by Teh Poh Ai
In 1982 Ciba-Geigy, a Swiss multinational company, detailed in an internal document the cost in terms of lives and health of two of its most popular antiarthritic pain killers-according to conservative company estimates, the two drugs had killed more than a thousand people and injured nearly 5,000.
Although consumer and health groups suspected that the number of injuries and deaths was even higher, when the document was leaked to the public in 1983 it confirmed the fears of many that Ciba-Geigy's concern with the health of the population was at best secondary to its concern with increasing worldwide corporate profits.
In the internal report Ciba-Geigy admitted to knowing of more than 700 deaths due to Butazolidin use even though only "72 deaths had been officially reported in the medical literature," according to the consumer group Heath Action International. With Tandearil, the company reported only 76 deaths in medical literature when the internal document showed the company knew of nearly 330 deaths.
Despite such knowledge and, later, public disclosure of Ciba-Geigy's damaging internal report, the company continued to market the two drugs, Tandearil and Butazolidin, for three years. Finally, in early April of this year CibaGeigy put severe restrictions on the marketing of Butazolidin, a popular brand of phenylbutazone, in the United States and on July 1 the company withdrew Tandearil, a brand of oxyphenbutazone, from international markets.
and phenylbutazone are
known to cause life-threatening blood disorders
inclucing leukemia, gastro-intestinal bleeding, peptic
ulceration and liver damage.
Ciba-Geigy, the largest
manufacturer of the two
drugs, announced its intention to withdraw Tandearil and restrict Butazolidin after meeting with representatives of Health Action International (HAI). Angered over the company's distortions of the drugs' affects and the dangers the drugs posed for most patients, HAI joined with other groups to urge a general ban of the two products.
By late 1984, Ciba-Geigy was concerned enough about the mounting opposition to call for a meeting between HAI representatives, medical experts and members of the International Organization of Consumers Unions. At that meeting in February of 1985, HAI threatened an international boycott of Ciba-Geigy products if the company continued marketing the two drugs without modification.
Within a month, Ciba-Geigy announced that it would severely restrict the use of Butazolidin, recommending it for use in the treatment of few severe rheumatic diseases, after all other non-steroidal, anti-inflammatory drugs (N.S.A.I.Ds) had been tried and found unsatisfactory and that it would withdraw Tandearil from the international market completely. A press statement released by CibaGeigy said the implementation of these decisions would be completed by the third quarter of 1985.
Although the company has discontinued all new production of the drug Tandearil, Ciba-Geigy will not recall stocks from hospital or pharmacy shelves.
"Any that is out there can be used," said a Ciba-Geigy spokesperson, since "[i]t wasn't a mandated withdrawal."
In the case of Butazolidin, Ciba-Geigy will leave the drug on the market with, what company officials deem
only, "minor changes in the
packaging." It will no longer
be suggested for treatment
of such minor ailments as
the "painful shoulder," and
patients over the age of 60
will be warned against using the product.
Despite the large number
of deaths admitted to in internal company documents,
consumer groups charged
that Ciba-Geigy had still severely underestimated the deaths and the suffering the drugs had left in their wake. In the United Kingdom alone it was estimated that the two painkillers had caused approximately 1,500 deaths.
Dr. Sidney Wolfe of Public Citizen's Health Research Group estimated that "over 10,000 deaths and hundreds of thousands of serious injuries had occurred worldwide since the drugs were first marketed." In 1983 Wolfe petitioned the Department of Health and Human Services for an "imminent hazard ban" on phenylbutazone and oxyphenbutazone.
According to the Health Research Group, Ciba-Geigy suppressed evidence of at least "400 deaths in patients using these drugs" abroad. The company reported this information to the FDA only in late 1983. The Heath Research Group called for the criminal prosecution of Ciba-Geigy for failing to supply such vital information to the FDA within 12 months.
Before the April action by Ciba-Geigy to restrict the marketing of the two drugs, drug regulatory authorities in a number of developed countries including the United Kingdom and Norway had already banned the two drugs. But they continued to be sold widely throughout the Third World.
Since the leak of the internal report, the campaign to pressure Ciba-Geiby to withdraw the two drugs from the international market had gained both force and urgency. During the meeting with Ciba-Geigy in London, HAI, which is a network of public interest groups working for a safe and rational use of drugs, along with several other consumer groups pressed the company for the total withdrawal of both Tandearil and Butazolidin.
"Ciba has only come part way to meeting our demands," said Dr. Andrew Herxheimer, who led the HAI team at the meeting.
In view of its serious side effects, HAI and other consumer groups around the world are dissatisfied with CibaGeigy's restriction on Butazolidin instead of a total withdrawal as in the case of Tandearil. Although Butazolidin is more widely used than Tandearil, they share many of the same hazardous qualities. The two drugs are "essentially one and the same," according to Ciba-Geigy officials, containing virtually identical package inserts and patient information. The company chose to withdraw Tandearil instead of Butazolidin, CibaGeigy officials said, because Tandearil is much less profitable and less well-known.
According to Ciba-Geigy the decision to keep only Butazolidin came after FDA hearings on the two drugs. The company apparently agreed to revise the package inserts and to give patients and doctors more information on the drugs. "It was very, very costly," and "it was decided at that time to keep the more profitable product and drop the other rather than duplicate everything."
The company decided "not to bother with Tandearil" because it "really doesn't offer any therapeutic value over Butazolidin," said a company spokesperson.
Even with the increased restrictions on the use of Butazolidin in the United States, consumer groups are still pushing for the withdrawal of the drug from international markets.
"Butazolidin must be clearly designated as a drug of last resort-to be used only when all other treatment has failed. This means keeping the drug for use in specialized hospitals only," said Herxheimer, senior pharmacologist at the Charing Cross Hospital in London.
The question of whether Butazolidin is a necessary addition to anti-arthritic drugs already on the market has been raised by both consumer groups and Ciba-Geigy itself. Although the company has refused to make public its hesitations about continued marketing of the drug, in internal documents the company acknowledged the fact that newer better drugs with fewer side effects mandated some type of company action. In an internal document from February of 1983 the company admitted that "the number of single case reports of major serious, u.e. (unwanted events), published on BUTAZOLIDIN and TANDEARIL are higher than those for the other drugs." And acknowledged that in "the presence of the many "newer" equally effective N.S.A.I.Ds [non-steroidal anti-inflammatory drugs] now available on the market with comparatively less toxicity, it is reasonable and necessary that the risk benefit ratio for BUTAZOLIDIN and TANDEARIL should be carefully reassessed..."
In public, Ciba-Geigy officials blame many of the problems with the drugs on incorrect prescribing by doctors. "It's not a drug of first choice," said a Ciba-Geigy doctor. "It never was, but physicians give things inappropriately. They were giving it to people with sprained ankles, really misusing it. That's what caused the problems."
But, in underdeveloped countries, Ciba-Geigy along with other multinational pharmaceutical companies often markets drugs with serious side effects for minor ailments. Increasingly these companies have come under fire for this double standard in marketing.
In promoting phenylbutazone and oxyphenbutazone to the Third World countries, pharmaceutical companies had ignored the drugs' toxic side effects and recommended them for the treatment of minor ailments and for use by young children and elderly patients.
The existence of double standards was revealed in a detailed study by the Consumers' Association of Penang (CAP) a consumer organization based in Malaysia.
CAP found that in the United States and European countries, drug companies provided detailed information warning doctors against giving the drugs for minor ailments or for use in young children and the elderly. Doctors were told to use the drugs for short term treatment of acute and severe rheumatic disorders and acute gout.
However, the same companies recommended the drugs for minor ailments in Third World countries. For example, in Malaysia they are recommended for "pain and stiffness in muscles and joints, lumbago, tension headache, virus infections and fever" and "for long term treatment."
According to the CAP report, the drugs were being prescribed for even the most minor ailments in Malaysia and other developing countries, endangering the lives of unwary patients.
The report cited the case of a Malaysian man who almost died after his doctor gave him phenylbutazone to treat a stiff neck. He suffered rashes which later erupted leaving raw flesh. Even the tissues of his eyes gave way and his nails dropped off. His doctor gave him only a 50 percent chance of survival.
"He was lucky to have survived," said CAP president, Mr. S.M. Mohd Idris. "Ciba-Geigy should have stopped the sale of phenylbutazone and oxyphenbutazone long ago but we look upon the recent withdrawal of Tandearil as a victory for Third World consumers."
Mr. Idris added, "We hope that the company will continue to monitor the use of Butazolidin and its other drugs, especially in the Third World, and stop the double standards in its marketing and labeling of drugs."
Teh Poh Ai is a reporter with Third World Network Features, a service of the Third World Network.
Counts of Callousness
When Ciba-Geigy began marketing its brand of the drug clioquinol internationally it periodically warned veterinarians that the drug could lead to epilepsy and death in animals, but for doctors and patients in much of the developing world such warnings were not included. In fact, Ciba-Geigy aggressively marketed the drug in many Third World countries and Japan as a general anti-diarrheal. The results were devastating.
Clioquinol caused SMON (subacute myelo-optic neuropathy), a drug-induced toxic degeneration of the nervous system that often left its victims in severe pain, blind, paraplegic and with irreversible damage to the nervous system. By the time Japan banned the drug in 1970, 10,000 to 30,000 people had been injured and almost 1,000 had died.
In 1978 a Tokyo District Court concluded that clioquinol had caused SMON and that Ciba-Geigy had failed to adequately inform Japanese consumers about the dangers of the drug. Although Ciba-Geigy has paid out more than $150 million to the thousands of Japanese affected and their families, the company continued to market the drug throughout much of the Third World for several more years. Even today, Ciba-Geigy continues to market two clioquinol-based creams, Vioform and Vioform-Hydrocortisone, in the United States for treatment of skin disorders as minor as diaper rash. Public Citizen's Heath Research Group has petitioned the Food and Drug Administration (FDA) to remove these drugs from the market because recent studies found that both death and paralysis had occurred in dogs externally treated with clioquinol cream after 15 days of use.
By early September 1976 the pesticide chlordimeform was withdrawn from the Swiss market after tests showed that laboratory animals exhibited "pathogenic symptoms" after being exposed to the pesticide. The only two manufacturers, Ciba-Geigy and Schering, quickly halted production of the pesticide and did not manufacture it again for another two years.
The pesticide had long been a suspected carcinogen. As early as the 1950s one of the by-products of chlordimeform was being tested for carcinogenic qualities and the pesticide was no longer used in China after 1974 because of its carcinogenic effects. Although the companies had been quick to pull the pesticide off the market in 1976, Ciba-Geigy continued to test its brand of this "promising insecticide." Only a short while after it was withdrawn from the Swiss market and production was interrupted, the company tried an unprecedented experiment in Egypt to determine how toxic the pesticide really was. The company asked six Egyptian boys between the ages of 10 and 18 to stand in a field and be sprayed with the carcinogenic pesticide. The boys were to wear no protective clothing. After the test confidential Ciba-Geigy documents, leaked to the public in 1982, showed that some of the boys were exposed to levels of the pesticide 30 times higher than the Acceptable Daily Intake.
Another drug, phenformin, was marketed by Ciba-Geigy as a drug for diabetics under the brand name DBI up until 1977, even though an FDA medical officer had estimated in 1973 that four out of every 1,000 users of phenformin had died from lactic acidosis after using the drug. Other studies estimated that the toll was much higher. In this country alone it was estimated that the number of deaths could be as high as 4,000 annually from phenformin. Such figures were alarming since an estimated 250,000 diabetics in the United States were still using the drug in 1977.
It was only when case after case of lactic acidosis deaths were reported in association with phenformin that the FDA, under pressure from the consumer groups, withdrew the drug from the market.
The Oraflex Fix
"You do know that Eli Lilly has strong ties to this administration," the Justice Department source said in a hushed tone. "They pulled out all the stops to get this thing killed."
"This thing" was a criminal indictment that culminated in Eli Lilly's August 21, 1985 guilty plea to 25 misdemeanor counts of failing to notify the U.S. government, as required by law, of numerous deaths and injuries overseas among users of Oraflex, an arthritis drug. Without knowledge of these overseas deaths, the U.S. Food and Drug Administration (FDA) approved Oraflex for use in the U.S. FDA records revealed that 49 Oraflex related deaths and 916 Oraflex related non-fatal injuries had occurred in the United States.
The "strong ties" between the Reagan Administration and Eli Lilly came primarily in the person of George Bush, currently Vice-President of the United States, but formerly a director of the Indianapolis, Indiana based pharmaceutical giant. When Bush took office in 1981, he held $180,000 worth of Eli Lilly stock.
And while the Reagan administration failed to completely derail the criminal prosecution of Lilly in the Oraflex case, Congressman John Conyers Jr., (D-Michigan) is considering investigating why higher ups in the Justice Department overruled staff attorneys who recommended that three Lilly officers be prosecuted. The Justice Department only prosecuted Lilly and William I. Shedden, the company's chief medical officer, the former was fined $25,000 and the latter pleaded no contest to fifteen misdemeanor counts and was fined $15,000.
The Justice Department only charged Lilly and Shedden with misdemeanor violations, even though it had evidence in its possession indicating that Lilly and its officers intentionally violated the law. Evidence of intent will sustain felony charges. Misdemeanors carry a maximum penalty of $1000 in fines and one year in jail per count, while felony charges carry maximum penalties of $10,000 and three years in jail per count. By limiting the charges to misdemeanors, the justice Department not only limited the possible sanctions, but gave Lilly the opportunity to avoid the total shame of a criminal guilty plea.
Following the announcement of the guilty pleas, Richard D. Wood, Lilly's chairman, told reporters that "the [Justice] Department has made no charge that Lilly ... intentionally violated the law in its handling of the Oraflex matter" and that "the Department's decision puts to rest any speculation regarding intentional misconduct by the company or its employees."
But an 18-page report prepared by justice Department prosecutors and attached to Lilly's guilty plea reveals a number of specific occasions when Lilly knew of overseas deaths and adverse reactions, had an opportunity to report them to the FDA, but did not report and/or mention them in the labeling. Dr. Sidney Wolfe, of Public Citizen's Health Research Group, said that the Justice Department's report proved that "the people in this company [Eli Lilly] ought to be put in jail."
The report is excerpted below:
- Beginning in 1974, a Lilly employee in the United Kingdom compiled quarterly summaries of significant adverse reaction reports received by Lilly in that country. Based on reports by physicians, they were prepared at the direction of Dr. Shedden, then Lilly's Director of Medicine, Research and Development in the United Kingdom. The quarterly summaries listed the number and type of each adverse reaction reported to U.K. Lilly, in order to keep corporate employees informed of important safety information about their company's products. While they did not contain details on individual patients, they did contain sufficient information to warn of potentially serious adverse reactions occurring overseas. Beginning in 1981, the quarterly summaries were sent to Lilly headquarters in Indianapolis. Each of these quarterly summaries included one or more unpublished reports of kidney and liver disease associated with the use of Oraflex, known as Opren in the United Kingdom, several of which were fatal.
- Lilly was kept regularly informed by telex and telephone, not only of reports of overseas adverse reactions, but also of the method and timing of sending such reports to regulatory authorities. For example, in October 1981, Dr. Shedden received a telex from a Lilly executive in the United Kingdom which stated that Lilly and the U.K. equivalent of the FDA had discussed revisions to the U.K. labeling for Oraflex, including the addition of adverse reactions such as "renal, including nephritis and renal failure, hepatic, including hepatitis, jaundice and hepatic failure." Shortly after this telex was received, Dr. Shedden held a meeting with Lilly's Vice President for Regulatory Affairs, the Medical Advisor for International Registration, and the medical monitor for Oraflex to discuss the label changes proposed at the meeting with the U.K. authorities.
- In January 1982, Dr. Shedden and two other Lilly physicians in Indianapolis received a U.K. government printout that listed numerous adverse reactions associated with Oraflex use in the United Kingdom, including 26 serious liver disorders (two of which were fatal) and 23 other fatalities.
- On February 5. 1982, information concerning foreign adverse reactions was presented at a meeting of Lilly executives in Indianapolis, attended by Dr. Shedden, the President of Lilly Research Laboratories, the Executive Vice President of the Pharmaceutical Division, the Executive Vice President of Lilly International Corporation, and by an employee who had just returned from the United Kingdom with a special report on adverse reactions to Oraflex in that country. The report, which had been prepared by Lilly's U.K. subsidiary, tabulated "serious" reactions associated with the use of Oraflex, including 27 kidney/liver reactions, 5 of which were fatal.
- Throughout the early part of 1982, Lilly officials held meetings with the FDA to discuss the content of the labeling that would accompany the soon-to-be-approved Oraflex. On January 14 and February 4, 1982, Dr. Shedden and the Vice President for Regulatory Affairs of Lilly Research Laboratories, and the Medical Advisor for International Registration met with the FDA for this purpose. At the February 4th meeting, the FDA requested an updated version of the labeling that presented more medical information and a more current adverse reaction section. On at least four additional occasions in February and March of 1982, the Medical Advisor had further contacts with the FDA to discuss labeling. Lilly did not tell the FDA of the adverse liver or kidney reactions abroad during any of these meetings or other contacts.
- On June 23, 1982, a number of Lilly officials, including Dr. Shedden, and the Vice President for Regulatory Affairs, met with the FDA to discuss Oraflex's safety. During that meeting, the FDA asked Lilly, and Lilly agreed, to prepare weekly reports of all adverse reactions, including reports of any serious liver and kidney reactions. Although, by the time of this meeting, Lilly knew of approximately fifty unpublished liver and kidney reactions that had occurred in the U.K., the company did not tell the FDA about any of the unpublished overseas reactions and discussed only those reactions that had been published in the medical literature. Nor did any of the weekly reports submitted to the FDA contain information regarding unpublished overseas adverse reactions. It was not until July 22, 1982, during the course of a meeting with the FDA, that Lilly gave the agency a one-page tabulation of 17 unpublished overseas liver and kidney reactions.