- Email: [email protected]
UNETHICAL TRIALS OF DIPYRONE IN THAILAND
1491 unreasonable. The situation changed substantially in 1984 and 1985, and your editorial acknowledges that the yellow-card scheme "did indeed pick up evidence of the problem". You make much of studies in Europe and the USA between 1979 and 1984 and suggest that the surge of reports in the UK in 1985 was "likely to have been the result of all the publicity at the time". What publicity? Are you suggesting that the British general practitioners who filled in yellow cards were influenced by their reading of an article in the German press in 1983,3aUS congressional subcommittee hearing of 1986,4 and a US Food and Drug Administration (FDA) report of 19875 (the last two being dated after the withdrawal of nomifensine in the UK)? The 1983 report3 antedated FDA approval ofnomifensine at the end of 1984. Why should the CSM use that paper as a basis for withdrawal of approval? The accounts of the yellow card reports with nomifensine and other antidepressants may have biased the data but this was taken into account in the evaluation. The reason for the increased reporting rates of serious adverse reactions, in which nomifensine was the suspected cause, in 1984/85 remains unclear. When considering action in situations such as this attention needs to be given to all the data provided by the CSM’s monitoring service;6,7 to the nature, frequency, severity, outcome, and treatability of the reactions; and to the presence of contributing factors, the seriousness of the disease for which the drug was used and its efficacy in that disease, the risks and benefits of alternatives, and the consequences of withdrawal in patients already taking the drug without adverse effects. Such complex considerations will always permit a spectrum of opinion: some would have favoured earlier withdrawal while others would argue that the action was draconian or precipitate. What matters is that we bear in mind the usefulness of our monitoring systems and the need to protect and improve them. Manor Cottage,
1. Committee on Safety of Drugs. Office, 1971
Report for
RONALD D. MANN 1969 and 1970. London: HM
Stationery
2. Anon. CSM update: withdrawal of nomifensine. Br Med J 1986; 293: 41. 3. Walti-ML, et al. Schweiz Med Wschr 1983; 113: 1865-67. 4. Hearing on May 22, 1986, before a US Congressional Subcommittee on the Oversight of the New Drug Review Process and FDA’s Regulation of Merital. 5. Anon. FDA’s regulation of the new drug Merital, 15th report. Committee on Government Operations, July 8, 1987. Washington, DC: Government Printing Office, 1987. 6. Mann RD, ed. Adverse drug reactions. Carnforth: Parthenon, 1987. 7. Mann RD. CSM monitoring today. Pharm Med 1988; 3: 275-89.
UNETHICAL TRIALS OF DIPYRONE IN THAILAND
SiR,—Three clinical trials in Thailand have drawn the attention consumer protection groups to what appears to be a widespread problem-namely, the promotional clinical trial. The first study is being done at a teaching hospital. Its aim is to "compare the analgesic efficacy and tolerability of dipyrone (metamizole) and pethidine in patients with postoperative pain after appendectomy". of Thai
two
Drug Information for Action Centre, 125/3 Soi Nomjit Nares Road, Bangkok 10500, Thailand
have been
completed and compared the antipyretic
efficacy of dipyrone and paracetamol (acetaminophen). One was in 60 children aged 4-7 years with fever (38’5°C or higher). All three trials violate the Helsinki declaration (1975).1 The first trial does not "conform to generally accepted scientific principles". The identities of the drugs are not masked and no precautions are taken to ensure that those assessing the action of the drugs are not the ones who administer them. The number of patients (130) is insufficient to permit assessment of the tolerability of dipyrone. In none of the trials is the importance of the objective "in proportion to the inherent risk to the subjects". Postappendicectomy pain can never justify exposing a patient to the risk of agranulocytosis or anaphylactic shock (the incidence of shock after dipyrone injection is now estimated at 1 in 5000). A comparison of the antipyretic efficacy of dipyrone (banned in many countries) with that of paracetamol in moderate fever is unjustifiable. None of the three trials was submitted to the clinical trial review committees of the hospitals concerned. The research on dipyrone in children violates proposed guidelines that state "that
PRASERT KIATBOONSRI
JUDITH RICHTER
1. Anon. Declaration of Helsinki: recommendations guiding medical doctors in biomedical research involving human subjects (as revised by the 19th World Medical Assembly, Tokyo, Japan, 1975).
2. Rummel
Petersfield Road, Midhurst, West Sussex GU29 9RL
The other
children should never be the subjects of research that might equally well be carried out in adults".3 Other important points, such as whether the participants gave their informed consent and who would be responsible for compensation should any accident occur, remain unresolved since the research-workers and the sponsoring company refuse to make any public statement on the need for and validity of the work. All three trials were designed, initiated, and sponsored by Hoechst, the world’s main manufacturer of dipyrone, at a time when consumer protection groups in Thailand have been calling for the withdrawal of this drug. Sponsoring clinical trials seems to be an integral part of Hoechst’s strategy to delay stricter regulation or withdrawal of dipyrone. Only a few months ago Hoechst obtained an injunction against an order from the Philippines Bureau of Food and Drugs banning dipyrone while a new study was done--on a drug that has been on the market for more than 65 years. While investigating these trials we were told by Thai scientists that it is not uncommon for foreign drug companies to perform unreviewed clinical trials. The analysis and publication of the data are often left entirely to the sponsoring company. It seems that legislation on clinical trials is urgently needed. This should ensure that trials are registered not only in the country where they are done but also in the home country of the sponsoring company. Clinical trials must be open to public scrutiny. We hope that medical journals will respect the Helsinki declaration and refuse to publish the trials described.
3.
W.
Metamizol:
Kommentar
zu
Berichten
uber
lebensbedrohliche
Kreislauferkrankungen. Dtsch Ärzteblatt 1987; 84: B2408-12. CIOMS/WHO. Proposed international guidelines for biomedical research involving human subjects: a joint project of the World Health Organisation (WHO) and the Council for International Organisations of Medical Sciences (CIOMS). Geneva: CIOMS, 1982: 24.
ACE INHIBITORS
SiR,—Itake issue with your editorial on angiotensin-converting enzyme (ACE) inhibitors (Oct 15, p 885). The likely production over the next few years of a series of "me too" ACE inhibitors is not hard to justify. It is the inevitable consequence of a highly competitive, free-enterprise pharmaceutical industry. With a development period for any drug exceeding a decade (and growing due to regulatory and safety requirements) additional compounds will appear after an initial drug has established the therapeutic niche. The system is open to the criticisms that it is inefficient and confusing to doctors. However, the alternative, non-competitive system of socialist republics has produced no drugs of any consequence (with the possible exception of L-deprenyl from Hungary) during the four decades of enormous therapeutic advances made in the west. My argument echoes Churchill defending democracy: the system may be terrible but everything else is worse. Is the production of a series of similar drugs without merit? There are at least two advantages. When toxicity is rare, it takes years of exposure in many hundreds of thousands of patients to decide that one drug is safer than another. The development of many non-steroidal anti-inflammatory drugs (NSAIDs) permitted withdrawal of phenylbutazone in most arthritic conditions. Without the irritating and commercially led development, the older and more toxic drug would not have been rendered obsolete. While the many similar NSAIDS cause professional irritation, most rheumatologists "shop around" between compounds to find the one most acceptable to the patient. The existence of these alternative drugs is a therapeutic advantage compared with twenty years ago when aspirin was the drug of first choice for rheumatoid arthiritis. Wellcome Foundation, Beckenham, Kent BR3 3BS
A. W. PECK
1. Committee on Safety of Drugs. Office, 1971
Report for
RONALD D. MANN 1969 and 1970. London: HM
Stationery
2. Anon. CSM update: withdrawal of nomifensine. Br Med J 1986; 293: 41. 3. Walti-ML, et al. Schweiz Med Wschr 1983; 113: 1865-67. 4. Hearing on May 22, 1986, before a US Congressional Subcommittee on the Oversight of the New Drug Review Process and FDA’s Regulation of Merital. 5. Anon. FDA’s regulation of the new drug Merital, 15th report. Committee on Government Operations, July 8, 1987. Washington, DC: Government Printing Office, 1987. 6. Mann RD, ed. Adverse drug reactions. Carnforth: Parthenon, 1987. 7. Mann RD. CSM monitoring today. Pharm Med 1988; 3: 275-89.
UNETHICAL TRIALS OF DIPYRONE IN THAILAND
SiR,—Three clinical trials in Thailand have drawn the attention consumer protection groups to what appears to be a widespread problem-namely, the promotional clinical trial. The first study is being done at a teaching hospital. Its aim is to "compare the analgesic efficacy and tolerability of dipyrone (metamizole) and pethidine in patients with postoperative pain after appendectomy". of Thai
two
Drug Information for Action Centre, 125/3 Soi Nomjit Nares Road, Bangkok 10500, Thailand
have been
completed and compared the antipyretic
efficacy of dipyrone and paracetamol (acetaminophen). One was in 60 children aged 4-7 years with fever (38’5°C or higher). All three trials violate the Helsinki declaration (1975).1 The first trial does not "conform to generally accepted scientific principles". The identities of the drugs are not masked and no precautions are taken to ensure that those assessing the action of the drugs are not the ones who administer them. The number of patients (130) is insufficient to permit assessment of the tolerability of dipyrone. In none of the trials is the importance of the objective "in proportion to the inherent risk to the subjects". Postappendicectomy pain can never justify exposing a patient to the risk of agranulocytosis or anaphylactic shock (the incidence of shock after dipyrone injection is now estimated at 1 in 5000). A comparison of the antipyretic efficacy of dipyrone (banned in many countries) with that of paracetamol in moderate fever is unjustifiable. None of the three trials was submitted to the clinical trial review committees of the hospitals concerned. The research on dipyrone in children violates proposed guidelines that state "that
PRASERT KIATBOONSRI
JUDITH RICHTER
1. Anon. Declaration of Helsinki: recommendations guiding medical doctors in biomedical research involving human subjects (as revised by the 19th World Medical Assembly, Tokyo, Japan, 1975).
2. Rummel
Petersfield Road, Midhurst, West Sussex GU29 9RL
The other
children should never be the subjects of research that might equally well be carried out in adults".3 Other important points, such as whether the participants gave their informed consent and who would be responsible for compensation should any accident occur, remain unresolved since the research-workers and the sponsoring company refuse to make any public statement on the need for and validity of the work. All three trials were designed, initiated, and sponsored by Hoechst, the world’s main manufacturer of dipyrone, at a time when consumer protection groups in Thailand have been calling for the withdrawal of this drug. Sponsoring clinical trials seems to be an integral part of Hoechst’s strategy to delay stricter regulation or withdrawal of dipyrone. Only a few months ago Hoechst obtained an injunction against an order from the Philippines Bureau of Food and Drugs banning dipyrone while a new study was done--on a drug that has been on the market for more than 65 years. While investigating these trials we were told by Thai scientists that it is not uncommon for foreign drug companies to perform unreviewed clinical trials. The analysis and publication of the data are often left entirely to the sponsoring company. It seems that legislation on clinical trials is urgently needed. This should ensure that trials are registered not only in the country where they are done but also in the home country of the sponsoring company. Clinical trials must be open to public scrutiny. We hope that medical journals will respect the Helsinki declaration and refuse to publish the trials described.
3.
W.
Metamizol:
Kommentar
zu
Berichten
uber
lebensbedrohliche
Kreislauferkrankungen. Dtsch Ärzteblatt 1987; 84: B2408-12. CIOMS/WHO. Proposed international guidelines for biomedical research involving human subjects: a joint project of the World Health Organisation (WHO) and the Council for International Organisations of Medical Sciences (CIOMS). Geneva: CIOMS, 1982: 24.
ACE INHIBITORS
SiR,—Itake issue with your editorial on angiotensin-converting enzyme (ACE) inhibitors (Oct 15, p 885). The likely production over the next few years of a series of "me too" ACE inhibitors is not hard to justify. It is the inevitable consequence of a highly competitive, free-enterprise pharmaceutical industry. With a development period for any drug exceeding a decade (and growing due to regulatory and safety requirements) additional compounds will appear after an initial drug has established the therapeutic niche. The system is open to the criticisms that it is inefficient and confusing to doctors. However, the alternative, non-competitive system of socialist republics has produced no drugs of any consequence (with the possible exception of L-deprenyl from Hungary) during the four decades of enormous therapeutic advances made in the west. My argument echoes Churchill defending democracy: the system may be terrible but everything else is worse. Is the production of a series of similar drugs without merit? There are at least two advantages. When toxicity is rare, it takes years of exposure in many hundreds of thousands of patients to decide that one drug is safer than another. The development of many non-steroidal anti-inflammatory drugs (NSAIDs) permitted withdrawal of phenylbutazone in most arthritic conditions. Without the irritating and commercially led development, the older and more toxic drug would not have been rendered obsolete. While the many similar NSAIDS cause professional irritation, most rheumatologists "shop around" between compounds to find the one most acceptable to the patient. The existence of these alternative drugs is a therapeutic advantage compared with twenty years ago when aspirin was the drug of first choice for rheumatoid arthiritis. Wellcome Foundation, Beckenham, Kent BR3 3BS
A. W. PECK