausibility
• R: reasonable possibility; facts or evidence to substantiate
relationship, and biologic plausibility
• Is there evidence to compel change in previous conclusions?
• Clear-cut case; easy to make a determination
• Not so clear-cut: use your best judgment based on
available information; assure adequacy of information
• Unless clear-cut case, there’s no absolute right or wrong;
give your best judgment; substantiate and follow-up
• Err on conservative side
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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:
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•
•
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Study subject characteristics
Therapy details
Medical history
Clinical course of the event(s)
Diagnosis (workup, relevant tests/procedures, lab results)
Other information that supports or refutes an AE
• > ICH E2D
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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: 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 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 Workup], [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 SAE
• Assemble all information available and use medical judgment
• Standard 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]?
45
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 care
• 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
46
Site vs. Sponsor Assessment
Site Assessment
Balancing
Both Roles
• Site advantage: has access to
subject; may elicit further info,
perform PE, obtain tests, labs,
records
• Information from self-report
(may lack validation)
• Know subject best
• Judgment stands
• Open to dialog with sponsor
Sponsor Assessment
• Information limited to what was submitted from
site
• May initiate queries to site: incur time and
delay
• Constraint: Must adhere to reporting timelines
to FDA
• MO level: Serious? Unexpected? Related?
• SPT level: sign-off, agree with Site PI, agree
with DAIDS MO. Any critical flaw in reasoning?
• Open to dialog with Site PI, DAIDS MO
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Questions?
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