Safety Workshop

1
Safety Workshop

• Ling Chin, MD, MPH
• Safety Pharmacovigilance Team,
• OPCRO, DAIDS, NIAID

2
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

3
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)

4
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

5
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

6
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

7
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

8
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

9
The times they are a changin
Then (1990s) 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) HIV and OIs, Co-morbidities and Other Chronic Illnesses, ART toxicities
Perspective Largely Clinical Clinical and Regulatory
10
Clinical Trial Continuum From Drug Development
to Optimal Regimensto Treatment Strategies
11
Safety Monitoring

• Why is safety monitoring required in all clinical
  trials?
• To ensure Subject Safety and Study Integrity

To Ensure Subject Safety and Study Integrity
12
Purpose of Safety Monitoring
13
Purpose of Safety Monitoring
14
Clinical Role vs. Research RoleBalancing Both
Roles

• Clinical Role Subject OK

• Research Role Study/Data 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 Subjects Primary Clinician

• 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/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
16
Roles and Responsibilities Study
Clinician/Physician
17
Assurance of Safety and Well-BeingResearch 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

18
Roles and Responsibilities Study
Clinician/Physician
19
Roles and Responsibilities Study Team
20
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

21
MentalBreak
Lands End at Cabo San LucasThe majestic stone
arch at the southern tip of Baja, where the Sea
of Cortez meets the Pacific Ocean
22
Safety Monitoring Environment
IND Trials Pre-market Postmarket
OHRP 45 CFR 46 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
22
23
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/cache/compo/276-254-1.html
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Drug Development ModelSafety Data Flow in
Clinical Trials
25
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

26
Adverse Event Flowchart
27
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

28
Documentation Differences Between AE CRF and
SAE/EAE Form
29
Documentation Differences Between AE CRF and
SAE/EAE Form Data Elements

• AE CRF
• Data Elements

• SAE/EAE Form
• Data Elements

• AE
• Start Date
• Start Date / Continuing
• Is it SAE?
• Severity
• Relatedness
• Action taken with Study Agent
• Outcome (study participation)

• Participant Identifiers
• Study Agent details
• Narrative
• Past medical history
• Relevant labs, tests, procedures
• Concomitant meds
• Outcome of SAE/EAE
• Other supporting information

30
StrechBreak
31
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)

32
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

33
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.

34
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 life-threatening 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 aboveshould also usually be
  considered serious.
• (ICH E2A)   

35
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.

36
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.

37
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)

38
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

39
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

40
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
• gt ICH E2B (R3)

41
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

42
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. Investigators Brochure
  for unapproved product, Package Insert for
  approved product)

43
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

44
Determination of Relatedness

• Standard determinations include
• Is there Drug Exposure and Temporal
  Association?
• Is there Dechallenge/Rechallenge or Dose
  Adjustments?
• Any known association per Investigators
  Brochure or Package Insert?
• Is there Biological Plausibility?
• Any other possible Etiology?

45
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, theres no absolute right
  or wrong give your best judgment substantiate
  and follow-up
• Err on conservative side contribute to knowledge
  base

46
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
• gt ICH E2D

46
47
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 mothers
  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.

47
48
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.

48
49
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?

49
50
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 subjects 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

51
Site vs. Sponsor Assessment
Balancing Both Roles
52
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