Patrick Archdeacon, MD Office of Medical Policy/CDER/FDA May 13, IND Safety Reporting

Transcription

1 Patrick Archdeacon, MD Office of Medical Policy/CDER/FDA May 13, 2015 IND Safety Reporting

2 Outline Background Rationale for and overview of the 2010 revisions to the IND safety reporting rule Challenges to implementation of the final IND safety reporting rule Efforts to facilitate implementation Looking forward 2

3 Overview of IND Safety Reporting Rule (21 CFR ) The final rule, published September 2010, Codifies FDA s expectations for timely review, evaluation, and submission of important and useful safety information Defines responsibilities of investigators Defines responsibilities of sponsors (specifically routine review of safety information and criteria for expedited safety reporting) Improves the utility of premarket safety reports and reduces the number of uninformative individual reports, thereby enhancing the ability of FDA, investigators, and IRBs to focus on safety issues that affect human subjects 3

4 Problem: Uninformative individual IND safety reports Sponsors often report serious adverse events as individual cases that are uninterpretable as single events (i.e., require evaluation in the aggregate to interpret) and/or Are likely to have been manifestations of the underlying disease (e.g., mortality or major morbidity) Commonly occur in the study population independent of drug exposure (e.g., strokes or acute myocardial infarctions in an elderly population) Are study endpoints (i.e., the study was evaluating whether the drug reduced the rate of these events)

5 Internal FDA Retrospective Review of Sample of IND Safety Reports Purpose: To understand distribution of types and volume of reports that are uninformative as individual cases Method: Retrospectively reviewed a sample of 94 initial IND safety reports for 3 INDs submitted prior to the IND safety reporting final rule (i.e., prior to September 2010) One IND large outcome trial (reviewed 50 reports) Two INDs smaller trials (reviewed 44 reports) 5

6 Highlights of Findings Very few of the reports were judged interpretable as single events Approximately 4-6% for each of 3 INDs Most of the events (over 90% for outcome trial) were either study endpoints, events listed as expected in the investigator brochure, or events anticipated in the study population and/or listed in the protocol Over same time period in large outcome trial, ~ 500 follow-up reports were submitted Differences in attribution (i.e., reasonable possibility that the event is related to the drug) Investigators rated ~90% of cases as at least possibly related Sponsors rated ~19% of cases as at least possibly related FDA rated ~5% of cases possibly related Overall quality of reports low incomplete; unclear if they were unblinded; lacked analysis with respect to similar, previous reports 6

7 But why are such uninformative reports a significant problem? Drain on limited FDA, investigator, and IRB resources May discourage potential investigators from participating in clinical trials enterprise (contributes to investigator turnover) Ability of investigators and regulators and IRBs to detect valid safety signals negatively impacted

8 How does 2010 IND Safety Rule improve utility of expedited safety reports? Clarifies reporting requirement: Report any suspected adverse reaction that is both serious and unexpected must meet all three definitions Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the drug caused the event Unexpected means not listed in the investigator brochure Serious means results in death, is life-threatening, hospitalization Report only if there is evidence to suggest a causal relationship between the drug and the adverse event (sponsor judgment) 8

9 Examples of Evidence that Suggest a Causal Relationship Single occurrence of an event that is uncommon and known to be strongly associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome) One or more occurrences of an event that is not commonly associated with drug exposure but is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture) An aggregate analysis of specific events observed in a clinical trial that indicates those events occur more frequently in the drug treatment group than in a concurrent or historical control group (e.g., known consequences of underlying disease, events common in study population) Determination of causality is critical to patient safety and only the sponsor has both the sufficient data and resources to make this determination for events requiring aggregate analyses 9

10 Implementation Challenges Comments on draft guidance (published September 2010) and concerns expressed by sponsors New requirement for aggregate reports Requested more detail on FDA s expectations (Thresholds) Concern about unblinding (Unblinding) Causality assessment is made by sponsors for US reports and by either the sponsor or investigator per ICH E2A Required changes in structure and processes for some sponsors of international trials (Harmonization) 10

11 Efforts to Facilitate Implementation of the IND Safety Reporting Rule Final guidance Safety Reporting Requirements for INDs and BA/BE Studies published December 2012 Clinical Trials Transformation Initiative (CTTI) projects on IND Safety Reporting 11

12 Final Guidance Overview Provides advice on other safety reporting issues that have generated questions Investigator brochure Aggegrate analyses Unblinding 12

13 2012 Guidance: Investigator Brochure Investigator brochure is basis for determining whether a suspected adverse reaction is unexpected IB should specifically list ARs for which a causal relationship is suspected or confirmed Sponsors should update the IB with new safety information, exercising judgment in determining threshold Until IB is updated, subsequent occurrences of SARs must be submitted in IND safety reports IBs can be updated with addendums, rather than reissuing entire brochures

14 2012 Guidance: Aggregate Analysis Protocol-specified serious adverse events Identify events and monitoring plan in the protocol Limit to events that are common in study population Safety team or independent group monitors the rates at appropriate intervals Report if an aggregate analysis indicates that events are occurring more frequently in the drug treatment group Non-protocol-specified serious adverse events Serious adverse event that is not protocol-specified still may not meet criteria for expedited reporting Sponsors should use judgment to determine if there is a reasonable possibility that the drug caused the event Final guidance describes sponsor s flexibility to report these events FDA will accept expedited reports for individual cases of unexpected serious adverse events that are not study endpoints and are not specified in the protocol as anticipated (e.g., they are known consequences of the disease being treated or common in the study population) to address concerns expressed by sponsors about not expeditiously reporting such cases. Note: This flexibility is an option. The preferred approach is to NOT report unless the event meets the criteria for reporting

15 2012 Guidance: Unblinding Blinds should ordinarily be broken for IND safety reports submitted to FDA and participating investigators Unblinding single or small numbers of serious and unexpected SARs should not compromise the integrity of the study, as such unblinding should be rare Aggregate reports should include the event rates in the treatment and comparator groups and also the unblinded individual reports. However, if sponsor has concern that such unblinding will compromise the integrity of the trial, this should be discussed with review division

16 International Harmonization ICH E2A states: All cases judged by either the reporting HCP or the sponsors as having reasonable suspected causal relationship to the medicinal product qualify as ADRs However, ICH E2A also states It may be appropriate to reach agreement with regulatory authorities in advance concerning serious events that would be treated as disease-related and not subject to routine expedited reporting. European Directive 2001/20/EC and the relevant guidance ( CT-3 ) also discuss provisions for not routinely reporting prespecified categories of serious adverse events Ultimately, sponsors have the option of developing a single approach that meets the requirements of various regulatory agencies or developing parallel reporting systems.

17 CTTI FDA and Duke University - founding members of a publicprivate partnership Members include stakeholders from government, industry, academia, patient and consumer representatives, clinical investigators, professional societies, and clinical research organizations Mission is to identify and promote practices that will increase the quality and efficiency of clinical trials Scope is to generate evidence about how to improve the design and execution of clinical trials and to foster widespread change based on evidence 17

18 CTTI Project: IND Safety Assessment and Communication Purpose: To promote responsible oversight of safety for premarket drugs consistent with the intent of the IND safety reporting final rule Project plan Collect sponsors current practices for premarket safety assessment (November-December 2011) Convened an expert meeting in February 2012 Convened a workgroup of biostatisticians Summarized current practices, concerns, and issued recommendations (November 2013) 18

19 Survey and Expert Meeting 54 question survey completed by 12 of the 14 sponsors who were solicited for input Survey results describe the methods and structures used in premarket safety surveillance and reporting Expert meeting held to discuss gaps between current practice and an optimal system for early detection of valid safety signals across a drug development program Organization of personnel and data Methods and processes developed to conduct aggregate product safety assessments Confirmation and escalation of potential safety signals Analysis of blinded studies 19

20 CTTI Recommendations on IND Safety Assessment and Communication* Upfront safety planning for a development program Implementation of safety assessment in clinical trials Threshold for expedited reporting of anticipated events Adverse events not pre-specified in the protocol * Full recommendations at Recommendations.pdf 20

21 CTTI recommendations: Upfront safety planning for development program Prospectively identify SAEs anticipated to commonly occur in the study population independent of drug exposure (e.g, AMI in elderly) Specify in trial protocols that such anticipated SAEs will not be reported as individual IND safety reports

22 CTTI recommendations: Implementation of safety assessment in clinical trials Sponsors should periodically evaluate totality of safety information As comparisons of event rates to a historical control are less sensitive than comparisons across treatment arms, unblinding of SAEs may be required. Unblinded analyses should be conducted by firewalled safety committees

23 CTTI recommendations: Threshold for expedited reporting Sponsors should not submit serious adverse events that are prospectively identified as anticipated to occur in the study population as individual IND safety reports. Instead, sponsors should report such events in aggregate at the point in time when the totality of the data may suggest a causal relationship.

24 CTTI recommendations: SAEs not specified as anticipated As with anticipated events, more than one occurrence may be necessary before the sponsor can judge that there is reasonable possibility of causality If there is uncertainty or weak evidence of causality, sponsors could consider reporting these as individual events

25 Impact of 2010 Rule, 2012 Guidance, and CTTI project Internal audits of FDA Document Archiving Reporting and Regulatory Tracking System indicate that numbers of expedited reports received have not decreased In CTTI follow on project focused on IND safety reports in oncology, 92% of 191 survey respondents reported no change (82%) or only slight change (10%) in quality of reports In contrast, in same survey, majority of industry sponsors reported that they had adopted new practices that decreased reports by greater than 50%

26 Follow-up CTTI Project: IND Safety Advancement Project objectives Understand sponsor challenges to implementation of the IND safety reporting rule in oncology trials Understand sponsor motivation to change practice of IND safety reporting in oncology trials to comply with the IND safety reporting rule Understand challenges to investigator receipt and management of IND safety reports Facilitate adoption of best practices for communicating and managing IND safety reports consistent with FDA guidance, the IND safety rule, and CTTI recommendations 26

27 Looking Forward Final rule has been in effect since March 28, 2011 To date, little to no evidence that sponsors have significantly changed practices (most of the evidence that has been gathered relates to oncology trials) Strongly encourage sponsors to develop protocols that identify adverse events that will not be submitted individually CTTI recommendations for ongoing IND Safety Advancement follow-up project FDA considering the need for additional guidance and/or other measures to decrease number of uninformative reports 27

28 Internet Locations Final rule, final guidance, and small entity compliance guide: alprocess/howdrugsaredevelopedandapproved/ ApprovalApplications/InvestigationalNewDrugIN DApplication/ucm htm CTTI IND Safety Assessment and Communication Project: CTTI IND Safety Advancement Follow-up Project: 28