The Devil's Alternative

Press conferences are ten-a-penny in Geneva. But the one which packed the Penta Hotel in that city last April was more than just another press gathering. For it amounted to a public trial of one of the world's largest drug companies - Switzerland's own CIBA-GEIGY.

The charge was the continued manufacture and sale in developing countries of a drug known to have caused a disabling disease in Japan - Sub acute Myelo-Optic Neuropathy (SMON). Medical and legal experts were called up by both prosecution and defence in the presence of mute but eloquent wheelchaired victims of the disease.

The defence
Admitting that they are paying compensation to Japanese victims of SMONwhilst at the same time continuing to sell the drug which causes it, CIBA-GEIGY nonetheless reconciles the two actions by claiming that the Japanese case is unique. Their defense -

`SMON was a Japanese disease of the nervous system that is the subject of litigation in which medicines containing clioquinol, used for the treatment of intestinal infections, are implicated as the cause of the disease ... Approximately 10,000 SMON cases have been reported from authoratitive sources covering the 15 years since SMON existed in Japan. But three-quarters of the patients suffered from other, often grave, diseases including cancer and tuberculosis, and in the 900 SMON patient deaths, such disease must have been relevant. These figures from Japan are in marked contrast to those from the rest of the world. In 40 years experience by millions of people, not one single death and only 40 to 60 cases have been reported which have any resemblance to SMON. Correctly used in products such as Entero-Vioform and Mexaform, clioquinol combines medical value with safety. CIBAGEIGY therefore continues to make them available.'

Suspicions
Not everyone agrees with the company's complacency about continuing sales of the drug. `This is CIBA-GEIGY's version of one of the greatest drug scandals of our time' commented Dr. Olle Hansson a prominent Swedish opponent of the drug, in a New Scientist article.

The story of clioquinol goes back to the beginning of the century when it was introduced - by CIBA - as a powder to put on wounds. In 1934 it was sold for oral use as a remedy for one of the vaguest and commonest complaints - traveller's tummy or holiday diarrhoea. Because of its apparently wide application to what The Lancet has called that `nebulous ragbag' of symptoms, sales climbed steadily. Meanwhile, a groundswell of medical opinion was rising against it - `just placebos' said the British Medical Journal in 1976.

Suspicions that clioquinol had a more sinister side had begun to creep in during the 1960s when a Swiss vet reported to CIBA that several dogs which had been treated with Entero-Vioform had succumbed to fatal epileptic fits. In the vet's view, the cause of the fits was clioquinol. Similar worries had ariseninCIBA's own laboratories. Two years later the company issued a warning to veterinarians. Commenting on this history during the ruling on compensation to Japanese men and women disabled by the drug, the Tokyo District Court declared `the company circulated a warning amongst veterinarians not to use this drug in treatment. However, although these drugs were produced for human use, they not only did not take any measures to warn about the dangers of use by humans, but also they continued to stress, thereafter, the safety of Entero-Vioform and Mexaform in Japan - which can only be considered deplorable.'

Cure is cause
Pains in the abdomen, diarrhoea, degeneration of the nervous system, weakness and paralysis in the legs - these were the symptoms which began to affect thousands of Japanese citizens in the sixties. In the ensuing panic, it was at first assumed that a contagious epidemic was on the loose. Publicity on radio and television sent thousands of people to medical centres to enquire anxiously about their stomachache or diarrhoea. In places like Ihara town, many were admitted to isolation wards and treated with -you guessed it - clioquinol.

Ghastly suspicions therefore became self-fulfilling and the confusion of cause and cure spread the disease and eventually exposed its real cause. Says Hansson `a banal case of diarrhoea which in all likelihood would have subsided within a few days without any treatment was to involve life-long illness for many'.

Of Japan's known SMON victims, 50 per cent returned to theirjobs within two years. Recovery for the remainder was slower - with 10 to 15 per cent unable to care for themselves again -and 7 per cent fatalities.

In 1970 the SMON epidemic came to an end with a final ban on all clioquinol drugs. A year later the number of cases had dwindled to 23 and in 1972 no new cases were reported.

Prescription
How many suffered during the period of unrestricted use is difficult to estimate. The government says 11,000. The College of Medicine at the University of Tokyc estimates 30,000 - pointing out most sufferers couldn't get a certificate proving that they had taken clioquinol because Japanese medical records are only preserved for five years and because doctors have not bent over backwards to co-operate in tracing disabilities to the drug.

The profusion of drugs which spill from the prescription pads of Japanese doctors is hardly something that the profession is proud of - especially as the drugs are usually sold not through independent pharmacies but through the doctor's own stores - helping to boost their incomes. And possibly the profits being made were one reason for the massive doses of clioquinol being prescribed in Japan in the 1960s. But, curiously, this is one of the main points in a CIBA-GEIGY defence which rests on three main arguments:-

• The Japanese case is exceptional because there was gross over-prescribing, compounded by the small physique of the Japanese compared to the European. Both of these factors increased the dose pet pound weight of the patient.

• The number of Japanese victims ha: been exaggerated due to hasty over diagnosis once an epidemic had started Few cases have been found elsewhere despite widespread use of the same drug.

• Where diarrhoea and stomach upsets arc endemic, as in many ThirdWorld countries the benefits of clioquinol outweigh the possible risks.

How valid are these reasons?

1 Overdose
Japanese doctors are not alone in profiting from the drugs they prescribe. The practice is common in many developing countries where clioquinol is sold. Taken ill with a stomach upset recently in Malaysia, I went to a local clinic where I found a doctor with his Parker pen poised over a pad. It took two minutes for my symptoms to be explained the prescription scribbled out. I took the order to another counter in the clinic where three sets of pills were given to me by a young girl along with mumbled instructions on which pills were to be taken after meals, which pills every four hours, and which pills twice every three hours. Confused, I asked for more specific directions - what set of pills were for what symptom and why did I need so many? A doctor had to be called to explain. It is unlikely that a rubber tapper or rice farmer coming to that same clinic would have insisted on specific instructions and answers. A local consumer group assured me that when unsure about how large a dose of pills to take the patient's reasoning would be `the more you take, the quicker the cure'.

The logical conclusion of doctors' earnings increasing with the number of drugs dispensed has been pointed out by the President of the International Organisation of Consumer Unions, Anwar Fazal -`It is easy for drug companies to influence them. A new factor determines their treatment of patients -the profit margin on the drugs they prescribe, Doctors become businessmen. And just like the shopkeeper, they have problems of stock. They buy the drugs, then they have to get rid of them - never mind if they are out of date or if side-effects have been discovered.'

It therefore seems sensible to assume that the possibilities for an over-dosage of clioquinol are as present in developing countries as they were in Japan.

2 Over-diagnosis
At that same crowded Geneva press conference, Professor P. K. Thomas testified about his own personal examination of Japanese SMON victims and reported that some were suffering from closely allied but distinctly different nervous conditions. He further suggested that it was not possible to establish how many supposed SMON victims were not due to clioquinol. Others also argued that `poor definition (of the symptoms) has probably led to erroneous over-diagnosis of clioquinol neurotoxicity (poisoning of the nerves).'

But such an argument is a double edged sword as many equally distinguished doctors were quick to point out. That same vagueness of symptoms and that same lack of information about the medication given, could equally well mean that there were more cases in Japan than actually came forward. And it could also account for the lack of reports from othercountries. National publicity in France and Sweden about the dangers of clioquinol, for example, prompted a number of SMON victims who did not know that they had the disease to seek help.

The chances of a correct diagnosis of SMON in the developing world are slim. Medical records are often poor or non-existent. Patients may not know what drugs they are given by doctors or sold by pharmacists. And amid so many other pressing health problems, a new case of disablement does not always mean that its cause is scrutinised. To complicate matters, SMON symptoms are very similar to those of multiple sclerosis - a disease whose causes still puzzle the most sophisticated research laboratories. For the most part, all that an overworked medical auxilliary can hope to do is to provide a pair of crutches.

3 Benefits and risks
The risk-benefit analysis is the final argument brought forward to defend the policy of selling a drug in the developing countries which is banned or highly restricted in industrialised nations. Severe diarrhoea is common in countries where water and sanitation are inadequate and a drug which lessens the suffering of millions, so the argument goes, is worth the risks to a few thousand.

Such logic would have a finer cutting edge if there were sharper evidence that sufferers were in fact relieved by the drug. Many doctors, like Sri Lanka's Professor N. D. W. Lionel, maintain that while clioquinol may be useful for those with amoebic cysts in their stools, there is no good evidence that it is useful for non-specific diarrhoea. Yet in most cases, that is what clioquinol is used for -and in large quantities. In 1977, according to Lionel, Sri Lanka imported 16.8 million clioquinol tablets for its 13 million people. The Indian Consumer Association maintains that the drug is in every middle-class family medicine box. And in Mozambique, the last national formulary of drugs in 1976 showed that clioquinol was tenth on the list of imported drugs.

Equally important is the thumbs down given to the drug by the World Heath Organisation. Clioquinol was conspicuously absent from the 300 essential drugs recommended by WHO for developing countries in 1977. When asked to justify the omission of a drug which is high on the lists of many developing countries, WHO replied - `The relative lack of benefit as compared with the definite risks, as well as alternative possibilities.'

Nevertheless, Entero-Vioform, Mexaform and other brands containing clioquinol are still widely available - with little or no guard against overdose. Obviously, where there are no doctor's instructions on how many pills to use, how regularly and for how long, then the dangers of overdosing are multiplied. Yet in the Third World the drug is available from pharmacists or street peddlars. Even those countries which have put the drug on prescription only - Lesotho, Yemen, India, Sri Lanka, Taiwan and Malaysia - do not appear to enforce the regulation strictly. I was sold the drug without fuss across the counter at a pharmacy in Penang, Malaysia. Independent checks in India and the Yemen confirm that the drug is freely available there. In Sri Lanka, also, the drug is available today in non-government controlled outlets.

The last word rests with CIBA-GEIGY: when asked at the Geneva press conference why they were not prepared to suspend the sale of the drug until its effects and side-effects were clarified, their reply was `We have no medical reason to be afraid of the drug. Do you think that a big multinational company would continue sales of a compound or of a product if this would mean danger to human lives?'