Practical Issues in the adjudication of events in device trials: Therapeutic Device Trials (e.g., Companion CHF)

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1 Practical Issues in the adjudication of events in device trials: Therapeutic Device Trials (e.g., Companion CHF) Peter Carson MD Washington D.C. VA Medical Center

2 SESSION ll Adjudicating endpoint occurrence Causality Blinding Committee composition Endpoint definitions Gathering endpoint data Clinical study operational issues

3 Adjudication committees and Clinical Trial Endpoints. Heart Fail Clin January ; 9(1): 15 28

4 SESSION ll Adjudicating endpoint occurrence Causality Blinding Committee composition Endpoint definitions Gathering endpoint data Clinical study operational issues

5 COMPANION Kaplan Meier Estimates of the Time to the Primary End Point of Death from or Hospitalization for Any Cause (Panel A), the Time to the Secondary End Point of Death from Any Cause (Panel B), the Time to Death from or Hospitalization for Cardiovascular Causes (Panel C), and the Time to Death from or Hospitalization for Heart Failure (Panel D). Bristow MR et al. N Engl J Med 2004;350:

6 Adjudicating endpoint occurrence Initially definition of a hospitalization as a study event required that it was at least 24 hours in duration; the CEC could not verify discharge times and after the second meeting used calendar date change. The FDA indicated that it was not notified of this alteration and considered that this was a major change in the protocol primary endpoint. The FDA raised concerns and a cardiorenal device panel voted against approval The FDA ultimately approved an expanded indication for resynchronization therapy based on the COMPANION data

9 Adjudicating endpoint occurrence Initially definition of a hospitalization as a study event required that it was at least 24 hours in duration; the CEC could not verify discharge times and after the second meeting used calendar date change. The FDA indicated that it was not notified of this alteration and considered that this was a major change in the protocol primary endpoint. The FDA raised concerns and a cardiorenal device panel voted against approval The FDA ultimately approved an expanded indication for resynchronization therapy based on the COMPANION data

10 Adjudicating endpoint occurrence Any change in wording relating to a primary or secondary outcome needs to be submitted to the FDA. Current trials seldom use a 24 hour duration hospitalization alone but use calendar date change either alone or in tandem 24 hours. The CEC chairman should be part of a steering committee so that communications are contained within the meeting minutes All hospital admissions, including those without a calendar date change, or for elective reasons should be collected and, optimally, adjudicated by a committee The FDA needs to consider the entire body of data relating to potential risk and benefit.

11 SESSION ll Adjudicating endpoint occurrence Causality Blinding Committee composition Endpoint definitions Gathering endpoint data Clinical study operational issues

12 Causality and Blinding How do the questions get answered if an adjudicator is blinded? How broad is the intent of the question? The default has been to assume everyone has a device Do the categories really help in determining safety? Or is it really the events themselves? Blinding usually involves redacting large parts of a clinical record which may be successful but also makes them difficult to read!

13 SESSION ll Adjudicating endpoint occurrence Causality Blinding Committee composition Endpoint definitions Gathering endpoint data Clinical study operational issues

14 Committee composition For device trials, members should include those with particular skills relating to the device and question. For example, a current clinical trial of a sleep apnea device includes a sleep physician, an electrophysiologist and other cardiologists (heart failure). Members would best be chosen by the steering committee. Sponsor input should go through the steering committee

15 SESSION ll Adjudicating endpoint occurrence Causality Blinding Committee composition Endpoint definitions Gathering endpoint data Clinical study operational issues

16 Endpoint definitions Mode of Death

17 COMPANION Hospitalization curves Hospital admission rate per patient is stratified by treatment arm. Inder S. Anand et al. Circulation. 2009;119: Copyright American Heart Association, Inc. All rights reserved.

18 CDC Causes of death 2014

19 Endpoint definitions For cause-specific mortality,there needs to be stated criteria but a result should be based on the event that changed the patient s course The default of cardiovascular cause for deaths in octogenarians and nonagenarians needs to be carefully considered i.e. should unknown deaths be CV? For a hospitalization, the duration should be defined by a calendar date change For hospitalization the primary reason for admission is most commonly used, although for or with a specific cause has been used. To assign a specific admit cause, there should be signs/symptoms, specific treatment for the condition, and optimally indication of response to the treatment.

20 SESSION ll Adjudicating endpoint occurrence Causality Blinding Committee composition Endpoint definitions Gathering endpoint data Clinical study operational issues

21 Gathering endpoint data/ Clinical study operational issues A committee charter should define source documents that are needed e.g. admitting notes, discharge summaries are particularly valuable A narrative on an event from the clinical site is helpful CRFs containing check boxes for signs, symptoms, therapy received, and site interpretation serve as a backstop if source documentation is inadequate Use of a CRO for a CEC, including participation at meetings, is optimal for trials that are unblinded or in which blinding may be incomplete. Remote adjudication by computer or teleconference is an expeditious approach, full committee meetings benefit overall group function and promote discussion.

Disclosures: Drs. Bristow, Saxon, Boehmer, Kass, and Feldman are consultants to Guidant (sponsor) HFSA Late-Breaker September 24, 2003

Disclosures: Drs. Bristow, Saxon, Boehmer, Kass, and Feldman are consultants to Guidant (sponsor) HFSA Late-Breaker September 24, 2003 Cardiac Resynchronization Therapy (CRT) Reduces Hospitalizations, and CRT with Implantable Defibrillator (CRT-D) Reduces Mortality in Chronic Heart Failure: The COMPANION Trial Bristow MR,(Co-Ch) Feldman