1. Ling Chin, MD, MPH Safety Pharmacovigilance Team, OPCRO, DAIDS, NIAID
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 (1990’s)
Now (2009)
HIV/AIDS
Fatal disease
Chronic illness
Focus
Any Treatment Efficacy (mortality)
Trade-offs between Treatment & Safety (morbidity)
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 Regimens to Treatment Strategies

11. Safety Monitoring To ensure Subject Safety and Study Integrity
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 Role Balancing 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 Subject’s 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

15. Roles and Responsibilities – Research Staff
Record AE and/or SAE/EAE per protocol specifications
Follow protocol toxicity management section
Follow site SOP for emergencies
Follow site SOP to notify study clinician/physician
Record the AE/SAE
Is immediate/emergency intervention needed?
Yes No

16. Roles and Responsibilities – Study Clinician/Physician
Subject reports AE
Documentation
Follow until AE resolution or condition stabilizes
Study clinician/physician will assess and manage the AE. Decide if SAE/EAE
Emergency intervention vs.
Non-emergency care
Research provisions vs.
Clinical care

17. 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

18. Roles and Responsibilities – Study Clinician/Physician
Study product: Per site, per study?
Study status: Safety pause, clinical hold, early termination?
Study product:
Dose held, changed,
or discontinued?
Study participation:
Continue, withdraw?
Action taken with Study product
Subject
Study

19. 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

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. 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

22. Safety Monitoring Environment
IND Trials
Pre-market
Postmarket
OHRP 45 CFR 46
FDA
21 CFR Part IND
21 CFR (IND Safety Reports)
21 CFR (Annual Reports)
21 CFR (IDE Reports)
21 CFR Part NDA
21 CFR (Postmarketing)
21 CFR (Generics)
21 CFR (Biologics)
21 CFR 803 (Medical Devices)
ICH E2A (Oct 1994)
ICH E2D (Nov 2003)
NIH Policy
Country/State Regulations
IRBs/ECs
Sponsor 22 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

24. Drug Development Model: Safety 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
Subject Enrolled
AE Reported
Record AE*
Yes
SAE?
EAE?
To Sponsor
Record SAE/EAE**
To IRB
To FDA
To other
Follow until Resolution or Stability
Outcome
Resolved/
Stable?
Update SAE/EAE No

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 27

28. Documentation Differences Between AE CRF and SAE/EAE Form28

29. Documentation Differences Between AE CRF and SAE/EAE Form: Data Elements
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. Strech Break

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. 33

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 above…should 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 39

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
> 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. Investigator’s 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 [Investigator’s 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, there’s 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
> ICH E2D 46 46 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 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]. 47 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 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 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 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 50

51. 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 from self-report (may lack validation)
Know subject best
Judgment stands
Open to dialog with sponsor
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
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