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Executive Summary

ANTITHROMBOTICS MUST SHOW SUPERIOR EFFICACY TO HEPARIN in clinical trials in order to receive FDA approval, FDA Gastrointestinal & Coagulation Drugs Division Director Stephen Fredd, MD, told the International Biotechnology Expo in San Francisco on Oct. 13. He advised companies developing novel antithrombotic agents to be prepared "to reject the null hypothesis -- that is you have got to say it is not as good as heparin, it has got to be better." Speaking at a session on recombinant cardiovascular agents, Fredd pointed out that heparin has not been clearly shown to be beneficial in at least two treatment areas: angioplasty and thrombolysis. "It is important to consider this," Fredd commented, "because in clinical trials of drugs like [Ciba-Geigy's] hirudin and other antithrombotic drugs, the comparator is going to be heparin." Fredd cited the results of the GISSI-2 thrombolysis trial as support for his views on heparin efficacy. While allowing that heparin was not used in the study in the same manner as in the U.S., Fredd said that "adding heparin in this setting did not give a clear result in terms of showing a mortality benefit." Citing another heparin study in angioplasty, he noted that "there is no effect of heparin in this situation but...there was a statistically significant increase in bleeding." He suggested that heparin may be effective in treating unstable angina, "but only if you continue it." Fredd contended that lack of efficacy and increased bleeding "is coming up more and more as a theme in terms of heparin in some of these situations." However, he added that just "because a trial turns out negative, as you well know, it does not mean a drug doesn't work, unless there [are] statistical results in the opposite direction. It just means the result is null." The FDAer outlined several points to consider in designing clinical trials to eliminate confounding factors that may contribute to negative trial results. The first consideration in the design of a clinical trial for antithrombotic drugs should be restrictive entry criteria, Fredd said. "If you were doing an angioplasty study, you could say you want studies of a certain type of lesion, so many vessels, etc." Studies should stratify for one factor; he recommended against hyperstratification. "It leads to a very intrusive process that is very difficult to control and makes for a lot of error and may undo your study," he noted. Sponsors must estimate covariate confounding and adjust their study sample size accordingly, Fredd emphasized. "Often when you have done a clinical trial -- and you could have 1,000 patients in each arm -- you will find when you come to the end of your clinical trial you will have an imbalance in one of these risk factors," he remarked. Fredd noted that statisticians in his division are working on a statistical model that would help companies determine "how many variables might there be that we are not controlling for in entry criteria, that we are not stratifying for, that we might have to augment the sample size to make sure that we are going to minimize this possibility of confounders." Fredd said that sponsors may be able to minimize their study sample size by adding composite endpoints to their studies, such as myocardial infarction or shock. A problem with composite endpoints, however, is that "when you get to the end [of the study] you may not have anything but a trend in several of [the endpoints], which may make labeling or what the drug does unclear," Fredd observed. Sponsors also may choose to use surrogate endpoints in their trials, such as patency in thrombolysis, Fredd said. However, he pointed out that patency "has not proven to be entirely predictive of clinical benefit" and noted that it is being further explored as a surrogate endpoint in Genentech's GUSTO trial, which is comparing TPA, anistreplase, and streptokinase. Expressing skepticism, Fredd described the large trial as having "a very limited design." Antithrombotic agents under development by biotechnology firms include: Biogen's hirulog, which is entering Phase III; recombinant hirudin in Phase II being developed by Ciba-Geigy; and thrombomodulin, in preclinical studies by Berlex. Berlex Preclinical R&D Director Robert Wydro, PhD, reported that the company is developing thrombomodulin for "prophylaxis after major orthopedic surgery for prevention of deep vein thrombosis and pulmonary embolism." Unlike heparin and hirudin, which directly inhibit thrombin, thrombomodulin down-regulates thrombin, Wydro said. He maintained that thrombomodulin prevents deep vein thrombosis without inducing the bleeding complications of heparin.

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