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Safety Workshop: Part I Clinical Trial Safety and Safety Monitoring

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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 California
28 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 Severity

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

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