875
Drug regulation
jan
Feb
Mar
Apr
May
Variation in haemoglobin (g/dl) and reticulocyte count (109/1) with
therapy.
weakness. The dose of prednisolone was rapidly reduced to 75 mg daily and treatment with cyclosporin was started. Cyclosporin proved ineffective and it was poorly tolerated. The patient remained transfusion-dependent and the decision was made to treat with rhEPO. A dose of 4000 IU subcutaneously six times a week was chosen, not only because it had been effective in the case described by Heyll et aP but also because our patient was a big man (95 kg). By day 14 of therapy with rhEPO he had a significant reticulocytosis and he was given his last blood transfusion on day 20. The health authority refused to cover the cost of the rhEPO which was purchased by the patient’s family. For economic reasons, only 18 doses were given over 3 weeks; fortunately, the haemoglobin started to rise and was normal 8 weeks after the treatment stopped (figure). As in the case described by Heyll et al, treatment with rhEPO was associated with complete remission of PRCA. The total cost of three weeks’ treatment with rhEPO in our patient was about C850. Although this represented a serious financial burden to his family, it is trivial in comparison with the cost to the health authority of treatment with immunosuppressive agents and repeated hospital admissions for blood transfusions. Either a licence should be granted for the use of rhEPO in patients with PRCA or health authorities should adopt a more enlightened attitude to financing the prescription of drugs for indications that are not yet well established. Department of Haematology, Mary’s Hospital Medical School, London W2 1PG, UK
St
H. DODSWORTH
1. Erslev AJ. Erythropoietin. N Engl J Med 1991; 324: 1339-45. 2. Finelli C, Visani G, Gamber B, et al. Steroid-resistant acquired pure red cell aplasia:
3
a
partial remission induced by recombinant human erythropoietin. Br J Haematol 1991, 79: 125. Heyll A, Aul C, Runde V, et al. Treatment of pure red cell aplasia after major
ABO-incompatible
bone
marrow
erythropoietin. Blood 1991; 77:
906.
transplantation
with
in Pakistan
SIR,-Dr Tahir (Feb 22, p 498) expresses concern about the relicensing of Piptal (phenobarbitone plus pipenzolate) by the Pakistan Ministry of Health (PMoH) a year after the drug had been banned. Lakeside Laboratories, USA, under whose licence Piptal is being marketed in Pakistan has been absorbed by Marion Merrell Dow (MMD). An inquiry to MMD revealed that Piptal, when marketed in the USA, contained pipenzolate alone and was available in tablet form with no paediatric dosage instruction. The drug was last sold in the USA in 1976 and was discontinued due to lack of commercial demand. A 1991 guide to therapeutic drugs available and approved outside the USA indicates that pipenzolate is "not recommended in children".’ Piptal is not the only drug to have been reintroduced in Pakistan after being banned. Other notable examples are combinations of dipyrone with a spasmolytic (Hoechst’s Baralgin and BoehringerIngelheim’s Buscopan Compositum) which were banned in 19872 and re-registered a year later when a handful of Pakistani medical experts selected by PMoH unanimously opined that these drugs were therapeutically effective. Another example is Organon’s Anaroxyl (carbazochrome) which is promoted for the "prevention and treatment of surgical and non-surgical capillary bleeding".3 This drug was registered by the Drug Registration Board of the PMoH from 1968 to 1981. An application for renewal of registration was rejected in 1986 on the grounds that the therapeutic efficacy of the drug has not been established. However, in 1988, the injectable form of Anaroxyl was re-registered. These are just a few examples of the many cases in which the drug regulators in Pakistan seemed to have failed to act long after risks or inefficacy of drugs have been proven.4 The Imodium (loperamide) example, in which a letter in The Lancet’ and the Yorkshire Television documentary Vicious CircleS6 prompted the PMoH to ban all paediatric formulations of antimotility drugs, stengthens my belief that international pressure is needed to clean the Pakistan market of dangerous and useless medicines.
recombinant
Departments of Pharmacology and Medicine, Clinical Pharmacology Division, Georgetown University Medical Center, SYED Washington, DC 20007, USA
RIZWANUDDIN AHMAD
1. Schlesser JL. Drugs available abroad. Detroit: Gale Research, 1991: 170. 2. Anon. Health Ministry bans dipyrone combinations. Lancet 1987; i: 905. 3. Quraishi AH. Quick index of medical preparations: vol XXI, nos 1/2. Karachi, 1989-90: 29. 4. Ahmad SR. Bitter facts about drugs. Karachi: HAI Pakistan, 1990. 5. Bhutta TI, Tahir KI. Loperamide poisoning in children. Lancet 1990; 335: 363. 6. Anon. Loperamide poisoning in children. Lancet 1990; 335: 1394.
Research in
developing countries
SIR,-We agree with Dr Patel and Dr Araya’s (Jan 11, p 110) views of reinstatement of researchers from developing countries trained in developed ones. We would go further than Patel and Araya and raise the issue of the difficulties of obtaining funds. In addition to the poor availability of local or foreign funds there is an important political issue. Most agencies from developed countries giving funds to developing ones have a policy that money will be allocated to specific areas. This implies that officers from developed countries decide what developing countries will investigate and which projects will receive support. We know that it is difficult for people living in a very different environment to understand our difficulties and they tend to impose priorities on the basis of their experiences, thus missing the target. An exception is the International Development Research Centre (IDRC) of Canada, which has supported many research projects in Latin America without imposing the subjects to be investigated. However, institutions supported by IDRC are concerned by some proposals at IDRC aimed at changing this policy, and introducing a focus for support. Another exception is the Human Reproduction Programme of the World Health Organisation (HRP/WHO) which provides institutional and training support for research institutions in developing countries. A very encouraging initiative is the one of the Task Force on Health Research for Development which is supporting local assessment of needs on health research.’1
876
We believe, first, that decisions about priorities for support in developing countries should be made by the countries themselves and not by officers from agencies located in developed countries. In addition to assessment of research design, the role of such agencies should be evaluation of the project, which should clearly show that the work is a local priority. Second, research institutions in developing countries need to collaborate well and strengthen their activities. Third, training of professionals from developing countries should be implemented by local institutions, which would ensure that the focus of training is closer to these countries’ needs, and an easier return home for the trainee. Our centre is presently providing a one-year postgraduate training course on research methodology for physicians in Latin America, supported by IDRC and HRP/WHO. In this course skills in the epidemiological and analytical methods to assess priorities are developed. In 1993, we will initiate a training programme for statisticians. However, every year our centre has to interrupt its activities because funds are obtained through a few institutions that provide non-aligned grants and because support for the training programme has to be renewed yearly. This situation leads to our last recommendation-to promote the long-term institutional support from funding agencies to guarantee the continuity of activities. Centro Rosarino de Estudios Perinatales, Orono 500, 2000 Rosario, Argentina
JOSÉ M. BELIZAN
1. The Commission on Health Research for Development. Health research: essential link to equity in development. Oxford: Oxford University Press, 1990.
Proof of causation SIR,-Mr Meeran (March 14, p 671) states that the standard of proof in legal cases is far less stringent than the standard applied in science. He suggests that experts called to present scientific evidence in court do not unduly restrict themselves to the traditional 95 % confidence interval (CI). The fallacy in his reasoning is that the "balance of probabilities" standard used in civil actions the (" > 50% rule") should not be compared to the CI (or degree-ofcertainty figure) used by epidemiologists. If anything, the burden of proof in civil actions is more comparable with the relative risk (RR) or the aetiological fraction (EF), and several US courts have recognised this. The causation issues dealt with in civil actions and by medical scientists are not the same. In a civil action the causation issue is typically whether the plaintiffs injuries were caused by agent X. Population-based studies by medical experts cannot answer the question of individual causation; they merely show whether an individual is at an increased risk if he or she is a member of a certain group. Since increased risk of future disease is generally not recoverable in American courts (unless the likelihood is > 50%), the broader question of whether a substance causes a statistically significant increased risk of disease is usually not in issue. It has been suggestedl that the > 50% burden of proof in civil cases is met when the EF exceeds 0-5 (RR > 20) because more than half the cases of the disease of interest in an exposed group are caused by exposure to agent X. While this is a more accurate analogy than the comparison to CI, this comparison is also vulnerable. The late Sir Austin-Bradford Hill pointed out many years ago that a statistically significant association is not equivalent to causation. Nor does the RR answer the issue of individual causation at issue in a tort action. If half the cases of the disease of interest in the exposed group may have been caused by agent X, half were not; and the study gives the jury and the judge no clue about which group the plaintiff falls into. Meeran’s suggestion that expert witnesses should consider using relaxed CIs is invalid. Judicial institutions do not and should not proceed oblivious to the well-established practices of scientific institutions. American courts typically require that methods used by testifying experts be generally accepted in the scientific discipline from which the expert comes. In fact, some American courts have specifically held that the 95% CIs must be applied by witnesses before their opinion will be allowed before a jury (eg, Brock v
Merrell Dow Pharm Inc [
1989] and Ealy v Richardson-Merrell Inc
[1990]). Traditional notions of causation in epidemiology (ie, RR > 2.0at 95 % CI) are not at all incompatible with the burden of proof in civil tort actions.2 Moreover, there is no rational public policy which would support the adoption of "second-tier" science in our judicial institutions. Sidley and Austin, One First National Plaza, Chicago, Illinois 60603, USA
TIMOTHY E. KAPSHANDY
1. Muscat JE, Huncharek MS. Causation and disease: biomedical science in toxic ton litigation. J Occup Med 1989, 31: 997-1002. 2. Kaye DH. Apples and oranges: confidence coefficients and the burden of persuasion Cornell Law Rev 1987; 73: 54-77.
Hazards of clinical trials SIR,—Your editorial (Dec 14, p 1495) points out the influence of controlled clinical trials on patient psychology. The possible adverse effects inherent in a trial may be termed trial morbidity, which might have contributed to the difference in mortality between the trial group and control group (who received "usual health care") seen several years after stopping the treatments in the Finnish Study. Another classic setting in which such morbidity might arise is an early intervention trial in patients with acute myocardial infarction. These patients are subjected to the mentally taxing process of decision making about participation in a trial while they are in emotional, physical, and psychological distress during the acute stages of the disease, and recent reports have implicated in-hospital psychological stress as a predictor for long-term cardiac mortality and re-infarction after acute myocardial infarction.2 It would be difficult to estimate trial morbidity, unless the intervention or drug is administered without the knowledge of the patient, which would be unethical. Follow-up of large trials and analysis at varying periods after the completion of the trial (with a knowledge of baseline psychological characteristics of different groups) may help to quantify and trace the causes of trial morbidity. Department of Medicine, Medical College, Calicut, Kerala, India 1.
2.
P. DILEEP KUMAR
Strandberg TE, Salomaa VV, Naukkarinen VA, Vanhanen HT, Sarna SJ, Miettinen TA. Long term mortality after 5 years multifactorial primary prevention of cardiovascular disease in middle aged men. JAMA 1991; 266: 1225-29. Frasure-Smith N. In-hospital symptoms of psychological stress as predictors of long-term outcome after acute myocardial infarction in men. Am J Cardiol 1991; 67: 121-27.
Chorionic villus sampling and limb abnormalities SIR,-Following reports of an association between chorionic villus sampling (CVS) and limb abnormalities,!,2an investigation was made in seven European Registration of Congenital Anomalies and Twins (EUROCAT) registries surveying altogether more than 600 000 births (table). These registries cover geographically defined populations. Malformations were registered for live births, stillbirths, and terminations after the diagnosis of malformation, except in Switzerland, where case-registration was restricted to live births. CVS exposure was recorded on the routine case-report forms of malformed babies, except in Odense, where registry data were matched to a known cohort of exposed women for this study. Where possible, extra information on the timing of exposure was sought. Chromosomal syndromes are not included in this report, since a high rate of exposure to CVS would be expected for such cases. Exposed cases with monogenic syndromes for which CVS could be indicated were also excluded. The exposure rate among cases of limb reduction is compared with the exposure rate among other anomalies in the table. 336 cases of limb reduction were reviewed, of which 4 (1-2%) had CVS exposure. In 11 883 cases of other congenital anomalies, 78 (066%) had CVS exposure, giving an odds ratio of 1 -8 (95% CI 0.66-4.99).
Drug regulation
jan
Feb
Mar
Apr
May
Variation in haemoglobin (g/dl) and reticulocyte count (109/1) with
therapy.
weakness. The dose of prednisolone was rapidly reduced to 75 mg daily and treatment with cyclosporin was started. Cyclosporin proved ineffective and it was poorly tolerated. The patient remained transfusion-dependent and the decision was made to treat with rhEPO. A dose of 4000 IU subcutaneously six times a week was chosen, not only because it had been effective in the case described by Heyll et aP but also because our patient was a big man (95 kg). By day 14 of therapy with rhEPO he had a significant reticulocytosis and he was given his last blood transfusion on day 20. The health authority refused to cover the cost of the rhEPO which was purchased by the patient’s family. For economic reasons, only 18 doses were given over 3 weeks; fortunately, the haemoglobin started to rise and was normal 8 weeks after the treatment stopped (figure). As in the case described by Heyll et al, treatment with rhEPO was associated with complete remission of PRCA. The total cost of three weeks’ treatment with rhEPO in our patient was about C850. Although this represented a serious financial burden to his family, it is trivial in comparison with the cost to the health authority of treatment with immunosuppressive agents and repeated hospital admissions for blood transfusions. Either a licence should be granted for the use of rhEPO in patients with PRCA or health authorities should adopt a more enlightened attitude to financing the prescription of drugs for indications that are not yet well established. Department of Haematology, Mary’s Hospital Medical School, London W2 1PG, UK
St
H. DODSWORTH
1. Erslev AJ. Erythropoietin. N Engl J Med 1991; 324: 1339-45. 2. Finelli C, Visani G, Gamber B, et al. Steroid-resistant acquired pure red cell aplasia:
3
a
partial remission induced by recombinant human erythropoietin. Br J Haematol 1991, 79: 125. Heyll A, Aul C, Runde V, et al. Treatment of pure red cell aplasia after major
ABO-incompatible
bone
marrow
erythropoietin. Blood 1991; 77:
906.
transplantation
with
in Pakistan
SIR,-Dr Tahir (Feb 22, p 498) expresses concern about the relicensing of Piptal (phenobarbitone plus pipenzolate) by the Pakistan Ministry of Health (PMoH) a year after the drug had been banned. Lakeside Laboratories, USA, under whose licence Piptal is being marketed in Pakistan has been absorbed by Marion Merrell Dow (MMD). An inquiry to MMD revealed that Piptal, when marketed in the USA, contained pipenzolate alone and was available in tablet form with no paediatric dosage instruction. The drug was last sold in the USA in 1976 and was discontinued due to lack of commercial demand. A 1991 guide to therapeutic drugs available and approved outside the USA indicates that pipenzolate is "not recommended in children".’ Piptal is not the only drug to have been reintroduced in Pakistan after being banned. Other notable examples are combinations of dipyrone with a spasmolytic (Hoechst’s Baralgin and BoehringerIngelheim’s Buscopan Compositum) which were banned in 19872 and re-registered a year later when a handful of Pakistani medical experts selected by PMoH unanimously opined that these drugs were therapeutically effective. Another example is Organon’s Anaroxyl (carbazochrome) which is promoted for the "prevention and treatment of surgical and non-surgical capillary bleeding".3 This drug was registered by the Drug Registration Board of the PMoH from 1968 to 1981. An application for renewal of registration was rejected in 1986 on the grounds that the therapeutic efficacy of the drug has not been established. However, in 1988, the injectable form of Anaroxyl was re-registered. These are just a few examples of the many cases in which the drug regulators in Pakistan seemed to have failed to act long after risks or inefficacy of drugs have been proven.4 The Imodium (loperamide) example, in which a letter in The Lancet’ and the Yorkshire Television documentary Vicious CircleS6 prompted the PMoH to ban all paediatric formulations of antimotility drugs, stengthens my belief that international pressure is needed to clean the Pakistan market of dangerous and useless medicines.
recombinant
Departments of Pharmacology and Medicine, Clinical Pharmacology Division, Georgetown University Medical Center, SYED Washington, DC 20007, USA
RIZWANUDDIN AHMAD
1. Schlesser JL. Drugs available abroad. Detroit: Gale Research, 1991: 170. 2. Anon. Health Ministry bans dipyrone combinations. Lancet 1987; i: 905. 3. Quraishi AH. Quick index of medical preparations: vol XXI, nos 1/2. Karachi, 1989-90: 29. 4. Ahmad SR. Bitter facts about drugs. Karachi: HAI Pakistan, 1990. 5. Bhutta TI, Tahir KI. Loperamide poisoning in children. Lancet 1990; 335: 363. 6. Anon. Loperamide poisoning in children. Lancet 1990; 335: 1394.
Research in
developing countries
SIR,-We agree with Dr Patel and Dr Araya’s (Jan 11, p 110) views of reinstatement of researchers from developing countries trained in developed ones. We would go further than Patel and Araya and raise the issue of the difficulties of obtaining funds. In addition to the poor availability of local or foreign funds there is an important political issue. Most agencies from developed countries giving funds to developing ones have a policy that money will be allocated to specific areas. This implies that officers from developed countries decide what developing countries will investigate and which projects will receive support. We know that it is difficult for people living in a very different environment to understand our difficulties and they tend to impose priorities on the basis of their experiences, thus missing the target. An exception is the International Development Research Centre (IDRC) of Canada, which has supported many research projects in Latin America without imposing the subjects to be investigated. However, institutions supported by IDRC are concerned by some proposals at IDRC aimed at changing this policy, and introducing a focus for support. Another exception is the Human Reproduction Programme of the World Health Organisation (HRP/WHO) which provides institutional and training support for research institutions in developing countries. A very encouraging initiative is the one of the Task Force on Health Research for Development which is supporting local assessment of needs on health research.’1
876
We believe, first, that decisions about priorities for support in developing countries should be made by the countries themselves and not by officers from agencies located in developed countries. In addition to assessment of research design, the role of such agencies should be evaluation of the project, which should clearly show that the work is a local priority. Second, research institutions in developing countries need to collaborate well and strengthen their activities. Third, training of professionals from developing countries should be implemented by local institutions, which would ensure that the focus of training is closer to these countries’ needs, and an easier return home for the trainee. Our centre is presently providing a one-year postgraduate training course on research methodology for physicians in Latin America, supported by IDRC and HRP/WHO. In this course skills in the epidemiological and analytical methods to assess priorities are developed. In 1993, we will initiate a training programme for statisticians. However, every year our centre has to interrupt its activities because funds are obtained through a few institutions that provide non-aligned grants and because support for the training programme has to be renewed yearly. This situation leads to our last recommendation-to promote the long-term institutional support from funding agencies to guarantee the continuity of activities. Centro Rosarino de Estudios Perinatales, Orono 500, 2000 Rosario, Argentina
JOSÉ M. BELIZAN
1. The Commission on Health Research for Development. Health research: essential link to equity in development. Oxford: Oxford University Press, 1990.
Proof of causation SIR,-Mr Meeran (March 14, p 671) states that the standard of proof in legal cases is far less stringent than the standard applied in science. He suggests that experts called to present scientific evidence in court do not unduly restrict themselves to the traditional 95 % confidence interval (CI). The fallacy in his reasoning is that the "balance of probabilities" standard used in civil actions the (" > 50% rule") should not be compared to the CI (or degree-ofcertainty figure) used by epidemiologists. If anything, the burden of proof in civil actions is more comparable with the relative risk (RR) or the aetiological fraction (EF), and several US courts have recognised this. The causation issues dealt with in civil actions and by medical scientists are not the same. In a civil action the causation issue is typically whether the plaintiffs injuries were caused by agent X. Population-based studies by medical experts cannot answer the question of individual causation; they merely show whether an individual is at an increased risk if he or she is a member of a certain group. Since increased risk of future disease is generally not recoverable in American courts (unless the likelihood is > 50%), the broader question of whether a substance causes a statistically significant increased risk of disease is usually not in issue. It has been suggestedl that the > 50% burden of proof in civil cases is met when the EF exceeds 0-5 (RR > 20) because more than half the cases of the disease of interest in an exposed group are caused by exposure to agent X. While this is a more accurate analogy than the comparison to CI, this comparison is also vulnerable. The late Sir Austin-Bradford Hill pointed out many years ago that a statistically significant association is not equivalent to causation. Nor does the RR answer the issue of individual causation at issue in a tort action. If half the cases of the disease of interest in the exposed group may have been caused by agent X, half were not; and the study gives the jury and the judge no clue about which group the plaintiff falls into. Meeran’s suggestion that expert witnesses should consider using relaxed CIs is invalid. Judicial institutions do not and should not proceed oblivious to the well-established practices of scientific institutions. American courts typically require that methods used by testifying experts be generally accepted in the scientific discipline from which the expert comes. In fact, some American courts have specifically held that the 95% CIs must be applied by witnesses before their opinion will be allowed before a jury (eg, Brock v
Merrell Dow Pharm Inc [
1989] and Ealy v Richardson-Merrell Inc
[1990]). Traditional notions of causation in epidemiology (ie, RR > 2.0at 95 % CI) are not at all incompatible with the burden of proof in civil tort actions.2 Moreover, there is no rational public policy which would support the adoption of "second-tier" science in our judicial institutions. Sidley and Austin, One First National Plaza, Chicago, Illinois 60603, USA
TIMOTHY E. KAPSHANDY
1. Muscat JE, Huncharek MS. Causation and disease: biomedical science in toxic ton litigation. J Occup Med 1989, 31: 997-1002. 2. Kaye DH. Apples and oranges: confidence coefficients and the burden of persuasion Cornell Law Rev 1987; 73: 54-77.
Hazards of clinical trials SIR,—Your editorial (Dec 14, p 1495) points out the influence of controlled clinical trials on patient psychology. The possible adverse effects inherent in a trial may be termed trial morbidity, which might have contributed to the difference in mortality between the trial group and control group (who received "usual health care") seen several years after stopping the treatments in the Finnish Study. Another classic setting in which such morbidity might arise is an early intervention trial in patients with acute myocardial infarction. These patients are subjected to the mentally taxing process of decision making about participation in a trial while they are in emotional, physical, and psychological distress during the acute stages of the disease, and recent reports have implicated in-hospital psychological stress as a predictor for long-term cardiac mortality and re-infarction after acute myocardial infarction.2 It would be difficult to estimate trial morbidity, unless the intervention or drug is administered without the knowledge of the patient, which would be unethical. Follow-up of large trials and analysis at varying periods after the completion of the trial (with a knowledge of baseline psychological characteristics of different groups) may help to quantify and trace the causes of trial morbidity. Department of Medicine, Medical College, Calicut, Kerala, India 1.
2.
P. DILEEP KUMAR
Strandberg TE, Salomaa VV, Naukkarinen VA, Vanhanen HT, Sarna SJ, Miettinen TA. Long term mortality after 5 years multifactorial primary prevention of cardiovascular disease in middle aged men. JAMA 1991; 266: 1225-29. Frasure-Smith N. In-hospital symptoms of psychological stress as predictors of long-term outcome after acute myocardial infarction in men. Am J Cardiol 1991; 67: 121-27.
Chorionic villus sampling and limb abnormalities SIR,-Following reports of an association between chorionic villus sampling (CVS) and limb abnormalities,!,2an investigation was made in seven European Registration of Congenital Anomalies and Twins (EUROCAT) registries surveying altogether more than 600 000 births (table). These registries cover geographically defined populations. Malformations were registered for live births, stillbirths, and terminations after the diagnosis of malformation, except in Switzerland, where case-registration was restricted to live births. CVS exposure was recorded on the routine case-report forms of malformed babies, except in Odense, where registry data were matched to a known cohort of exposed women for this study. Where possible, extra information on the timing of exposure was sought. Chromosomal syndromes are not included in this report, since a high rate of exposure to CVS would be expected for such cases. Exposed cases with monogenic syndromes for which CVS could be indicated were also excluded. The exposure rate among cases of limb reduction is compared with the exposure rate among other anomalies in the table. 336 cases of limb reduction were reviewed, of which 4 (1-2%) had CVS exposure. In 11 883 cases of other congenital anomalies, 78 (066%) had CVS exposure, giving an odds ratio of 1 -8 (95% CI 0.66-4.99).
