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Testimony on Accelerated Approval: September 1994

By Carlton Hogan

November 2003

In 1994, Carlton Hogan testified before an FDA Antiviral Advisory Committee about the risks of letting drugs loose in the population without a rigorous method to detect and report late emerging toxicity. In 2003, AIDS activists met with FDA and repeated many of the concerns that Hogan outlined: the need for post-marketing follow-up, the failure of drug companies to live up to commitments made to study drugs after they are approved, the inadequacy of penalties available to FDA for enforcing those commitments. Hogan's testimony seems especially prescient as it was made before the advent of truly effective antiretroviral therapy -- and well before lipodystrophy and other complications associated with the new regimens had come to light. Carlton Hogan was an intellectual and moral leader in the AIDS treatment activist movement at a critical time and these excerpts from his testimony remain provocative today.

Access to promising new drugs is a right one cannot deny patients with a fatal illness. However, this right carries with it the responsibility to provide information that will advance science and help future generations of patients.

Despite the serious nature of my personal circumstances, I am loath to ingest any more potentially useless and toxic therapies. Poisoning myself seems an irrational response to a threat on my life. I think there is a very natural tendency to trust medicine in this age of antibiotics, and to believe a priori that taking "something" is always better than taking "nothing." While comforting, this notion is also quite incorrect.

The current accelerated approval regulations are adequate, albeit somewhat ambiguous, hence this meeting. One of the more important components, to my mind, is the provision for FDA to ask for further post-marketing (phase IV) studies if they have concerns as to the efficacy or safety of a drug receiving accelerated approval. Unfortunately this component, while reasonable in conception, has proved unworkable in execution. ddC received approval on the basis of little clinical information, conditional on Roche later making a determination of clinical efficacy. Of course as everyone in this room no doubt knows, Roche did not follow through, and those studies have not been done to date.

Unfortunately it appears that FDA’s only recourse in such a situation would be to withdraw a drug from market, a politically difficult solution, and a cruel one as well, as persons taking ddC would be abruptly dropped. [The neurotoxicity of ddC subsequently became apparent and the drug, while still available, is now rarely used. Ed.] Clearly, in the absence of evidence of harm from ddC this would be an unacceptable solution, even were it politically possible. I think it is highly unlikely that we will see an HIV drug withdrawn from market unless it proves overwhelmingly toxic (and given AZT's toxicities, it is hard to imagine how bad that might be), or unless there is a replacement that is so clearly superior as to make much of this discussion moot. Therefore much of the requisite information will have to continue to be collected prior to full unrestricted approval.

It would be great if early testing of toxicity, such as occurs in Phase I trials, could be counted on to uncover all of a drug’s deleterious effects. But some toxicities develop only in some persons, or only over longer periods of time. None of the phase I or II trials of AZT revealed the now widely recognized side effect of myopathy. It was only after large numbers of patients had taken AZT over long periods of time that myopathy became apparent. I believe it eminently possible, and even probable, that there are many compounds biologically active against HIV, which are able to clear short term toxicology testing, have a pronounced biological effect on the surrogate of your choice, yet in the long run do more harm than good. In the quest for an effective anti-HIV treatment, we are looking for something to interfere in intercellular processes. I fear that our biochemical "fingers" are still a little too thick and blunt to "fix" that finely machined watch without perturbing the system in unknown, and possibly untoward ways. And perhaps we may be a little too arrogant and insecure to admit the limitations of our knowledge and skill.

Carlton Hogan, born on July 28, 1961, passed away on November 18, 2003.


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