ddC: Developer Speeds FDA Application

Hoffmann-La Roche, the developer of the anti-HIV drug ddC, has arranged with the U. S. Food and Drug Administration to submit its New Drug Application (NDA) for that drug in sections as they are ready, for stepwise review by the FDA, instead of the usual procedure of waiting until the whole NDA is finished. The company estimates that the submission process should be completed by midyear. In addition, Hoffmann-La Roche will seek marketing approval for ddC in combination with AZT, as well as approval for use of ddC alone as an alternative to AZT. These efforts to speed the approval are important for several reasons:

* Each NDA is a large document, with many volumes of paperwork; it is submitted by one large organization (a pharmaceutical company) for evaluation by another (the FDA). In any such procedure, the differences in corporate culture between the organizations, as well as the effects of staff turnover, will invariably lead to points of friction, requiring sometimes lengthy negotiations to resolve. This organizational dynamic alone can lead to major delays in drug approval, quite aside from any substantive scientific, medical, or policy questions. Submitting the NDA in sections allows early issues to be addressed immediately, and later frictions to be reduced as the individuals involved develop working relationships.

* The FDA has traditionally leaned strongly toward first evaluating a drug by itself, and considering combinations only after efficacy has been shown for the drug alone. ddC, however, is showing unexpectedly good results in combination with AZT, in a small study. (See AIDS TREATMENT NEWS #115, November 23, 1990, for early news about this combination. The study results have not yet been formally published.) If Hoffmann-La Roche had not applied for combination approval at this time, then the combination data would have been irrelevant to the FDA's evaluation of the NDA, and the drug would have been judged without this strong support.

* AIDS treatment activists had also feared that ddC approval would be delayed by the serious staff shortages at the FDA -- that the Agency could not afford to assign people to evaluate the NDA for ddC until the NDA for ddI was finished. The staff shortages are very much a problem; but at least the wait behind ddI seems unlikely to happen with ddC.

There are still concerns about how much if any of the data from the major controlled trials now ongoing can be used in the current evaluation of ddC (and also ddI). Some experts fear that using the data being generated by these trials, before the trials have ended, might bias the studies or even lead to their discontinuation. The existing studies are automatically reviewed anyway, by a Data Safety Monitoring Board (DSMB); however, the DSMB operates secretly, even from the FDA, and it only looks for extreme differences between the study drugs, differences which would make it unethical to continue the study. For drug approval, the question is not whether the new drug is very different from an already-approved therapy, or even whether the two are equivalent; instead, the key question is whether the new drug has efficacy and value as a treatment. We are concerned that ddC (and ddI) may be evaluated without considering all of the important existing data. We do not know how this complex issue will be resolved.