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Medicine and the Law

Product Liability Suit Leads US GenericManufacturers to Withdraw Butazones

IN February, 1985, a 44-year-old IBM technician in Boulder,Colorado, died of toxic epidermal necrolysis caused by phenylbut-azone. An orthopaedic surgeon had prescribed the drug for an acuteexacerbation of shoulder pain caused by osteoarthritis of theacromioclavicular joint. He had prescribed it as ’Butazolidin’, but ithad been dispensed as generic tablets manufactured by DanburyPharmacal Inc. The patient’s widow brought a malpractice suitagainst the surgeon, and a product liability suit against themanufacturer. Last month a jury concluded after a trial lasting8 days that the surgeon had not been negligent. The company hadsettled out of court, but, to avoid prejudicing the case against thesurgeon, details were not revealed until the jury had reached itsverdict. The plaintiffs attorneys then announced that Danbury andits parent company, Henry Schein Inc, had agreed to pay the widowdamages of$800 000 and to stop the manufacture, sale, anddistribution of phenylbutazone and oxyphenbutazone. As a

precaution Danbury had in fact halted their manufacture and salesoon after the patient died, though the drugs were and are still beingsupplied in limited amounts to fulfil a contract with the US military.The plaintiffs attorneys believe that product withdrawal as a

condition of settlement of a product liability lawsuit may be

unprecedented. Although the plaintiff could have won damages hadthe case against the company gone to trial, a court could not haveordered the withdrawal of the offending drugs from the market.The case shows how litigation may carry forward the sometimesonly partially effective workings of the regulatory process. Bothphenylbutazone and oxyphenbutazone are still freely available onprescription in the United States, although they have been bannedor severely restricted in many other countries. Ciba-Geigy, the

principal manufacturer, voluntarily withdrew its oxyphenbutazonefrom all markets in 1985, but many other companies continue to sellit and phenylbutazone where they can-and it seems thatmanufacturers of bulk chemicals (for example, in Hungary andSpain) continue to supply them.The central issue in the case was the nature of the responsibilities

of generic drug companies for the safety of their products aftermarketing. Danbury’s defence was that as a generic manufacturer itwas not obliged to monitor actively for adverse reactions to its

products, to communicate with the medical profession about safetyconcerns, or to inform itself fully about its products’ hazards.According to the plaintiffs attorneys, this issue had never

previously been determined as a matter of law in the United Statesand, because of the settlement, remains unresolved.Mr William Haddad, the chief executive officer of Danbury and

chairman of the US Generic Pharmaceutical Industry Association,had been expected to give his opinions at trial on differencesbetween the responsibilities of generic and brand-name pharma-ceutical companies, but after the settlement he said that he sawabsolutely no difference in the post-marketing safetyresponsibilities between the two types of company. This is certainlythe view of Dr Arthur Hull Hayes, Jr, Commissioner of the USFood and Drug Administration from 1981 to 1983, who was to havebeen an expert witness for the plaintiff. Other experts who hadagreed to appear for the plaintiff included Dr Andrew Herxheimer,Editor of the Drug and Therapeutics Bulletin in London, who hadtaken part in discussions about the butazones with Ciba-Geigy in1984-85, and Dr Paul Stolley, co-director of the clinical

epidemiology unit at the University of Pennsylvania.

Baisley f Cavanaugh, Danbury Pharmacal and others. Judge J. Belliganni,Boulder District Court, Colorado. Case no 85-CV-0725-5. Oct 29,1986. Forthe plaintiff: Baine P. Kerr of Hutchmson, Black, Hill & Cook, Boulder; forDanbury: Frank R. Kennedy of Cooper & Kelley, PC, Denver.

Conference

GAMETE INTRAFALLOPIAN TRANSFER

SINCE Dr Ricardo Asch and his colleagues first published theirwork on gamete intrafallopian transfer (GIFT) in a letter to TheLancet in 1984,’ interest in this new method of treating infertility hasbeen increasing world-wide. The extent of the practice of GIFTwas revealed at the 12th World Congress on Fertility and Sterilityheld in Singapore last month. Interest in this method stems not onlyfrom the good results achieved but also from the low cost comparedwith that of in-vitro fertilisation (IVF). This means that GIFT cannow be considered as a treatment for infertility in smaller districthospitals and in less affluent parts of the world.Asch (California) and his colleagues use clomiphene citrate and

human menopausal gonadotropin (hMG) to induce follicular

development. Follicular aspiration is carried out 36 hours after

injection of human chorionic gonadotropin (hCG). 2 hours beforeGIFT a semen sample is obtained, prepared with a wash and swimtechnique, and treated with antibiotics. 100 000 motile sperms areplaced in the fallopian tube, followed, if possible, by two oocytes. In80% of the 800 cases reported by Asch this procedure was done bylaparoscopy and in the rest mini-laparotomy was used. With theGIFT technique Asch and his colleagues have so far achieved 275(34-4%) pregnancies, which have resulted in 201 deliveries.

Unexplained infertility was by far the commonest indication forGIFT (499 cases). Other indications included endometriosis (91),male factors such as oligospermia (84), and failed artificialinsemination by donor (65). The technique was used successfully in2 cases of oocyte donation. Pregnancy was achieved in 38 % ofwomen with endometriosis and 35% of those with unexplainedinfertility. With regard to endometriosis, Asch explained, thesuccess rate depended on the severity of the disorder: the moresevere the disorder, the harder it was to achieve a pregnancy.

Another factor that influenced the overall outcome was the

quality of the oocytes. In Asch’s view, oocytes mature poorly in thefallopian tube, and he recommended that they should be matured inthe laboratory. Although in this study Asch and his colleagues used100 000 sperms for each procedure, he said that this was an arbitraryfigure, since the ideal number had not been determined.He emphasised that GIFT does not mean the end of IVF, since

GIFT is successful only if at least one tube is patent. His mainpriorities for GIFT are "simplicity, a higher success rate, less costand above all safety". Although in the long term he would like to seeGIFT develop into an "office" procedure within the capability ofevery gynaecologist, a first step, he suggested, would be theestablishment of regional GIFT centres of excellence, consisting ofa research unit, a clinical unit, and a laboratory.Asch wanted to see the development of methods to enhance the

growth of the embryo in the tube. This, he predicted, would beachieved within the next three to five years. Better concentration of

sperms and improvement in motility were other areas in which hewould like to see further research take place. In addition,improvement in the procedure for collection and transfer of oocytesby means of small fibreoptic systems under local anaesthesia has agood potential for future development in his view.Dr Matts Wikland and his colleagues at the University of

Gothenburg, Sweden, have devised a method for selection of motilespermatozoa that could be applied to GIFT as well as to IVF. Theyfound that addition of an inert substance to the medium to increaseits viscosity would select spermatozoa by allowing only the mostmotile sperm to swim up to the top layer. The additive, which theycall "sperm select", contains a highly purified preparation ofhyaluronate, a connective-tissue polysaccharide. Since they startedusing the "self-migration" technique in April, 1986, Dr Wiklandand his colleagues have achieved a higher proportion of pregnanciesin their IVF patients.

1 Asch RH, Ellsworth LR, Balmaceda JP, Wong PC Pregnancy after translaparoscopicgamete intrafallopian transfer. Lancet 1984, ii: 1034-35.