1. Safety Workshop: Part I Clinical Trial Safety and Safety Monitoring
Ling Chin, MD, MPH
NIAID/DAIDS/Office of Policy for Clinical Research Operations
Durban, South Africa
May 13, 2011

2. Objectives
At the conclusion of this workshop, participants will be able to demonstrate an understanding of:
Clinical research involving human subjects
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 - continued
Assuring 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. History of research involving humans
1747: Lind: first recorded clinical trial: British Navy surgeon, evaluated 6 different interventions on 12 sailors for the treatment of scurvy
1897: Sanarelli: discovered bacillus of yellow fever, produced yellow fever in 5 patients
1898: Osler: “To deliberately inject a poison of known high degree of virulency into a human being, unless you obtain that man’s sanction, is not ridiculous, it is criminal”
1901: Walter Reed: yellow fever research that included: Self-experimentation, Written agreements with other subjects, Payment in gold, Restriction to adult subjects, Using the phrase “with his full consent”
: Nazi medical war experiments
: Tuskegee Study of Untreated Syphilis in the Negro Male
Lind thought that scurvy was due to putrefaction of the body which could be helped by acids, and thus included a dietary supplement of an acidic quality in the experiment. This began after two months at sea when the ship was afflicted with scurvy. He divided twelve scorbutic sailors into six groups. They all received the same diet but, in addition, group one was given a quart of cider daily, group two twenty-five drops of elixir of vitriol (sulfuric acid), group three six spoonfuls of vinegar, group four half a pint of seawater, group five received two oranges and one lemon, and the last group a spicy paste plus a drink of barley water. The treatment of group five stopped after six days when they ran out of fruit, but by that time one sailor was fit for duty while the other had almost recovered. Apart from that, only group one also showed some effect of its treatment.
1897 Sanarelli announced he discovered the bacillus of yellow fever and produced yellow fever in 5 patients.
Tuskegee Syphilis Study ( ). An equally well known chapter in history occurred during a research project conducted by the U.S. Public Health Service. Six hundred low-income African-American males, 400 of whom were infected with syphilis, were monitored for 40 years. Free medical examinations were given; however, subjects were not told about their disease. Even though a proven cure (penicillin) became available in the 1950s, the study continued until 1972 with participants being denied treatment. In some cases, when subjects were diagnosed as having syphilis by other physicians, researchers intervened to prevent treatment. Many subjects died of syphilis during the study. The study was stopped in 1973 by the U.S. Department of Health, Education, and Welfare only after its existence was publicized and it became a political embarrassment. In 1997, under mounting pressure, President Clinton apologized to the study subjects and their families. 4

5. History of research involving humans

6. 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

7. 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

8. NIH Research
Must comply with regulations pertaining to research involving human subjects, investigations of new drugs, biologics, or devices, or new indications, or use in new populations
HHS, OHRP
FDA
Must adhere to NIH and Institute Policies for clinical research and conduct of clinical trials
Additional monitoring bodies: Network-specific clinical safety monitors/groups, IRBs, DSMBs

9. IRB Review Initial and continuing review
At convened meetings (at intervals appropriate to level of risk; not less than 1/year)
Majority of members are present; Approval by majority
Approval of Informed Consent
Unanticipated problems involving risks to human subjects or others
Any instance of serious or continuing non-compliance with regulations, requirements, or determinations of the IRB 9 9 9

10. IRB Review: Approval Criteria
Risks to subjects are minimized:
By using procedures consistent with sound research design which do not unnecessarily expose subjects to risk
Whenever appropriate, by using procedures already being performed for diagnostic or treatment purposes
Risks to subjects are reasonable in relation to anticipated benefits, and the importance of the knowledge that may reasonably be expected to result
Other criteria 45 CFR or 21 CFR
§ Criteria for IRB approval of research.
(a) In order to approve research covered by this policy the IRB shall determine that all of the following requirements are satisfied:
(1) Risks to subjects are minimized: (i) By using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk, and (ii) whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes.
(2) Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result. In evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research (as distinguished from risks and benefits of therapies subjects would receive even if not participating in the research). The IRB should not consider possible long-range effects of applying knowledge gained in the research (for example, the possible effects of the research on public policy) as among those research risks that fall within the purview of its responsibility.
(3) Selection of subjects is equitable. In making this assessment the IRB should take into account the purposes of the research and the setting in which the research will be conducted and should be particularly cognizant of the special problems of research involving vulnerable populations, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons.
(4) Informed consent will be sought from each prospective subject or the subject's legally authorized representative, in accordance with, and to the extent required by §
(5) Informed consent will be appropriately documented, in accordance with, and to the extent required by §
(6) When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects.
(7) When appropriate, there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data. 10 10 10

11. Safety Monitoring Committee
Internal process, NOT independent
Members include DAIDS MO, DMC clinical affairs safety associates, Protocol Co-chairs, Protocol Study Physician
Review safety events as study is ongoing
Review of AEs at stated frequency e.g. monthly
Assure reportable events are submitted to DAIDS
Address safety concerns e.g. if safety rules are met (a-priori specification)

12. Data Safety and Monitoring Boards (DSMBs) / Data Monitoring Committees (DMCs)
Government agencies e.g. NIH and the VA, have required the use of DSMBs in certain trials
Current FDA regulations, impose no such requirements except under 21 CFR 50.24(a)(7)(iv) for research studies in emergency settings in which Informed Consent is excepted
Independent group
Guidance for Clinical Trial Sponsors Establishment and Operation of
Clinical Trial Data Monitoring Committees March 2006
DMCs have been a component of some clinical trials since at least the early 1960's.
used primarily in large randomized multicenter trials sponsored by federal agencies, NIH and VA and similar bodies abroad, that targeted improved survival or reduced risk of major morbidity (e.g., acute myocardial infarction) as the primary objective. In 1967, an NIH external advisory group first introduced the concept of a formal committee charged with reviewing the accumulating data as the trial progressed to monitor safety, effectiveness, and trial conduct issues in a set of recommendations to the then-National Heart Institute. (Heart Special Project Committee, 'Organization, Review and Administration of Cooperative Studies (Greenberg Report): A Report from the Heart Special Project Committee to the National Advisory Heart Council, May 1967;' Controlled Clinical Trials, vol. 9, , 1988.)
interim monitoring of accumulating study data was essential to ensure the ongoing
safety of trial participants, but that individuals closely involved with the design and
conduct of a trial may not be able to be fully objective in reviewing the interim data for
any emerging concerns. The involvement of expert advisors external to the trial
organizers, sponsors, and investigators was intended to ensure that such problems would
be addressed in an unbiased way by the trial leadership
relevant expertise, experience in clinical trials and in serving on other DMCs, and
absence of serious conflicts of interest as discussed below. The objectives and design of
the trial and the scope of the responsibilities given to the DMC determine the types of
expertise needed for a particular DMC. 12 12 12

13. Data Safety and Monitoring Boards (DSMBs) / Data Monitoring Committees (DMCs)
Group of individuals with pertinent expertise; reviews accumulating data from one or more ongoing clinical trials:
Clinicians with expertise in relevant clinical specialties
At least one biostatistician knowledgeable about statistical methods for clinical trials and sequential analysis of trial data
A medical ethicist, and/or patient advocate
Other scientific areas: toxicologist, clinical pharmacologist, epidemiologist
Advises the sponsor:
Continuing safety of trial subjects and those to be recruited
Continuing validity and scientific merit of the trial
2 important considerations: Confidentiality, COI.
Knowledge of interim results could influence conduct of the trial 13 13 13

14. Perspective Differing viewpoints on safety requirements:
Impose a burden on investigators
Cumbersome bureaucratic hindrance
Holds back pace of science
Delays availability of new or much needed treatments
Represent only a minimal standard
What is at least reasonable, practical
Not what would be most ideal

15. Perspective Participants in research are voluntary
Placed their faith in the investigators
Participation is a gift in the service of the public interest
Investigators must not betray the public trust
Must conduct trials with ethical and scientific integrity
Must implement high standards for human subject protections
Must assure participant well-being and safety at all times

16. Current Safety Environment
Increasing public demands for safety data
Fast track approvals
Post-market events leading to changes in labeling e.g. additonal precautions, black box warnings
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 EMA and regulatory agencies of European Union (EU) member states, other countries throughout the world
New Final Rule 21 CFR : focus on signal detection (only submit evidence-based Serious Unexpected Suspected Adverse Reactions), encourage noise reduction (less submission). Sponsor and investigator responsibilities to report.

17. Clinical Trial Continuum: From Drug Development to Optimal Regimens to Treatment Strategies
SCHARP
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).

18. Safety Monitoring

19. Roles and Responsibilities – Site Investigator

20. Roles and Responsibilities – Research Staff
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.

21. Roles and Responsibilities – Study Clinician/Physician
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.

22. 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

23. 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
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”

24. 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

25. Roles and Responsibilities – Study Clinician/Physician
Action taken with Study product
after AE
Subject
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?

26. 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

27. 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

28. Joshua Tree National Park in Southern California28
Joshua Tree National Park in Southern California

29. Safety Monitoring Environment
IND Trials: Pre-market
Postmarket
OHRP 45 CFR 46
FDA
21 CFR Part 312 – 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

30. 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

31. 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 Report Form 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.

32. 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

33. 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

34. 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

35. 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

36. 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 then an SAE type form
Goes to safety database (unless a linked system)
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

37. Stretch
Break

38. Adverse Event ICH E2A: 21 CFR 312.32 Sep, 2011
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.
21 CFR Sep, 2011
Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.

39. 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

40. 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.

41. 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
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect
Is a congenital anomaly/birth defect
Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition
(ICH E2A, New Final Rule)

42. Suspected Adverse Reaction Adverse Reaction
21 CFR Sep, 2011
Suspected Adverse Reaction: Any adverse event for which there is a reasonable possibility that the drug caused the adverse event.
Adverse Reaction: Any adverse event caused by a drug
Suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction

43. The Universe of Adverse Events
Suspected Adverse Reactions
Adverse Events
Adverse Reactions

44. 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.

45. 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)
Manual v2.0:
The following types of hospitalization do not require expedited reporting to DAIDS:
Any admission unrelated to an AE (e.g., for labor/delivery, cosmetic surgery, administrative or social admission for temporary placement for lack of a place to sleep)
Protocol-specified admission (e.g., for a procedure required by protocol)
Admission for diagnosis or therapy of a condition that existed before receipt of study agent(s) and has not increased in severity or frequency as judged by the clinical investigator.
A new AIDS-defining event in a subject already known to be HIV-infected would be considered an increase in severity of a pre-existing condition [HIV infection] and would be reportable as an expedited AE

46. 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

47. Seriousness is NOT the same as Severity47

48. Action Taken with Drug Action Taken with Drug: Refer to protocol
Withdrawn
Dose reduced
Dose increased
Dose not changed
Unknown
Not applicable > ICH E2B (R3)
Refer to protocol
Refer to DAERS

49. 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

50. Unexpected Adverse Event
21 CFR Sep, 2011
Considered unexpected if not listed in the IB or is not listed in the specificity or severity that has been observed; …… or is not consistent with the risk information described in the general investigational plan….
Hepatic necrosis vs. elevated hepatic enzymes (↑ severity)
Cerebral thromboembolism vs. cerebral vascular accidents (specificity)
Also… mentioned as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned with the particular drug under investigation
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)

51. Causality 21 CFR 312.32 Sep, 2011 ICH E2A
For the purposes of IND safety reporting, “reasonable possibility” means that there is evidence to suggest a causal relationship between the drug and the adverse event
ICH E2A
Conveys that a “causal relationship” between the study product and the adverse event is “at least a reasonable possibility”
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
No standard international nomenclature

52. Examples of Reasonable Possibility
Individual occurrence
a single occurrence of an event that is uncommon and known to be strongly associated with drug exposure
Angiodema
Anaphylaxis
Hepatic Injury
Blood Dyscrasias
Stevens-Johnson Syndrome
Rhabdomyolysis

53. Examples of Reasonable Possibility
One or more occurrences
a single occurrence, or a small number of occurrences, of an event:
(i) is not commonly associated with drug exposure
(ii) is otherwise uncommon in the population exposed to the drug;
esp. if the event occurs in association with other factors strongly suggesting causation (e.g., strong temporal association, event recurs on rechallenge)
Tendon Rupture
Heart Valve Lesions in young adults
Intussusception in healthy infants

54. Examples of Reasonable Possibility
Aggregate analysis of specific events
an analysis of events observed in a clinical trial that indicates those events occur more frequently in the drug treatment group than in a control group, e.g.
known consequences of underlying disease
events common in study pop independent of drug therapy
i. non-acute death in a cancer trial
ii. acute MI in a long-duration trial with an elderly population with cancer

55. 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]?
[More on this during case discussion on causality]

56. 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

57. 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].

58. 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].

59. 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]?

60. 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
21 CFR Sep, 2011
IND Safety Reports
Sponsor must notify FDA and all participating investigators, in an IND safety report of potential serious risks,
from clinical trials or any other source, as soon as possible, but in no case later than 15 calendar days
after the sponsor determines that the information qualifies for reporting under [IND rules]

61. Site vs. Sponsor Assessment
Site Assessment
Site advantage: access to subject; may elicit further info, perform PE, obtain tests, labs, records
Information from self- report (may lack validation)
Know subject
Judgment stands
Open to dialog with sponsor
Sponsor Assessment
Information limited to that provided by site
Information on product will be more extensive than site
May initiate queries to site: incur time and delay
Constraint: must comply to regulatory reporting timelines
MO level: Serious? Unexpected? Related?
SPT level: consultative role for MOs
Open to dialog with site
SAE Form contains more information

62. Questions?

63. Appendix

64. 1947: Nuremberg Code: Ten Directives for Human Experimentation
Voluntary consent of the human subject is absolutely essential:
The experiment must yield generalizable knowledge that could not be obtained in any other way and is not random and unnecessary in nature
Animal experimentation should precede human experimentation
All unnecessary physical and mental suffering and injury should be avoided
No experiment should be conducted if there is reason to believe that death or disabling injury will occur
The degree of risk to subjects should never exceed the humanitarian importance of the problem
Risks … should be minimized through proper preparations
Experiments … conducted by scientifically qualified investigators
Subjects … at liberty to withdraw from experiments
Investigators must be ready to end the experiment at any stage if there is cause to believe that continuing the experiment is likely to result in injury, disability or death to the subject
Code established the basic principles that must be observed in order to satisfy
moral, ethical, and legal concepts in the conduct of human subject research
Code has been the model for many professional and governmental codes since the 1950s
and has, in effect, served as the first international standard for the conduct of research. 64

65. 1948: Universal Declaration of Human Rights
The UN General Assembly proclaims THIS UNIVERSAL DECLARATION OF HUMAN RIGHTS as a common standard of achievement for all peoples and all nations
All human beings are born free and equal in dignity and rights
Everyone has the right to life, liberty and security of person
No one shall be subjected to torture or to cruel, inhuman or degrading treatment or punishment
The UDHR is the first international statement to use the term "human rights",
and has been adopted by the Human Rights movement as a charter.
Preamble and 30 Articles 65

66. 1964: Declaration of Helsinki: INTRODUCTION
Statement of ethical principles to provide guidance to physicians and other participants in medical research involving human subjects
Considerations related to the well-being of the human subject should take precedence over the interests of science and society
Medical research subject to ethical standards that promote respect for all human beings and protect their health and rights
Vulnerable populations need special protection
Research Investigators should be aware of the ethical, legal and regulatory requirements for research on human subjects in their own countries as well as applicable international requirements
Risks involved have been adequately assessed and can be satisfactorily managed
Cease any investigation if risks found to outweigh potential benefits or if conclusive proof of positive and beneficial results
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI
Ethical Principles for Medical Research Involving Human Subjects
35 Articles
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 29th WMA General Assembly, Tokyo, Japan, October th WMA General Assembly, Venice, Italy, October st WMA General Assembly, Hong Kong, September th WMA General Assembly, Somerset West, Republic of South Africa, October nd WMA General Assembly, Edinburgh, Scotland, October rd WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 59th WMA General Assembly, Seoul, October 2008
Vulnerable populations: The particular needs of the economically and medically disadvantaged must be recognized. Special attention is also required for those who cannot give or refuse consent for themselves, for those who may be subject to giving consent under duress, for those who will not benefit personally from the research and for those for whom the research is combined with care
“The declaration has only limited legal authority but has gained considerable moral authority. As such it is more symbolic than instrumental”
Goodyear M et al. BMJ 29 Sept 2007 66

67. 1964: Declaration of Helsinki: PRINCIPLES FOR ALL MEDICAL RESEARCH
Must conform to generally accepted scientific principles … thorough knowledge of the scientific literature, other relevant sources of information, adequate laboratory and … animal experimentation
Design … experimental procedure should be clearly formulated in an experimental protocol. … submitted for consideration, approval to a specially appointed ethical review committee, … independent of the investigator, sponsor or any other kind of undue influence. The committee has the right to monitor ongoing trials
Should be conducted only by scientifically qualified persons …. under supervision of a clinically competent medical person
Participation by competent individuals as subjects must be voluntary 67

68. 1964: Declaration of Helsinki: PRINCIPLES FOR ALL MEDICAL RESEARCH
Every precaution to protect privacy … and confidentiality of personal information … and to minimize the impact of the study on their physical, mental and social integrity
Right to abstain from participation or to withdraw consent … at any time without reprisal. … obtain the subject's freely-given informed consent … in writing
Both authors and publishers have ethical obligations. … preserve the accuracy of the results. Reports of experimentation not in accordance with principles of DoH should not be accepted for publication 68

69. 1964: Declaration of Helsinki: MEDICAL RESEARCH and MEDICAL CARE
May combine medical research with medical care only to extent justified by its potential preventive, diagnostic or therapeutic value and … participation will not adversely affect the health of the patients who serve as research subjects.
Benefits, risks, burdens and effectiveness of a new intervention must be tested against best current proven intervention, except in the following circumstances:
Use of placebo, or no treatment, is acceptable where no current proven intervention exists; or
For compelling and scientifically sound methodological reasons, placebo is necessary to determine efficacy or safety of an intervention
patients who receive placebo/no treatment will not be subject to any risk of serious or irreversible harm
extreme care to avoid abuse of this option 69

70. 1964: Declaration of Helsinki: MEDICAL RESEARCH and MEDICAL CARE
At conclusion, patients are entitled to be informed about outcome of the study and to share any benefits that result from it, for example, access to interventions identified as beneficial in the study
Refusal of a patient to participate or to withdraw from the study must never interfere with the patient-physician relationship

71. 1966: International Covenant on Civil and Political Rights
Adopted by UN General Assembly
Article 7:
No one shall be subjected to torture or to cruel, inhuman or degrading treatment or punishment. In particular, no one shall be subjected without his free consent to medical or scientific experimentation
The Universal Declaration of Human Rights of 1948 was codified into two Covenants,
which the General Assembly adopted on 16 December Together with the
Optional Protocols, they constitute the "International Bill of Human Rights".
The Covenant is a landmark in the efforts of the international community to promote human rights.
It defends the right to life and stipulates that no individual can be subjected to torture, enslavement,
forced labour and arbitrary detention or be restricted from such freedoms as movement, expression and association.
Covenant on Civil and Political Rights 1948
Optional Protocol to the Covenant on Civil and Political Rights
Covenant on Economic, Social, and Cultural Rights 1966
Preamble and 53 Articles
The Covenant is divided into six parts. Part I reaffirms the right of self-determination.
Part II formulates general obligations by States parties, notably to implement the Covenant
through legislative and other measures, to provide effective remedies to victims and
to ensure gender equality, and it restricts the possibility of derogation.
Part III spells out the classical civil and political rights, including the right to life,
the prohibition of torture, the right to liberty and security of person,
the right to freedom of movement, the right to a fair hearing, the right to privacy,
the right to freedom of religion, freedom of expression, freedom of peaceful assembly,
the right to family life, the rights of children to special protection,
the right to participate in the conduct of public affairs,
the over-arching right to equal treatment, and the special rights of persons
belonging to ethnic, religious and linguistic minorities.
Part IV regulates the election of members of the Human Rights Committee,
the State reporting procedure and the inter-State complaints mechanism.
Part V stipulates that nothing in the Covenant shall be interpreted as impairing
the inherent right of all peoples to enjoy and to utilize fully their natural resources.
Part VI provides that the Covenant shall extend to all parts of federal States
and sets out the amendment procedure. The Covenant is not subject to denunciation. 71

72. 1979: The Belmont Report
Issued by National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research
Boundaries between research and practice
3 ethical principles for research:
Respect for Persons
Beneficence
Justice
Interests other than those of the subject may on some occasions be sufficient by themselves to justify the risks involved in the research, so long as the subjects’ rights have been protected 72

73. 1979: The Belmont Report Respect for Persons Beneficence Justice
Individuals should be treated as autonomous agents (capable of self determination)
Persons with diminished autonomy deserve protection
Application: Informed consent
Beneficence
Two general complementary rules:
Do not harm
Maximize possible benefits and minimize possible harms
Application: Risk/Benefit assessment
Justice
Fairness in the distribution of the benefits and burdens of research
Application: Fair procedures and outcomes in the selection of subjects

74. 1982: International Ethical Guidelines For Biomedical Research Involving Human Subjects
Prepared by the Council for International Organizations of Medical Sciences (CIOMS)
Responsiveness to the health needs and priorities of the community
Biomedical research with human subjects is to be distinguished from the practice of medicine, public health and other forms of health care, which is designed to contribute directly to the health of individuals or communities
2002 Revision:
Ethical justification & scientific validity (#1), Ethical review (#2-3)
Informed consent (#4-6), Inducement to Participate (#7)
Benefits and Risks (#8) Choice of control (#10)
Equitable distribution of burdens and benefits (#12)
Special pops: vulnerable, children, incapable of consent, women, pregnant women (#13-17)
Right of injured subjects to treatment and compensation (#19)
Obligation of external sponsors to provide health care services (#21)
CIOMS, in association with WHO, undertook its work on ethics in relation to biomedical research in the late 1970s. At that time, newly
independent WHO Member States were setting up health-care systems. WHO was not then in a position to promote ethics as an
aspect of health care or research. It was thus that CIOMS set out, in cooperation with WHO, to prepare guidelines ‘‘to indicate how the
ethical principles that should guide the conduct of biomedical research involving human subjects, as set forth in the Declaration of
Helsinki, could be effectively applied, particularly in developing countries, given their socioeconomic circumstances, laws and regulations,
and executive and administrative arrangements’’. The World Medical Association had issued the original Declaration of Helsinki
in 1964 and an amended version in The outcome of the CIOMS/WHO undertaking was, in 1982, Proposed International Ethical
Guidelines for Biomedical Research Involving Human Subjects.
After 1993, ethical issues arose for which the CIOMS Guidelines had no specific provision. They related mainly to controlled clinical
trials, with external sponsors and investigators, carried out in low resource countries and to the use of comparators other than an
established effective intervention. The issue in question was the perceived need in those countries for low-cost, technologically
appropriate, public-health solutions, and in particular for HIV/AIDS treatment drugs or vaccines that poorer countries could afford.
Commentators took opposing sides on this issue. One advocated, for low-resource countries, trials of interventions that might be less
effective than the treatment available in the better-off countries, but also would be less expensive. All research efforts for public solutions
appropriate to developing countries should not be rejected as unethical, they claimed. The research context should be considered.
Local decision-making should be the norm. Paternalism on the part of the richer countries towards poorer countries should be avoided. The
challenge was to encourage research for local solutions to the burden of disease in much of the world, while providing clear guidance on
protecting against exploitation of vulnerable communities and individuals.
The other side argued that such trials constituted, or risked constituting, exploitation of poor countries by rich countries and were
inherently unethical. Economic factors should not influence ethical considerations. It was within the capacity of rich countries or the
pharmaceutical industry to make established effective treatment available for comparator purposes. Certain low-resource countries
had already made available from their own resources established effective treatment for their HIV/AIDS patients.
The issue concerns largely, though not exclusively, two principles: respect for autonomy and protection of dependent or vulnerable persons and populations.
In relation to the use of comparators in controls, commentators have raised the the question of standard of care to be provided to a
control group. They emphasize that standard of care refers to more than the comparator drug or other intervention, and that research
subjects in the poorer countries do not usually enjoy the same standard of all-round care enjoyed by subjects in richer countries. This
issue is not addressed specifically in the Guidelines.
In one respect the Guidelines depart from the terminology of the Declaration of Helsinki. ‘Best current intervention’ is the term most
commonly used to describe the active comparator that is ethically preferred in controlled clinical trials. For many indications, however,
there is more than one established ‘current’ intervention and expert clinicians do not agree on which is superior. In other circumstances in
which there are several established ‘current’ interventions, some expert clinicians recognize one as superior to the rest; some commonly
prescribe another because the superior intervention may be locally unavailable, for example, or prohibitively expensive or unsuited to the
capability of particular patients to adhere to a complex and rigorous regimen. ‘Established effective intervention’ is the term used in
Guideline 11 to refer to all such interventions, including the best and the various alternatives to the best. In some cases an ethical review
committee may determine that it is ethically acceptable to use an established effective intervention as a comparator, even in cases where
such an intervention is not considered the best current intervention.
Application of the Declaration of Helsinki to the particular circumstances of developing countries
Ethical Guidelines 1982, Updates: 1993, 2002 (#1 to #21) 74

75. 1995: Guidelines for Good Clinical Practice (GCP) for Trials on Pharmaceutical Products
GCP Definition:
(globally applicable) standard for clinical studies
encompasses the design, conduct, monitoring, termination, audit, analyses, reporting and documentation of the studies
ensures studies are scientifically and ethically sound
clinical properties of the pharmaceutical product (diagnostic, therapeutic or prophylactic) under investigation are properly documented
Guidelines developed by WHO in consultation with national drug regulatory authorities within WHO’s Member States
Handbook for Good Clinical Research Practice (GCP) as an adjunct to Guidelines
Adopted by International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use
The Guidelines are addressed not only to investigators, but also to ethics review committees,
pharmaceutical manufacturers and other sponsors of research and drug regulatory authorities.
By providing a basis both for the scientific and ethical integrity of research involving human
subjects and for generating valid observations and sound documentation of the findings, these
Guidelines not only serve the interests of the parties actively involved in the research process,
but protect the rights and safety of subjects, including patients, and ensure that the investigations
are directed to the advancement of public health objectives.
The Guidelines are intended specifically to be applied during all stages of drug development
both prior to and subsequent to product registration and marketing, but they are also applicable,
in whole or in part, to biomedical research in general. They should also provide a resource for
editors to determine the acceptability of reported research for publication and, specifically, of any
study that could influence the use or the terms of registration of a pharmaceutical product. Not
least, they provide an educational tool that should become familiar to everyone engaged in
biomedical research and, in particular, to every newly-trained doctor.
Objectives of the Handbook for Good Clinical Research Practice
• To support and promote the achievement of a globally applicable unified standard for the conduct of all clinical research studies on
human subjects;
• To provide an overview and practical advice on the application and implementation of internationally accepted principles for GCP and
clinical research in human subjects;
• To provide an educational and reference tool for anyone interested in, or intending to become or already actively engaged in, clinical
research by providing the necessary background and insight into the reasons for the requirements of GCP and their efficient application;
• To assist editors in evaluating the acceptability of reported research for publication, and regulators in evaluating the acceptability
of any study that could affect the use or the terms of registration of a medical product. 75

76. 1995: Guidelines for Good Clinical Practice (GCP) for Trials on Pharmaceutical Products
Compliance with this standard provides public assurance that:
The rights, safety, and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki
Clinical data are credible
Facilitates mutual acceptance of clinical data internationally among regulatory authorities in participating regions
Defines specific responsibilities:
Institutional Review Boards/Independent Ethics Committees
Investigators
Sponsors
Monitors