Transcript Safety Workshop - DAIDS Regulatory Support Center

Safety Workshop
Ling Chin, MD, MPH
Safety Pharmacovigilance Team,
OPCRO, DAIDS, NIAID
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
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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 (attribution)
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Current FDAAA Environment
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
• New authorities to require postmarket studies and clinical trials,
safety labeling changes, and Risk Evaluation and Mitigation
Strategies (REMS)
• Increased activities for active post market risk identification and
analysis
• New reporting of adverse events related to food and new
regulations for pet food labeling, ingredients, and processing
standards
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Current FDAAA Environment
FDAAA Implementation – Examples
 Required postmarketing studies, or clinical trials to address safety issues
(21 letters); postmarketing commitments now required (previously
voluntary) and established timeframes are enforceable
 Required safety label changes (4 times)
 Can require REMS to ensure that the benefits of a drug outweigh its risks
(13 REMS)
 Sentinel Initiative (launched May 08):
• Create and implement a nation-wide active, electronic surveillance system
for monitoring medical product safety
• Develop methods to obtain access to disparate data sources and to
establish a postmarket risk identification and analysis system
• Requires FDA to work closely with partners from public, academic, and
private entities
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Framing the context
 Impact relevant to DAIDS:
• When DAIDS holds the Investigational New Drug (IND):
increased requirements for safety assessment,
pharmacovigilance, risk evaluation
• Clinical Trial Agreements (CTAs ) with pharmaceutical
companies:
– Increasing demands for safety data and safety reports,
increasingly shortened timelines
– Postmarketing requirements on Marketing Authorizing Holders
(MAHs) irrespective of DAIDS obligations for IND studies vs.
non-IND studies: expect final safety reports in 15 days or less
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Framing the context
 Impact relevant to pharmaceutical companies:
• Increased requirements for safety assessment,
pharmacovigilance, risk evaluation, and risk mitigation/
minimization
– Parallel and additional requirements may be required by other
authorities globally, including European Medicine Evaluation
Agency (EMEA)
• FDA can penalize pharmaceutical companies for a variety of
noncompliance issues
• Civil monetary penalties (CMPs): can be assessed for an
assortment of violations such as violations of new REMS
provisions, postmarket study requirements, or labeling violation
• CMPs can reach substantial amounts, e.g. maximum of $10
million in a single proceeding
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Framing the context
 Increasing demands for safety data:
• All Serious Adverse Events (SAEs)
• Follow all AEs/SAEs till resolved or stable
• Additional adverse events of interest:
– Cancers
– Myocardial Infarctions (MIs)
– Hepatic events
• Pregnancy outcomes
• 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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The times they are a changin’
Then (1990’s)
Now (2009)
HIV/AIDS
Fatal disease
Chronic illness
Focus
Any Treatment
Efficacy
(mortality)
Trade-offs between
Treatment & Safety
(morbidity)
Focus
HIV and
Opportunistic
Infections (OIs)
Largely Clinical
HIV and OIs, Co-morbidities
and Other Chronic
Illnesses, ART toxicities
Perspective
Clinical and Regulatory
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Clinical Trial Continuum:
From Drug Development to Optimal Regimens
to Treatment Strategies
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Safety Monitoring
Why is safety monitoring required in
all clinical trials?
EnsureSafety and
To ensure To
Subject
Subject
and
Study Safety
Integrity
Study Integrity
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Purpose of Safety Monitoring
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Purpose of Safety Monitoring
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Clinical Role vs. Research Role
Balancing Both Roles
Clinical Role: Subject OK
Research Role: Study/Data OK
•
Is subject in imminent jeopardy?
• Identification of adverse event
•
Provide appropriate management
commensurate with clinical situation,
e.g. toxicity management
• Immediate notification necessary? To
whom? [per protocol and safety
monitoring plans]
•
Provide appropriate referral: emergent
care or back to regular care
•
Follow up with subject status
• Complete documentation of adverse
event. Follow until resolution/stability
including updating records
Not Subject’s Primary Clinician
• Determine if AE meets criteria for
SAE/EAE
• Adhere to reporting requirements
• Adhere to toxicity management as
specified
• Adhere to stopping rules as specified
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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
• Record the AE/SAE
No
• Record AE and/or
SAE/EAE per protocol
specifications
• Follow protocol toxicity
management section
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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/EAE
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
 Therapeutic misconception
• Subjects think they are receiving proven interventions, per their usual
clinical care, despite being in a research study
• Physicians think they can provide interventions, per usual practice
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Roles and Responsibilities –
Study Clinician/Physician
Action taken with Study
product
Subject
Study product:
Dose held, changed,
or discontinued?
Study participation:
Continue, withdraw?
Study
Study product:
Per site, per study?
Study status:
Safety pause, clinical hold,
early termination?
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Roles and Responsibilities –
Study Team
Safety: Ensure safety and well being of
subjects at all times
Data: Ensure data integrity to assess the
risks/safety profile of the study intervention




Data capture; in particular, the collection of safety data
Overall monitoring of adverse events occurring in study
Take timely action regarding subject participation status in study
Be cognizant of expedited reporting requirements for safety data
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Roles and Responsibilities –
Study Team vs. Sponsor/RCC
 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/RCC
• SAE/EAE sent to RCC
• RCC is not part of discussions that occur within study/safety monitoring
teams regarding the event
• The RCC only has information about the event from the EAE Form; site
should include relevant information from study team discussions
• RCC processes event and sends queries to site to obtain additional
information
• All follow-up information should be provided to RCC
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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

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


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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Safety Data from Clinical Trials
Obligations to report data from DAIDS clinical trials irrespective
of IND status. For both 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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Adverse Event Flowchart
Subject
Enrolled
To other
To IRB
AE Reported
To Sponsor
SAE?
EAE?
Record AE*
Yes
Record
SAE/EAE**
To FDA
Follow until
Resolution or
Stability
No
Outcome
Resolved/
Stable?
Update
SAE/EAE
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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/EAE
• Criteria
• Expedited time frames
• Form e.g. SAE, EAE form
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Documentation Differences Between
AE CRF and SAE/EAE Form
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Documentation Differences Between
AE CRF and SAE/EAE Form: Data
Elements
AE CRF
Data Elements
SAE/EAE Form
Data Elements
• AE
• Participant Identifiers
•
Start Date
•
Study Agent details
•
Start Date / Continuing
•
Narrative
•
Is it SAE?
•
Past medical history
•
Severity
•
Relevant labs, tests, procedures
•
Relatedness
•
Concomitant meds
•
Action taken with Study Agent
•
Outcome of SAE/EAE
•
Outcome (study participation)
•
Other supporting information
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Strech
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 reported with “rash, dyspnea,
hypotension, and laryngospasm,” selecting “anaphylactic
reaction” alone is considered appropriate.
 If “myocardial infarction” is reported with “chest pain,
dyspnea, diaphoresis, ECG changes and jaundice,” it
would be considered appropriate to select terms for both
“myocardial infarction” and “jaundice.”
 EAE Form: List only one primary AE. Choose the one term
that best describes the nature of the adverse event being
reported.
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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, or
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
Death
 Death is an outcome and is not usually considered to be
an AE.
• Example: If “death due to myocardial infarction” is reported,
“myocardial infarction” can be selected and death should be
captured as the outcome.
 If the only information reported is death, then the most
specific death term available should be selected.
• Example: If a reporter states only that “a study subject was found
dead,” “found dead” can be selected.
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Adverse Event vs. Event Outcome
Hospitalization
 Hospitalization is a consequence and is not usually
considered an AE.
• Example: If “hospitalization due to congestive heart failure” is
reported, “congestive heart failure” can be selected and
hospitalization should be captured as the consequence of the
event.
 If the only information reported is the outcome term, then
the most specific term available should be selected.
• Example: If a reporter states only that “a study subject was
hospitalized,” “hospitalization” can be selected.
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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.
 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 existing condition
persistent 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
 Example:
• Mild, Moderate, Severe
• Numeric Scale e.g. 1 to 5
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Severity vs. Serious
 Severity is not the same as Serious
 Severity = Intensity
• e.g., chest pain, moderate severity
 Serious (SAE) = Based on patient/event outcome or
action criteria
• Used to define regulatory reporting obligations
 AE classification: must divorce usage of serious in a
clinical sense from serious in a regulatory sense
 For clinical connotations, use severity descriptors
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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 DAIDS EAE Form
> ICH E2B (R3)
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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
 Outcome of subject in study
•
•
•
•
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/EAEs generally incomplete when first received
• Follow-up information actively pursued
 Judged by:
• Reporting health professional
• Sponsor
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Determination of Relatedness
 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 Relatedness
 ‘May be more art than science’
• 1st level of review: NR
• 2nd level of review: any degree R
• 3rd level of review: any evidence to compel moving in one
direction or the other; i.e. from NR to any reasonable possibility
of R, or from any R to NR
 Clear-cut case; easy to make a determination
 Not so clear-cut: use your best judgment based on available
information; assure adequacy of information; obtain more
whenever
 Unless clear-cut case, there’s no absolute right or wrong; give
your best judgment; substantiate and follow-up
 Err on conservative side; contribute to knowledge base
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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:
•
•
•
•
•
•
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 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 SAE/EAE
 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/EAE]. 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 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
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Site vs. Sponsor Assessment
Site Assessment
•
Balancing Both Roles
Sponsor Assessment
Site advantage: has access to
subject; may elicit further info,
perform PE, obtain tests, labs,
records
• Information limited to what was submitted from
site
•
Information from self-report
(may lack validation)
• Constraint: Must adhere to reporting timelines
to FDA
•
Know subject best
• MO level: Serious? Unexpected? Related?
•
Judgment stands
•
Open to dialog with sponsor
• SPT level: sign-off, agree with Site PI, agree
with DAIDS MO. Any critical flaw in reasoning?
• May initiate queries to site: incur time and
delay
• Open to dialog with Site PI, DAIDS MO
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Acknowledgements
 Safety Teams at DAIDS/SPT and RCC, especially:
• Larry Allan
• Adeola Adeyeye, and
• Daniel Dondero
 DAIDS Training Group, especially
• Jane Reynolds
 Members present at this Workshop:
• DAIDS/SPT: Larry Allan, Ling Chin
• RCC: Oluwadamilola Ogunyankin, Albert Yoyin, Anu Jasti,
Sandy Butler, Nadine Pakker
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