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FDA's ACCELERATED DRUG APPROVAL PROPOSAL WOULD PERMIT RESTRICTED DISTRIBUTION OF HIGHLY TOXIC, BENEFICIAL PRODUCTS; REQUIRE REVIEW OF PROMOTIONAL MATERIALS

Executive Summary

An early version of FDA's proposed rule for accelerated drug approvals would give FDA the authority to restrict distribution of "clinically beneficial" drugs and biologics that are highly toxic. The draft proposal states that some drugs eligible for accelerated approval might be "so inherently toxic or otherwise potentially harmful" that they could be "used safely only if distribution and use are modified and restricted." The document says "FDA is prepared to approve such high-risk drugs for early marketing if the agency can be assured that postmarketing restrictions will be in place to counterbalance the known safety concerns." The type of restrictions that FDA has in mind "may include" limiting distribution to "certain facilities or to physicians with special training or experience" or "conditioning distribution on the performance of specified medical procedures." For example, the draft states, distribution could be restricted to "settings in which emergency capabilities and equipment are readily available." A requirement for medical procedures might be similar to the mandate that distribution of Sandoz' Clozaril was contingent on weekly blood monitoring. The draft states that such "restrictions will be considered necessary only rarely and in extraordinary cases." The safe use of most products approved through the accelerated process would "continue to be ensured through traditional patient management by health professionals and through necessary safety warnings on the drug's labeling," FDA said. Some pre-approval plans for expanded access, such as the NCI Group C plan, already have restrictive aspects. If FDA were to go ahead with its accelerated approval plan, however, it would be stretching those distribution restrictions into the post-approval period. The draft proposal currently circulating in Washington bears the signatures of HHS Secretary Sullivan and FDA Commissioner Kessler, indicating a substantial level of clearance. The Vice President's Competitiveness Council has also been looking into the accelerated approval issue. FDA would limit accelerated approval procedures to drugs and biologicals for serious and life-threatening diseases for which no adequate alternative therapy exists. Therefore, the draft states, the proposal covers AIDS, HIV infection, Alzheimer's disease, "psychoses, depression, angina pectoris, heart failure, inflammatory bowel disease, asthma, cancer, rheumatoid arthritis, diabetes mellitus and many other diseases [that] are serious in some or all of their phases." The agency said it will "consider granting" accelerated approvals that rely on surrogate endpoints and on postmarketing studies "to elaborate on the evidence" of safety and effectiveness found in clinical trials. The draft notes that surrogate endpoints may indicate safety and effectiveness "before there is a demonstrated effect on patients' survival or overall well-being." FDA said sponsors of products whose approvals are based on such markers "would be required to conduct any clinical studies necessary to ascertain the actual clinical benefit of the drug on such endpoints as survival, disease complications or longer-term symptoms." The draft also requires sponsors to submit all promotional materials for FDA review before accelerated approval can be granted. "Because drugs approved under the restricted use provision may be highly toxic or otherwise potentially harmful, FDA is concerned that certain promotional claims could cause inappropriate and, therefore, unsafe use," the document states. FDA also is proposing that drugs approved through an accelerated process be subject to "streamlined withdrawal procedures" if they are shown to be unsafe or ineffective. A "streamlined, expeditious" withdrawal would be indicated if "(1) a postmarketing clinical study fails to verify clinical benefit; (2) the drug's sponsor fails to perform the required postmarketing study with due diligence; (3) experience with the drug after marketing demonstrates that restrictions on distribution or use are inadequate to ensure safe use; (4) the drug's sponsor fails to adhere to the postmarketing restrictions agreed upon; or (5) other evidence demonstrates that the drug product is not shown to be safe and effective under its conditions of use."
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