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Accelerated Approval Guidelines Expedite Bristol’s Launch of New Nucleoside — In the Absence of Any Proof That It Works

Specter of Fast Track Review Haunts Those Who Spawned It

“FDA Panel Recommends Drug Despite Incomplete Data.” So read the New York Times headlines emblazoned above the brief article summarizing the proceedings of the May 20th regulatory hearing charged with reviewing the new drug application (NDA) for Bristol-Myers Squibb’s new nucleoside, stavudine (d4T). The wire story went on to explain that, “An advisory committee to the FDA said that d4T, or stavudine, probably provided some benefit over the three existing AIDS drugs. But the panel could not say just who would benefit, just how safe it was or whether the manufacturer was on the right track to answer the many questions.” And thus, haunted by the very Accelerated Approval guidelines they had fought for years to put in place, New York treatment activists found themselves further submerged in the ever-murkier ooze that has become AIDS clinical drug development and licensure.

Stavudine (trade name, Zerit) is the second nucleoside antiretroviral therapy to be licensed through the FDA’s new Accelerated Approval guidelines. Roche’s ddC (Hivid) received Accelerated Approval for use in combination with AZT back in June of 1992, but the “conditional” approval was later recommended for revocation subsequent to follow-up data which failed to corroborate the combination’s preliminary indications of efficacy.

Bristol’s case for d4T was based on interim results from a 359-patient study, AI455-019 (dubbed “019”), which began in May of last year and compares d4T to AZT in persons who have had six months or more of prior AZT therapy. The 019 data was complemented by results from Bristol’s d4T expanded access program through which over 10,000 persons (no longer benefiting from or otherwise intolerant to currently available nucleoside therapies) received d4T, half assigned to receive 20 mg twice daily and the other half, 40. Data on only 3,786 of the total patients enrolled was available for the committee’s review.

While the 019 study reported the drug to be “safe” at a dose of 40 mg twice daily, that dose was found to be too toxic among persons receiving d4T through expanded access. Peripheral neuropathy, a painful and sometimes irreversible throbbing, tingling or numbing of hands and feet, was reported in over 20% of patients enrolled in the d4T expanded access program. At the 20 mg (twice daily) dose, d4T-induced peripheral neuropathy was reported at a more modest 15%.

The 019 study showed that after a median of six months’ follow-up, CD4+ T cell counts in the d4T group had risen 20-25 cells and by week 24 fallen back to baseline. Persons who continued on AZT, however, showed continued declines of up to 50 cells or so. One might recall that ddI’s (Videx) approval rests on the Orwellian construct of a “50:50 dichotomous change” as a definition of efficacy; that is, a CD4+ T cell count rise of 50% or — as was more often the case — 50 cells. With the d4T application as with both ddI and ddC before it, in order to evaluate the drug’s ability to slow progression to disease or death, reviewers had only this so-called “surrogate” CD4+ T cell data from which to extrapolate expected clinical benefit — markers which remain, at best, unvalidated and increasingly appear on their way to becoming invalidated.

Perhaps the most puzzling aspect of the d4T application was the data on antiviral activity. Changes in p24 antigen were reported to be “non-significant” in patients given d4T (although at higher, poorly tolerated doses antiviral activity comparable to that of AZT has been demonstrated). No anti-HIV drug has ever before been recommended for approval without evidence of antiviral activity. In the expanded access program too, when measured by survival and/or CD4+ T cell responses, no difference was found between the 20 mg dose and the 40 mg dose, suggesting that the 20 mg dose might be as effective — or as ineffective — as the 40 mg dose.

After the hearing, one committee member, defending the decision to recommend approval, commented to an activist that “CD4 cell increases combined with evidence of antiviral activity are reasonably predictive of clinical outcome.” When reminded that d4T, at tolerable doses, failed to demonstrate antiviral activity he shrugged, grimaced, and said “Oh, yeah.” AI455-019 will continue through December 1994.

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