Bram Zuckerman MD, FACC Bram.zuckerman@fda.hhs Director, Division of Cardiovascular Devices

1. Use of Data Monitoring Committees (DMC) in Device Trials: An FDA Division of Cardiovascular Devices (DCD) Perspective Bram Zuckerman MD, FACC Bram.zuckerman@fda.hhs.gov Director, Division of Cardiovascular Devices Center for Devices and Radiological Health

2. Introduction • Most literature on Data Monitoring Committees (DMC) deals with drug trial applications • DMCs have been employed at FDA Device Center (CDRH) over the last decade Today's goals: • Talk about use of DMCs at CDRH • Comment on FDA DMC Guidance Document

3. CDRH and Data Monitoring Committees (DMCs) • HHS Office of Inspector General recommended in 1998 that FDA clarify appropriate role and procedure for DMCs • In 2006 FDA issued the DMC Guidance www.fda.gov/cber/gdlns/clintrialdmc.htm • The Guidance is applicable to CBER, CDER, and CDRH trials

4. What is a Clinical Trial Data Monitoring Committee? • A Clinical Trial Data Monitoring Committee (DMC) is a group of individuals with pertinent expertise that reviews on a regular basis accumulating data from an ongoing clinical trial • The DMC advises the sponsor regarding the continuing safety of current participants and those yet to be recruited, as well as the continuing validity and scientific merit of the trial

5. Other Oversight Groups Interact with DMCs • Clinical Endpoints Committee (CEC) – independently reviews important endpoints reported by trial investigators to determine whether they meet protocol-specified criteria • Institutional Review Board (IRB) – responsible for evaluating a trial to determine whether “risks to subjects are minimized” and “risks to subjects are reasonable in relation to anticipated benefits” (21 CFR 56.111(a)(1) and (3))

6. Which Device Trials need DMCs? • All clinical trials require safety monitoring (21 CFR312.32 (c)) but this does mean that every trial needs a formal committee external to the trial organizers and investigators • A DMC is required by FDA in the case of waived informed consent (21 CFR 50.24) (e.g., emergency research for CPR devices) • A DMC is not needed or advised for every clinical trial, although it may prove valuable and Least Burdensome

7. Which Device Trials Need DMCs? • Consider relevant ethical and scientific reasons (i.e., high risk to trial participants, long-term trial) for institution of a Data Monitoring Committee in large multisite studies • For cardiovascular disease trials the primary (or secondary) endpoint is often mortality or major morbidity for pivotal trials of arrhythmia, heart failure, myocardial infarction, and anti-restenosis therapies • Would a favorable or unfavorable result ethically and\or scientifically require early termination?

8. Which Device Trials Need DMCs? Will institution of a DMC allow for the use of optimal statistical and clinical trial methodologies? A) If differences in major response variables are unimpressive at an interim analysis is it justifiable in terms of time, money, and effort to continue? B) Alternatively, if the difference in the primary endpoint is less than expected a DMC might be useful for legitimately helping to modify inclusion\exclusion criteria or sample size

9. Which Device Trials Need DMCs? Special concerns about risks to trial participants: A) Is the treatment to be tested novel, so that there is little prior information on clinical safety, or is there prior information that raises concerns about the potential for serious problems? (e.g., DMCs are useful in feasibility device trials as well as pivotal trials) B) Safety concerns are usually heightened in studies performed in potentially fragile populations (e.g., children or the elderly)

10. Which Cardiovascular Device Trials Need DMCs? • Last decade has seen increasing importance of device therapy for treatment of cardiovascular disease • Most of the prior bullet points apply to the cardiovascular device trials arena • DCD use of DMCs has been extensive • DCD recommends use of DMCs for feasibility and pivotal trials when dealing with complex product development

11. General Operational Issues • DMCs should have well-defined standard operating procedures • The DMC and Sponsor should be able to operate per the planned operational timeline • Members should be carefully selected (experienced biostatistician, independent and objective expert clinicians, DMC Chair should have experience in clinical trials as well as the disease of interest)

12. General Operational Issues • The plan for interim looks at data and the alpha spending function need to be prospectively defined in the IDE protocol • Any plan for possible increase of sample size needs to be prospectively stated in the IDE protocol • It is not uncommon in the “closed” section of a DMC meeting that the DMC may need to see unblinded trial results in order to effectively determine the risk/benefit profile at an interim analysis

13. Operational Problems Encountered by DCD • In many cases DMCs have not been able to operate per the planned operational timeline • As a result DCD often only gives “conditional approval” for IDE studies • Full IDE approval is dependent on the Sponsor and DMC demonstrating that they can operate effectively • DCD may not agree with evaluation strategy and conclusions reached by DMC and exercise its authority accordingly [21CFR 812.150(b)10]

14. Major Reasons for Early Termination of a Trial • The trial may show serious adverse effects in the entire intervention group or in a dominating subgroup • There may be greater than expected beneficial effects • It may become clear that a statistically significant difference by the end of the trial is improbable • Logistical or data-quality problems may be so severe that correction is not feasible

15. The Early Termination of a Clinical Trial Can be Difficult • Issues involved may be complex because study results are often mixed • Statistical stopping “rules” are useful guides in this process but should not be viewed as an absolute • Examine differences in prognostic factors, possible role of bias due to non-blinding, impact of missing data, side effects and outcomes of secondary response variables, internal consistency across subgroups and between centers, outcomes of similar trials, and impact of early termination on general acceptance of results in clinical practice

16. DCD Experience with Early Trial Termination • Sponsor Consultation with FDA on implications of early stopping may be helpful • FDA will rarely, if ever, tell a sponsor which decision to make but only provide scientific and regulatory guidance on the possible implications of early termination • Percusurge Panel Transcript (2/05/01) on FDA website provides one detailed DCD device example

17. Conclusions • Use of DMC is recommended for many device trials • General DMC principals apply to device and drug trials even though devices are not drugs • Real time DMC implementation has been a challenge for many DCD trials • A “conditional IDE approval” mechanism has been helpful for practically improving DMC performance