- Email: [email protected]
Ethics review and clinical trials
CORRESPONDENCE
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1995; 82: 849–51. Nathanson LK, Shimi S, Cuschieri A. Laparoscopic cholecystectomy: the Dundee technique. Br J Surg 1991; 78: 155–59. Cuschieri A, Wilson RG, Sunderland G, et al. Training initiative list scheme (TILS) for minimal access therapy: the MATTUS experience. J R Coll Surg Edin 1997; 42: 295–302.
Sir—Your editorial (Jan 24, p 225) advocating pragmatism in research ethics is of concern, particularly in view of The Lancet’s willingness to lower its ethical standards for studies carried out in tyrannies.1,2 The proposed pragmatism of “compatible with the realities of health care in the country where the study is to be conducted” would sanction the work of Josef Mengele.3 Responsibility for ethical standards cannot be completely devolved to local ethical committees because many factors other than ethical matters might influence their decisions. Questions need to be raised about why a particular population was chosen, who will benefit, and who has financed the research and why. The reason that trials of antiviral agents for the treatment of HIV are liable to be unethical in African countries is that the local population is unlikely to benefit from the results of the trial because of the cost of the drug. It is unethical to conduct research on a population when the results of that research will not be of use to that population. The non-availability of standard therapy in a particular healthcare system is not sufficient grounds to make placebo control still ethical. Those who want to pursue placebo-controlled trials of one agent may have had a hand in influencing the health authorities not to make standard treatment available, as might have happened in the UK with respect to -interferon for multiple sclerosis. International journals are a major bastion against unethical practice. The test is whether a journal such as The Lancet would refuse to publish a wellconducted and scientifically important study because it was unethical. A pragmatic approach suggests it would publish, giving the green light to unscrupulous investigators to travel the world looking for opportunities to conduct ethically dubious research. Simon J Ellis North Staffordshire Royal Infirmary, Keele University, Princes Road, Hartshill, Stoke-onTrent, Staffordshire, ST4 7LN, UK 1
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CAST collaborative group. CAST: randomised placebo-controlled trial of early aspirin use in 20 000 patients with acute ischaemic stroke. Lancet 1997; 349: 1641–49. Ellis SJ. Interpretation of IST and CAST stroke trials. Lancet 1997; 350: 443. Gilbert M. The holocaust: the Jewish tragedy. London: Fontana Press, 1987; 687–89.
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Sir—Vigorous debate has taken place on the ethics of conducting clinical trials in the developing world.1–3 However, one fundamental issue has not been directly addressed: that the study population should benefit from the trial in which they have taken part. The HIV-1 trials clearly address the needs of developing countries, but most of their study populations will not benefit from the trials, simply because the cheaper zidovudine regimens are beyond their limited means and will probably remain so for some time to come. The clinical trials have become separated from the implementation of their findings, probably because the populations’ actual health needs and resources were not taken into account during the trial design. We believe that trialists should take responsibility for not only testing an intervention’s efficacy, but also for ensuring its local adoption once the trial is over. This approach requires collaboration between trialists, national ministries of health, and drug manufacturers. Indeed, many such collaborations already exist. The UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases is co-developing drugs for tropical diseases with the pharmaceutical industry. This collaboration should make it possible for effective drugs to be approved rapidly and made available at concessionary prices for public-sector use in affected countries.4 On occasions, pharmaceutical companies have unilaterally donated large quantities of drugs to support worldwide WHO eradication campaigns. The first was Merck Sharp & Dohme’s donation of ivermectin for onchocerciasis; a more recent example is SmithKline Beecham’s offer of albendazole for WHO’s Filariasis Control Programme. Agreements have also been set up between national drug regulatory authorities (DRA) and individual drug companies. In Sri Lanka, the manufacturer of the antibiotic, vancomycin, provides the drug at a reduced price to the local distributor in return for a guarantee that the drug will not be re-exported and sold at a profit in another country. This arrangement was set up because the local DRA was concerned that a drug considered essential in specific situations was basically unaffordable. A different form of collaboration has been developed between WHO, UNICEF, and vaccine manufacturers. In this arrangement, countries are able to buy the vaccines at prices that reflect their ability to pay. In return for
charging poor countries lower prices, the manufacturers gain a large market which could not otherwise afford the vaccines. The developed world has much to gain from clinical trials in the developing world,5 but we must not forget that the primary responsibility of any trial is to directly benefit the population in which it is being conducted. *Michael Eddleston, Krisantha Weerasuriya, Piero Olliaro *Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK; Department of Pharmacology, University of Colombo, Colombo, Sri Lanka; and UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), Geneva, Switzerland (e-mail: [email protected]) 1
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Halsey NA, Sommer A, Henderson DA, Black RE. Ethics and international research. Research standards are the same throughout the world; medical care is not. BMJ 1997; 315: 965–66. Aaby P, et al; DeCock K, et al; Semba RD; Cooper PA; Vaughan W. Ethics of HIV trials. Lancet 1997; 350: 1546–47. Mann JM. Leadership is a global issue. Lancet 1997; 350 (suppl III): 23. Olliaro P. Will the fight against tropical diseases benefit from orphan drug status? Trop Med Int Health 1997; 2: 113–15. Mittra I. Clinical cancer trials in developing countries. Lancet 1997; 349: 290.
Hyphenosis Sir—The Lancet is suffering from a nasty case of hyphenosis. I made a tentative diagnosis when I came across “public-health professionals” (p 591) and “practice-GPs” (p 593) in two adjacent papers (Feb 21). Supportive evidence was not hard to find; “medical-school education” (p 535), “upper-airway sphincter” (p 539), and “solid-organ transplants” (p 540). The diagnosis was clinched by the discovery of the rare “internal-mammary-artery grafts” (p 570). I was surprised that “league table” (p 555) had escaped and puzzled to see that “strip tests” and “strip-test results” (p 564) had and had not. I recognise that the hyphen can be used flexibly to join words both semantically and syntactically, but imagine that most of your readers are able to make these connections for themselves. I write, I should add, as an editor with an international reputation for the over-use of the semi-colon. Roger Jones UMDS, Department of General Practice, Division of Primary Health Care, London SE11 6SP, UK
THE LANCET • Vol 351 • April 4, 1998
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1995; 82: 849–51. Nathanson LK, Shimi S, Cuschieri A. Laparoscopic cholecystectomy: the Dundee technique. Br J Surg 1991; 78: 155–59. Cuschieri A, Wilson RG, Sunderland G, et al. Training initiative list scheme (TILS) for minimal access therapy: the MATTUS experience. J R Coll Surg Edin 1997; 42: 295–302.
Sir—Your editorial (Jan 24, p 225) advocating pragmatism in research ethics is of concern, particularly in view of The Lancet’s willingness to lower its ethical standards for studies carried out in tyrannies.1,2 The proposed pragmatism of “compatible with the realities of health care in the country where the study is to be conducted” would sanction the work of Josef Mengele.3 Responsibility for ethical standards cannot be completely devolved to local ethical committees because many factors other than ethical matters might influence their decisions. Questions need to be raised about why a particular population was chosen, who will benefit, and who has financed the research and why. The reason that trials of antiviral agents for the treatment of HIV are liable to be unethical in African countries is that the local population is unlikely to benefit from the results of the trial because of the cost of the drug. It is unethical to conduct research on a population when the results of that research will not be of use to that population. The non-availability of standard therapy in a particular healthcare system is not sufficient grounds to make placebo control still ethical. Those who want to pursue placebo-controlled trials of one agent may have had a hand in influencing the health authorities not to make standard treatment available, as might have happened in the UK with respect to -interferon for multiple sclerosis. International journals are a major bastion against unethical practice. The test is whether a journal such as The Lancet would refuse to publish a wellconducted and scientifically important study because it was unethical. A pragmatic approach suggests it would publish, giving the green light to unscrupulous investigators to travel the world looking for opportunities to conduct ethically dubious research. Simon J Ellis North Staffordshire Royal Infirmary, Keele University, Princes Road, Hartshill, Stoke-onTrent, Staffordshire, ST4 7LN, UK 1
2 3
CAST collaborative group. CAST: randomised placebo-controlled trial of early aspirin use in 20 000 patients with acute ischaemic stroke. Lancet 1997; 349: 1641–49. Ellis SJ. Interpretation of IST and CAST stroke trials. Lancet 1997; 350: 443. Gilbert M. The holocaust: the Jewish tragedy. London: Fontana Press, 1987; 687–89.
1066
Sir—Vigorous debate has taken place on the ethics of conducting clinical trials in the developing world.1–3 However, one fundamental issue has not been directly addressed: that the study population should benefit from the trial in which they have taken part. The HIV-1 trials clearly address the needs of developing countries, but most of their study populations will not benefit from the trials, simply because the cheaper zidovudine regimens are beyond their limited means and will probably remain so for some time to come. The clinical trials have become separated from the implementation of their findings, probably because the populations’ actual health needs and resources were not taken into account during the trial design. We believe that trialists should take responsibility for not only testing an intervention’s efficacy, but also for ensuring its local adoption once the trial is over. This approach requires collaboration between trialists, national ministries of health, and drug manufacturers. Indeed, many such collaborations already exist. The UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases is co-developing drugs for tropical diseases with the pharmaceutical industry. This collaboration should make it possible for effective drugs to be approved rapidly and made available at concessionary prices for public-sector use in affected countries.4 On occasions, pharmaceutical companies have unilaterally donated large quantities of drugs to support worldwide WHO eradication campaigns. The first was Merck Sharp & Dohme’s donation of ivermectin for onchocerciasis; a more recent example is SmithKline Beecham’s offer of albendazole for WHO’s Filariasis Control Programme. Agreements have also been set up between national drug regulatory authorities (DRA) and individual drug companies. In Sri Lanka, the manufacturer of the antibiotic, vancomycin, provides the drug at a reduced price to the local distributor in return for a guarantee that the drug will not be re-exported and sold at a profit in another country. This arrangement was set up because the local DRA was concerned that a drug considered essential in specific situations was basically unaffordable. A different form of collaboration has been developed between WHO, UNICEF, and vaccine manufacturers. In this arrangement, countries are able to buy the vaccines at prices that reflect their ability to pay. In return for
charging poor countries lower prices, the manufacturers gain a large market which could not otherwise afford the vaccines. The developed world has much to gain from clinical trials in the developing world,5 but we must not forget that the primary responsibility of any trial is to directly benefit the population in which it is being conducted. *Michael Eddleston, Krisantha Weerasuriya, Piero Olliaro *Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK; Department of Pharmacology, University of Colombo, Colombo, Sri Lanka; and UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), Geneva, Switzerland (e-mail: [email protected]) 1
2
3 4
5
Halsey NA, Sommer A, Henderson DA, Black RE. Ethics and international research. Research standards are the same throughout the world; medical care is not. BMJ 1997; 315: 965–66. Aaby P, et al; DeCock K, et al; Semba RD; Cooper PA; Vaughan W. Ethics of HIV trials. Lancet 1997; 350: 1546–47. Mann JM. Leadership is a global issue. Lancet 1997; 350 (suppl III): 23. Olliaro P. Will the fight against tropical diseases benefit from orphan drug status? Trop Med Int Health 1997; 2: 113–15. Mittra I. Clinical cancer trials in developing countries. Lancet 1997; 349: 290.
Hyphenosis Sir—The Lancet is suffering from a nasty case of hyphenosis. I made a tentative diagnosis when I came across “public-health professionals” (p 591) and “practice-GPs” (p 593) in two adjacent papers (Feb 21). Supportive evidence was not hard to find; “medical-school education” (p 535), “upper-airway sphincter” (p 539), and “solid-organ transplants” (p 540). The diagnosis was clinched by the discovery of the rare “internal-mammary-artery grafts” (p 570). I was surprised that “league table” (p 555) had escaped and puzzled to see that “strip tests” and “strip-test results” (p 564) had and had not. I recognise that the hyphen can be used flexibly to join words both semantically and syntactically, but imagine that most of your readers are able to make these connections for themselves. I write, I should add, as an editor with an international reputation for the over-use of the semi-colon. Roger Jones UMDS, Department of General Practice, Division of Primary Health Care, London SE11 6SP, UK
THE LANCET • Vol 351 • April 4, 1998