KEY CRITERIA FOR DETERMINING WHEN AN IND DRUG CAN BE WIDELY DISTRIBUTED AND/OR SOLD UNDER FDA's "REPROPOSAL" OF TREATMENT USE AND SALE REGS

The information below has been taken from the regulatory language and explanatory preamble in FDA's Treatment Use and Sale IND regs. The proposal appeared in the March 19 Federal Register. It was listed separately from the final IND Rewrite reg. The highlights excerpted on this page and the following page are the cornerstones for FDA's criteria to determine under what circumstances an investigational drug can be sold and when a sponsor can apply for wider distribution of an investigational product prior to NDA or PLA approval. To define treatment use, FDA differentiates between two situations: (1) immediately life-threatening illnesses; and (2) serious disease states. Those two situations are used below as subheadings below the general criteria for treatment use of investigational drugs. Similarly, FDA distinguishes between two situations for the sale of IND-stage products: (1) sale for treatment use in the case of serious and/or life-threatening disease; and (2) sales during traditional clinical trials. Those two situations are also used as subheadings under the general provisions for sales of investigational drugs. TREATMENT USE (GENERAL CONDITIONS) "... treatment use of an investigational drug would be permitted where: the drug is intended to treat an immediately life-threatening or otherwise serious disease; there is no satisfactory alternative drug or other therapy available to treat the disease; the drug is under investigation in a controlled clinical trial under an IND in effect for the trial; and the sponsor of the controlled clinical trial is pursuing marketing approval of the investigational drug with due diligence." TREATMENT USE IN IMMEDIATELY LIFE-THREATENING SITUATIONS [DATA TO SUPPORT A TREATMENT IND] "... for a drug intended to treat an 'immediately life-threatening' disease, the Commissioner may deny a request for treatment use if he or she finds that, on the basis of clinical data or other reliable scientific evidence in the IND file, the drug clearly does not provide a therapeutic benefit; or the drug would expose the patients to whom the drug is to be administered to an unreasonable and significant additional risk of illness or injury." "... it is expected that data from controlled clinical trials will ordinarily be available at the time a treatment IND is requested. Even so, there may be circumstances where little data are available concerning the therapeutic benefit of a drug, particularly if Phase I studies have just ended or Phase II testing has only recently begun ... the reproposal requires that the Commissioner have adequate support for a determination that there is an unreasonable and additional risk or clearly no therapeutic benefit for the Commissioner to deny treatment use." "It is expected that the Commissioner will be provided with sufficient data to make the specified determination." [DEFINITION OF "IMMEDIATELY LIFE-THREATENING" DISEASE] "What constitutes an immediately life-threatening illness cannot be rigorously defined. The medical judgment of the sponsor or treating physician must carry considerable weight in deciding whether an illness poses a sufficient threat to justify treating patients with a drug for which safety or effectiveness has not been demonstrated fully." "Generally, an immediately life-threatening illness is one that poses a significant threat of the patient's dying unless the course of the disease is promptly altered to reduce that possibility. As used in this context, the term 'immediately' refers to the need to treat the illness quickly, without implying any particular time within which death is expected to occur (though such time is expected to be reasonably short)." "The term 'life-threatening' extends both to situations in which it is certain that patient's disease will result in death and to situations in which death is a highly probable outcome of the disease." [EXAMPLES] "The procedures for immediately life-threatening diseases would apply, for example, to advanced cases of Acquired Immune Deficiency Syndrome (AIDS) and certain uncontrollable cardiac arrhythmias." TREATMENT USE IN SERIOUS DISEASES [DATA TO SUPPORT A TREATMENT IND] "... the denial of treatment use for serious, but not life-threatening, disease conditions can be based on a finding of insufficient evidence of safety and effectiveness to support such use." "Ordinarily, in the case of a serious disease, a drug may be made available for treatment under this section after Phase II investigations have been completed. . ." [EXAMPLES] "... the procedures for other serious diseases would apply, for example, to Alzheimer's and multiple sclerosis." SALES OF INVESTIGATIONAL DRUGS (GENERAL) [DELEGATION OF AUTHORITY] "On reconsideration, FDA has revised the rule to authorize the directors of the review offices [Director, Office of Drugs and Director, Office of Biologics] to approve sale requests in [addition to] the Director [of the Center for Drugs & Biologics]." [RATIONALE] "... these procedures would benefit sponsors of unusually expensive drugs and/or sponsors whose size and resources make it difficult to finance new drug development." "With the revolution in biotechnology, it is important to recognize the need to provide sufficient incentives for the rapid development of drug and biological agents." [FDA CONTROL OF IND PRICES] "... to curb any possible abuse, under the reproposal FDA could withdraw authorization for sale of a drug, distributed under either a clinical trial or a treatment IND, if it determines that a charge for the drug is manifestly unfair." "... it would be inappropriate to introduce into the sale provision specific price controls or a procedure in which the agency becomes a price regulator. The sponsor is in the best position to know the costs involved in the manufacturing of a drug." SALES OF TREATMENT IND DRUGS [RATIONALE] "... costs of treatment use drugs will be costs incurred beyond those needed to obtain marketing approval." [FDA PERMISSION] "... in the case of sale of a drug intended for treatment use, notification by the sponsor is required and after 10 days sale would be allowed unless FDA disapproves." "Prior approval of the sale by FDA is not required." "... affirmative approval would unnecessarily delay the availability of treatment use drugs that have met the criteria for treatment use." [RESTRICTIONS ON SALES] "A sponsor or investigator may sell an investigational drug for a treatment use under a treatment protocol or treatment IND that is in effect for the treatment use provided (i) the sale does not constitute commercial marketing of a new drug for which a marketing application has not been approved; (ii) the drug is not being commercially promoted or advertised; and (iii) the sponsor of the drug is actively pursuing clinical studies and marketing approval with due diligence." SALES DURING TRADITIONAL CLINICAL TRIALS [RATIONALE] "An explanation of specific modern advances in science and technology that create an environment of extremely high costs could warrant the sale of drugs used in clinical trials." "... Permitting sale in such cases should permit greater competition in drug development by permitting small and fledgling companies to test products that are extremely expensive to produce, providing all ethical concerns are met." [FDA PERMISSION] "The traditional notion that clinical trial costs are a cost of doing business should hold unless the sponsor provides adequate explanation for the sale and receives affirmative FDA approval." "... FDA does not believe it should commit to respond to requests for sale of drugs in clinical trials within a specified time frame. Nevertheless, FDA is committed to expediting review of these requests within the constraints imposed by available resources and other priorities." "... prior written approval ... [is required from] the Director of the Center for Drugs & Biologics, the Director of the Office of Drug Research & Review, or the Director of the Office of Biologics Research & Review, as the case may be, upon a full written explanation by the sponsor that sale is required in order for the sponsor to undertake or continue the clinical trial."