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Ethical dilemmas encountered during clinical drug trials
International Journal of Antimicrobial Agents 24 (2004) 24–31
Commentary
Ethical dilemmas encountered during clinical drug trials George K. Daikos∗ Aphiareion Foundation for Chemotherapeutic Studies, Athens University School of Medicine, 12 Stratiotikou Syndesmou Street, GR 10676 Athens, Greece
Abstract Ethical standards have a basis in antiquity and changes in practice need to be measured by moral considerations that are slower to change. This paper considers present day ethical problems in clinical trials—especially in infection, conflict of interest, financing of scientific studies and publishing (or non-publishing) of the results. © 2004 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Ethics; Clinical trials; Placebo; Active controls
1. Introduction Clinical trials and especially controlled randomized trials are fundamental to the advancement of evidence-based medicine. It is widely accepted that, if the evidence does not support a new treatment, a diagnostic method, or another practices, they should not be accepted as good, scientific medicine. Open, that is not controlled observations are seen as subject to bias and hence cannot contribute to evidence-based medicine. It is most interesting that the Hippocratic corpus, contains a passage that talks about evidence-based medicine: Do not rely on conclusions that result from mere reasoning, but (rely) on evidence. Arguments in the form of plain rhetoric are false and easily defeated. Therefore, you should stick to the facts and scrutinize them, if you are going to acquire faultless capability, which we call Medicine. Hippocrates: Parangeliai (Recommendations) [1]. The present paper will discuss some of the ethical dilemmas encountered during the conduct of clinical drug trials. The controlled randomized trials that are required for the approval of the distribution of a drug should prove its efficacy and safety. The agent chosen for comparison (the control) preferably should be a placebo or an earlier active drug already used in practice. The new agent must be shown to be ∗
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pharmacologically equal to, or more active than the control. The patients who are assigned to the control arm of placebo, will remain without treatment for the duration of the trial. For decades, observers have asked whether it is ethical to leave an individual without treatment for the observation period and thus risk a worsening of the disease.
2. Historical As the first clinical trial, we can consider the limited scale experimentation that happened on board the ship, the Salisbury. Different treatments were given to small groups of sailors for scurvy prevention. Only those who ate oranges or lemons were capable for work the following 6 days [2]. Antimicrobial chemotherapy was neither discovered nor were its benefits established on the basis of clinical trials. Under modern systems of regulatory control, sulphonamides and penicillin would not have been approved for human use. One could also cite many other examples of major therapeutic advances that have not followed the path of randomized clinical trials (RCT). The Medical Research Council (UK) instituted the first controlled clinical trial for infection during the investigation of the treatment of tuberculosis (1948) [3]. That study led to the formation of the first protocols for co-operative studies designed to recruit a statistically significant number of patients. Cancer chemotherapy and large scale (multicentre) studies followed later in an analogous manner. Following the same protocol, the combination of related active agents led to real progress in cancer chemotherapy.
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3. The ignoble Tuskegee Syphilis Study (America’s Nüremberg) On the occasion of the 50th anniversary of the introduction of the Nüremberg Code, Wolinsky has drawn the attention of ethicists and the medical profession to the Tuskegee Syphilis Study, which otherwise might have been overlooked [4]. In Macon County, Alabama, the US Public Health Service (USPHS) placed 431 black agricultural labourers, who had seropositive latent syphilis in a prospective study for the purpose of observing the natural history of the disease [5]. The investigation sought to determine whether syphilis caused cardiovascular lesions more frequently than neurological damage and whether the course of the infection followed a different course in blacks than in whites. Participants were observed only and were not treated. The study began in 1932 at a time when only bismuth and salvarsan were available for the treatment of syphilis. The only explanation the USPHS gave the patients was that the study was meant to ‘cure their bad blood’. These individuals were recruited to the trial by the offer of food and other small gifts. USPH officials supervised the study, taking care that these poor people received no treatment. In order to recruit more people, the health service associated itself with the prestigious Tuskegee Institute in the area. The study, which was a crude and ruthless human experimentation, continued through 1972, well beyond 1947 when penicillin was proven as the best and most effective treatment for syphilis. The same year the code of Nüremberg was introduced (1947) and accepted by all nations as the ethical standard for all human investigations; among other things, it required the investigators to obtain an informed consent from all participants. This ignoble experiment was publicised by a reporter in Washington Post in 1972. As the Houston historian, James Jones [6] noted in his comments on the behaviour of the USPH investigators, even as evidence was accumulating concerning the benefits of penicillin, the patients were pressed to continue without any treatment because such investigation was ‘a never-again-to be repeated-opportunity!’. In 1997, President Clinton of the USA was obliged to offer a formal apology for this ignoble affair, but the government granted no compensation to the survivors, despite the efforts of a volunteer lawyer.
4. The 10/90 dis-equilibrium: economic context of research expenditure As the WHO has emphasised, of the US$ 50–60 billion world-wide annual expenditure on health research by both the private and public sectors, only 10% is devoted to the health problems of 90% of the world’s population [7].
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5. Contemporary systems of clinical drug research The development of a new drug from the laboratory to clinical use, costs approximately US$ 300–600 million dollars. Seventy percent of the money for clinical trials come from the pharmaceutical industry, the rest from National Institutes of Health (NIH), or other government sources. During the last 10 years, new types of clinical networks for drug investigation have been developed, such as the Contract Research Organisations (CRO) and the Site Management Organisations (SMO) which have entirely changed the process of data acquisition. Such organisations specialise in a fast recruitment of the required number of patients, who will agree by written consent to be subjects in the assessment of the new treatment. The policies of academic centres impose delays on the recruitment of patients, especially for controlled clinical trials that require a large number of patients. Organisations such as CROs and SMOs, which sometimes are organised by the industry themselves, have at their disposal investigator-designers, clinicians, and statisticians and often are able to collect large numbers of patients in a short time. They work through community general practitioners, who are paid by case and often do not inform their own patients that they are participants in a clinical trial. This new trend has developed quickly and is creating new problems, even in academic centres and large hospitals [8].
6. Conflict of interest This conflict arises because well-known physicians are co-operating with pharmaceutical industries, either as consultants or investigators, while at the same time holding university or government positions. Many also have financial interests, as stockholders or through other mechanisms. The conflict may not only be of financial but also of scientific (originality, publication, etc.) nature. The subject has drawn much attention lately. The New England Journal of Medicine, in its November 30, 2000 issue had two special articles [9,10] on such conflicts of interest, an editorial [11] and a ‘sounding board’ article [12]. The authors found that only one of 20 centres, observed guidelines such as the one proposed by Harvard University that requires physicians to abstain from industry activities. These observers suggest that scientist investigators especially clinicians should remain scientifically and ethically beyond and above conflicts of interest. It seems that the conflict(s) of interest are now of such an extent that it creates problems even in NIH. The trust that the American people place in this federal government agency and its employees has been called into question lately by a report in the Los Angeles Times about consulting payments from pharmaceutical companies to high ranking NIH officials [13].
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The New England Journal of Medicine had a policy of excluding those with any financial conflict from writing reviews or editorials. The policy proved impossible to adhere to in practice. In 2002, the Journal revised its policy to exclude only authors with ‘significant’ financial interests from writing reviews or editorials, stating that it was impossible to find experts without some conflicts [14]. Since the beginning of January 2003, the Lancet has elected to avoid commissioning commentaries, etc. from those with substantial financial interests in a company that makes a product or competitor to be discussed in the paper [15]. In 2004, Lancet and its speciality review journals took an even tougher stance. They avoided commissioning commentaries, rapid reviews, or series . . . ‘From anyone who, within the past 3 years, and with a relevant company, or competitor, has any stocks or shares, equity, a contract of employment, or a named position on a company board; holds a relevant patent; or has received a fee . . . to write, be named on, or to submit the paper’ [16]. Financial conflicts of interest that are not exclusions . . . but must be declared in the published paper are: consultancies, honoraria, speaker’s fees; research funding; . . . travel or accommodation payments; expert testimony fees [16]. In a perspective article in The New England Journal of Medicine [17], Steinbrook examines this subject at length and discusses what is the best policy on financial conflicts of interest for NIH employees. According to Dr. E.A. Zerhouni, the Director of NIH, strict measures are considered. There is no question that the co-operation of NIH with industry should lead to beneficial coexistence [17].
order to write the paper. His name does not appear in the paper, while the investigators are cited as the authors. Usually, the ghost-writer adds an interpretation favourable to the manufacturer’s product. The ‘guest author’ is a clinical investigator who appears as the author, without having written the paper or having analysed the data [8,20]. In the September 13, 2001 issue of The New England Journal of Medicine an important editorial deals with the problems of publication of the results of clinical trials. ‘Sponsorship, authorship and accountability’ [21], is signed by the editors of 12 leading Medical Journals. These included F. Davidoff (Annals of Internal Medicine), Catherine DeAngelis (The Journal of American Medical Association), J. Drazen (The New England Journal of Medicine), J. Hoey (Canadian Medical Association Journal), Liselotte Hojgaard (Danish Medical Association Journal), Richard Horton (Lancet), and Sheldon Kotzin (Medline/Index Medicus) amongst others. The editors felt compelled to make clear statements in order to protect the independent investigator in publishing his/her results free from the pressures of the sponsors. They state: ‘As editors of general medical journals, we recognise that the publication of clinical research findings in respected peer-reviewed journals is the ultimate basis for most treatment decisions. We are concerned that the current intellectual environment in which some clinical research is conceived, study subjects are recruited and the data analysed and reported (or not reported) may threaten this precious objectivity. Patients participate in clinical trials for altruistic reasons—that is, to advance the standard of care. As editors, we strongly oppose contractual agreements that deny investigators the right to examine the data independently or submit a manuscript for publication without first obtaining the consent of the sponsor.’
7. Publication of scientific findings The findings of these clinical trials accumulate in the data bases of the pharmaceutical companies that are developing the drugs and, if the results are not favourable, they may not publish their findings. The firms’ marketing departments are interested mainly in FDA approval, while the scientists are looking forward to publication in peer-reviewed journals of prestige. Usually, upon accepting the assignment to conduct a clinical trial, the investigator signs a restrictive contract and agrees, for a given time interval, not to publish the results, without the approval of the industry. Those that have dared to publish, against the will of the industry, have lived through a bitter experience [18,19]. The ‘non-writing author–non-author writer’ syndrome, or briefly ‘guest–ghost syndrome’, is a growing phenomenon, particularly in the commercial sector, where community-physician investigators have little interest in authorship. A ‘ghost-writer’ is a professional medical writer who is given the data by the pharmaceutical company, or CRO, in
8. Registering all clinical trials—reporting negative results Another difficult subject is the premature interruption of a clinical trial because of negative results that remain unpublished. Observers have proposed that the scientific community establish a registry of all clinical trials, no matter what stage, which will be accessible electronically. NIH has already set up such a registry (http://www.clinicaltrials.gov), which presently displays data from trials supported by NIH, but not those supported by the industry. It is expected that industry data will follow soon. The British publishers have set up a registry (http://www.controlledtrials.com). The Cochrane collaboration had also organised a systematic registry, but thus far only of the finished trials. Ioannidis and Lau [22] have recently assessed the amount of the space allocated to the incidence, severity and nature of adverse events in published reports of 192 randomised, controlled trials. Reporting of adverse events was considered adequate in only 39% of the trials.
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9. Recruitment of study patients There is a heavy demand for clinical trial participants because the number of drugs in the pre-clinical phase is growing. The Lancet in an editorial [23], commented recently on an important study [24] conducted by the Office of Inspector General of USA (OIG) entitled ‘Recruiting human subjects, pressures in industry-sponsored clinical research’, where the need is emphasised for strict controls on the recruitment of participants for clinical trials. Physicians are paid considerable amounts of money to collect patients and to open their records so that the companies can select those they want. Often such patients are not aware that they are being assigned as participants in a trial. On the other hand, physicians often become side-tracked when advertisements in the press or messages of other mass media addressed to the patients describe a new wonder drug and as a consequence, people demand that their doctors included them in the trial of the promising substance [25]. The advertisement of over-the-counter drugs has become big business and as a consequence, the public is conditioned to accept experimental drugs. 9.1. Patients influence doctors’ treatment decisions The direct to consumer advertising (DTCA) is increasing rapidly. It is allowed in USA and New Zealand, and in July 2001, the European Commission has proposed that it be accepted in Europe as well.
10. Physician–pharmaceutical industry relationships It is true that industry is the greatest contributor to drug development. It applies biological knowledge to produce products that are useful drugs. It does so for profit of course, but it is important that it does it. Research, development and marketing are intertwined and not easy to separate. Marketing often has the greatest influence in decision making [8]. These departments use every legal means to keep physicians happy, because they are the ones who prescribe the drugs. As Marcia Angell, then Editor of The New England Journal of Medicine, noted among other things: ‘Travelling around the world to appear at industry-sponsored symposiums has much more to do with marketing than with technology transfer’ [26]. Many non-investigator physicians are offered complimentary travel to international symposia and congresses during which they are offered special dinners, excursions and gifts [27]. Of course such events may be educational occasions as well, but usually the presentations are restricted to the promoted drug. In an editorial of The New England Journal of Medicine, Drazen comments: ‘No matter how altruistic the motive, investigators must recognise that research performed under these contracts is a business transaction . . . It is imperative
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that the terms . . . guarantee the safety and confidentiality of patients’ [28].
11. Are the randomized control clinical trials ethical? They are meant to be ethical and usually they are. It is unfortunate, however, that the effort to achieve scientific precision, if not restricted by ethical principles, may eventuate in criminal actions (e.g. experiment by Nazi doctors, the Tuskegee study). Guidelines derived from declarations of human rights concerning human experimentation (Nuremberg, Helsinki and its modifications), are intended to define the precise conditions and limits of clinical trials. In practice, however, these codes are not followed or respected [29].
12. Randomized clinical trials in developing countries Recently the ethics of human experimentation are being widely discussed because clinical trials on AIDS are being conducted in Africa without honouring the codes observed in developed countries. The March 30, 2000 issue of The New England Journal of Medicine reported such a trial [30] and in an accompanying editorial, Marcia Angell commented: ‘It is important to be clear about what this study meant for the participants. It meant that for up to 30 months, several hundred people with HIV infection were observed but not treated’ [31]. The usual excuse offered is that in those countries, HIV patients cannot afford and hence do not receive treatment anyway. The fact though is that, for research workers in developing countries, it is cheaper and easier to recruit large numbers of ‘drug-na¨ıve’ patients. The problem has created the proper reactions and decisions have been taken very recently for the regulation of the trials in developing countries [32,33]. As has been emphasised, ‘clinical trials in developing countries should meet all ethical and scientific standards of trials performed in developed countries’ and ‘ an experimental intervention should normally be compared with an established, effective treatment, whether or not that treatment is available in the host country’. Therefore, the presumption is that a placebo control or any other control that is less effective than an established, effective treatment is not ethically acceptable [32,33]. The scientific community accepts the compassionate use of an investigational drug and such use has been undertaken in AIDS patients with the approval of FDA. On the other hand, severe infections caused by micro-organisms resistant to existing drugs are appearing, and lives may be saved by a new active antibiotic. On such occasions it would be unethical to stick to the existing protocol and not provide a potentially lifesaving drug. Most clinicians involved in an early-phase drug trial would feel the need to use an exper-
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imental drug out of the protocol to fight a resistant infection. Eventually, such observations may prove valuable even though the study was aborted. On the other hand, an ethical practitioner should inform a desperate cancer patient that there is a new promising drug that might help him or her and the patient may accept the rules of the protocol and give his really informed consent. It is interesting that now the scientific community is reconsidering and re-evaluating the value of the observational studies. These generally are considered to be subject to personal bias and therefore less significant. Under the title: ‘Randomized trials or observational tribulations’, The New England Journal of Medicine in an editorial [34] on two papers [35,36] in the same issue asserts that the results obtained with control trials and random observations are comparable.
13. Is the use of a placebo group unethical? This question is asked more and more in recent times. The most articulate criticism has been mounted by Rothman and Michels [37] of Boston University based on the Declaration of Helsinki, concerning the ethics of human experimentation, which was adopted by the World Medical Association in 1964. The declaration was revised in 1975, and again in 2000 (Edinburgh, http://www.wma.net) amid sharp debate. An international conference on the implementation of the new provisions of the declaration was held in Pretoria, South Africa in March 2001 [34]. The Declaration demands that ‘In any clinical study, every patient, including those of a control group (if any), should be assured of the best diagnostic and therapeutic methods’, and in the Edinburgh new version—‘The benefits, risks, burdens and effectiveness of the new methods should be tested against those of the best current prophylactic, diagnostic and therapeutic methods.’ The literal interpretation of that requirement precludes the use of a placebo if an active treatment is available. The new provisions are stricter and are considered ‘too rigid’ by many. Several groups, including the FDA, do not want to accept those restrictions. The placebo is too powerful! The September 19, 2000 issue of the Annals of Internal Medicine has two articles by two FDA members who discussed the subject extensively [38,39]; an editorial by R. Simon [40] of the National Cancer Institute, and a report on The ethics of placebo-controlled trials [41]. The inclusion and exclusion criteria usually determine which patients should be accepted in, or excluded from a clinical trial, e.g. life-threatening conditions, severe septic cases, or analogous situations are not allowed in a randomized control clinical trial, especially in a trial that has a placebo arm. The scientific community seems to have reached a consensus that use of a placebo control is always unethical in severe illness for which there is a treatment which improves survival, or ameliorates morbidity.
13.1. Active-control equivalence trials (ACET) These trials compare a new treatment with an existing active treatment. The new treatment should prove superior, or at least equivalent to the existing and accepted one. It seems to be conceded that this frequently used method plays an essential role. Such a search for new drugs except for the purely commercial purpose (the ‘me-too’ principle), aims at efficacy, pharmacokinetic improvements or a reduction in toxicity, which do not necessitate the use of a placebo (control) arm. A good example of ACET are the many and successful hypolipidaemic drugs, which have been introduced to the market in the last few years. Although the differences between them are not large, the market and the need for them are great and hence the offer of better substances is welcome and profitable. In a perspective article, The New England Journal of Medicine (January 15, 2004) discusses the ‘me-too’ principle [42]. ‘There is another side to the story. “Me-too” products reflect and create competition among drug and device manufacturers, and that competition is also a powerful driver of better quality and lower costs.’ In trying a new drug, the use of a placebo is proposed when there is already an effective drug, but with an uncertain and moderate efficacy and if the new treatment is not expected to be much superior. If the existing treatment is clearly effective and well established, the comparison should be with that agent (ACET). Here there is no justifiable reason for a placebo (control) arm [43,44]. 13.2. The equipoise principle A fundamental ethical and scientific principle of human experimentation states that the patient should be enrolled in a randomised, controlled trial only if there is substantial uncertainty about which of the trial treatments would benefit a patient most [44,45]. A non-treatment–non-placebo arm is introduced to isolate and control the placebo effect. Because of a growing criticism of the placebo effect, many have suggested that a third arm be included in the randomized clinical trial, i.e. a group that does not receive either the substance under trial, nor a placebo [45]. Such a method does prove that no placebo effect exists. Our confidence in the ‘powerful placebo’ is being shaken and we are being forced to discuss the possible existence of regression to the mean, natural history, or concurrent interventions. In the September 20, 2001 issue of The New England Journal of Medicine, the problem of ethics in withholding existing treatment in placebo control trials, especially as it arose after the stricter criteria of the revised Declaration of Helsinki, is discussed in an editorial [46] and a sounding board article [47]. It is argued that where there is an already active drug, a middle ground to establish placebo control can be found. As Emmanuel and Miller of the National Institutes of Health propose in the sounding board article,
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placebo-controlled trials are permissible when proven therapies exist but only if certain ethical and methodological criteria are met. I cannot enter into details, but their arguments are not convincing, as they favour placebo use, even when there is an active substance to compare with.
14. Informed consent Informed consent is the cornerstone of the code of Nüremberg. It is essential to obtain a truly informed consent from the participant in any human experimentation. This does not always happen. Often participants are not explicitly informed as to the consequences, benefits, or risks of the trial. As one critic has noted: ‘Obtaining a signature on a paper does not ensure that a participant understands the proposed research’ [26]. The quality of informed consent was evaluated in 287 cancer patients participating in clinical trials in three co-operating oncology centres in Boston. Ninety percent answered that they have been properly informed but 74% had not understood that it was a research project; 63% had not appreciated the risks, 29% the uncertainty of the benefit and only 25% realised that the investigation concerned mainly future patients [48]. A vivid example of that 25% part is the following reaction of a physician suffering from myeloid leukemia. ‘My life changed again when a medical writer colleague heard Brian Drucker speak about a new drug . . . an inhibitor of the Bcr-Abl tyrosine kinase {produced by the chromosome translocation in CML (Clivec). I decided to get enrolled in the trial. I had an excellent response. I realised that even if I wasn’t cured, many people with cancers caused by chromosome or protein abnormalities would be beneficiaries of this work’ [49]. As it has been mentioned already commonly, during the recruitment of participants, CROs do not make explicit information available to the patient. On the other hand, in developing countries many participants cannot write, or, for that matter, understand what the study is all about. In a critical analysis of the concept of informed consent as it applies to the clinical trial, Truog et al. ask whether it is always necessary to obtain such consent in RCT [50]. They argue that a physician, when choosing a form of therapy always conducts an experiment. During everyday practice, e.g. in an acutely ill patient in an ICU the physician might decide to apply a new method that he has read about recently. He may do so if the patient or his agent has given a general consent. He does not need approval by the Institutional Review Board (IRB). However, if he/she wants to determine which of two commonly used antibiotics works better in acute bronchitis, he/she must prepare a protocol, obtain approval from IRB, and seek written consent from the participants. Studies have shown that patients rarely demonstrate an adequate understanding of consent forms. Although this reasoning looks valid in such instances, we cannot waive
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the protection offered by informed consent that safeguards patients from scientific exploitation. The National Bioethics Advisory Commission has proposed new safeguards for clinical research with adults who are unable to consent. This issue arises when an important research project concerns people who cannot consent or dissent. Wendler and Prasad in a publication in the October 2, 2001 issue of the Annals of Internal Medicine [51] discuss the guidelines proposed by six groups for such patients and they endorse six core safeguards: (1) (2) (3) (4)
institutional risk-benefit assessment; consent assessment; necessity requirement; proxy decision maker and sufficient evidence of patients remaining preferences and interests; (5) respect for patient assent and dissent; and (6) independent monitors. They conclude that: ‘In the absence of specific safeguards, research with adults who are unable to consent presents an increased potential for subject abuse.’ However, ‘Inappropriately stringent safeguards could halt important research and block improvement in medical care for the very groups the safeguards are designed to protect’ [52]. Informing versus counselling the patient comes up often when discussing a randomized clinical trial. The expert advice of the personal physician, especially if he is a specialist (e.g. oncologist) usually prevails over the proposal to conduct an RCT. It is not possible that in this circumstance the physician only informs but does not counsel his patient. On the other hand, the line between informing and persuading is a thin one.
15. Protection of research subjects The participants in RCTs are not always informed explicitly about the risk of the experimental treatment. Of course, often even the investigator may not know what this risk is. The Office of Inspector General of USA, in a recent study entitled ‘Recruiting human subjects, pressures in industry-sponsored clinical research’ emphasises the need for strict control measures for such recruitment. The Lancet on this occasion, underlines the need for the protection of the participants in an editorial [23]. The tragic death of an 18-year-old boy, during gene therapy, greatly moved the authorities and all the scientific community. In a sounding board article in The New England Journal of Medicine [52], the then Secretary of Health and Human Services (USA), Donna Shalala, discussed at length the safety of patients in clinical research. ‘This young man’s death led to the discovery by National Institutes of Health of many hundreds of unreported adverse events among volunteers enrolled in gene-transfer experiments.’ Ellen Roche, a 24-year-old technician at the John Hopkins Asthma and Allergy Center and a healthy volunteer in
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a study of asthma funded by NIH died on June 2, 2001. She was given hexamethonium inhalations. In 2 days, she developed respiratory problems and died after about 1 month. Reacting immediately, the Office for Human Research Protections suspended 2500 active protocols of John Hopkins group. Widespread deficiencies were found. The suspension was soon reversed, after the proper measures have been taken [53].
16. Participation of the patients ‘HIV-AIDS changed forever the expectations of consumers in clinical research. Instead of participating in clinical trials as “subjects”, consumers became equal partners with their physicians’ [54]. Activist HIV-AIDS patients succeeded in having their terms accepted and somehow have opposed paternalistic behaviour in medical research, in part because the nature of the infection, which was acutely fatal did not allow for the bureaucratic delays of the past. They have pressed for more active research and for quicker drug authorisation by FDA. They also obtained compassionate release of ‘not-yet-thoroughly-studied drugs’. This participation of the patient-activists has had both positive and negative results. A positive effect is the shortening of the time of drug authorisation by FDA. In 1986, on average, 34.1 months were required for such authorisation; however, by 1999 the time was reduced to 12.6 months. 16.1. Epilogue: the golden rule εεε ␣ε [55] (Do good or do no harm). In trying new investigational drugs on humans one should not forget this fundamental Hippocratic moral principle. As in all Medicine, what makes the difference is the physician and his attitude. If he/she is highly motivated and faces the patient as a suffering fellow man, not a client or a subject, even more if he/she feels towards him as his neighbour whom he should love as himself, then he will practice good Medicine, a real ‘Humane Medicine’. Then, he will construct and execute an ethical RCT, if that is really necessary to prove the uncertain, and he will handle experimental drugs with real loving care. If he is a mere technocrat, perhaps a great scientist, capable of handling all molecular and sub-molecular knowledge, but without due respect for the suffering man, he may end up in real criminal actions. In an older issue (Autumn of 1990) of Humane Medicine [56], Gail Stephens presented the view that unless we stick to the golden rule, we cannot practice good medicine, that is true for the clinical trials as well. In his most interesting and very important article ‘Compassion and mercy in the practice of medicine’ in the first publication (2001) of the electronic edition of Humane Health Care, Oreopoulos [57] emphasises the proper way
and attitude to the patient, which is no other than compassion and mercy, the real agape we owe to our fellow man. That of course, applies first and foremost to the clinical trials.
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G.K. Daikos / International Journal of Antimicrobial Agents 24 (2004) 24–31 [28] Drazen JM. Institutions, contracts and academic freedom. N Engl J Med 2002;347:1362–3. [29] Pellegrino ED. The Nazi doctors and Nüremberg: some moral lessons revisited. Ann Intern Med 1997;127:307–8. [30] Quinn TC, Wawer MJ, Sewankambo N, et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. N Engl J Med 2000;342:921–9. [31] Angell M. Investigators’ responsibilities for human subjects in developing countries. N Engl J Med 2000;342:967–9. [32] Shapiro HT, Meslin EM. Ethical issues in the design and conduct of clinical trials in developing countries. N Engl J Med 2001;345:139– 41. [33] Koski G, Nightingale SL. Research involving human subjects in developing countries. N Engl J Med 2001;345:136–8. [34] Pocock SJ, Elbourne DR. Randomized trials or observational tribulations? N Engl J Med 2000;342:1907–9. [35] Benson K, Hartz AJ. A comparison of observational studies and randomised, controlled trials. N Engl J Med 2000;342:1878–86. [36] Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and their hierarchy of research decisions. N Engl J Med 2000;342:1887–92. [37] Rothman K, Michels KB. The continuing unethical use of placebo controls. N Engl J Med 1994;331:394–8. [38] Temple R, Ellenberg SS. Placebo-controlled trials and active control trials in the evaluation of new treatments. Part 1. Ethical and scientific issues. Ann Intern Med 2000;133:455–63. [39] Ellenberg SS, Temple R. Placebo-controlled trials and active control trials in the evaluation of new treatments. Part 2. Practical issues and specific cases. Ann Intern Med 2000;133:464–70. [40] Simon R. Are placebo-controlled clinical trials ethical or needed when alternative treatment exists? Ann Intern Med 2000;133:474–5 [Editorial]. [41] Reynolds T. The ethics of placebo-controlled trials. Ann Intern Med 2000;133:491–2.
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[42] Lee TH. “Me-too” products—friend or foe? N Engl J Med 2004;350:221–2. [43] Edwards S, Lilford R, Braunholz D, Jackson J, Hewison J, Thornton J. Ethical issues in the design and conduct of randomised controlled trials. Health Tech Assess 1998;2:1–132. [44] Djulbegovic B. Placebo-controlled trials. Ann Intern Med 2001;135:62–3. [45] Kaptchuk TJ. Powerful placebo: the dark side of the randomised control trial. Lancet 1998;351:1722–5. [46] Huston P, Peterson R. Withholding proven treatment in clinical research. N Engl J Med 2001;345:912–4. [47] Emanuel EJ, Miller FG. The ethics of placebo-controlled trials. A middle ground. N Engl J Med 2001;345:915–9. [48] Joffe S, Cook FE, Cleary PD, et al. Quality of informed consent in cancer clinical trials, a cross-sectional survey. Lancet 2001;358: 1772. [49] Morris RH. Thriving with CML. Lancet 2001;358(Suppl):S12. [50] Truog RD, Robinson W, Randolph A, Morris A. Is informed consent always necessary for randomised controlled trials? N Engl J Med 1999;340:804–8. [51] Wendler D, Prasad K. Core safeguards for clinical research with adults who are unable to consent. Ann Intern Med 2001;135:514–23. [52] Shalala D. Protecting research subjects—what must be done. N Engl J Med 2000;343:808–10. [53] Steinbrook R. Protecting research subjects—the crisis at John Hopkins. N Engl J Med 2002;346:716–20. [54] How consumers can and should improve clinical trials. Lancet 2001;357:1721 [Editorial]. [55] Hippocrates. Epidemics 1st 11. Hippokratic Writings. London: Penguin Classics; 1978. p. 93–4. [56] Stephens GG. Minding others’ bodies: the golden rule in medical practice. Humane Med 1990;6:255–9. [57] Oreopoulos DG. Compassion and mercy in the practice of medicine. Humane Health Care 2001;1:1.
Commentary
Ethical dilemmas encountered during clinical drug trials George K. Daikos∗ Aphiareion Foundation for Chemotherapeutic Studies, Athens University School of Medicine, 12 Stratiotikou Syndesmou Street, GR 10676 Athens, Greece
Abstract Ethical standards have a basis in antiquity and changes in practice need to be measured by moral considerations that are slower to change. This paper considers present day ethical problems in clinical trials—especially in infection, conflict of interest, financing of scientific studies and publishing (or non-publishing) of the results. © 2004 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Ethics; Clinical trials; Placebo; Active controls
1. Introduction Clinical trials and especially controlled randomized trials are fundamental to the advancement of evidence-based medicine. It is widely accepted that, if the evidence does not support a new treatment, a diagnostic method, or another practices, they should not be accepted as good, scientific medicine. Open, that is not controlled observations are seen as subject to bias and hence cannot contribute to evidence-based medicine. It is most interesting that the Hippocratic corpus, contains a passage that talks about evidence-based medicine: Do not rely on conclusions that result from mere reasoning, but (rely) on evidence. Arguments in the form of plain rhetoric are false and easily defeated. Therefore, you should stick to the facts and scrutinize them, if you are going to acquire faultless capability, which we call Medicine. Hippocrates: Parangeliai (Recommendations) [1]. The present paper will discuss some of the ethical dilemmas encountered during the conduct of clinical drug trials. The controlled randomized trials that are required for the approval of the distribution of a drug should prove its efficacy and safety. The agent chosen for comparison (the control) preferably should be a placebo or an earlier active drug already used in practice. The new agent must be shown to be ∗
Tel.: +30-210-3637024; fax: +30-210-3628108. E-mail address: [email protected] (G.K. Daikos).
pharmacologically equal to, or more active than the control. The patients who are assigned to the control arm of placebo, will remain without treatment for the duration of the trial. For decades, observers have asked whether it is ethical to leave an individual without treatment for the observation period and thus risk a worsening of the disease.
2. Historical As the first clinical trial, we can consider the limited scale experimentation that happened on board the ship, the Salisbury. Different treatments were given to small groups of sailors for scurvy prevention. Only those who ate oranges or lemons were capable for work the following 6 days [2]. Antimicrobial chemotherapy was neither discovered nor were its benefits established on the basis of clinical trials. Under modern systems of regulatory control, sulphonamides and penicillin would not have been approved for human use. One could also cite many other examples of major therapeutic advances that have not followed the path of randomized clinical trials (RCT). The Medical Research Council (UK) instituted the first controlled clinical trial for infection during the investigation of the treatment of tuberculosis (1948) [3]. That study led to the formation of the first protocols for co-operative studies designed to recruit a statistically significant number of patients. Cancer chemotherapy and large scale (multicentre) studies followed later in an analogous manner. Following the same protocol, the combination of related active agents led to real progress in cancer chemotherapy.
0924-8579/$ – see front matter © 2004 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2004.03.004
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3. The ignoble Tuskegee Syphilis Study (America’s Nüremberg) On the occasion of the 50th anniversary of the introduction of the Nüremberg Code, Wolinsky has drawn the attention of ethicists and the medical profession to the Tuskegee Syphilis Study, which otherwise might have been overlooked [4]. In Macon County, Alabama, the US Public Health Service (USPHS) placed 431 black agricultural labourers, who had seropositive latent syphilis in a prospective study for the purpose of observing the natural history of the disease [5]. The investigation sought to determine whether syphilis caused cardiovascular lesions more frequently than neurological damage and whether the course of the infection followed a different course in blacks than in whites. Participants were observed only and were not treated. The study began in 1932 at a time when only bismuth and salvarsan were available for the treatment of syphilis. The only explanation the USPHS gave the patients was that the study was meant to ‘cure their bad blood’. These individuals were recruited to the trial by the offer of food and other small gifts. USPH officials supervised the study, taking care that these poor people received no treatment. In order to recruit more people, the health service associated itself with the prestigious Tuskegee Institute in the area. The study, which was a crude and ruthless human experimentation, continued through 1972, well beyond 1947 when penicillin was proven as the best and most effective treatment for syphilis. The same year the code of Nüremberg was introduced (1947) and accepted by all nations as the ethical standard for all human investigations; among other things, it required the investigators to obtain an informed consent from all participants. This ignoble experiment was publicised by a reporter in Washington Post in 1972. As the Houston historian, James Jones [6] noted in his comments on the behaviour of the USPH investigators, even as evidence was accumulating concerning the benefits of penicillin, the patients were pressed to continue without any treatment because such investigation was ‘a never-again-to be repeated-opportunity!’. In 1997, President Clinton of the USA was obliged to offer a formal apology for this ignoble affair, but the government granted no compensation to the survivors, despite the efforts of a volunteer lawyer.
4. The 10/90 dis-equilibrium: economic context of research expenditure As the WHO has emphasised, of the US$ 50–60 billion world-wide annual expenditure on health research by both the private and public sectors, only 10% is devoted to the health problems of 90% of the world’s population [7].
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5. Contemporary systems of clinical drug research The development of a new drug from the laboratory to clinical use, costs approximately US$ 300–600 million dollars. Seventy percent of the money for clinical trials come from the pharmaceutical industry, the rest from National Institutes of Health (NIH), or other government sources. During the last 10 years, new types of clinical networks for drug investigation have been developed, such as the Contract Research Organisations (CRO) and the Site Management Organisations (SMO) which have entirely changed the process of data acquisition. Such organisations specialise in a fast recruitment of the required number of patients, who will agree by written consent to be subjects in the assessment of the new treatment. The policies of academic centres impose delays on the recruitment of patients, especially for controlled clinical trials that require a large number of patients. Organisations such as CROs and SMOs, which sometimes are organised by the industry themselves, have at their disposal investigator-designers, clinicians, and statisticians and often are able to collect large numbers of patients in a short time. They work through community general practitioners, who are paid by case and often do not inform their own patients that they are participants in a clinical trial. This new trend has developed quickly and is creating new problems, even in academic centres and large hospitals [8].
6. Conflict of interest This conflict arises because well-known physicians are co-operating with pharmaceutical industries, either as consultants or investigators, while at the same time holding university or government positions. Many also have financial interests, as stockholders or through other mechanisms. The conflict may not only be of financial but also of scientific (originality, publication, etc.) nature. The subject has drawn much attention lately. The New England Journal of Medicine, in its November 30, 2000 issue had two special articles [9,10] on such conflicts of interest, an editorial [11] and a ‘sounding board’ article [12]. The authors found that only one of 20 centres, observed guidelines such as the one proposed by Harvard University that requires physicians to abstain from industry activities. These observers suggest that scientist investigators especially clinicians should remain scientifically and ethically beyond and above conflicts of interest. It seems that the conflict(s) of interest are now of such an extent that it creates problems even in NIH. The trust that the American people place in this federal government agency and its employees has been called into question lately by a report in the Los Angeles Times about consulting payments from pharmaceutical companies to high ranking NIH officials [13].
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The New England Journal of Medicine had a policy of excluding those with any financial conflict from writing reviews or editorials. The policy proved impossible to adhere to in practice. In 2002, the Journal revised its policy to exclude only authors with ‘significant’ financial interests from writing reviews or editorials, stating that it was impossible to find experts without some conflicts [14]. Since the beginning of January 2003, the Lancet has elected to avoid commissioning commentaries, etc. from those with substantial financial interests in a company that makes a product or competitor to be discussed in the paper [15]. In 2004, Lancet and its speciality review journals took an even tougher stance. They avoided commissioning commentaries, rapid reviews, or series . . . ‘From anyone who, within the past 3 years, and with a relevant company, or competitor, has any stocks or shares, equity, a contract of employment, or a named position on a company board; holds a relevant patent; or has received a fee . . . to write, be named on, or to submit the paper’ [16]. Financial conflicts of interest that are not exclusions . . . but must be declared in the published paper are: consultancies, honoraria, speaker’s fees; research funding; . . . travel or accommodation payments; expert testimony fees [16]. In a perspective article in The New England Journal of Medicine [17], Steinbrook examines this subject at length and discusses what is the best policy on financial conflicts of interest for NIH employees. According to Dr. E.A. Zerhouni, the Director of NIH, strict measures are considered. There is no question that the co-operation of NIH with industry should lead to beneficial coexistence [17].
order to write the paper. His name does not appear in the paper, while the investigators are cited as the authors. Usually, the ghost-writer adds an interpretation favourable to the manufacturer’s product. The ‘guest author’ is a clinical investigator who appears as the author, without having written the paper or having analysed the data [8,20]. In the September 13, 2001 issue of The New England Journal of Medicine an important editorial deals with the problems of publication of the results of clinical trials. ‘Sponsorship, authorship and accountability’ [21], is signed by the editors of 12 leading Medical Journals. These included F. Davidoff (Annals of Internal Medicine), Catherine DeAngelis (The Journal of American Medical Association), J. Drazen (The New England Journal of Medicine), J. Hoey (Canadian Medical Association Journal), Liselotte Hojgaard (Danish Medical Association Journal), Richard Horton (Lancet), and Sheldon Kotzin (Medline/Index Medicus) amongst others. The editors felt compelled to make clear statements in order to protect the independent investigator in publishing his/her results free from the pressures of the sponsors. They state: ‘As editors of general medical journals, we recognise that the publication of clinical research findings in respected peer-reviewed journals is the ultimate basis for most treatment decisions. We are concerned that the current intellectual environment in which some clinical research is conceived, study subjects are recruited and the data analysed and reported (or not reported) may threaten this precious objectivity. Patients participate in clinical trials for altruistic reasons—that is, to advance the standard of care. As editors, we strongly oppose contractual agreements that deny investigators the right to examine the data independently or submit a manuscript for publication without first obtaining the consent of the sponsor.’
7. Publication of scientific findings The findings of these clinical trials accumulate in the data bases of the pharmaceutical companies that are developing the drugs and, if the results are not favourable, they may not publish their findings. The firms’ marketing departments are interested mainly in FDA approval, while the scientists are looking forward to publication in peer-reviewed journals of prestige. Usually, upon accepting the assignment to conduct a clinical trial, the investigator signs a restrictive contract and agrees, for a given time interval, not to publish the results, without the approval of the industry. Those that have dared to publish, against the will of the industry, have lived through a bitter experience [18,19]. The ‘non-writing author–non-author writer’ syndrome, or briefly ‘guest–ghost syndrome’, is a growing phenomenon, particularly in the commercial sector, where community-physician investigators have little interest in authorship. A ‘ghost-writer’ is a professional medical writer who is given the data by the pharmaceutical company, or CRO, in
8. Registering all clinical trials—reporting negative results Another difficult subject is the premature interruption of a clinical trial because of negative results that remain unpublished. Observers have proposed that the scientific community establish a registry of all clinical trials, no matter what stage, which will be accessible electronically. NIH has already set up such a registry (http://www.clinicaltrials.gov), which presently displays data from trials supported by NIH, but not those supported by the industry. It is expected that industry data will follow soon. The British publishers have set up a registry (http://www.controlledtrials.com). The Cochrane collaboration had also organised a systematic registry, but thus far only of the finished trials. Ioannidis and Lau [22] have recently assessed the amount of the space allocated to the incidence, severity and nature of adverse events in published reports of 192 randomised, controlled trials. Reporting of adverse events was considered adequate in only 39% of the trials.
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9. Recruitment of study patients There is a heavy demand for clinical trial participants because the number of drugs in the pre-clinical phase is growing. The Lancet in an editorial [23], commented recently on an important study [24] conducted by the Office of Inspector General of USA (OIG) entitled ‘Recruiting human subjects, pressures in industry-sponsored clinical research’, where the need is emphasised for strict controls on the recruitment of participants for clinical trials. Physicians are paid considerable amounts of money to collect patients and to open their records so that the companies can select those they want. Often such patients are not aware that they are being assigned as participants in a trial. On the other hand, physicians often become side-tracked when advertisements in the press or messages of other mass media addressed to the patients describe a new wonder drug and as a consequence, people demand that their doctors included them in the trial of the promising substance [25]. The advertisement of over-the-counter drugs has become big business and as a consequence, the public is conditioned to accept experimental drugs. 9.1. Patients influence doctors’ treatment decisions The direct to consumer advertising (DTCA) is increasing rapidly. It is allowed in USA and New Zealand, and in July 2001, the European Commission has proposed that it be accepted in Europe as well.
10. Physician–pharmaceutical industry relationships It is true that industry is the greatest contributor to drug development. It applies biological knowledge to produce products that are useful drugs. It does so for profit of course, but it is important that it does it. Research, development and marketing are intertwined and not easy to separate. Marketing often has the greatest influence in decision making [8]. These departments use every legal means to keep physicians happy, because they are the ones who prescribe the drugs. As Marcia Angell, then Editor of The New England Journal of Medicine, noted among other things: ‘Travelling around the world to appear at industry-sponsored symposiums has much more to do with marketing than with technology transfer’ [26]. Many non-investigator physicians are offered complimentary travel to international symposia and congresses during which they are offered special dinners, excursions and gifts [27]. Of course such events may be educational occasions as well, but usually the presentations are restricted to the promoted drug. In an editorial of The New England Journal of Medicine, Drazen comments: ‘No matter how altruistic the motive, investigators must recognise that research performed under these contracts is a business transaction . . . It is imperative
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that the terms . . . guarantee the safety and confidentiality of patients’ [28].
11. Are the randomized control clinical trials ethical? They are meant to be ethical and usually they are. It is unfortunate, however, that the effort to achieve scientific precision, if not restricted by ethical principles, may eventuate in criminal actions (e.g. experiment by Nazi doctors, the Tuskegee study). Guidelines derived from declarations of human rights concerning human experimentation (Nuremberg, Helsinki and its modifications), are intended to define the precise conditions and limits of clinical trials. In practice, however, these codes are not followed or respected [29].
12. Randomized clinical trials in developing countries Recently the ethics of human experimentation are being widely discussed because clinical trials on AIDS are being conducted in Africa without honouring the codes observed in developed countries. The March 30, 2000 issue of The New England Journal of Medicine reported such a trial [30] and in an accompanying editorial, Marcia Angell commented: ‘It is important to be clear about what this study meant for the participants. It meant that for up to 30 months, several hundred people with HIV infection were observed but not treated’ [31]. The usual excuse offered is that in those countries, HIV patients cannot afford and hence do not receive treatment anyway. The fact though is that, for research workers in developing countries, it is cheaper and easier to recruit large numbers of ‘drug-na¨ıve’ patients. The problem has created the proper reactions and decisions have been taken very recently for the regulation of the trials in developing countries [32,33]. As has been emphasised, ‘clinical trials in developing countries should meet all ethical and scientific standards of trials performed in developed countries’ and ‘ an experimental intervention should normally be compared with an established, effective treatment, whether or not that treatment is available in the host country’. Therefore, the presumption is that a placebo control or any other control that is less effective than an established, effective treatment is not ethically acceptable [32,33]. The scientific community accepts the compassionate use of an investigational drug and such use has been undertaken in AIDS patients with the approval of FDA. On the other hand, severe infections caused by micro-organisms resistant to existing drugs are appearing, and lives may be saved by a new active antibiotic. On such occasions it would be unethical to stick to the existing protocol and not provide a potentially lifesaving drug. Most clinicians involved in an early-phase drug trial would feel the need to use an exper-
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imental drug out of the protocol to fight a resistant infection. Eventually, such observations may prove valuable even though the study was aborted. On the other hand, an ethical practitioner should inform a desperate cancer patient that there is a new promising drug that might help him or her and the patient may accept the rules of the protocol and give his really informed consent. It is interesting that now the scientific community is reconsidering and re-evaluating the value of the observational studies. These generally are considered to be subject to personal bias and therefore less significant. Under the title: ‘Randomized trials or observational tribulations’, The New England Journal of Medicine in an editorial [34] on two papers [35,36] in the same issue asserts that the results obtained with control trials and random observations are comparable.
13. Is the use of a placebo group unethical? This question is asked more and more in recent times. The most articulate criticism has been mounted by Rothman and Michels [37] of Boston University based on the Declaration of Helsinki, concerning the ethics of human experimentation, which was adopted by the World Medical Association in 1964. The declaration was revised in 1975, and again in 2000 (Edinburgh, http://www.wma.net) amid sharp debate. An international conference on the implementation of the new provisions of the declaration was held in Pretoria, South Africa in March 2001 [34]. The Declaration demands that ‘In any clinical study, every patient, including those of a control group (if any), should be assured of the best diagnostic and therapeutic methods’, and in the Edinburgh new version—‘The benefits, risks, burdens and effectiveness of the new methods should be tested against those of the best current prophylactic, diagnostic and therapeutic methods.’ The literal interpretation of that requirement precludes the use of a placebo if an active treatment is available. The new provisions are stricter and are considered ‘too rigid’ by many. Several groups, including the FDA, do not want to accept those restrictions. The placebo is too powerful! The September 19, 2000 issue of the Annals of Internal Medicine has two articles by two FDA members who discussed the subject extensively [38,39]; an editorial by R. Simon [40] of the National Cancer Institute, and a report on The ethics of placebo-controlled trials [41]. The inclusion and exclusion criteria usually determine which patients should be accepted in, or excluded from a clinical trial, e.g. life-threatening conditions, severe septic cases, or analogous situations are not allowed in a randomized control clinical trial, especially in a trial that has a placebo arm. The scientific community seems to have reached a consensus that use of a placebo control is always unethical in severe illness for which there is a treatment which improves survival, or ameliorates morbidity.
13.1. Active-control equivalence trials (ACET) These trials compare a new treatment with an existing active treatment. The new treatment should prove superior, or at least equivalent to the existing and accepted one. It seems to be conceded that this frequently used method plays an essential role. Such a search for new drugs except for the purely commercial purpose (the ‘me-too’ principle), aims at efficacy, pharmacokinetic improvements or a reduction in toxicity, which do not necessitate the use of a placebo (control) arm. A good example of ACET are the many and successful hypolipidaemic drugs, which have been introduced to the market in the last few years. Although the differences between them are not large, the market and the need for them are great and hence the offer of better substances is welcome and profitable. In a perspective article, The New England Journal of Medicine (January 15, 2004) discusses the ‘me-too’ principle [42]. ‘There is another side to the story. “Me-too” products reflect and create competition among drug and device manufacturers, and that competition is also a powerful driver of better quality and lower costs.’ In trying a new drug, the use of a placebo is proposed when there is already an effective drug, but with an uncertain and moderate efficacy and if the new treatment is not expected to be much superior. If the existing treatment is clearly effective and well established, the comparison should be with that agent (ACET). Here there is no justifiable reason for a placebo (control) arm [43,44]. 13.2. The equipoise principle A fundamental ethical and scientific principle of human experimentation states that the patient should be enrolled in a randomised, controlled trial only if there is substantial uncertainty about which of the trial treatments would benefit a patient most [44,45]. A non-treatment–non-placebo arm is introduced to isolate and control the placebo effect. Because of a growing criticism of the placebo effect, many have suggested that a third arm be included in the randomized clinical trial, i.e. a group that does not receive either the substance under trial, nor a placebo [45]. Such a method does prove that no placebo effect exists. Our confidence in the ‘powerful placebo’ is being shaken and we are being forced to discuss the possible existence of regression to the mean, natural history, or concurrent interventions. In the September 20, 2001 issue of The New England Journal of Medicine, the problem of ethics in withholding existing treatment in placebo control trials, especially as it arose after the stricter criteria of the revised Declaration of Helsinki, is discussed in an editorial [46] and a sounding board article [47]. It is argued that where there is an already active drug, a middle ground to establish placebo control can be found. As Emmanuel and Miller of the National Institutes of Health propose in the sounding board article,
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placebo-controlled trials are permissible when proven therapies exist but only if certain ethical and methodological criteria are met. I cannot enter into details, but their arguments are not convincing, as they favour placebo use, even when there is an active substance to compare with.
14. Informed consent Informed consent is the cornerstone of the code of Nüremberg. It is essential to obtain a truly informed consent from the participant in any human experimentation. This does not always happen. Often participants are not explicitly informed as to the consequences, benefits, or risks of the trial. As one critic has noted: ‘Obtaining a signature on a paper does not ensure that a participant understands the proposed research’ [26]. The quality of informed consent was evaluated in 287 cancer patients participating in clinical trials in three co-operating oncology centres in Boston. Ninety percent answered that they have been properly informed but 74% had not understood that it was a research project; 63% had not appreciated the risks, 29% the uncertainty of the benefit and only 25% realised that the investigation concerned mainly future patients [48]. A vivid example of that 25% part is the following reaction of a physician suffering from myeloid leukemia. ‘My life changed again when a medical writer colleague heard Brian Drucker speak about a new drug . . . an inhibitor of the Bcr-Abl tyrosine kinase {produced by the chromosome translocation in CML (Clivec). I decided to get enrolled in the trial. I had an excellent response. I realised that even if I wasn’t cured, many people with cancers caused by chromosome or protein abnormalities would be beneficiaries of this work’ [49]. As it has been mentioned already commonly, during the recruitment of participants, CROs do not make explicit information available to the patient. On the other hand, in developing countries many participants cannot write, or, for that matter, understand what the study is all about. In a critical analysis of the concept of informed consent as it applies to the clinical trial, Truog et al. ask whether it is always necessary to obtain such consent in RCT [50]. They argue that a physician, when choosing a form of therapy always conducts an experiment. During everyday practice, e.g. in an acutely ill patient in an ICU the physician might decide to apply a new method that he has read about recently. He may do so if the patient or his agent has given a general consent. He does not need approval by the Institutional Review Board (IRB). However, if he/she wants to determine which of two commonly used antibiotics works better in acute bronchitis, he/she must prepare a protocol, obtain approval from IRB, and seek written consent from the participants. Studies have shown that patients rarely demonstrate an adequate understanding of consent forms. Although this reasoning looks valid in such instances, we cannot waive
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the protection offered by informed consent that safeguards patients from scientific exploitation. The National Bioethics Advisory Commission has proposed new safeguards for clinical research with adults who are unable to consent. This issue arises when an important research project concerns people who cannot consent or dissent. Wendler and Prasad in a publication in the October 2, 2001 issue of the Annals of Internal Medicine [51] discuss the guidelines proposed by six groups for such patients and they endorse six core safeguards: (1) (2) (3) (4)
institutional risk-benefit assessment; consent assessment; necessity requirement; proxy decision maker and sufficient evidence of patients remaining preferences and interests; (5) respect for patient assent and dissent; and (6) independent monitors. They conclude that: ‘In the absence of specific safeguards, research with adults who are unable to consent presents an increased potential for subject abuse.’ However, ‘Inappropriately stringent safeguards could halt important research and block improvement in medical care for the very groups the safeguards are designed to protect’ [52]. Informing versus counselling the patient comes up often when discussing a randomized clinical trial. The expert advice of the personal physician, especially if he is a specialist (e.g. oncologist) usually prevails over the proposal to conduct an RCT. It is not possible that in this circumstance the physician only informs but does not counsel his patient. On the other hand, the line between informing and persuading is a thin one.
15. Protection of research subjects The participants in RCTs are not always informed explicitly about the risk of the experimental treatment. Of course, often even the investigator may not know what this risk is. The Office of Inspector General of USA, in a recent study entitled ‘Recruiting human subjects, pressures in industry-sponsored clinical research’ emphasises the need for strict control measures for such recruitment. The Lancet on this occasion, underlines the need for the protection of the participants in an editorial [23]. The tragic death of an 18-year-old boy, during gene therapy, greatly moved the authorities and all the scientific community. In a sounding board article in The New England Journal of Medicine [52], the then Secretary of Health and Human Services (USA), Donna Shalala, discussed at length the safety of patients in clinical research. ‘This young man’s death led to the discovery by National Institutes of Health of many hundreds of unreported adverse events among volunteers enrolled in gene-transfer experiments.’ Ellen Roche, a 24-year-old technician at the John Hopkins Asthma and Allergy Center and a healthy volunteer in
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a study of asthma funded by NIH died on June 2, 2001. She was given hexamethonium inhalations. In 2 days, she developed respiratory problems and died after about 1 month. Reacting immediately, the Office for Human Research Protections suspended 2500 active protocols of John Hopkins group. Widespread deficiencies were found. The suspension was soon reversed, after the proper measures have been taken [53].
16. Participation of the patients ‘HIV-AIDS changed forever the expectations of consumers in clinical research. Instead of participating in clinical trials as “subjects”, consumers became equal partners with their physicians’ [54]. Activist HIV-AIDS patients succeeded in having their terms accepted and somehow have opposed paternalistic behaviour in medical research, in part because the nature of the infection, which was acutely fatal did not allow for the bureaucratic delays of the past. They have pressed for more active research and for quicker drug authorisation by FDA. They also obtained compassionate release of ‘not-yet-thoroughly-studied drugs’. This participation of the patient-activists has had both positive and negative results. A positive effect is the shortening of the time of drug authorisation by FDA. In 1986, on average, 34.1 months were required for such authorisation; however, by 1999 the time was reduced to 12.6 months. 16.1. Epilogue: the golden rule εεε ␣ε [55] (Do good or do no harm). In trying new investigational drugs on humans one should not forget this fundamental Hippocratic moral principle. As in all Medicine, what makes the difference is the physician and his attitude. If he/she is highly motivated and faces the patient as a suffering fellow man, not a client or a subject, even more if he/she feels towards him as his neighbour whom he should love as himself, then he will practice good Medicine, a real ‘Humane Medicine’. Then, he will construct and execute an ethical RCT, if that is really necessary to prove the uncertain, and he will handle experimental drugs with real loving care. If he is a mere technocrat, perhaps a great scientist, capable of handling all molecular and sub-molecular knowledge, but without due respect for the suffering man, he may end up in real criminal actions. In an older issue (Autumn of 1990) of Humane Medicine [56], Gail Stephens presented the view that unless we stick to the golden rule, we cannot practice good medicine, that is true for the clinical trials as well. In his most interesting and very important article ‘Compassion and mercy in the practice of medicine’ in the first publication (2001) of the electronic edition of Humane Health Care, Oreopoulos [57] emphasises the proper way
and attitude to the patient, which is no other than compassion and mercy, the real agape we owe to our fellow man. That of course, applies first and foremost to the clinical trials.
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