The Ethics of Halting a Clinical Trial: A Controversial Decision

1. CONVINCE: The ethics of stopping a clinical trial Eric J Topol MDProvost and Chief Academic Officer Chairman, Department of Cardiovascular Medicine The Cleveland Clinic Foundation Cleveland, OH Robert M Califf MDProfessor of Medicine Associate Vice Chancellor for Clinical Research Director, Duke Clinical Research Institute Duke University Medical Center Durham, NC

2. 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. 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. CONVINCE: Blood pressure Black HR et al. JAMA 2003;289:2073-82

5. CONVINCE: CV events Black HR et al. JAMA 2003;289:2073-82.

6. 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. CONVINCE: Adverse events Black HR et al. JAMA 2003;289:2073-82

8. 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. 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. 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. 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. 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. 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. 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. 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. 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. "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. 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. 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. 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. 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. 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. 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 • 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. CONVINCE: The ethics of stopping a clinical trial Eric J Topol MDProvost and Chief Academic Officer Chairman, Department of Cardiovascular Medicine The Cleveland Clinic Foundation Cleveland, OH Robert M Califf MDProfessor of Medicine Associate Vice Chancellor for Clinical Research Director, Duke Clinical Research Institute Duke University Medical Center Durham, NC