1. Safety Workshop: Part I Clinical Trial Safety and Safety Monitoring
August 18, 2010
Albert Yoyin, M.D.
DAIDS Regulatory Support Center (RSC)

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 assessment

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
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
Requirements for IRB review
Membership, functions, review procedures, etc
Criteria for IRB approval

6. 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

7. Clinical Trial Continuum: From Drug Development to Optimal Regimens to Treatment Strategies
SCHARP
FSTRF
U MN
HVTN
MTN
HPTN
IMPAACT
ACTG
INSIGHT
PHASE I PHASE II PHASE III PHASE IV POST PHASE III/IV
This slide illustrates that DAIDS sponsors clinical trials that span a clinical trial continuum, such as the type of clinical trial, marketing status, and experimental setting.
Usually, the arrow points in one direction along a developmental path, from Phase I to Phase II to Phase III trials etc, such as for the development of a new agent. However, for DAIDS trials, the arrow is bi-directional, because we have trials that are on new products (e.g. new vaccines) or approved products (e.g. ART), and we can take an approved ART back to Phase I trials for expansion of the indication or the patient population.
We are dealing with trials that are testing either in the pre-market environment or the post-market environment, and this has implications for expedited adverse event reporting obligations to regulatory authorities. Finally, our trials can be conducted under tightly controlled settings (e.g. new vaccine development) or real world settings (e.g. treatment strategy trials).
PRE-MARKET POSTMARKET
CONTROLLED SETTING REAL-WORLD SETTING

8. Why is safety monitoring required in all clinical trials?
To Ensure Subject Safety and Study Integrity

9. 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

10. Roles and Responsibilities – Research Staff
Is immediate/emergency intervention needed?
Yes No
Follow site SOP for emergencies
Follow site SOP to notify study clinician/physician
Record the AE/SAE
Record AE and/or SAE per protocol specifications
Follow protocol toxicity management section
The most important responsibility for research staff is to assure subject safety and well-being. Research staff must determine if immediate/emergency intervention is needed for an AE. If yes, one must (1) follow the site SOP for emergencies, (2) follow site SOP to notify study clinician/physician, and (3) record the AE/SAE. If immediate/emergency intervention is not needed, research staff must record the AE and/or SAE per protogol specifications and follow the protocol toxicity management section.

11. Roles and Responsibilities – Study Clinician/Physician
Subject reports AE
Emergency intervention vs.
Non-emergency care
Study clinician/physician
will assess and manage
the AE Decide if SAE
Research provisions
vs.
Clinical care
The roles and responsibilities of a study clinician/physician are as follows:
When a subject reports an adverse event, the study clinician/physician will assess and manage the adverse event.  The study clinician/physician needs to decide whether the subject needs emergency intervention or non-emergency care to manage the AE.  They will also determine if the AE meets SAE/EAE reporting criteria.  So the role of the study clinician/physician is dual- responsibility for the clinical care of the subject as well as to fulfill the research provisions.  We will discuss this a bit more in detail in our next slide.
The study clinician/physician then needs to document the AE reported by the subject.  The AE has to be followed until it has resolved or the subject’s condition has stabilized.
Documentation
Follow until AE resolution
or condition stabilizes

12. 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

13. Clinical Role vs. Research Role
Balancing Both Roles
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
Adhere to reporting requirements
Adhere to toxicity management as specified
Adhere to stopping rules as specified
To assure safety for study participants REQUIRES a balance in the clinical role and the research role
Reminder: However, the study site clinician in their research capacity is NOT the Subject’s Primary Clinician
Work within the confines of the protocol
If necessary to deviate from the protocol in subject’s interest, must withdraw subject from study
Return to protocol is a clinical decision within protocol specifications
“Stopping” rules in the last bullet on the right refers to “Pausing”

14. 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

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

16. 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

17. 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

18. 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

19. 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

20. 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

21. Drug Development Model: Safety Data Flow in Clinical Trials
When an AE occurs, a multistep process begins. The site records the AE in the Case Review File and submits it to the Data Management Center where it is stored in the Study Database. Additionally, the site assesses if the AE is a Serious Adverse Event (SAE) per DAIDS (according to the study protocol and the Manual for Expedited Reporting).
If the AE is found to be a SAE, an SAE form is completed and submitted in an expedited timeframe to the DAIDS RCC. All reports received by the DAIDS RCC are stored in the RCC Safety Database. DAIDS RCC then determines if the AE meets the regulatory safety reporting requirements needed for the report to be sent to the Food and Drug Administration (FDA). If so, the report is sent to the FDA.

22. Adverse Event Flowchart
Subject Enrolled
AE Reported
Record AE*
Yes
SAE?
To Sponsor
Record SAE**
To IRB
To FDA
To other
Follow until Resolution
or Stability
Outcome:
Resolved/
Stable?
Update SAE No
To other
Subject Enrolled
To IRB
AE Reported
SAE?
To Sponsor
Yes
Record SAE**
Record AE*
To FDA
Outcome:
Resolved/
Stable?
Follow until Resolution
or Stability
AE Process
When a subject is participating in a DAIDS study, an AE is reported, and the AE is recorded in the CRF. An assessment is made regarding whether the AE is an SAE / EAE. If so, it is recorded in the SAE/EAE form as an SAE / EAE and reported to the IRB, other entities as required, and sponsor who then reports it to the FDA if needed. The site follows the AE until resolution or stability at which point the SAE/EAE is updated and reported again to the IRB, other entities as required, and sponsor. No
Update SAE

23. * Protocol specifications for AE
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)
Read

24. 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?
Documentation differences between AE CRF and SAE/EAE form
When an AE occurs first record the AE in the source document
Then record the AE in the case report form (CRF)
Determine if the AE meets SAE/EAE criteria?
If yes, record the event on the SAE/EAE form (this form includes narrative the section)
Attach any additional documentation to this form such as relevant hospital progress notes, discharge summary, laboratory test results, diagnostic test reports, death certificate etc.
Yes

25. Documentation Differences Between AE CRF and SAE Form: Data Elements
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
SAE Form contains more information

26. 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
Clinical database: FSTRF for IMPAACT and ACTG
SCHARP for HVTN, MTN and HPTN
UMN for INSIGHT – See Slide #7
Safety database: RSC

27. Stretch
Break

28. 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)

29. 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

30. 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.

31. 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 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)   

32. 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.

33. 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)

34. Describes the intensity of the event
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

35. Seriousness is NOT the same as 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 35

36. 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

37. 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

38. 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)

39. 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

40. 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]?

41. 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

42. Comprehensive, stand-alone “medical story”
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

43. 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].

44. 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].

45. 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]?

46. 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

47. Site vs. Sponsor Assessment
Site Assessment
Sponsor 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
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

48. Questions?