BMJ  2007;334:326 (17 February), doi:10.1136/bmj.39113.534919.80

Editorials

Early termination of drug trials

What are the ramifications for drug companies and drug safety monitoring boards?

In December 2006 a randomised controlled trial of torcetrapib (a cholesteryl ester transfer protein inhibitor aimed at increasing high density lipoprotein cholesterol) was stopped after an unexpected increase in mortality in people taking the drug.¹ The implications are widespread, ranging from the future direction of cardiovascular prevention, the willingness of drug companies to develop new drugs in the face of massive financial risk, to the role of data and safety monitoring boards.

More than 12% of global mortality is caused by coronary heart disease.² Reduction of low density lipoprotein cholesterol with statins has been successful in primary and secondary prevention of such disease, although mortality rates remain high. Because high density lipoprotein cholesterol is inversely associated with risk of cardiovascular disease, much investment has gone into newer drugs that increase concentrations of high density lipoprotein cholesterol (such as torcetrapib).

Phase II trials found that torcetrapib increases high density lipoprotein cholesterol in a dose dependent manner when given with³ and without statins, and smaller trials found no significant increase in adverse events.³⁴ High density lipoprotein increases by 46% with 120 mg torcetrapib daily (P<0.001) and 106% with 120 mg twice daily (P<0.001).⁵

Despite these promising results, improvements in surrogate endpoints do not always translate to lower mortality. For example, it was thought that controlling ventricular extrasystole would reduce death in patients with coronary heart disease. However, the CAST trial found that although several anti-arrhythmic drugs did reduce ventricular extrasystole, mortality was also increased.⁶ A similar unexpected increase in mortality was seen for cyclo-oxygenase-2 inhibitors⁷ and clarithromycin.⁸

After successfully completing earlier phase trials, torcetrapib was tested in a randomised controlled phase III trial. The ILLUMINATOR trial, sponsored by Pfizer, planned to recruit 15 000 patients to be randomised to take torcetrapib combined with atorvastatin or atorvastatin alone. Follow-up was planned to continue until 2009, but on 3 December 2006 the trial was stopped prematurely, on the advice of the data and safety monitoring board, because of significant excess mortality in patients taking torcetrapib and atorvastin compared with those taking atorvastatin alone (82 compared with 51 deaths).¹ The cause of the increased mortality was not known.

The outcome illustrates, among other things, the importance of data and safety monitoring boards in monitoring the progress of trials. It is simplistic to say that the trial caused 31 unnecessary deaths because even though the difference between treatments groups was statistically significant, this difference could still be a chance finding. As results accumulate over time, outcomes often differ between treatment groups. The challenge for the safety monitoring board is to judge whether such differences are statistically and clinically convincing. Only when a sufficient number of deaths have occurred can there be any confidence in the validity of the observation.

The data and safety monitoring board reviews these differences according to a predefined plan as the results unfold. Such boards often establish their own guidelines to indicate when the steering committee should be advised to discontinue a trial on the grounds of benefit or harm from a new treatment. Typically, a data and safety monitoring board will use "asymmetric" guidelines, so that less certainty is needed to advise stopping the trial on the grounds of harm than when the treatment under investigation seems to be beneficial.

Data and safety monitoring boards walk a narrow line; patients volunteering to participate in trials should not be exposed to undue risks from drugs, yet if a trial is stopped without compelling evidence of harm or benefit many more patients may later be denied potentially useful treatments. In the ILLUMINATOR trial, no indication or hypothesis suggested that inhibition of cholesteryl ester transfer protein had serious adverse effects, and the data and safety monitoring board was correct to allow the trial to continue until harm had been demonstrated with a reasonable degree of confidence. The potential benefit of the new treatment to vast numbers of patients cannot be underestimated.

Should data and safety monitoring boards have the responsibility of observing excess deaths yet allowing treatment to continue? Although these boards face many problems,⁹ no alternative exists; if the hypothesis on which the trial was based is convincing it can only be tested by a large phase III trial. Also, the role of data and safety monitoring boards in such trials is mandatory according to binding international guidelines.¹⁰

Bearing in mind their crucial role how can the functioning of these boards be optimised? They should comprise clinicians and statisticians who thoroughly understand the clinical area of the trial, who are experienced in the vagaries of trials, and who have no financial or other competing interest in the outcome of the trial. They should be small, at the most five members, to allow rapid communication among members. Because of the size of many clinical trials, information delays are inevitable. Much attention should be given to the speedy production and transmission of data from the trial organisation to the board, so that decisions can be made in a timely manner. These boards carry heavy responsibilities, and the scientific merits of being a member of one should be recognised as equivalent to coauthorship.

Finally, the impact on drug companies of such an event cannot be underestimated. Pfizer's action of withdrawing the drug appears entirely proper, yet the decision to terminate the ILLUMINATOR trial must have been difficult. The financial costs to the company are substantial, but keeping the drug alive might have been even more costly, as demonstrated by the Vioxx tragedy.¹¹ It must be hoped that the drug industry does not as a result of this and similar events lose the will to engage in the development of innovative drugs, for which phase III trials remain essential.

¹ Department of Cardiology, Copenhagen University Hospital, 2650 Hvidovre, Denmark, ² Queen's Medical Centre, Nottingham NG7 2UH

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Competing interests: GBJ and JH have served on many data and safety monitoring boards. GBJ is chairman of the Danish Board of Registration of Medicines and a past member of CPMP, the scientific board of the European Medicines Agency.

Provenance and peer review: Commissioned; not externally peer reviewed.

References

1. US Food and Drug Administration. Pfizer stops all torcetrapib clinical trials in the interest of patient safety. 3 December 2006. www.FDA.gov/bbs/topics/news/2006/new01514.html
2. Mathers CD, Bernard C, Iburg KM, InoueM, Fat DM, Shibuya K, et al. Global burden of diseases 2002: data sources, methods and results. Global Programme on Evidence for Health Policy Discussion. Paper No. 54. Geneva: World Health Organization, 2003. www.who.int/healthinfo/paper54.pdf
3. McKenney JM, Davidson MH, Shear CL, Revkin JH. Efficacy and safety of torcetrapib, a novel cholesteryl ester transfer protein inhibitor, in individuals with below-average high-density lipoprotein cholesterol levels on a background of atorvastatin. J Am Coll Cardiol 2006;48:1782-90.[Abstract/Free Full Text]
4. Davidson MH, McKenney JM, Shear CL, Revkin JH. Efficacy and safety of torcetrapib, a novel cholesteryl ester transfer protein inhibitor, in individuals with below-average high-density lipoprotein levels. J Am Coll Cardiol 2006;48:1774-81.[Abstract/Free Full Text]
5. Brousseau ME, Schaefer EJ, Wolfe ML, Bloedon LT, Digenio AG, Clark RW, et al. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med 2004;350:1505-15.[Abstract/Free Full Text]
6. Cardiac Arrhythmia Suppression Trial Investigators. Preliminary results: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989;321:406-12.[Abstract]
7. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibition. JAMA 2001;286:954-9.[Abstract/Free Full Text]
8. Jespersen CM, Als-Nielsen B, Damgaard M, Hansen JF, Hansen S, Helo OH, et al. Randomised placebo controlled multicenter trial to assess short term clarithromycin for patients with stable coronary heart disease: the CLARICOR trial. BMJ 2006;332:22-7.[Abstract/Free Full Text]
9. DeMets DM, Furberg CD, Friedman LM, eds. Data monitoring in clinical trials. A case studies approach. New York: Springer, 2006.
10. European Medicines Agency. Committee for Medicinal Products for Human Use. Guideline on data monitoring committees. 27 July 2006. www.emea.europa.eu/pdfs/human/ewp/587203en.pdf
11. Krumholz HM, Ross JS, Presler AH, Egilman DS. What have we learnt from Vioxx? BMJ 2007;334:120-3.

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