FDA's ¹ proposed rule on expanded access to investigational drugs separates the eligible population for such treatments into three tiers based on the number of patients.

The proposed rule, released Dec. 11, clarifies existing regulations on expanded access by specifically outlining criteria for individuals, intermediate-size populations and larger populations under an IND protocol.

The agency also released a separate ² proposal on charging for investigational drugs. The documents will be published in the Federal Register Dec. 14.

FDA revealed the two proposed rules were under development this spring. The agency has been under pressure from patient advocacy groups to loosen restrictions on unapproved drugs. The Abigail Alliance and the Washington Legal Foundation filed a lawsuit against FDA claiming its policy barring the sale of experimental drugs is unconstitutional. In 2004, a D.C. federal court ruled that there is no constitutional right of access to experimental drugs and dismissed the case, but, in May, a D.C. federal appeals panel remanded the suit to the district court level (³ Also see "FDA Will Solicit sNDAs For Well-Researched Off-Label Uses, Gottlieb Says" - Pink Sheet, 10 May, 2006.).

In a Dec. 11 media briefing discussing the proposed rules, FDA Deputy Commissioner for Operations Janet Woodcock noted that "the reason for these proposed changes is after almost 20 years of experience with these regulations, we find that we need to clarify the provisions."

Under the proposed rule, "the level of evidence that you need to have about the drug, its potential for benefit and what's known about its risks would be proportional to the seriousness of the disease as well as the number of people proposed to be exposed to the drug," Woodcock explained.

For all expanded access uses, FDA details three criteria: first, patients must have serious or immediately life-threatening diseases or conditions with no comparable or satisfactory alternative therapy; second, the potential benefits outweighs the risks involved, and those risks are not unreasonable in the context of the disease; and third, providing the drug for the requested use will not interfere with the initiation, conduct or completion of trials that would support regulatory approval of the expanded access use.

Individual patients must meet two additional criteria to gain access to an investigational treatment - a physician has determined the probable risks from the drug are not greater than the probable risk from the disease, and FDA must determine that the patient is unable to obtain the drug under another type of IND or protocol.

The threshold is raised for intermediate-size populations, which the proposed rule defines as "a patient population smaller than that of a typical treatment IND or treatment protocol."

According to the proposed rule, two additional criteria must be met for intermediate-size groups: FDA determines that "there is enough evidence that the drug is safe at the dose and duration proposed for expanded access use to justify a clinical trial" in the approximate number of patients expected to receive the drug; and that there is "at least preliminary clinical evidence of the effectiveness of the drugs, or of a plausible pharmacologic effect of the drugs to make expanded access use a reasonable therapeutic option in the anticipated patient population."

Intermediate-size groups may be formed if FDA asks a sponsor to "consolidate expanded access under this section when the agency has received a significant number of requests for individual patient expanded access to an investigational drug for the same use."

The need for expanded access in this size group, according to the proposed rule, may stem from the fact that "the drug is not being developed, for example, because the disease or condition is so rare that the sponsor is unable to recruit patients for a clinical trial." The need also may exist if the drug is being developed, but the patients are unable to participate in the clinical trial, or if the drug is approved but is no longer marketed due to safety or other reasons.

Under a treatment IND, FDA would permit use of an investigational drug if three criteria are met. First, the drug must be under evaluation in a controlled trial under an IND designed to support a marketing application for the expanded access use, or all clinical trials of that drug have been completed. Second, the sponsor is seeking FDA approval with due diligence.

Finally, when the expanded access use is for a serious disease, "there is sufficient clinical evidence of safety and effectiveness to support the expanded access use," based on Phase III trials, or "compelling" Phase II data. For immediately life-threatening conditions, the available evidence should prove the drug may be effective while not exposing the patient to "unreasonable or significant" risk. That evidence could come from Phase II or Phase III studies, but also may be based on more preliminary data.

-Brooke McManus (b.mcmanus@elsevier.com)

Access To Investigational Drugs Under FDA Proposed Rule Depends On Size Of Treatment Group

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