580 PHARMACEUTICAL COMPANIES AND UNEXPECTED DRUG SIDE-EFFECTS
SIR,-How should a pharmaceutical company react when faced by unexpected side-effects of a drug about to be licensed or already on the market? There have been several such incidents in the past decade, but companies often behave curiously by denying or playing down the problem. Why is an industry with sales worth billions of dollars and tens of thousands of employees so badly prepared for problems involving unexpected side-effects of their products? A contributing factor may be the structure of top management in many large drug companies these days. There seem to be too many brilliant young economists but very few medical people at the level of strategic decision taking. Economists seem to have difficulties with the special kind of products that drug companies market, and prefer strategies more suitable for products such as cars or hair shampoo when serious side-effects occur. I suggest that pharmaceutical companies use independent external advisory committees to handle reports on severe drug sideeffects of a product and to advise on action. Committee members should not be on the company’s payroll; they should be clinical pharmacologists or clinicians outside the drug industry and would get expenses only. Such groups might be put together whenever a major problem of unexpected side-effects arises. The advantage of external professional people rather than employees is freedom from bias and financial ties. In my experience the use of company staff to judge these delicate matters does not always work. One could argue that national drug regulatory authorities have the power and the responsibility to act in these situations. However, ideally the company should be at least one step ahead of the authorities; they will not want to be forced to withdraw products. Besides, there is often limited time to act when the first reports of unexpected side-effects occur, and rapid action by regulatory authorities is not the rule. Department of Infectious Diseases, Östra Hospital, S-416 85 Göteborg, Sweden
STEN IWARSON
BUTAZONES UNDER FIRE
SIR,-In Ciba-Geigy’s view both phenylbutazone (’Butazolidin’) and oxyphenbutazone (’Tanderil’) continue to be valuable for selective use under medical supervision. This view is now pretty well indefensible, as was clear at last month’s meeting, reported by Mr Loshak (Feb 16, p 410). As a result of the meeting the company undertook to "look over matters again". Ciba-Geigy informed us of the decisions that regulatory authorities had made on the drugs by December, 1984. The major decisions are:
Drug Phenylbutazone
Removed from market Bahrain, Jordan, Norway, United Arab Emirates (UAE) (not available in
Restrzcted
to use
in
ankylosing spondylitis Finland, UK, Zimbabwe, New Zealand, South Africa
Kuwait,
Israel)
Oxyphenbutazone Bahrain, Jordan, Norway, Israel, Italy, Kuwait, Zealand, South Africa Decisions are pending in several other countries, among them the USA. The US authorities denied a petition by the Health Research Group of Washington for removal of the drugs as an imminent hazard, arguing that the hazard had been known for many years and could not be called "imminent". The Department of Health and Human Services concluded optimistically that with relabelling and special unprecedented educational programmes phenylbutazone and oxyphenbutazone could be safely used as "drugs of last resort". The DHHS has not explained the use of two drugs of last resort. So far very few health authorities have recognised that if a butazone is needed at all, one is enough, and that oxyphenbutazone offers nothing that1 phenylbutazone does not have, except possibly greater toxicity. Two indications for oxyphenbutazone, now claimed by CibaGeigy in Switzerland and in most third-world countries, stuck out as absurd; the company has not proposed them to the US authorities,
UAE, Finland, UK, Zimbabwe
New
and they could not be defended by its representatives, who included the head of the medical department. One is "short-term treatment (1 week) of acute severe inflammation after surgical interventions". As we said at the meeting, postoperative kidney failure is a risk, and since non-steroidal anti-inflammatory (NSAI) drugs reduce renal function their use is especially dangerous. Another indication is treatment for up to 1 week of "acute forms of soft-tissue rheumatism where the patient has not responded adequately to other NSAI drugs". We could not discover which forms of acute soft-tissue rheumatism go on for long enough to allow time for adequate trial of, say, three other NSAI drugs. Much of what was said at the meeting concerned the impossibility of approximating careful use under medical supervision in developing countries. Just because the environments are uncontrolled, evidence of the damage the drugs do will remain undetected. The company’s representatives acknowledged these problems, but said that withdrawal of their products would not mean the disappearance of butazones in these countries: they would continue to be marketed by other, often less scrupulous, producers. This lame excuse for inaction ill befits the international brand leader. We recognise that a voluntary decision to withdraw the drugs is not easy for Ciba-Geigy, but the longer the delay the harder it will be for the company to emerge with credit. We advised Ciba-Geigy at the end of the meeting that continued marketing of the drugs could only mean trouble, first and foremost for the patients using them, but also increasingly for the company itself. Charing Cross and Westminster
ANDREW HERXHEIMER
Medical School, London St George’s London
Hospital Medical School,
JOE COLLIER
University of Newcastle, Newcastle upon Tyne
M. D. RAWLINS
Zentralkrankenhaus, St Jurgens Str, Bremen, West Germany
P. SCHONHÖFER
Social Audit, London NW1
CHARLES MEDAWAR
Oxfam, Oxford
DIANNA MELROSE
WEMOS, Amsterdam
WILBERT BANNENBERG
International Organization of Consumers The Hague, Netherlands
Unions,
VIRGINIA BEARDSHAW
Study of fatal bone marrow depression with special phenylbutazone and oxyphenbutazone. Br Med J 1977; i. 1500-05.
1 Inman WHW.
reference
to
SAFETY OF ANGIOTENSIN-CONVERTING-ENZYME INHIBITORS
SIR,-Professor Edwards and Dr Padfield’s review (Jan 5, p 30) of angiotensin-converting-enzyme (ACE) inhibitors is most timely because enalapril, a non-sulphydryl ACE inhibitor, is now available in the UK. The article supports the concept of ACE inhibition in the treatment of hypertension and congestive cardiac failure. We would like to comment on the relative safety aspects of captopril and enalapril, the two ACE inhibitors now on the market in the UK. We believe that it is inappropriate to extrapolate the safety concerns connected with the use of one compound to those of ACE inhibitors in general. Clinical experience points to the following differences between the two drugs: (1) Agranulocytosis (<300 neutrophils/µl) has not occurred with enalapril. The single case that appeared to be associated with does not meet the criteria for neutropenia used by enalapril Frohlich et al2 in their extensive review of captopril. Edwards and Padfield refer to the fact that one of three patients in whom leucopenia developed on captopril therapy had a recurrence while on enalapril. In subsequent months, when this patient was off all ACE inhibitors, a similar haematological pattern recurred, which is consistent with the possibility that the earlier low white-blood-cell counts were manifestations of the disease rather than the treatment. (2) The incidence of rash and taste disturbances is higher with captopril even at low doses, which Edwards and Padfield
therapy’
acknowledge.