Data Monitoring & Patient Safety Estelle Russek-Cohen CDER OB

Disclaimer The views expressed are those of the author and should not be construed as FDA’s views or policies Note: I have been a statistician in each of the three medical centers but each center evolves…..conversations with staff in the three centers have been helpful.

Center for Biologics Evaluation and Research Center for Devices and Radiological Health Center for Drug Evaluation and Research National Center for Toxicological Research Center for Food Safety and Applied Nutrition Center for Veterinary Medicine Office of Regulatory Affairs Center for Tobacco Products

Data monitoring committees An external group that has two key roles: Protecting patients: considering benefits and risks of an intervention. Help maintain trial integrity in a clinical trial With or without a DMC, sponsors of clinical trials are expected to protect patients and maintain trial integrity.

When are DMCs required? When cannot obtain individual informed consent Typically in treatments for trauma subjects Need community consent Requirements spelled out in guidance FDA Guidance for Institutional Review Boards, Clinical investigators and Sponsors Exception from Informed Consent Requirements for Emergency Research (50.24 studies) IND or IDE required. FDA had an Ethicist on the review team! NIH funded studies may come with additional requirement for a DMC

Role of Guidances at FDA Current thinking on a topic Not same as regulation Draft guidances are posted to solicit public comments Guidances can be issued by agency, a center, an office, ….. FDA Final Guidance on DMCs: 2006 Guidance from 3 medical centers (CDER, CBER and CDRH) Some things have changed even if the basics have not.

Other guidances and safety reporting Drugs and biologics (safety under an IND) 2012 guidance…individual serious event reporting https://www.fda.gov/regulatory-information/search-fda-guidance-documents/safety-reporting-requirements-inds-investigational-new-drug-applications-and-babe 2015 draft guidance….aggregated events and causality https://www.fda.gov/regulatory-information/search-fda-guidance-documents/safety-assessment-ind-safety-reporting-guidance-industry Unanticipated serious events must be reported ASAP if causality is clear eg acute event right after drug administered (by 7 days or 15 days) If an aggregated analysis of a serious event suggests causality and the event is not in the Investigator Brochure or events are more common than expected… a report to FDA is expected Medical devices (safety under an IDE) https://www.fda.gov/medical-devices/device-advice-investigational-device-exemption-ide/ide-reports Unanticipated serious events must be reported ASAP ( by 10 days) Everyone submits annual reports (IND/IDE) and safety summaries come with marketing application (NDA/BLA; PMA/510(k)).

DMCs DMCs are expected to be independent of the sponsor Recommended in FDA Guidance when: studying patients with severe morbidity and/or mortality studying vulnerable patients (eg pediatrics, elderly,…) Primary roles: protect the subjects in the study from unwarranted risks and help maintain trial integrity Helps to put knowledgeable experienced people on the DMC. Want people with minimal to no conflicts of interest

Since 2006 More trials have a DMC (see clinicaltrials.gov) Greater use of DMCs for a program rather than a single trial See more in earlier phases NIH requires them in many instances Use of DMCs to implement some adaptive designs Increase in multi-regional trials and that can add complexity Charters for DMCs seem to be more complex FDA (Under IND) is asking for review of aggregate data for safety reporting: assessing causality of serious adverse events

Trial Management can be complex: vary with size of trial & safety concerns Steering committee (often includes sponsor employees) Internal safety monitoring groups (role vs DMC?) Endpoints adjudication committee (if appropriate) Adaptation committee (if adaptive) IRB: Institutional review board(s): can have centralized IRB structure Data monitoring committee: …do not want a DMC adjudicating endpoints …do not want a DMC designing adaptations after looking at data Important: knowing when to communicate and how. who has which responsibility (eg meeting accrual targets..)

Expertise on a DMC Right medical disciplines…ability to add expertise if warranted Some (especially chair) ought to have experience Statisticians need to have the right skillset: Must understand Bayesian or Adaptive aspects in the SAP Practical experience with data and clinical trials Often an independent statistician generates reports to the DMC. If internal statistician prepares reports….what firewalls are in place? Should have policy on conflict of interest and process to vet members for conflicts of interest

DMC charter Criteria for selection of members Meeting times and who can attend open and closed sessions Planned analyses in protocol and SAP Some challenges: is protocol and SAP final by time trial starts? Maintaining confidentiality Who will have access to what information (eg indep statistician) Role in study conduct; interim analyses; DMC should be informed of FDA concerns on safety

Statistical Methods: DMC may do exploratory analyses Not all methods will be in the SAP submitted to FDA DMC may need to consider benefit and risk and unblinding may be essential to sensibly reach a conclusion Since DMC is likely to hold open and closed meetings, it is imperative that any summaries presented in open meeting not unmask results prematurely. (If randomization ratio is not 1:1, think twice about how results are reported. )

DMC versus Internal Safety group Internal group ought to be blinded to/firewalled from efficacy data If possible safety signal is identified, need to designate how everyone is to be informed. Since timelines are short for mandatory reports to the FDA, it is best if this is spelled out in advance. Safety signals may need to be communicated in the investigator brochure and identified in informed consent Any safety signals from internal group ought to be communicated to the DMC Obviously egregious safety concerns may result in halting the trial.

DMCs used in place of internal safety monitoring group for aggregate safety analyses Is the DMC meeting often enough to spot issues in a timely fashion? Who will inform the FDA including actions needed (see 2015 guidance): Stop the trial? Amend the informed consent? Amend the investigator brochure? Note: threshold needed to modify brochure or consent form can differ from putting specific info in the label after drug is approved. Sponsor needs to have a safety surveillance plan in place and DMC would need to have input.

Safety is harder than efficacy Cannot anticipate all safety concerns; Studies with active controls may pose challenge Safety coding isn’t always suited for aggregating events for analysis Statisticians should expect to collaborate with MDs Acute events such as anaphylaxis close to administration of a drug or vaccine could make causation appear obvious but anaphylaxis isn’t always captured via a medDRA code If you are treating patients with a serious condition, some events may be due to the underlying medical condition (eg CVOT randomized trials in diabetics are run because diabetics more susceptible to cardiovascular disease) FDA is not anticipating additional randomized trials for every safety concern, but informing investigators and subjects about potential risks is important. Multiplicity adjustments for safety at FDA….. Are rare.

Role of statistician…… Hypothetical Case of a vaccine for healthy subjects: Vaccine arm…..2 events out of 5000 subjects Placebo arm…..0 events out of 5000 subjects What do you know about the rate of the event in the background population? Suppose it is a rare autoimmune disease that occurs less than 1 in 100,000. In vaccines with healthy subjects: may know the background rate of some adverse events and expect the physician to pick up on it. Clinical significance is not statistical significance

Statisticians can find patterns: It will never be one size fits all: Depends on: patterns of drug exposure, if there are multiple dose groups in the trial, anticipated heterogeneity in patient population Beware of issues like pooling across previous trials to develop thresholds (eg Simpson’s paradox) ….FDA Draft Guidance on Meta-Analysis for Safety for Drugs and Biologics If using external data to generate thresholds be aware of data quality, limitations and relevance to current trial Graphic and Statistical methods can be useful.

Conclusions Statisticians have a key role to play in monitoring a trial including monitoring for safety However, statisticians and medical experts have to work together for the best result. Don’t expect a single approach to managing a trial Don’t expect a single statistical approach to identify signals… however research in this area is always welcome.

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