1. Clinical trials in crisis Clinical Trial Commentary Dr Eric Topol Chairman and Professor, Department of Cardiology Director of the Joseph J Jacobs Center for Thrombosis and Vascular Biology at the Cleveland Clinic Dr Robert Califf Professor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University

2. Rigging trials for marketing Clinical trials in crisis New York Times expose on underpowered trials made the argument that the pharmaceutical industry has grown sophisticated enough to deliberately engineer results of trials for greater marketing effect. There may be some truth to those concerns. -Topol Stolberg SG and Gerth J. Drug Makers Design Studies With Eye to Competitive Edge. New York Times 2000 Dec 23:A1.

3. “The principle here that you’re alluding to is that finding a p-value of greater than.05 - or in other words, failing to find evidence of a difference - is not the same as finding evidence of no difference.” Dr Robert Califf Professor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University Clinical trials in crisis Evidence of difference

4. Power Clinical trials in crisis It is not the number of patients you enroll in a trial that determines power, it is the number of events. A trial of 1 million healthy college students for 5 years will still be underpowered for CV events. -Califf

5. TARGET 4812 patients from 18 countries who were undergoing coronary stenting. Primary endpoint: 30-day outcomes of death, MI, and urgent revascularization. TirofibanAbciximabORp-value 7.55%6.01%1.260.037 OR = odds ratio Clinical trials in crisis

6. PROVE-IT PRavastatin Or atorVastatin Evaluation and Infection Therapy Statins require a lag phase of 1 year to 18 months to show benefit against placebo. PROVE-IT designed to last 2 years, with active control, and so wouldn’t be expected to show benefit. -Topol Clinical trials in crisis

7. Evidence-based marketing Positioning a drug based on clinical trials is fine as long as the trials are well done. Better to have marketing based on trials than on belief, testimony, or pathophysiological construct. -Califf There are dangers of marketing with pseudo- evidence. -Topol Clinical trials in crisis

8. Constructing an equivalence trial For true equivalence you need hundreds of thousands of patients. The best you can do is declare “non-inferiority”. -Topol The best way to determine the boundary is to determine with experts and patients how much of a difference do you need in clinical outcomes to convince you to switch from one treatment to the other. -Califf Clinical trials in crisis

9. MIRACL Primary endpoint: death, MI, and refractory recurrent ischemia requiring hospitalization. 3000 patients following an acute coronary event were randomized to either 80 mg atorvastatin or placebo for a period of 3 months. Primary endpoint results: 14.8% with atorvastatin vs 17.4% on placebo (16% reduction, p=0.048). Reduction was primarily due to effect of atorvastatin on recurrent symptomatic myocardial ischemia (26% reduction, p=0.02). Clinical trials in crisis

10. PROVE-IT vs MIRACL PROVE-IT active control pravastatin vs atorvastatin MIRACL placebo control atorvastatin vs placebo Clinical trials in crisis

11. Sample size Method A: $/cost per patient = # of patients enrolled Then you figure out “how can we justify the sample size we can afford?” Used more often than people like to admit. Method B: “the right way” Decide the minimal difference that would change clinical practice and size your sample to detect that difference in an event-driven clinical trial. -Califf Clinical trials in crisis

12. Deliberate underpowering? The worst case scenario: Deliberately designing a trial to have insufficient events in order to declare non- inferiority at the end of the trial. -Topol Clinical trials in crisis

13. GUSTO-III Reteplase vs tPA Had a limited number of patients in order to cut costs, which resulted in extreme difficulty in drawing any clinically useful conclusions. Not deliberately done, but nonetheless caused problems with interpretation. -Topol Clinical trials in crisis

14. Some data better than none? If you can generate some randomized data, but not enough to generate the definitive answer, is it better to do the non-definitive trial? The danger is when a trial is non-definitive, but an effort is made to turn it into a definitive non-inferiority trial. -Califf Clinical trials in crisis

15. “I think that pharmaceutical companies have a lot of really bright folks working for them who have figured it out and can help to engineer the results of a trial … to be able to make the claim about non-inferiority, at least to the medical community. So we’ve gotta keep an eye on them for that.” Dr Eric Topol Chairman and Professor, Department of Cardiology Director of the Joseph J Jacobs Center for Thrombosis and Vascular Biology at the Cleveland Clinic Clinical trials in crisis Staying alert

16. ASSENT-3 ASsessment of the Safety and Efficacy of New Thrombolytic Regimens - 3 6,000 patients with AMI presenting within 6 hours of symptom onset randomized into 3 groups: (Group A) – full dose tenecteplase with heparin sodium (Group B) – full dose tenecteplase with enoxaparin sodium (Group C) – half dose tenecteplase with abciximab and heparin sodium combined clinical endpoints: death, AMI, refractory ischemia, intracranial hemorrhage and major bleeding Clinical trials in crisis

17. Follow-up trials There is the danger that the definitive follow-up trials will not be done despite promises to the contrary. Will there be a follow-up to ASSENT-3? Will there be a follow-up to ESPRIT? -Topol Clinical trials in crisis

18. Power of capitalism Head-to-head trials will happen because the market demands it. Market is set by what physicians demand in terms of this practice. -Califf Clinical trials in crisis

19. Who will do active control trials? These trials cost a great deal of money. The trials are either not undertaken as they ought to be, or they are undertaken with insufficient amount of study. -Topol

20. Clinical trials in crisis PROVE-IT redux There are lots of reasons to do a clinical trial comparing atorvastatin vs other statins: differences in effects on HDL fibrinogin inflammation Comparing a potent LDL lowering statin vs one with other effects could be very important if it was done properly – with longer duration and greater numbers than PROVE-IT. -Topol

21. “[Bristol-Myers Squibb] are a company that put everything on the line and did definitive mortality trials and the response of the clinical community has been to prescribe [pravastatin] at about one seventh or one eighth the rate as atorvastatin which has not had any definitive clinical outcome trial.” Dr Robert Califf Professor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University Clinical trials in crisis Doing the right thing

22. “The medical community has been seduced by the ease of lowering LDL. But it may not even have much to do with the LDL per se as to the clinical benefits. That’s why we need a definitive trial in this area and that’s why we don’t have an adequate governmental or honest broker support.” Dr Eric Topol Chairman and Professor, Department of Cardiology Director of the Joseph J Jacobs Center for Thrombosis and Vascular Biology at the Cleveland Clinic Clinical trials in crisis Honest brokers

23. Clinical trials in crisis Critical trials Certain trials are crucial but don’t get done: Drugs with extensive track records put against newer drugs with lots of uncertainty. Drugs that are commonly prescribed and worth vast amounts to the pharmaceutical industry, but there remain large gaps in our knowledge. -Califf

24. Clinical trials in crisis How do you solve the problem? A government agency to force definitive trials? Does the market work through physicians? Or does the market control physicians? Where these uncertainties exist, will any company give an objective answer?

25. Clinical trials in crisis Comparing treatments “[These trials] are so easy to do. […] We could get the answers to these questions in no time, don’t you agree? -Topol “It’s not rocket science. It’s things that doctors do every day and it is just randomly allocating whether you do A or B where you don’t know which is better.” -Califf

26. Clinical trials in crisis Consumer reports An ideal world would have a system where patients and doctors would set the top 10 questions to be answered. Need to reward the R&D dollars for the best quality, not the best marketing. There’s a reason we have Consumer Reports for cars: you don’t just trust the salesman. -Califf