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DIPYRONE TRIALS IN THAILAND
107 At the 7th International
Symposium
on
Prevention and
Detection of Cancer (Nice, April, 1989) Richard Peto estimated that on current trends
in smoking habits 500 million people will die from
tobacco-related diseases before the year 2050. The tobacco
industry’s offer to the Karolinska Institute is an attempt to promote itself indirectly and to gain credibility. It will help to foster the myth that more research on the risks associated with tobacco is needed, and the World Health Organisation’s message and objectives will be
ignored. What is needed now is not additional medical research but political and medical action to create a tobacco-free society. The wish of the Swedish Tobacco Group to establish a chair on the occasion of its 75th anniversary is ironic. What are they celebrating? Being the major contributor to ill-health in Sweden for the past 75 years? It is inconceivable that the Karolinska Institute could even consider accepting money from this source. Most doctors have to battle with the consequences of smoking while a prestigious institute in its hunger for more funds accepts any kind of money. What next? A Bofors chair for research on the effects of weapons-or an Absolute Vodka chair to study the social and medical effects of alcohol? The Nice symposium in its last plenary meeting accepted that medical faculties and scientists should not accept money from the tobacco industry. Physicians must protest against this attempt by the Swedish Tobacco Group to buy credibility from the Karolinska Institute and from the Nobel prize. If the donation goes through, the Karolinska’s reputation will be soiled. Department of Cancer Prevention, Radiumhemmet, Karolinska Institute and Hospital, S-104 01 Stockholm, Sweden
LARS-ERIK HOLM
DIPYRONE TRIALS IN THAILAND
SfR,— Dr Hanpadungdhama and Dr Sriwatanakul, both lecturers at Mahidol University (April 8, p 788), are critical of our analysis1 of three clinical trials on dipyrone (metamizole) in Thailand. Neither letter dispels our doubts. Neither correspondent explains why no attempt was made to mask the drugs. Dr Timmers, head of Hoechst medical affairs international, has stated in response to our letter that "the drugs will not be given blind to the patients because they are unaware of the treatment being administered ... they are still partially sedated during the first 2-3 days after surgery"How valid, in partly sedated patients, is the assessment of pain relief using a visual analogue scale? Why did Timmers not comment on our criticism that the identity of the drug is known to the nurses evaluating their effects? Hanpadungdhama states that the study was not intended to prove dipyrone’s safety, but to assess adverse events such as nausea, dizziness, and respiratory depression. If the definition of tolerability is restricted to frequent adverse effects the comparison between the two drugs is predictably biased in favour of dipyrone. Dipyrone will appear to be "very well tolerated". Its rare, but potentially fatal adverse effects (shock and agranulocytosis) are unlikely to occur in a sample of only 65 patients. Pethidine, however, is known to cause some unpleasant (but treatable) effects. The Drug Information for Action Centre (DIAC) rejects Hanpadungdhama’s claim that the question of dipyrone’s safety has been answered by the Hoechst sponsored International Agranulocytosis and Aplastic Anemia Study (the Boston study).3 This study has been misinterpreted by Hoechst as proof of dipyrone’s safety since 1984, when preliminary results were releasedYet when the first report was published in 1986, scientists worldwide voiced doubts about its validity.5-1O The main question that has arisen is why the Boston study found a strong link between dipyrone use and agranulocytosis in some study regions but no link in others. Many critics believe that the study underestimated the true incidence of dipyrone-induced agranulocytosis. Offerhaus reports that at the onset of the study two large hospitals in Berlin were not aware that a trial of this kind was going on, and that the population estimate given for the Ulm region (53 million) is about ten times the true figure.9,1O The final report of the Boston study remains unpublished, precluding further analysis.
In
than ten countries the known risks of dipyrone to the health have led to withdrawal of the drug. DIAC asked the public drug regulatory authorities in the UK and US for their current view on dipyrone. A senior official in the UK licensing authority replied that " ... although arguments continue about the true incidence of serious and fatal adverse reactions to amidopyrine and dipyrone, I personally consider the frequency unacceptable". The US Food and Drug Administration has reaffirmed its 1977 decision to ban dipyrone on the grounds that "these drug products ... are not shown to be safe for use". It is calculated (based on 20 million doses dispensed daily and an excess risk of 1 1 cases of agranulocytosis and 20 cases of shock per million users) that dipyrone yearly causes at least 7000 cases of agranulocytosis and another 145 000 cases of shock world wide. How much longer will Hoechst delay the withdrawal of dipyrone, an urgent matter in third-world countries? Both your correspondents accuse DIAC of not attempting to contact the clinicians involved. DIAC tried to contact Hanpadungdhama at the beginning of the clinical trial at Ramathibodi Hospital. We were informed that he was on a trip abroad and would not return for some time. The medical adviser of Hoechst (Thailand) was also abroad. A Thai journalist who tried to investigate the trials, after the doctors returned, was referred from one person to another, without success. We did reach the clinician who had been responsible for the dipyrone trial in children. She could give no information on her results because she had entrusted all data to Hoechst. Available information was sufficient, however, to conclude that all three trials violated the Declaration of Helsinki. Although we would have preferred to have access to all information concerning the trials, we felt a pressing need for public debate. We filed a complaint with the Thai Medical Council (which has not yet taken a stand) in October, 1988, and wrote to The Lancet. It is unfair to accuse DIAC of insulting "the Thai medical profession in general" and the "Thai drug licensing authority". In our letter we did not reveal the names of the scientists and hospitals involved, nor did we speculate on the reaction of the Thai licensing authority but concentrated solely on the problem of insufficient legislation against unethical clinical trials. Sriwatanakul’s report that we are not medically qualified implies that only doctors are allowed to discuss the ethics in clinical trials. We are both pharmacists and DIAC relies on several health professionals for advice. History shows that discussion limited to the medical profession often fails to safeguard subjects’ rights and wellbeing. The patient must have the right to contribute to the decisions and to be represented in the ethics committees. DIAC believes that legislation is needed on ethics in clinical trials, to prevent the misuse of patients in promotional clinical trials. DIAC is particularly concerned about Timmers’ statement that the trial on dipyrone’s analgesic efficacy described above "is only the first of many such trials due to be conducted in several other countries, including some in Western Europe".2 more
Drug Information for Action Centre, DSG 125/3 Soi Nomjit Nares Road, Bangkok 10500, Thailand
PRASERT KIATBOONSRI
JUDITH RICHTER
1. Kiatboonsri P, Richter J. Unethical trials of dipyrone in Thailand. Lancet 1988; ii: 1491. 2. Anon. Dispute over Thai dipyrone trials Scrip 1989; 1378: 28. 3. The International Agranulocytosis and Aplastic Anemia Study. Risks of agranulocytosis and aplastic anemia. JAMA 1986; 256: 1749-57 4. Anon. Dipyrone: hearing by the German Drug Authority Lancet 1986; ii: 737-38. 5. Anon. Analgesics, agranulocytosis, and aplastic anaemia: a major case-control study. Lancet 1986; ii: 899-900. 6. del Favero A. Anti-inflammatory analgesics. In: Dukes MNG, ed. Meyler’s side effects of drugs. Vol XI. Amsterdam: Elsevier. 1987: 89-91. 7. Kramer MS, Lane DA, Hutchinson TA. Analgesic use, blood dyscrasias, and case-control pharmacoepidemiology: a critique of the International Agranulocytosis and Aplastic Anemia Study. J Chronic Dis 1987; 40: 1073-81. 8. van Dijke CPH. Analgesic use, agranulocytosis and aplastic anemia. JAMA 1987; 257: 1590. 9. Offerhaus L. Metamizol: een honderdjarige treunis (Dipyrone: the sadness of a centenary). Ned Tijdschr Geneesk 1987; 131: 479-81 (Dutch). 10. Offerhaus L. Rejoinder to Levy & Shapiro. Ned Tydschr Geneesk 1987; 131: 1681-83
(English).
Symposium
on
Prevention and
Detection of Cancer (Nice, April, 1989) Richard Peto estimated that on current trends
in smoking habits 500 million people will die from
tobacco-related diseases before the year 2050. The tobacco
industry’s offer to the Karolinska Institute is an attempt to promote itself indirectly and to gain credibility. It will help to foster the myth that more research on the risks associated with tobacco is needed, and the World Health Organisation’s message and objectives will be
ignored. What is needed now is not additional medical research but political and medical action to create a tobacco-free society. The wish of the Swedish Tobacco Group to establish a chair on the occasion of its 75th anniversary is ironic. What are they celebrating? Being the major contributor to ill-health in Sweden for the past 75 years? It is inconceivable that the Karolinska Institute could even consider accepting money from this source. Most doctors have to battle with the consequences of smoking while a prestigious institute in its hunger for more funds accepts any kind of money. What next? A Bofors chair for research on the effects of weapons-or an Absolute Vodka chair to study the social and medical effects of alcohol? The Nice symposium in its last plenary meeting accepted that medical faculties and scientists should not accept money from the tobacco industry. Physicians must protest against this attempt by the Swedish Tobacco Group to buy credibility from the Karolinska Institute and from the Nobel prize. If the donation goes through, the Karolinska’s reputation will be soiled. Department of Cancer Prevention, Radiumhemmet, Karolinska Institute and Hospital, S-104 01 Stockholm, Sweden
LARS-ERIK HOLM
DIPYRONE TRIALS IN THAILAND
SfR,— Dr Hanpadungdhama and Dr Sriwatanakul, both lecturers at Mahidol University (April 8, p 788), are critical of our analysis1 of three clinical trials on dipyrone (metamizole) in Thailand. Neither letter dispels our doubts. Neither correspondent explains why no attempt was made to mask the drugs. Dr Timmers, head of Hoechst medical affairs international, has stated in response to our letter that "the drugs will not be given blind to the patients because they are unaware of the treatment being administered ... they are still partially sedated during the first 2-3 days after surgery"How valid, in partly sedated patients, is the assessment of pain relief using a visual analogue scale? Why did Timmers not comment on our criticism that the identity of the drug is known to the nurses evaluating their effects? Hanpadungdhama states that the study was not intended to prove dipyrone’s safety, but to assess adverse events such as nausea, dizziness, and respiratory depression. If the definition of tolerability is restricted to frequent adverse effects the comparison between the two drugs is predictably biased in favour of dipyrone. Dipyrone will appear to be "very well tolerated". Its rare, but potentially fatal adverse effects (shock and agranulocytosis) are unlikely to occur in a sample of only 65 patients. Pethidine, however, is known to cause some unpleasant (but treatable) effects. The Drug Information for Action Centre (DIAC) rejects Hanpadungdhama’s claim that the question of dipyrone’s safety has been answered by the Hoechst sponsored International Agranulocytosis and Aplastic Anemia Study (the Boston study).3 This study has been misinterpreted by Hoechst as proof of dipyrone’s safety since 1984, when preliminary results were releasedYet when the first report was published in 1986, scientists worldwide voiced doubts about its validity.5-1O The main question that has arisen is why the Boston study found a strong link between dipyrone use and agranulocytosis in some study regions but no link in others. Many critics believe that the study underestimated the true incidence of dipyrone-induced agranulocytosis. Offerhaus reports that at the onset of the study two large hospitals in Berlin were not aware that a trial of this kind was going on, and that the population estimate given for the Ulm region (53 million) is about ten times the true figure.9,1O The final report of the Boston study remains unpublished, precluding further analysis.
In
than ten countries the known risks of dipyrone to the health have led to withdrawal of the drug. DIAC asked the public drug regulatory authorities in the UK and US for their current view on dipyrone. A senior official in the UK licensing authority replied that " ... although arguments continue about the true incidence of serious and fatal adverse reactions to amidopyrine and dipyrone, I personally consider the frequency unacceptable". The US Food and Drug Administration has reaffirmed its 1977 decision to ban dipyrone on the grounds that "these drug products ... are not shown to be safe for use". It is calculated (based on 20 million doses dispensed daily and an excess risk of 1 1 cases of agranulocytosis and 20 cases of shock per million users) that dipyrone yearly causes at least 7000 cases of agranulocytosis and another 145 000 cases of shock world wide. How much longer will Hoechst delay the withdrawal of dipyrone, an urgent matter in third-world countries? Both your correspondents accuse DIAC of not attempting to contact the clinicians involved. DIAC tried to contact Hanpadungdhama at the beginning of the clinical trial at Ramathibodi Hospital. We were informed that he was on a trip abroad and would not return for some time. The medical adviser of Hoechst (Thailand) was also abroad. A Thai journalist who tried to investigate the trials, after the doctors returned, was referred from one person to another, without success. We did reach the clinician who had been responsible for the dipyrone trial in children. She could give no information on her results because she had entrusted all data to Hoechst. Available information was sufficient, however, to conclude that all three trials violated the Declaration of Helsinki. Although we would have preferred to have access to all information concerning the trials, we felt a pressing need for public debate. We filed a complaint with the Thai Medical Council (which has not yet taken a stand) in October, 1988, and wrote to The Lancet. It is unfair to accuse DIAC of insulting "the Thai medical profession in general" and the "Thai drug licensing authority". In our letter we did not reveal the names of the scientists and hospitals involved, nor did we speculate on the reaction of the Thai licensing authority but concentrated solely on the problem of insufficient legislation against unethical clinical trials. Sriwatanakul’s report that we are not medically qualified implies that only doctors are allowed to discuss the ethics in clinical trials. We are both pharmacists and DIAC relies on several health professionals for advice. History shows that discussion limited to the medical profession often fails to safeguard subjects’ rights and wellbeing. The patient must have the right to contribute to the decisions and to be represented in the ethics committees. DIAC believes that legislation is needed on ethics in clinical trials, to prevent the misuse of patients in promotional clinical trials. DIAC is particularly concerned about Timmers’ statement that the trial on dipyrone’s analgesic efficacy described above "is only the first of many such trials due to be conducted in several other countries, including some in Western Europe".2 more
Drug Information for Action Centre, DSG 125/3 Soi Nomjit Nares Road, Bangkok 10500, Thailand
PRASERT KIATBOONSRI
JUDITH RICHTER
1. Kiatboonsri P, Richter J. Unethical trials of dipyrone in Thailand. Lancet 1988; ii: 1491. 2. Anon. Dispute over Thai dipyrone trials Scrip 1989; 1378: 28. 3. The International Agranulocytosis and Aplastic Anemia Study. Risks of agranulocytosis and aplastic anemia. JAMA 1986; 256: 1749-57 4. Anon. Dipyrone: hearing by the German Drug Authority Lancet 1986; ii: 737-38. 5. Anon. Analgesics, agranulocytosis, and aplastic anaemia: a major case-control study. Lancet 1986; ii: 899-900. 6. del Favero A. Anti-inflammatory analgesics. In: Dukes MNG, ed. Meyler’s side effects of drugs. Vol XI. Amsterdam: Elsevier. 1987: 89-91. 7. Kramer MS, Lane DA, Hutchinson TA. Analgesic use, blood dyscrasias, and case-control pharmacoepidemiology: a critique of the International Agranulocytosis and Aplastic Anemia Study. J Chronic Dis 1987; 40: 1073-81. 8. van Dijke CPH. Analgesic use, agranulocytosis and aplastic anemia. JAMA 1987; 257: 1590. 9. Offerhaus L. Metamizol: een honderdjarige treunis (Dipyrone: the sadness of a centenary). Ned Tijdschr Geneesk 1987; 131: 479-81 (Dutch). 10. Offerhaus L. Rejoinder to Levy & Shapiro. Ned Tydschr Geneesk 1987; 131: 1681-83
(English).