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Fed Regist 73 May 21, A well-designed trial should answer important public health questions without impairing the welfare of individuals.
In such instances, the needs of the patient must predominate. Ethical issues apply in all stages of a clinical trial. As will be noted, several of the issues are unsettled and have no easy solution. We expect, however, that investigators will at least consider these issues in the planning stages of trials so that high ethical standards can be applied to all trials. Emanuel et al. Although the role of ethics review committees is discussed later in this chapter under Informed Consent, it must be emphasized that independent review by these committees and others, such as data and safety monitoring boards, applies to all aspects of a trial.
We encourage the reader to seek out any of the many books and journals devoted to ethical aspects of clinical research. Those go into the issues, including ones we do not address, in considerable depth. A particularly relevant book is the Oxford Textbook of Clinical Research Ethics, many chapters of which relate directly to clinical trials [2]. The reader is also referred to several key documents [3—6].
An early decision relates to whether a clinical trial is even necessary. Sometimes, other kinds of clinical studies may be able to address the question at least as well as, or even better than, a clinical trial.
Even if the answer may not be quite as good, the added benefits from the trial may not be worth the added risk. The question being addressed by the clinical trial, therefore, must be important enough to justify the possible adverse events. A trivial question should not expose study participants to risk of harm, either physical or emotional. Harm can be either a direct result of the intervention or indirect, from withholding something beneficial. The study investigator, sponsor or funder, and institutions where the study will be performed must all ensure that the question is sufficiently important and the trial is appropriately conducted to justify those risks.
Though the question may be important, the clinical trial may be infeasible or unethical. An obvious example is cigarette smoking. After two of the three antiarrhythmic drugs were seen to be harmful and stopped, some asked whether the study might be continued, but reconfigured to demonstrate that quinidine, a long-used drug with some properties similar to the two discontinued agents, would also be harmful. Although the outcome of a trial is uncertain, the primary response variable should always be one where either benefit or noninferiority is potentially achievable.
Planning and Design 21 Two kinds of trials raise ethical issues because of concerns about the balance between potential benefits to society and perhaps to participants and the risks of harm and discomfort to participants.
In both, the likelihood of immediate benefit to the study participants exists, but is remote. Such clinical trials are conducted to show that a new drug or new version of an old drug is at least as good as noninferior to a drug already proven to be beneficial. Other than enhancing the financial status of the industry sponsor, there may be little benefit to the new drug.
Yet trial participants are being put at risk from a drug with unknown adverse effects, some of which might be serious. If the new drug has some potential improvement over the existing one, the trial might be justified. Perhaps the new drug is easier to take e. One could also argue that having more than one drug with similar benefits is good for the economy, fostering lower medical care costs.
But in the end, those conducting such trials should show how the question is important and how there will be meaningful benefits for patients. A second kind of trial, the ethics of which have been debated, is the early phase study. If these studies are performed in healthy volunteers, there is a nontrivial chance that they will be harmed, but have no opportunity to benefit, other than from whatever payment they receive as a result of their participation.
It has been argued that with proper attention to study design and safety monitoring, appropriate evaluation by ethics review committees, and true informed consent, these studies are ethical [9]. As always, risk must be kept to a minimum and the payment must not be so great as to encourage participants to do something that would place them at serious risk. As with other clinical research, early phase studies are only ethical if investigators and sponsors do whatever is necessary to minimize risk.
Unfortunately, instances when investigators may not have taken proper care have occurred and received widespread attention [11—13]. Some early phase studies are conducted with participants who have a disease or condition. Given the small size of these studies and the unfortunate fact that most interventions early in their development do not prove beneficial, some have even questioned the ethics of these trials. But even if there is only a slight possibility of improvement, as long as there is adequate informed consent and the expectation of benefit to society from the knowledge to be gained, most would agree that these trials can be conducted in an ethical manner [14, 15].
The special 22 2 Ethical Issues issues related to noninferiority trials are discussed in Chap. Randomization has often been a problem for physicians and other clinicians who believe they must be able to convey to their patients a treatment course of action.
The researcher, however, must accept uncertainty. Therefore, an objection to random assignment should only apply if the investigator believes that a superior therapy exists. If that is the case, she should not participate in a trial that involves the preferred therapy.
On the other hand, if she truly cannot say that one treatment is better than another, there should be no ethical problem with randomization. Such judgments regarding efficacy obviously vary among investigators. In this concept, the presence of uncertainty as to the benefits or harm from an intervention among the expert medical community, rather than in the individual investigator, is a justification for a clinical trial.
Some have maintained that until an intervention has been proven beneficial, randomization is the most ethical approach and one that will provide the correct answer soonest [17—20]. Control Group Choice of the control group is a major design issue in all clinical trials. But the optimal therapy may not be widely used for various reasons. These could include cost, unavailability of the therapy or lack of sufficient clinicians competent to administer it, lack of acceptance by the practicing clinical community, socioeconomic and cultural differences, or other factors.
Depending on these circumstances, some trials may not use the best known therapy or standard of care as the control. They may rely on what the practicing communities typically do, or usual therapy [21]. Investigators and ethics review committees need to judge whether the usual therapy deprives participants of a proven better treatment that they would otherwise receive.
If so, serious ethical concerns arise. A major area of disagreement has been the degree of responsibility of investigators to ensure that all participants receive the best proven therapy as a control or background care, even if usual care in the community in which the trial is being conducted is not up to that standard [22].
See also the section below, Trials in Developing Countries. Considerable confusion has arisen when people talk about placebo-controlled trials, as they may refer to different kinds of designs. Often, a new intervention is added to usual care or standard care, and compared against that care plus placebo. Sometimes, a new intervention is seen as a possible replacement for an existing therapy, yet for various reasons, it is not thought appropriate to compare the new intervention against the existing therapy.
The commonly used therapy, for example, may not have been proven to be beneficial, or it may be poorly tolerated. Therefore, a placebo comparator is used instead of the existing therapy. For conditions causing only mild to moderate discomfort, it may be acceptable.
For example, investigators evaluating new analgesic agents might choose to use a placebo control, as long as any pain or discomfort is treated promptly. As always, there will be borderline cases that require discussion and review by ethics review committees [23]. Freedman et al. They argued that if an accepted treatment exists, much of the time a placebo control is unethical and, indeed, unnecessary. Rothman and Michels [26, 27] also maintained that in many cases, a placebo has been used inappropriately because a proven therapy existed.
We think that this is a valid argument only if all investigators including referring clinicians have been informed about the current evidence and make the decision to conduct another placebo-controlled trial because they question the applicability of that evidence.
Ethics review committees must have full knowledge, and informed consent must contain the relevant information. Whenever an investigator considers using a placebo control, she must assess whether it will provide the most meaningful answer to the question being addressed, and will not cause serious harm. Importantly, all participants must be told that there is a specified probability, e. Miller summarizes the issues that must be considered by investigators [32]. Protection from Conflict of Interest A widely expressed concern in much clinical research is the potential for conflict of interest on the part of the investigators.
Conflict of interest is generally considered in the financial context, but intellectual or other conflicts may also occur [33]. Ideally, no investigator would have any interests other than the well-being of the study participants and the generation of new knowledge that will improve clinical care and public health. That is unrealistic, however, given that most investigators receive research funding from government, industry, or others with considerable interest in the outcome of the study.
We think that disclosure and IRB or other oversight may be sufficient for early phase studies. It may not be sufficient, however, for late phase trials: those that are designed to have major implications for clinical practice. Therefore, all data collection and analysis should be conducted by groups independent of the industry sponsor. Ideally, this should also occur in trials sponsored by others. This may mean that the lead investigator in multi-investigator studies or the investigator in single investigator studies should have no conflicts if the study is one likely to change practice.
If the investigators have limited roles or only small financial investments, it may be acceptable for them to participate. We recognize that the situation is more complicated when those designing and overseeing, and perhaps coauthoring publications, are employees of the company sponsoring the trial.
The use of external independent oversight bodies and clear lines of authority may mitigate conflict of interest.
In the end, however, clinical trial results must be believed and accepted by the clinical communities. To the extent that conflict of interest real or perceived lessens that acceptance, the study is impaired. Informed Consent Proper informed consent is essential.
Partly as a result of terrible things done in the name of clinical research, various bodies developed guidelines such as the Nuremberg Code [4], the Declaration of Helsinki [5], the Belmont Report [3], and the International Ethical Guidelines for Biomedical Research Involving Human Subjects [6]. These regulations require that clinical research studies be reviewed by IRBs and establish the membership and procedures that IRBs must follow.
Planning and Design 25 One of the primary roles of the IRB is to ensure that there is true, voluntary informed consent. Table 2. Informed consent is a process that can take considerable time and effort; it is not simply a matter of getting a form signed.
In many, perhaps most, clinical trial settings, true informed consent can be obtained. As discussed in the Privacy and Confidentiality section below, investigators may share data and biospecimens with other researchers. If such sharing is planned or required by the sponsor, the informed consent must make it clear that sharing will occur and that the data may be used for purposes other that those of the trial for which the person is volunteering.
Sometimes, people who are ill may not understand that a clinical trial is a research endeavor. This may happen in early phase trials of new drugs that are being developed for serious, untreatable diseases, or in any clinical trial testing, a promising intervention for a serious or chronic condition.
Patients may view the trial as the last or best possibility for cure. Sometimes, clinicians are also researchers, and may seek to enroll their own patients into clinical trials. The distinction between research, in essence an experiment, and clinical care may blur.
We do not advocate preventing clinicians from enrolling their own patients into clinical trials. However, extra effort must be made to provide the patients with the information needed to judge the merits of volunteering to enter the research, separate from their clinical care.
The situations where participant enrollment must be done immediately, in comatose patients, or in highly stressful circumstances and where the prospective participants are minors or not fully competent to understand the study are more complicated and may not have optimal solutions. In the U. Under these regulations, IRBs may approve the study as long as a series of special conditions has been met, including that there has been community consultation and a safety committee is formed to monitor accumulating data.
A trial of thrombolytics versus placebo in the context of resuscitation for cardiac arrest was successfully conducted under the EMA guidelines [45]. In this trial, local ethics committees agreed that the trial could be done without informed consent prior to enrollment. Instead, consent was later given by surviving participants or their family members or others. An example is a trial of a product intended to be used as a blood substitute in trauma patients [46].
Because patients were unconscious at the time of administration of the blood substitute, consent could not be obtained. Therefore, community consultation was obtained before local IRBs approved the study. However, there were allegations that safety problems noted in earlier trials of the agent were not published or otherwise disclosed to those bodies.
We do not take a position on the merits of this particular trial, and we support the concept of being able to conduct important research in settings where full informed consent before enrollment is not possible. The sponsors and investigators, though, must be completely open about all data relevant to the conduct of such studies and must follow all local regulations [47]. Conduct 27 Failure to do so harms not only the unwitting participants but also the entire field of research in emergency settings.
Also contentious is the role of consent from participant surrogates when the study participant is unable to provide fully informed consent. Less clear is the use of surrogate consent for potential study participants who are temporality unable to understand the nature of the study and give consent. This issue arose in research in people with the acute respiratory distress syndrome [50].
Suggestions for accommodating research in such situations include risk assessment, determination of patient capacity, and reconsent [51]. As in all such situations, judgment on the part of investigators, sponsors, IRBs, and others will be required and secondguessing will inevitably occur.
Conduct Trials in Developing Countries Many clinical trials are international. The ability to enroll and follow participants in more than one country assists in enrollment and may assist in generalizing the results of the trial to different populations and settings.
However, trials that are conducted in developing areas raise ethical issues. Are they conducted in those regions because the disease of interest is prevalent there, and the results relevant to the region? Or are the countries or regions selected primarily for convenience, low cost, or fewer administrative and regulatory burdens?
The control group may be receiving less than optimal care, and thus may have a higher event rate, permitting a smaller, shorter, and less expensive trial. If the trial is conducted for those reasons, it is unethical. Others have maintained that it is sufficient if the participants receive care at least as good as what they would receive had they not been in the trial.
This was the argument of the investigators in the Vietnam Tamoxifen Trial of adjuvant oophorectomy and tamoxifen in treatment of breast cancer. State of the art treatment by US standards including radiation was not available and not likely to be available. What was being tested was whether a simple and affordable treatment like tamoxifen would be better than what was available [52].
Extrapolation of study results from less developed regions to highly developed countries with very different health care systems and standards of care, and vice versa, has also been questioned. Some studies suggest that the outcomes may indeed be different [53, 54]. This and other issues have no easy answers. We believe, however, that trials should only be conducted in places and with participants likely to benefit from the results and with informed consents that clearly describe what will be done at the end of the trial.
The results from the trial must be able to be applied to clinical practice in the population from which the participants came [55]. Recruitment Recruitment of trial participants is often one of the more challenging aspects of conducting a clinical trial see Chap. Unless an adequate number of participants is entered, the trial will not be able to answer the questions about benefit and risk.
Therefore, there is great pressure to recruit an adequate number of participants and to do so as quickly as possible. This differs from the common and accepted practice of paying investigators a certain amount for the cost and effort of recruiting each enrolled participant. Even this practice becomes questionable if the amount of the payment is so great as to induce the investigator to enroll inappropriate participants [10].
Study participants may be paid for their involvement in clinical trials. Typically, payment is meant to compensate them for the time, effort, and expense of attending clinic visits. Studies that enroll healthy volunteers usually phase I trials will often provide payment beyond reimbursement for expenses.
As with paying investigators, when the amount is such that people, whether they are healthy volunteers or patients, might make unwise or dangerous decisions, it becomes excessive. Participants should never be paid more for taking on more risk.
Ethics review committees often have guidelines as to appropriate amounts for various kinds of studies and procedures and must ensure that the amount provided does not create an undue influence. As discussed in Chap. This treatment may be for the condition that will be studied or some other reason. For example, one might be interested in enrolling people at high risk of cardiovascular disease, and thus try to accrue those with hypertension.
But an accurate baseline blood pressure might not be obtainable in those already on treatment. It might not even be clear that the participant already on antihypertensive drugs would have met the eligibility criteria if not on medication.
Should one withdraw the drug or simply accept that those on treatment probably truly had hypertension, especially if on treatment they still have high normal blood pressures?
Conduct 29 Safety and Efficacy Monitoring Occasionally, during a trial, important information relevant to informed consent derives either from other studies or from the trial being conducted. In such cases, the investigator is obligated to update the consent form and notify current participants in an appropriate manner. A trial of antioxidants in Finnish male smokers the Alpha-Tocopherol Beta Carotene Prevention Study indicated that beta carotene and vitamin E may have been harmful with respect to cancer or cardiovascular diseases, rather than beneficial [57].
CARET was subsequently stopped earlier than planned because of adverse events similar to those seen in the Finnish trial. Five trials of warfarin in patients with atrial fibrillation were being conducted at approximately the same time [61].
The trials continued, but participants in those trials and medical communities were notified of these interim findings [64, 65]. Not only is such a practice an ethical stance, but a well-informed participant is usually a better trial participant. The issue of how to handle accumulating data from an ongoing trial is a difficult one, and is further discussed in Chap. With advance understanding by both participants and investigators that they will not be told interim results unless they show clear benefit or harm, and that there is a responsible safety monitoring group, ethical concerns should be lessened, if not totally alleviated.
Early Termination for Other than Scientific or Safety Reasons Clinical trials are only ethical if there are adequate resources to conduct them and see them to completion. Trials may and should be stopped early if there are safety concerns or if there are scientific reasons to do so see Chap. It is inappropriate, however, to stop a trial early because the sponsor changes its mind about marketing priorities or failed to adequately plan for sufficient resources.
Partway through follow-up, the sponsor ended the study for other than scientific or safety reasons. Because the trial was being conducted in patients with a fatal condition, amyotrophic lateral sclerosis, the study participants viewed the trial as a last hope and were therefore under considerable pressure to donate. We view such actions as completely unethical. Plans for conducting the trial, including obtaining experimental agents, must be in place before the trial begins.
With all trials, investigators need to plan in advance how they will handle end of study issues such as whether participants will have continued access to the intervention and transition to appropriate medical care. Privacy and Confidentiality The issues of privacy and confidentiality have received considerable attention. The widespread uses of electronic media have made many people concerned about the privacy of their medical records, including research records.
They have also led to laws restricting what kinds of medical records can be shared and with whom, in the absence of clear permission from the patients. However, there are clinical research provisions that affect how investigators identify, contact, and obtain informed consent from prospective participants, and how study data are maintained and provided to others [70] see also Chap.
These laws, in turn, have generated articles pointing out the increased difficulty in conducting clinical research. If data are shared with other researchers for unspecified purposes, might participants who volunteered for a trial object to their data being used for goals of which they might not approve? The increasing availability and use of genetic material adds to this conflict.
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