NTZ: Advisory Committee Votes Against Approval
On May 6 the FDA's Antiviral Drugs Advisory Committee voted 9-1 against approval of NTZ for treatment of cryptosporidiosis, which causes severe diarrhea in persons with AIDS. The one community representative on the panel, Michael Marco of the Treatment Action Group (TAG), cast the vote for approval. A number of treatment activist and patient groups (including AIDS Treatment News) had urged that NTZ be approved, despite disappointment that better data was not available. "Even though the quality of data UNIMED has presented is marginal, undeniably there is a documented clinical response with an excellent safety profile" (quoted from the consensus letter).A government-sponsored placebo-controlled trial (ACTG 336) was supposed to provide the most important data to support the approval. But this study was closed recently when it proved impossible to enroll. Sixty volunteers were needed, but only 10 had entered in 15 months. The main reason the ACTG trial could not recruit is that peoples' health has greatly improved as a result of the new combination antiretrovirals, reducing the incidence of cryptosporidiosis to a fraction of what it used to be. Also, the trial was unattractive because volunteers had to remain untreated until a positive diagnosis was made, and then risk being assigned to a placebo for the first part of the treatment period.
The FDA acknowledged that it would not be possible to get placebo-controlled data for this drug, and invited the company to submit the results it had. FDA analysts could not find proof of efficacy in the company's data.
NTZ, which "has the broadest spectrum of antiparasitic activity ever achieved with a single drug"1, is chemically related to metronidazole (Flagyl), but does not have the severe side effects of the latter. Since NTZ is only partially absorbed from the gut, it is most likely to be useful against pathogens in the intestines. Almost everyone familiar with this drug believes that it does have activity against cryptosporidiosis--although this parasite is difficult to cure in many cases, possibly because it can get into places where NTZ cannot reach it well. In these cases, treatment may need to be continued. Also, there is still disagreement and confusion about the best strategies for dosing NTZ.
For background on NTZ, see AIDS Treatment News #239 (January 19, 1996), #250 (July 5, 1996), #258 (November 1, 1996), and #288 (December 6, 1997).
Comment
We are concerned about the future of NTZ for several reasons:
A significant number of people will still need this drug. It is approved in Mexico and available there, but most U.S. patients who need NTZ will not know about it, or be able to obtain it easily.
NTZ may have major uses aside from cryptosporidiosis. It appears to be effective for microsporidiosis as well, although no trial has been done. It may also be an important contribution against giardia and other parasites which can be difficult to treat in some cases, even though there are approved drugs available.
Diarrhea caused by parasites is often difficult to diagnose--especially in cost-constrained public clinics or managed-care settings. Patients and physicians should have the option of trying a broad-spectrum treatment which may be effective against organisms which, for various reasons, could not be identified.
What should be done now? Clearly a controlled trial for cryptosporidiosis is not feasible today--as the FDA, and most of the members of its advisory committee, apparently recognize. What seems to have gone wrong in this case is that once the classical placebo-trial model was rejected, the development of this drug was on new, unfamiliar ground--and the company did not get the guidance it needed on how to operate in this new environment in a way that would develop data useful for the regulatory process.
We are preparing a separate article on study designs that would be appropriate for NTZ today--or for similar situations when they occur in the future.
References
1. Dubreuil L, Houcke I, Mouton Y, and Rossignol JF. In vitro evaluation of activities of nitazoxanide and tizoxanide against anaerobes and aerobic organisms. Antimicrobial Agents and Chemotherapy. October 1996; volume 40, number 10, pages 2266-2270.
