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SURROGATE ENDPOINTS FOR TUBERCULOSIS DRUGS,

Executive Summary

SURROGATE ENDPOINTS FOR TUBERCULOSIS DRUGS, such as sputum conversion rates, are being evaluated by FDA's Antiviral Drugs Division, a supervisory medical officer for the division told the Antiviral Drugs Advisory Committee at its Feb. 19 meeting. Mark Goldberger, MD, updated the committee on the division's activities in encouraging drug companies to develop, make and supply drugs that are increasing in demand, but low in supply, such as drugs for treating tuberculosis. The antivirals division is considering different incentives, such as use of accelerated approval, to get drug companies to develop products that may not be profitable, but for which there is a public health need, Goldberger reported. Noting that the committee has endorsed the use of CD4 cell count levels as a surrogate endpoint for antiretroviral drugs, he said: "As far as trials for TB, the endpoint for these has in past been... looking at the relapse rate after therapy has been completed and this often required two years or so of follow-up after a treatment regimen that would be in the range of six to nine months." The FDAer noted that "the last two TB trials done in the United States took, I think, five to nine years to complete." The antiviral division is considering whether there is "a way that we can use the accelerated approval approach to perhaps look at some surrogate that is likely to predict the ultimate relapse rates," Goldberger said. "I think one thing that has been talked about is eight-week sputum conversion rates," Goldberger said. He added that the division is "actively working now with people from [the Centers for Disease Control and Prevention], NIH [and] a number of other people in the field of tuberculosis to get a sense of whether there is the kind of information that might allow this to become a reasonable endpoint in [a] trial, and I would hope that when these ideas are better developed they would probably be brought before the committee for some additional discussion." To speed up approval of new tuberculosis drugs, the division also is looking into using targeted drug development studies to determine into what treatment regimen the drug candidate may eventually fit. "Something that we're working on a lot right now with tuberculosis, and certainly it has been done with other products as well, is the integration of preclinical and early clinical data," Goldberger said. "Obviously there's a role in doing this in terms of safety, but one should also keep in mind, that for instance, if you were looking at doing a trial for tuberculosis, you're going to be taking a new drug and likely substituting it for another drug or combining it with a couple of other drugs in that trial." Goldberger stated that "one of the hopes is that by targeted preclinical and early clinical development, one would be able to understand how to best do this." He added: "I think we would prefer to do that through some early preclinical and clinical development rather than investing the resources that a large clinical trial would take to come to the same answer." Goldberger noted: "I got a call the other day from a major company who is interested in doing some work with developing... several combination tablets for TB." The company is "probably" going to come in for a meeting, he said. Another incentive for drug firms to develop TB drugs or products for other diseases is orphan drug exclusivity, Goldberger noted. For drugs that are in demand and already have approved applications, but are no longer marketed, the division has been asking the companies that formerly made the drugs to start manufacturing them again, and in some cases looking for alternative manufacturing or supply sources. Most recently, FDA approved an IND application for CDC to distribute sulfadiazine, which is used with pyrimethamine for treating CNS toxoplasmosis in AIDS patients and newborns with congenital infections, at no cost to physicians ("The Pink Sheet" Feb. 22, T&G-6). Stanley Pharmaceuticals agreed to supply CDC with the drug. The company that was selling the drug stopped manufacturing it in October 1992. In another recent case, Pfizer restarted manufacture of streptomycin following a nationwide shortage of the TB drug ("The Pink Sheet" Oct. 19, 1992, T&G-10).
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