1. Thumbs up/Thumbs down – May 2003 CONVINCE CONVINCE: The ethics of stopping a clinical trial Eric J Topol MD Provost and Chief Academic Officer Chairman, Department of Cardiovascular Medicine The Cleveland Clinic Foundation Cleveland, OH Robert M Califf MD Professor of Medicine Associate Vice Chancellor for Clinical Research Director, Duke Clinical Research Institute Duke University Medical Center Durham, NC

2. Thumbs up/Thumbs down – May 2003 CONVINCE CONVINCE: Trial design Controlled Onset Verapamil Investigation of Cardiovascular End Points 661 centers in 15 countries, 16 602 hypertension patients with at least 1 additional CVD risk factor Randomized to controlled-onset extended-release (COER) verapamil or standard therapy (initial atenolol or hydrochlorothiazide) Primary end point: fatal and nonfatal MI, fatal and nonfatal stroke, and death from cardiovascular disease

3. Thumbs up/Thumbs down – May 2003 CONVINCE Reasons for stopping the trial Pharmacia chose to stop the trial, citing "business reasons" Societal responsibilities of clinical trial sponsors. Lack of commercial pay-off is not a legitimate reason for stopping a trial Evans S, Pocock S. BMJ 2001; 322: 569-70 A "tremendous effort" was made by the investigators to gather all the data and present it Califf

4. Thumbs up/Thumbs down – May 2003 CONVINCE Black HR et al. JAMA 2003;289:2073-82 CONVINCE: Blood pressure

5. Thumbs up/Thumbs down – May 2003 CONVINCE EventHazard ratio*95% CIp Primary CVD events 1.020.88-1.180.77 Stroke (fatal or nonfatal) 1.150.90-1.480.26 MI (fatal or nonfatal) 0.820.65-1.030.09 CVD mortality1.090.87-1.370.47 All-cause mortality1.080.93-1.260.32 *verapamil vs atenolol or hydrochlorothiazide Black HR et al. JAMA 2003;289:2073-82. CONVINCE: CV events

6. Thumbs up/Thumbs down – May 2003 CONVINCE Falling short Unable to show superiority of verapamil for events between 6 AM and noon Unable to declare superiority or noninferiority due to lack of statistical power Prespecified boundary for noninferiority: HR=1.16 Upper bound for primary events: HR=1.18 Califf

7. Thumbs up/Thumbs down – May 2003 CONVINCE Black HR et al. JAMA 2003;289:2073-82 CONVINCE: Adverse events

8. Thumbs up/Thumbs down – May 2003 CONVINCE First drug Thiazide diuretic remains the standard drug to start with for hypertension patients Race doesn't seem to modify the advantage of starting on a thiazide but does influence the choice of using an ACE inhibitor in addition Topol

9. Thumbs up/Thumbs down – May 2003 CONVINCE First drug Everyone should be started on a thiazide unless there is some specific countervailing issue (ie) Post-MI patient with mild hypertension who should be on a beta blocker ACE-inhibitor is the next line of therapy in many people Califf

10. Thumbs up/Thumbs down – May 2003 CONVINCE A new precedent This decision sets a new precedent. It was a pathetic decision Stopping medical research to save money: a broken pact with researchers and patients. Psaty BM, Rennie D. JAMA 2003; 289:2128-31 "It was unthinkable to me that a large-scale trial could be stopped by industry because of purely business reasons." Topol

11. Thumbs up/Thumbs down – May 2003 CONVINCE Crimes of clinical research Patients were taken advantage of "I don't know that it crosses the line of crimes against humanity, but it's definitely crimes of clinical research." Patients volunteer and end up suffering possible adverse events for no meaningful data "The whole thing is a disaster." Topol

12. Thumbs up/Thumbs down – May 2003 CONVINCE Why was the trial done? How many people already get verapamil as a sole drug? The primary point was to show noninferiority Major subgroup was to look at early- morning events

13. Thumbs up/Thumbs down – May 2003 CONVINCE Better care Blood-pressure reductions seen in the trial were better than general practice in all arms Patients got better than usual care and were monitored over time Nothing experimental or invasive about the treatment Califf

14. Thumbs up/Thumbs down – May 2003 CONVINCE Prioritizing research A company has a portfolio of research to do and choices must be made because a profit must be made "If this trial had been continued there would have been products that would not be developed... because it would have taken money that would have gone to develop new things, one of which was eplerenone." Califf

15. Thumbs up/Thumbs down – May 2003 CONVINCE Respecting human research These decisions of priorities must be made when a trial is started Once started, a trial must be allowed to go to its natural completion Companies have multiyear planning and can't suddenly change their minds "That whimsical nature is not allowed. It's unethical and unacceptable." Topol

16. Thumbs up/Thumbs down – May 2003 CONVINCE Financial woes Bankruptcy might be a legitimate reason to stop a trial Bankruptcy in the middle of a large, multicenter trial would catch researchers by surprise "Anytime you're going into a megatrial... that assumes the resources are there to complete the experiment." Topol

17. Thumbs up/Thumbs down – May 2003 CONVINCE "Whatever it takes" Centecor ran out of money in midstream on its sepsis drug "We floated them to get the darn thing done because we would never have accepted stopping a trial or stopping a follow-up. That would be untenable." "Whatever it takes, they've gone this far, they've got to get the thing done." Topol

18. Thumbs up/Thumbs down – May 2003 CONVINCE Tightening the ship It is possible the pending sale of Pharmacia to Pfizer influenced the decision "Tightening the ship" to make the company a more attractive purchase It never has been stated exactly what the business case was Califf

19. Thumbs up/Thumbs down – May 2003 CONVINCE Hospital priorities There is always a problem factoring human ethical concerns into the medical business How different is this from a hospital pushing patients to the most profitable DRG categories? Califf

20. Thumbs up/Thumbs down – May 2003 CONVINCE Ethics of research Clinical research is a bilateral consent of patients and investigators "The ethical standards of research, and selling out human beings for business purposes, we can't let that ride." "Industry needs to take notice that we're not going to put up with this kind of thing." "There should never be another CONVINCE misadventure in the future." Topol

21. Thumbs up/Thumbs down – May 2003 CONVINCE A human on the balance sheet Happy to lose this argument "I'm afraid that in today's society, many components of the medical products business and even the hospital industry lose sight of the fact that there's a human being at the other end of the balance sheet." Califf

22. Thumbs up/Thumbs down – May 2003 CONVINCE Bivalirudin Bivalirudin trials were stopped for business reasons Dr Eugene Braunwald was not consulted, just called into an investigators’ meeting and told the trial would be stopped In retrospect, bivalirudin has been shown to be an interesting drug

23. Thumbs up/Thumbs down – May 2003 CONVINCE Exploitation The same message to industry being sent now should have been sent then "Once a decision's been made to go forward with a trial, that's a pact that has to go to a natural completion. Otherwise it is exploiting human beings, which we don't want to be party to." Topol

24. Thumbs up/Thumbs down – May 2003 CONVINCE Thumbs Califf: "Two thumbs down to the trial and two thumbs up to the steering committee, who heroically persisted in getting the data." Two thumbs down Topol: "I completely agree with you." Two thumbs down

25. Thumbs up/Thumbs down – May 2003 CONVINCE CONVINCE: The ethics of stopping a clinical trial Eric J Topol MD Provost and Chief Academic Officer Chairman, Department of Cardiovascular Medicine The Cleveland Clinic Foundation Cleveland, OH Robert M Califf MD Professor of Medicine Associate Vice Chancellor for Clinical Research Director, Duke Clinical Research Institute Duke University Medical Center Durham, NC