FDA ACCELERATED APPROVAL REG IS "INCONSISTENT" WITH FD&C ACT, NEUROPHARM DIRECTOR LEBER MAINTAINS; BRISTOL-MYERS SQUIBB ALSO OPPOSES PROPOSAL

FDA's proposed accelerated approval regulation is "inconsistent with the 'substantial evidence' requirements of [the FD&C] Act," FDA Neuropharmacological Drug Products Division Director Paul Leber, MD, argued in June 15 comments opposing the proposal. The agency traditionally has interpreted the act's requirement for "substantial evidence" of safety and efficacy to mean "empirical evidence adduced in clinical investigations that is of such quality and character that it would allow a representative, fair minded, impartial, disinterested, and appropriately qualified expert to conclude reasonably from that evidence alone that the drug product in question will have the effect claimed," Leber wrote. FDA's "longstanding" interpretation of "substantial evidence" is difficult to square with the surrogate marker approach taken in accelerated approvals, Leber maintained. "It is difficult to reconcile the agency's longstanding interpretation of the 'substantial evidence' of efficacy requirement with the rule's proposal to rely on the speculations of experts about the capacity of unvalidated surrogate indicators to predict the efficacy of experimental new drug products," Leber stated. The proposed accelerated approval regulation was published in the April 15 Federal Register ("The Pink Sheet" April 20, p. 8). Leber's comments are among 22 responses to the proposal submitted ahead of the original June 15 deadline. The comment period since has been extended to July 15. Commissioner Kessler has maintained publicly that accelerated approval "does not represent a change in FDA's traditional standard." The commissioner asserted that the reg "is an acknowledgment of what we have always stated, that we must be prepared to accept greater risks from a drug when greater benefits are possible" ("The Pink Sheet" April 27, p. 16). Other commenters, however, agree at least in part with Leber's contention that FDA is in fact changing its standards. Anti-Viral Drugs Advisory Committee member Paul Meier, PhD, University of Chicago, member Paul Meier, PhD, University of Chicago, remarked in Jan. 23 comments that if drugs approved under the proposed regulation have "met the same standards that would be required under the ordinary procedure, one might then ask why additional post-marketing requirements need be applied." Meier proposed that the reg be renamed "conditional approval," its original title, "which seems to me better to represent the facts" by emphasizing the importance of postmarketing follow-up. Overall, Meier said he supports the goals of the regulation. * While it is somewhat unusual for agency insiders publicly to criticize FDA policy, proposed or otherwise, it is not unprecedented. For example, Oncology Division Medical Reviewer Grant Williams, MD, sent a letter last year to Vice President Quayle objecting to a proposal for Institutional Review Board review of INDs ("The Pink Sheet" Dec. 2, 1991, p. 15). On a less public level, a poll conducted by Public Citizen's Health Research Group of FDA medical officers indicated high levels of disapproval for the IRB review proposal and a proposal for outside NDA reviews ("The Pink Sheet" Dec. 23, T&G-4). HRG submitted comments opposing the accelerated approval reg on June 15 ("The Pink Sheet" June 22, T&G-15). As head of the Neuropharm Division, Leber will be responsible for the review of Alzheimer's drugs, a category that Kessler and other Administration officials have emphasized in discussing the reg. The agency has been criticized already for its handling of Warner-Lambert's Cognex (tacrine), which was deemed not approvable by an advisory committee last March for failing to show clear clinical efficacy. Depression and psychoses are also specifically named as disease targets eligible for accelerated approval in the regs. "The preamble to the proposed rule asserts," Leber said, "that it is in the public interest to make 'promising' new treatments available at the earliest possible point in time for use in life- threatening and serious illnesses." However, he said, "early access to so-called 'promising' drugs is not one and the same as early access to safe and effective drugs." * Leber maintained that the proposal may "lead to the marketing of large numbers of clinically ineffective but pharmacologically active drugs and this may not be in the interest of the public health." The FDAer noted that the availability of such drugs could lead to delays in the delivery of effective therapy and could make clinical trials of other new therapies difficult. "Society should be given adequate opportunity to debate the wisdom of allowing pharmacologically active drugs without established efficacy to be marketed on the basis of what is essentially the speculative opinions of individuals," Leber concluded. Leber also objects to the proposal's "streamlined withdrawal" process, which he suggested does "not seem adequate to protect the armamentarium." The proposed withdrawal procedure "may not function efficiently or effectively," Leber said, and "there will invariably be political pressure not to rescind the approval... especially if no clearly effective alternative treatments are available." Meier also expressed this concern: "More important than the regulations is the determination of the agency to enforce them... The only sanction available appears to be withdrawal of approval -- a step hard to take if the drug has been well received and no issue of toxicity has arisen." While the majority of comments submitted so far generally are favorable, at least one industry representative, Bristol-Myers Squibb, is opposing the reg. The approval of BMS' Videx (ddI) in October is the model on which the proposal is based. The company argued that the approval of Videx demonstrates that "new regulations are not needed" for the agency "to selectively base approvals on surrogate endpoints when appropriate." Likewise, BMS said, the requirement for postmarketing studies "can be (and has been) accomplished without the need for new regulations." BMS is "not aware of major disagreements between FDA and sponsors" over postmarketing studies voluntarily agreed to under the current system. BMS also challenged FDA's authority to implement two features of the regulation: the proposal to condition some approvals on restricted distribution of the product and the proposed requirement for preclearance of promotional goods for accelerated approval drugs. "The FDA does not have the legal authority to impose...[distribution or use] restrictions," Bristol-Myers Squibb declared, and "prior review of promotional materials is not only beyond FDA's statutory authority, but is unnecessary." The American Pharmaceutical Association and the American Medical Association also questioned FDA's authority to impose restricted distribution on an approved drug. The American Society of Hospital Pharmacists acknowledged that "there may be limited circumstances in which restraints on the traditional drug distribution mechanism may be appropriate" but asked the agency to define more clearly the conditions for restricted distribution. The National Wholesale Druggists Association expressed concern that the proposal "could be read to restrict or eliminate the wholesale distribution of drugs approved through the accelerated approval process." NWDA does "not believe that there should be any restriction or limitation on their ability to handle any approved drug or biological product." On the issue of preclearance of promotional products, ICI Pharmaceuticals said in its June 15 comments that "it is unclear why presubmission of all promotional material would continue after marketing approval. We also question the legal foundation" of the requirement. Immunex, however, pointed out that biologic promotional materials already must be precleared and said it supports "the implementation of consistent requirements for drugs and biologics."