- Email: [email protected]
Ethics of large clinical trials in rapidly lethal diseases
CORRESPONDENCE
COMMENTARY
CORRESPONDENCE e-mail submissions to [email protected]
Ethics of large clinical trials in rapidly lethal diseases David Horrobin died on April 1, 2003, after this group of letters was received by the journal. An obituary will be published in The Lancet shortly.
Sir—My first reaction to David Horrobin’s Personal paper (Feb 22, p 695),1 on whether large clinical trials in rapidly lethal diseases are ethical, was elation: it is always a pleasure to read his original and thought-provoking commentaries. Elation quickly gave way to gloom on learning that Horrobin himself had mantle cell lymphoma. I was relieved, however, to learn that he had achieved some control through unconventional treatments administered with the help of sympathetic physicians. These treatments involved unpatentable substances that had shown encouraging results in biochemical studies, animal experiments, and pilot studies in human beings. Horrobin’s experience taught him that the benefits of taking part in clinical trials might be far outweighed by the disadvantages, and that large clinical trials that involve patients with rapidly lethal cancers are unethical. In such trials, many more patients are recruited than are needed to show significant differences in outcome, partly to compensate for high dropout rates because of toxic side-effects. Clinical trials also tend to be large because treatments seldom have an effect-size greater than 50%—most are based on the expectation of a 10–20% improvement in outcome.2 Worst of all, severely ill patients usually die before the trials are completed. None of these issues are explained to patients entering such trials. A further disadvantage for these patients is that many potentially valuable treatments are never adequately tested because they are unpatentable. The cost of large clinical trials is also prohibitive for all but the wealthiest companies. Horrobin, therefore, concludes that the requirement for adequate statistical power in clinical trials3 is counterproductive and unethical insofar as it obliges many more patients to undergo harsh and generally ineffective treatments than are helped by them. Horrobin has issued a major challenge to the regulators, pharmaceutical companies, clinical trialists, ethics committees, and participating institutions. The plight of patients with rapidly lethal diseases calls for a new approach to
1296
clinical trials. Smaller numbers of patients should be able to take part in preliminary studies of treatments that have a strong likelihood of efficacy. In this way, many more potentially useful treatments could be tested, fewer patients would be needed, costs would be reduced, and greater numbers of eligible patients would be available to take part in other trials. Anthony R Mawson Institute of Epidemiology and Health Services Research, Department of Public Health, School of Allied Health Sciences, Jackson State University, Jackson, MS 39213, USA (e-mail: [email protected]) 1
2
3
Horrobin DF. Are large clinical trials in rapidly lethal diseases usually unethical? Lancet 2003; 361: 695–97. Hennekens CH, Buring JE, Mayrent SL. Epidemiology in Medicine. Boston: Little, Brown and Company, 1987: 198. Halpern SD, Karlawish JHT, Berlin JA. The continuing unethical conduct of underpowered clinical trials. JAMA 2002; 288: 358–62.
Sir—David Horrobin1 takes issue with large, industry-funded trials designed to show small effects of expensive patentprotected drugs on fatal diseases. However, he condemns all large clinical trials on the basis of his professional and personal experience of oncology trials in developed countries. We do not believe that Horrobin’s argument can be extended to large clinical trials of rapidly lethal infectious diseases in developing countries. Infectious diseases, such as malaria, tuberculosis, and tetanus are among the leading causes of rapidly fatal diseases outside the developed world. The benefits of successful treatment are enormous for the individual and the population. Affordable drugs often exist, but uncertainty remains about the best combinations, doses, and duration of treatment for maximum curative effect. Large clinical trials of affordable treatments are the only way to meet this challenge. Trials of expensive patent-protected drugs are usually inappropriate in places where such drugs will be too costly to use after the trial. Therefore, the limited clinical research that does occur in developing countries tends to be funded by charitable or public means. This type
of funding reduces conflicts of interest, and encourages independent and efficient research of the type advocated by Horrobin. Indeed, such funding is critical to continuing research and health-care improvement among the poorer populations of the world whose health priorities are quite different to the ones described by Horrobin. Large trials of affordable treatments for rapidly fatal infectious diseases in developing countries are urgently needed. Our work is funded by The Wellcome Trust, UK.
*Guy Thwaites, Louise Thwaites, Tran Tinh Hien, Jeremy Farrar *Oxford University Clinical Research Unit (GT, LT, JF) and, Hospital for Tropical Diseases (TTN), 190 Ben Ham Tu, Quan 5, Ho Chi Minh City, Vietnam; and Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, UK (GT, LT, JF) (e-mail: [email protected]) 1
Horrobin DF. Are large clinical trials in rapidly lethal diseases usually unethical? Lancet 2003; 361: 695–97.
Sir—To hear how mantle cell lymphoma changed David Horrobin’s life1 is thought-provoking, but this experience is not unique. I am a palliative care doctor and every day I meet people whose perspectives and goals have changed forever. The fact that 2 years ago Horrobin’s prognosis was only 6 months shows how well his treatment plan seems to be working and how inaccurate prognostication can be. Patients often focus on the times they are given when told the diagnosis—times that are invariably wrong. Research in terminal patients can, however, be ethical and, indeed, vital. Palliative medicine relies on case reports and anecdotes, and we encounter many logistical and ethical problems when trying to do research.2 The kind of trials with 30–40 patients, of which Horrobin writes, are the kind of trials that are undertaken in a palliative setting. It is vital that we continue to investigate the evidence behind our anecdotes, so that we can give our patients the best treatments. Only by continuing to be patientcentred, honest, and ethically aware can we do this work. Horrobin is perhaps right that we
THE LANCET • Vol 361 • April 12, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
COMMENTARY
CORRESPONDENCE e-mail submissions to [email protected]
Ethics of large clinical trials in rapidly lethal diseases David Horrobin died on April 1, 2003, after this group of letters was received by the journal. An obituary will be published in The Lancet shortly.
Sir—My first reaction to David Horrobin’s Personal paper (Feb 22, p 695),1 on whether large clinical trials in rapidly lethal diseases are ethical, was elation: it is always a pleasure to read his original and thought-provoking commentaries. Elation quickly gave way to gloom on learning that Horrobin himself had mantle cell lymphoma. I was relieved, however, to learn that he had achieved some control through unconventional treatments administered with the help of sympathetic physicians. These treatments involved unpatentable substances that had shown encouraging results in biochemical studies, animal experiments, and pilot studies in human beings. Horrobin’s experience taught him that the benefits of taking part in clinical trials might be far outweighed by the disadvantages, and that large clinical trials that involve patients with rapidly lethal cancers are unethical. In such trials, many more patients are recruited than are needed to show significant differences in outcome, partly to compensate for high dropout rates because of toxic side-effects. Clinical trials also tend to be large because treatments seldom have an effect-size greater than 50%—most are based on the expectation of a 10–20% improvement in outcome.2 Worst of all, severely ill patients usually die before the trials are completed. None of these issues are explained to patients entering such trials. A further disadvantage for these patients is that many potentially valuable treatments are never adequately tested because they are unpatentable. The cost of large clinical trials is also prohibitive for all but the wealthiest companies. Horrobin, therefore, concludes that the requirement for adequate statistical power in clinical trials3 is counterproductive and unethical insofar as it obliges many more patients to undergo harsh and generally ineffective treatments than are helped by them. Horrobin has issued a major challenge to the regulators, pharmaceutical companies, clinical trialists, ethics committees, and participating institutions. The plight of patients with rapidly lethal diseases calls for a new approach to
1296
clinical trials. Smaller numbers of patients should be able to take part in preliminary studies of treatments that have a strong likelihood of efficacy. In this way, many more potentially useful treatments could be tested, fewer patients would be needed, costs would be reduced, and greater numbers of eligible patients would be available to take part in other trials. Anthony R Mawson Institute of Epidemiology and Health Services Research, Department of Public Health, School of Allied Health Sciences, Jackson State University, Jackson, MS 39213, USA (e-mail: [email protected]) 1
2
3
Horrobin DF. Are large clinical trials in rapidly lethal diseases usually unethical? Lancet 2003; 361: 695–97. Hennekens CH, Buring JE, Mayrent SL. Epidemiology in Medicine. Boston: Little, Brown and Company, 1987: 198. Halpern SD, Karlawish JHT, Berlin JA. The continuing unethical conduct of underpowered clinical trials. JAMA 2002; 288: 358–62.
Sir—David Horrobin1 takes issue with large, industry-funded trials designed to show small effects of expensive patentprotected drugs on fatal diseases. However, he condemns all large clinical trials on the basis of his professional and personal experience of oncology trials in developed countries. We do not believe that Horrobin’s argument can be extended to large clinical trials of rapidly lethal infectious diseases in developing countries. Infectious diseases, such as malaria, tuberculosis, and tetanus are among the leading causes of rapidly fatal diseases outside the developed world. The benefits of successful treatment are enormous for the individual and the population. Affordable drugs often exist, but uncertainty remains about the best combinations, doses, and duration of treatment for maximum curative effect. Large clinical trials of affordable treatments are the only way to meet this challenge. Trials of expensive patent-protected drugs are usually inappropriate in places where such drugs will be too costly to use after the trial. Therefore, the limited clinical research that does occur in developing countries tends to be funded by charitable or public means. This type
of funding reduces conflicts of interest, and encourages independent and efficient research of the type advocated by Horrobin. Indeed, such funding is critical to continuing research and health-care improvement among the poorer populations of the world whose health priorities are quite different to the ones described by Horrobin. Large trials of affordable treatments for rapidly fatal infectious diseases in developing countries are urgently needed. Our work is funded by The Wellcome Trust, UK.
*Guy Thwaites, Louise Thwaites, Tran Tinh Hien, Jeremy Farrar *Oxford University Clinical Research Unit (GT, LT, JF) and, Hospital for Tropical Diseases (TTN), 190 Ben Ham Tu, Quan 5, Ho Chi Minh City, Vietnam; and Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, UK (GT, LT, JF) (e-mail: [email protected]) 1
Horrobin DF. Are large clinical trials in rapidly lethal diseases usually unethical? Lancet 2003; 361: 695–97.
Sir—To hear how mantle cell lymphoma changed David Horrobin’s life1 is thought-provoking, but this experience is not unique. I am a palliative care doctor and every day I meet people whose perspectives and goals have changed forever. The fact that 2 years ago Horrobin’s prognosis was only 6 months shows how well his treatment plan seems to be working and how inaccurate prognostication can be. Patients often focus on the times they are given when told the diagnosis—times that are invariably wrong. Research in terminal patients can, however, be ethical and, indeed, vital. Palliative medicine relies on case reports and anecdotes, and we encounter many logistical and ethical problems when trying to do research.2 The kind of trials with 30–40 patients, of which Horrobin writes, are the kind of trials that are undertaken in a palliative setting. It is vital that we continue to investigate the evidence behind our anecdotes, so that we can give our patients the best treatments. Only by continuing to be patientcentred, honest, and ethically aware can we do this work. Horrobin is perhaps right that we
THE LANCET • Vol 361 • April 12, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.