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Congress Finds FDA Wanting Drug Evaluation, Agreed Nature Vol. 298 12 August 1982 597 US drug regulation observed after the cut-off date. At the subcommittee hearings, Dr Robert Temple, acting director of the office of new Congress finds FDA wanting drug evaluation, agreed. He called it a Washington application was made in December 1979. "defect in the regulations". Eli Lilly and Company has repeatedly These effects were principally A similar mix-up occurred over the failed to report adverse findings about photosensitivity and onycholysis reporting of four deaths from jaundice drugs it was testing or marketing, (loosening of the fingernails), and all associated with the drug. Attention was according to Food and Drug occurred after the "cut-off date" of focused on this matter by reports (Goudie, Administration (FDA) documents made November 1978 that Lilly had set on data E.M. et at. Lancet i, 959; 1982/Halsey, public last week. Sales of one of the drugs that were to go into their application. The J.P. & Cardoe, N. Br. med. J. 284, 1365; mentioned in the documents, Oraflex cut-off is apparently a usual procedure. 1982.) of several jaundice deaths in Britain (benoxaprofen), were suspended last week But the Lilly employee in charge of the associated with Oraflex. On 23 June, FDA in both Britain and the United States after a application, Dr H.A. Bartlett, did review officials met Lilly officials to discuss the review of British data revealed 61 deaths the adverse effect reports from trials that matter, and "expressed surprise that associated with its use (see box). continued after the "cut-off date", and (American) cases of jaundice had not been The allegations against Lilly are spelled included "serious" reactions in the submitted prominently to the NDA (new out in a series of internal FDA memoranda application, according to a memorandum drug application) prior to its approval". released by the House intergovernmental written by Dr Hensley on 16 September "I' I'\ AFI\AID Vou HAVE relations subcommittee, which was holding 1981. This memorandum then states that hearings on FDA's proposed streamlining Dr Bartlett instructed an employee ''not to Dow JoNts of the new drug evaluation process. report others (such as onycholysis and One of the most serious charges is that photosensitivity) which he allegedly felt "data for benoxaprofen appear to have were, because of their frequent occurrence, been deliberately withheld, thus biasing the no longer alarming" (sic). In fact, the new NDA (new drug application) in favour of data showed a sharp increase in the approval". The investigator who reached incidence of these side effects. A letter that conclusion, Dr Michael Hensley, from Dr Marion Finkel, then associate recommended last September that FDA director for new drug evaluation, to R.D. "consider prosecution of appropriate Lilly Wood, chairman of the board of Lilly, on employees". 12 March this year charges that "the Dr Hensley's investigation revealed in consequence was a biased presentation particular that 65 adverse effects that clearly more favourable to the drug than occurred during the clinical trials of was warranted by the data". Lilly officials claimed that they had in fact Oraflex were not reported to FDA, even Lilly's answer is that FDA regulations submitted two reports to the IND file though they were apparently related to the simply do not require applications to before approval. At the subcommittee drug, and were in Lilly's files when the include data on all adverse reactions hearings, FDA officials said they had had no way of checking that, since there was a six-month backlog in processing the IND Arthritis drug proscribed in Britain files. They said they have since found that A voluntary decision by Eli Lilly to both sides of the Atlantic. all four cases were reported to FDA by Lilly withdraw the anti-arthritis drug Benoxaprofen is undoubtedly effective - but that FDA reviewers apparently benoxaprofen from sale in all countries in many cases of rheumatoid arthritis and approved the application without seeing came soon after the imposition of a osteoarthritis but it is probably not the reports. FDA Commissioner Arthur 90-day ban on UK sale by the Committee irreplaceable - other non-steroid anti­ Hayes Jr says that it "wouldn't have made on Safety of Medicines (CMS). The inflammatory agents with similar activity any difference" in the approval, since the Department of Health withdrew the. include aspirin, naproxen, ibuprofen and reviewers knew about the problem. product licence for the drug (sold under fenoprofen. For Eli Lilly, though, the Dr Hensley's memorandum of 29 the trade name Opren in the United whole episode is a major setback. Even if September 1981, in which he recommended Kingdom) to allow time to assess the benoxaprofen is allowed back onto the possible prosecution of Lilly employees, alarming total of 3,500 reports of serious market, the damage will have been done referred to three other drugs about which side effects, especially in the elderly. and doctors will be reluctant to prescribe he said "allegations .... that Lilly has Benoxaprofen had rapidly become one it and patients to take it. repeatedly failed to make required reports of the most prescribed of anti-rheumatic The latest events surrounding of important adverse findings" had been drugs since the UK product licence was benoxaprofen provide another reminder "confirmed" by FDA investigators. issued in 1980, and the CMS review cites of the high risks involved for companies About aprindine, an anti-arrhythmia drug, 61 deaths associated with its use. In the attempting to reap the high rewards that Dr Hensley found that "Lilly employees United States the drug (sold as Oraflex) accompany a successful new drug launch. may have engaged in highly objectionable, was given FDA approval only in April of Only two weeks ago the London Stock perhaps ethically questionable practices in this year, but already at least 11 deaths Market witnessed extraordinary their handling of the aprindine clinical have been linked with benoxaprofen, fluctuations in the price of shares in the programme". Furthermore, Lilly again mostly in elderly patients and pharmaceuticals company Glaxo. High apparently ignored findings from its own mostly involving liver or kidney damage. hopes of massive profits from sales of the experiments with dogs of a possibly lethal In withdrawing the drug, Eli Lilly was new anti-ulcer drug Zantac (ranitidine) side effect of the drug, fibrillation. It was at pains to explain that it still believed were dampened when a few reports of not until January 1974, after four patients benoxaprofen to be safe and effective if possible side effects were publicized with in the aprindine clinical trials had died, that used as directed. But after seven years of little analysis in the financial press. Share the dog studies were reviewed and finally development before being allowed on the prices recovered when Glaxo and others reported to FDA on 4 February 1974. An market, the question of why possible pointed out the relatively minor nature of FDA memorandum dated 4 February 1982 contraindications seem to be emerging the reported effects, but predictably the recommends that Lilly be issued a only at this stage will be taxing regulatory price has not matched the high levels seen "Notification of Adverse Findings" for authorities and Lilly's medical teams on before the fracas. Charles Wenz failing to incorporate the data from the 0028.0836/82/320597.02$01.00 101982 Macmillan Journals Ltd .
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