- Email: [email protected]
The ethics of randomized controlled trials
European Journal of Surgical Oncology 1995; 21:136-139
CLINICAL TRIALS
The ethics of randomized controlled trials
M. Baum Professor of Surgery, Royal Marsden Hospital, London, UK
The contemporary ethical paradigm within which all clinical research is conducted is based on the four principles: respect for autonomy, beneficence and non-maleficence and justice. The fierce debate that often rages around the conduct of clinical trials results from the disagreement about the scope of application of these categorical imperatives and the inevitable clash between the principles of autonomy and justice. In order to practice beneficence and non-maleficence we need empirical information about the probabilities of the various harms and benefits that may result from proposed healthcare interventions. This information has to come from effective medical research which according to Raanan Gillon is therefore a prima facie moral obligation. ~ The gold standard for the accurate estimate of cost vs benefits of any new intervention is the randomized controlled trial. Yet patients within randomized controlled trials are to some extent objects rather than subjects and therefore according to Kant's definition have lost their right to self-determination. Here we observe a classic clash of categorical imperatives. The conventional argument in dealing with this paradox is that patients can retain their autonomy by volunteering for these trials with full informed consent. Yet how often is this consent fully informed, 2 and what about the danger when seeking consent of alarming patients by unsolicited and frightening information which in itself is a breach of the moral principles of beneficence and non-maleficence. Tobias and Houghton have restated this critique in their usual robust style 'The constraints of universal informed consent can obstruct the doctor/patient partnership and inhibit both good doctoring (the pastoral aspects of care), as well as making essential research more difficult. In the lofty interests of helping the patients towards a well-informed insightful judgement we seem to have thrown out common sense somewhere along the line. It is high time we gave it back its rightful place'. 3 Another problem arises when increasing numbers of patients exercise their right to self-determination by refusing to participate in the randomized controlled trial whilst at the same time demanding the best treatments based on the outcomes of volunteers from previous generations of trials. Do such patients have the right to autonomy whilst denying their responsibilities to the very society which presumably confers these rights. 4 The current asymmetry or imbalance 0748-7983/95/020136+04 $08.00/0
between rights and responsibilities was described graphically by Chief Rabbi Jonathan Sacks in an article in The Times in May 1994 'When rights are claimed in isolation from the rest of moral and political life, they devastate public debate. Rights-talk leads to a politics of single interest lobbies, pressure groups and competing claims which cannot all be satisfied. The result is disillusionment and cynicism, the most notable features of societies where rights-talk has prevailed'.5 Arguing against this view Raanan Gillon rejects any attempt to coerce patients into participation "The participation of patients in clinical trials is admirable, but not morally obligatory. Even if it were it is not our job as doctors to keep our patients up to the moral mark. Overall we are likely to accrue far fewer research subjects by moral arm twisting than if we ask our patients nicely, pointing out the great benefits of their participation in clinical trials, but gracefully accepting any refusals'. 6 Of course I ask my patients nicely to join clinical trials and gracefully accept their refusals. I also provide them with much written information and access to a clinical nurse specialist for counselling together with an interactive video system to help them through their decision making process. Yet the more information I give them, the nicer I am, the easier they find it to refuse to enter clinical trials and this to my mind is the major rate limiting factor in advancing the subject of the treatment of early breast cancer. I certainly would accept that it is cruel in the extreme to remind patients of these moral obligations at a time when they are having to come to terms with the diagnosis of a life threatening disease together with an attempt at comprehension of the meaning of the various treatment options on offer. I would argue therefore that the time for women to learn about these moral obligations and volunteer for clinical trials is paradoxically when they are well and yet in a group at a relatively high risk of developing a malignant disease. As far ds breast cancer is concerned, this would apply to most post-menopausal women in North America and Northern Europe. It is therefore about time that consumers advocates, women's organizations and female opinion leaders grasped this nettle and did their best to educate their sisterhood about the necessity of clinical trials and the fact that their participation would be in their enlightened self,interest, because by and large patients treated in clinical trials do better than patients treated in an ad-hoc w a y . 7 © 1995 W.B. SaundersCompany Limited
Clinical trials However, to fully mobilize this workforce, it has to be perceived that the women or consumers themselves have a stake in the clinical trial and that the questions we address and the method of addressing these questions has been scrutinized and perhaps modified by these special interest groups. As an experiment in this direction, I have just established a consumers' advisory group chaired by Mrs Hazel Thornton, a well-known and outspoken advocate of the patients' needs in clinical trials. 8 This new group has been given the task of advising on the design and conduct of a trial of hormone replacement therapy for women with acute or chronic menopausal problems who have been treated for breast cancer in the past. The need for such a trial has been well documented already and yet the ethical dilemma of conducting such a trial is enormous. 9 What better way for such a committee to cut its teeth and to set an agenda for the future. In my opinion, the only way of resolving these dilemmas are for the clinical trial organizations to be perceived as providers and the women themselves as the purchasers. We have the expertise and the scientific methodology to help those women who want to see advances in the prevention and cure of breast cancer. Only by this kind of partnership can we reverse the trend to 'rightism' and protect ourselves
137
from the ill-informed attacks from the self-appointed arm-. chair ethicists.
References 1. Gillon R. Medical ethics: four principles plus attention to scope. BMJ 1994; 309: 184-88. 2. Williams CJ, Zwitter M. Informed consent in European multicentre randomized clinical trials--are patients really informed? European Journal of Cancer 1994; 30A: 907-10. 3. Tobias JS, Houghton J. Is informed consent essential for all chemotherapy studies? Eur J Cancer 1994; 30A: 897-9. 4. Baum M. New approach for recruitment into randomised controlled trials. Lancet 1993; 341: 812-3. 5. Sacks J. Putting duties to rights. The Times Tuesday 31 May 1994. 6. Gillon R. Medical Ethics, Authors reply. BMJ 1994; 30~: 115960. 7. Stiller C. Survival of patients in clinical trials and at specialist centres. In: CJ Williams (Ed.) Introducing New Treatments for Cancer: Practical, Ethical and Legal Problems. John Wiley & Sons: Chichester, 1992:119-36. 8. Baum M. Clinical trials--a brave new partnership: a response to Mrs Thornton. J Med Ethics 1994; 20: 23-25. 9. Theriault RL, Sellin RV. A clinical dilemma: oestrogen replacement therapy in post menopausal women with a background of primary breast cancer. Ann Oncol 1991; 2: 709.
Making randomised trials larger: a simple solution? Richard Gray, Mike Clarke, Rory Collins and Richard Peto M R C / I C R F Clinical Trial Service Unit, Radcliffe Infirmary, O x f o r d O X 2 6 H E , U K
Worldwide, hundreds of thousands of deaths a year could be avoided by seeking large-scale randomized evidence about various widely practicable treatments for cancer and for other common causes of death and by disseminating such evidence effectively. Likewise, appropriately large-scale randomized evidence could substantially improve the management of these diseases even if survival were not improved. The chief techniques for obtaining large-scale randomized evidence are large, simple trials (or 'mega-trials') such as the ISIS trials in acute myocardial infarction,~-3 and large systematic overviews (or 'meta-analyses') such as those from the worldwide collaborative group of breast cancer trialists? Over the past decade, the introduction of these complementary techniques has already yielded a succession of striking and definite findings that have improved the treatment of millions of patients. But, what has been achieved so far is only a fraction of what could be achieved by such research strategies. There are two fundamental medical assumptions that underlie the need for really large-scale randomized studies, and these have important ramifications for the design of
such studies. First, any difference in survival between two treatments is unlikely to be large, but even a moderate difference in survival in a common disease is important. Second, if there really is, for one particular category of patient, a survival difference between two treatments, then this difference may be smaller or larger in some other category of patient, but it is very unlikely to be reversed. One of the most serious obstacles to progress over the past few decades has been the unrealistic expectation of discovering large treatment effects. This hope has misleadingly led many researchers into undertaking non-randomized studies which, whatever precautions are taken, are likely to be subject to moderate biases, the direction and size of which cannot be predicted reliably. No reliable assessment of a moderate treatment effect is possible if the method of assessment is subject to moderate biases. Ineffective treatments can appear moderately effective when they are not, and effective treatments can appear misleadingly ineffective. There is no way round this problem other than randomization. This principle has, at last, been generally accepted after a long experience with treatments that have appeared"
CLINICAL TRIALS
The ethics of randomized controlled trials
M. Baum Professor of Surgery, Royal Marsden Hospital, London, UK
The contemporary ethical paradigm within which all clinical research is conducted is based on the four principles: respect for autonomy, beneficence and non-maleficence and justice. The fierce debate that often rages around the conduct of clinical trials results from the disagreement about the scope of application of these categorical imperatives and the inevitable clash between the principles of autonomy and justice. In order to practice beneficence and non-maleficence we need empirical information about the probabilities of the various harms and benefits that may result from proposed healthcare interventions. This information has to come from effective medical research which according to Raanan Gillon is therefore a prima facie moral obligation. ~ The gold standard for the accurate estimate of cost vs benefits of any new intervention is the randomized controlled trial. Yet patients within randomized controlled trials are to some extent objects rather than subjects and therefore according to Kant's definition have lost their right to self-determination. Here we observe a classic clash of categorical imperatives. The conventional argument in dealing with this paradox is that patients can retain their autonomy by volunteering for these trials with full informed consent. Yet how often is this consent fully informed, 2 and what about the danger when seeking consent of alarming patients by unsolicited and frightening information which in itself is a breach of the moral principles of beneficence and non-maleficence. Tobias and Houghton have restated this critique in their usual robust style 'The constraints of universal informed consent can obstruct the doctor/patient partnership and inhibit both good doctoring (the pastoral aspects of care), as well as making essential research more difficult. In the lofty interests of helping the patients towards a well-informed insightful judgement we seem to have thrown out common sense somewhere along the line. It is high time we gave it back its rightful place'. 3 Another problem arises when increasing numbers of patients exercise their right to self-determination by refusing to participate in the randomized controlled trial whilst at the same time demanding the best treatments based on the outcomes of volunteers from previous generations of trials. Do such patients have the right to autonomy whilst denying their responsibilities to the very society which presumably confers these rights. 4 The current asymmetry or imbalance 0748-7983/95/020136+04 $08.00/0
between rights and responsibilities was described graphically by Chief Rabbi Jonathan Sacks in an article in The Times in May 1994 'When rights are claimed in isolation from the rest of moral and political life, they devastate public debate. Rights-talk leads to a politics of single interest lobbies, pressure groups and competing claims which cannot all be satisfied. The result is disillusionment and cynicism, the most notable features of societies where rights-talk has prevailed'.5 Arguing against this view Raanan Gillon rejects any attempt to coerce patients into participation "The participation of patients in clinical trials is admirable, but not morally obligatory. Even if it were it is not our job as doctors to keep our patients up to the moral mark. Overall we are likely to accrue far fewer research subjects by moral arm twisting than if we ask our patients nicely, pointing out the great benefits of their participation in clinical trials, but gracefully accepting any refusals'. 6 Of course I ask my patients nicely to join clinical trials and gracefully accept their refusals. I also provide them with much written information and access to a clinical nurse specialist for counselling together with an interactive video system to help them through their decision making process. Yet the more information I give them, the nicer I am, the easier they find it to refuse to enter clinical trials and this to my mind is the major rate limiting factor in advancing the subject of the treatment of early breast cancer. I certainly would accept that it is cruel in the extreme to remind patients of these moral obligations at a time when they are having to come to terms with the diagnosis of a life threatening disease together with an attempt at comprehension of the meaning of the various treatment options on offer. I would argue therefore that the time for women to learn about these moral obligations and volunteer for clinical trials is paradoxically when they are well and yet in a group at a relatively high risk of developing a malignant disease. As far ds breast cancer is concerned, this would apply to most post-menopausal women in North America and Northern Europe. It is therefore about time that consumers advocates, women's organizations and female opinion leaders grasped this nettle and did their best to educate their sisterhood about the necessity of clinical trials and the fact that their participation would be in their enlightened self,interest, because by and large patients treated in clinical trials do better than patients treated in an ad-hoc w a y . 7 © 1995 W.B. SaundersCompany Limited
Clinical trials However, to fully mobilize this workforce, it has to be perceived that the women or consumers themselves have a stake in the clinical trial and that the questions we address and the method of addressing these questions has been scrutinized and perhaps modified by these special interest groups. As an experiment in this direction, I have just established a consumers' advisory group chaired by Mrs Hazel Thornton, a well-known and outspoken advocate of the patients' needs in clinical trials. 8 This new group has been given the task of advising on the design and conduct of a trial of hormone replacement therapy for women with acute or chronic menopausal problems who have been treated for breast cancer in the past. The need for such a trial has been well documented already and yet the ethical dilemma of conducting such a trial is enormous. 9 What better way for such a committee to cut its teeth and to set an agenda for the future. In my opinion, the only way of resolving these dilemmas are for the clinical trial organizations to be perceived as providers and the women themselves as the purchasers. We have the expertise and the scientific methodology to help those women who want to see advances in the prevention and cure of breast cancer. Only by this kind of partnership can we reverse the trend to 'rightism' and protect ourselves
137
from the ill-informed attacks from the self-appointed arm-. chair ethicists.
References 1. Gillon R. Medical ethics: four principles plus attention to scope. BMJ 1994; 309: 184-88. 2. Williams CJ, Zwitter M. Informed consent in European multicentre randomized clinical trials--are patients really informed? European Journal of Cancer 1994; 30A: 907-10. 3. Tobias JS, Houghton J. Is informed consent essential for all chemotherapy studies? Eur J Cancer 1994; 30A: 897-9. 4. Baum M. New approach for recruitment into randomised controlled trials. Lancet 1993; 341: 812-3. 5. Sacks J. Putting duties to rights. The Times Tuesday 31 May 1994. 6. Gillon R. Medical Ethics, Authors reply. BMJ 1994; 30~: 115960. 7. Stiller C. Survival of patients in clinical trials and at specialist centres. In: CJ Williams (Ed.) Introducing New Treatments for Cancer: Practical, Ethical and Legal Problems. John Wiley & Sons: Chichester, 1992:119-36. 8. Baum M. Clinical trials--a brave new partnership: a response to Mrs Thornton. J Med Ethics 1994; 20: 23-25. 9. Theriault RL, Sellin RV. A clinical dilemma: oestrogen replacement therapy in post menopausal women with a background of primary breast cancer. Ann Oncol 1991; 2: 709.
Making randomised trials larger: a simple solution? Richard Gray, Mike Clarke, Rory Collins and Richard Peto M R C / I C R F Clinical Trial Service Unit, Radcliffe Infirmary, O x f o r d O X 2 6 H E , U K
Worldwide, hundreds of thousands of deaths a year could be avoided by seeking large-scale randomized evidence about various widely practicable treatments for cancer and for other common causes of death and by disseminating such evidence effectively. Likewise, appropriately large-scale randomized evidence could substantially improve the management of these diseases even if survival were not improved. The chief techniques for obtaining large-scale randomized evidence are large, simple trials (or 'mega-trials') such as the ISIS trials in acute myocardial infarction,~-3 and large systematic overviews (or 'meta-analyses') such as those from the worldwide collaborative group of breast cancer trialists? Over the past decade, the introduction of these complementary techniques has already yielded a succession of striking and definite findings that have improved the treatment of millions of patients. But, what has been achieved so far is only a fraction of what could be achieved by such research strategies. There are two fundamental medical assumptions that underlie the need for really large-scale randomized studies, and these have important ramifications for the design of
such studies. First, any difference in survival between two treatments is unlikely to be large, but even a moderate difference in survival in a common disease is important. Second, if there really is, for one particular category of patient, a survival difference between two treatments, then this difference may be smaller or larger in some other category of patient, but it is very unlikely to be reversed. One of the most serious obstacles to progress over the past few decades has been the unrealistic expectation of discovering large treatment effects. This hope has misleadingly led many researchers into undertaking non-randomized studies which, whatever precautions are taken, are likely to be subject to moderate biases, the direction and size of which cannot be predicted reliably. No reliable assessment of a moderate treatment effect is possible if the method of assessment is subject to moderate biases. Ineffective treatments can appear moderately effective when they are not, and effective treatments can appear misleadingly ineffective. There is no way round this problem other than randomization. This principle has, at last, been generally accepted after a long experience with treatments that have appeared"