Safety Workshop: Part I Clinical Trial Safety and Safety Monitoring

1. Safety Workshop: Part IClinical 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” 1939-45: Nazi medical war experiments 1938-72: Tuskegee Study of Untreated Syphilis in the Negro Male

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 • Clinical investigations regulated by FDA • 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

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 46.111 or 21 CFR 56.111

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

13. 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 Data Safety and Monitoring Boards (DSMBs) / Data Monitoring Committees (DMCs)

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. 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 Perspective

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 312.32: 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

18. Safety Monitoring

19. Roles and Responsibilities – Site Investigator

20. Roles and Responsibilities – Research Staff

21. Roles and Responsibilities – Study Clinician/Physician

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

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. 28 Joshua Tree National Park in Southern California

29. Safety Monitoring Environment

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 http://www.ich.org/cache/compo/276-254-1.html

31. Drug Development Model:Safety Data Flow in Clinical Trials

32. Adverse Event Flowchart To other To other Subject Enrolled Subject Enrolled To IRB To IRB AE Reported AE Reported SAE? SAE? To Sponsor To Sponsor Yes Yes Record SAE** Record SAE** Record AE* Record AE* To FDA To FDA Outcome: Resolved/ Stable? Outcome: Resolved/ Stable? Follow until Resolution or Stability Follow until Resolution or Stability No No Update SAE 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)

34. Documentation Differences Between AE CRF and SAE Form Record on SAE Form (includes narrative) Record in source document Attach additional documentation Record on AE case report form Does AE meet SAE criteria? Yes

35. Documentation Differences Between AE CRF and SAE Form: Data Elements

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

37. Stretch Break

38. Adverse Event ICH E2A: 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 312.32 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 ReactionAdverse Reaction 21 CFR 312.32 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)

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 Severity

48. 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

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 312.32 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