Ethical considerations in biomedical research: A personal view

Abstract

Premise

Ethical considerations are made when an experiment is planned and take a regulatory system of moral principles into account.

Discussion

Ethical considerations should first and foremost be made in order to protect the individual subject/animal from being exposed to any unethical and perhaps even illegal intervention and to ensure that the experimental conditions used are appropriate.

Summary

The main role of research ethics committees is to assess the scientific and ethical aspects of submitted protocols and follow up the trial until its closure.

Introduction

The fundamental and most important ethical considerations are contained by the question: “Is it ethically defensible to expose a human being or an animal to a certain procedure in order to gain information about a given disease or treatment?” The study would be unethical, obviously, if it is unlikely that the modus operandi according to the study protocol can provide us with a valid answer. The reasons for such a situation can be abundant, e.g. inappropriate sample sizes, inappropriate controls, or irrelevant experimental procedures.

Predictably, the condition studied will have an impact on the ethical considerations made. A question about a harmless condition would demand a risk-free procedure to achieve the answer, whereas an imperative question related to a serious disease would allow for a protocol with calculated risks.

Ethical guidelines

An important document in this respect is the Belmont Report, which is a report created by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research that was prompted by ethical problems within a clinical trial (1). The Belmont Report identified the three pillars of medical ethics: “respect for persons,” that is, recognizing individuals as autonomous and voluntary decision-makers possessed of free will; “beneficence,” that is, ensuring the safety of the individuals by first causing no harm either through acts of commission or omission and by acting in the individual patients’ best interests, an axiomatic concept in medicine; and “justice,” that is, ensuring that the patients benefit from participating in the research and that care is equitably distributed among groups and individuals during and after the trials. A critical extension of the principle of “respect for persons” and autonomy is the concept of informed consent. This ensures that the individual participating in the clinical trial is making the decision based on free will without coercion or outside influence, understands the risks involved, is aware of any potential benefits, and his or her right to back out at any time. Today the Belmont Report serves as a historical document and provides the moral framework for understanding regulations on the use of humans in experimental research.

The most widely accepted international ethical guideline for medical research is the regularly updated Helsinki Declaration. This was adopted for the first time in 1964 by the World Medical Association, a body representing physicians worldwide (2). Randomized placebo-controlled clinical trials have been the “gold standard” during the last decades in the development of new drug therapies. This scientifically valid approach has recently been questioned in the fifth revised version of the Declaration of Helsinki, which states that the use of placebo-controlled clinical trials is acceptable only when no proven treatment exists for the studied disease (3). An intense international debate forced a convoluted amendment that allowed for placebo-controlled trials in light of the availability of proven therapy, “where for compelling and scientifically sound methodological reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic and therapeutic method” (2).

Ethics and monitoring committees

The main role of research ethics committees is to assess the scientific and ethical aspects of submitted protocols and follow up the trial until its closure. Traditionally, drugs are tested on animals first and then, in a series of phases that may take several years, on human subjects.

Issues surrounding the ethics of preclinical and clinical trials have always been the source of much controversy. For example, patients and healthy volunteers have and may continue to participate in underpowered clinical trials that, due to this fact, become of only limited clinical value. Perhaps most concerning are the scenarios in which investigators conduct an appropriate power analysis, find they will be unlikely to recruit an adequate number of participants, yet choose to proceed without conveying this information to participants in the informed consent process (4). Under-reporting of clinical trials is another example of unethical actions taken by the pharmaceutical industry (sponsor) or the clinical investigator.

In response to accusations of biased under-reporting of research, new government regulations have been implemented. Under the United States Food and Drug Administration (FDA) Amendments Act of 2007, it is expected for any applicable clinical trial that it be required to be registered with ClinicalTrials.gov and that the responsible party will submit basic results information, a certification, or a request for extension not later than one year after the earlier of the estimated or actual completion date (primary completion date) of the trial (5).

Sponsors of studies evaluating new drugs, biologics, and devices are required to monitor these studies. In order to keep better track of drug-related non-serious and serious adverse events (AEs), the guidance proposed by the FDA for data safety committees recommends two separate committees: a Clinical Events Committee (CEC) and a Data Safety Monitoring Board (DSMB). The primary responsibility of the CEC is to review all study AEs and adjudicate individual AEs as appropriate. The primary responsibility of the DSMB is to ensure the safety of study participants by a thorough review of the safety, efficacy and compliance data. In addition, the DSMB advises the sponsor regarding the continuing safety of trial subjects and those yet to be recruited to the trial, as well as the continuing validity and scientific merit of the trial.

Without doubt, the quality of preclinical and clinical trials has improved continuously during the last two to three decades. This improvement has mainly been forced by the strong recommendations from crafters of international guidelines and members of ethics review boards, research funding agencies, and medical journal editors, all of whom maintain strict requirements for adequate research methods, including appropriate statistical power, for any clinical trial to be approved, funded, or published, respectively (4,6–8).

Personal reflections

In the following part of this paper I will give my personal view and some examples where I think that either the innovative pharmaceutical industry or the clinical investigators or both have violated fundamental ethical principles. The two expressions “failing is inherent in human nature” and “the end justifies the means” create a dangerous combination that may put our ethical principles at risk. In addition, human weaknesses for fame and money sometimes set aside our normally strict ethical values and allow for a different set of values to be engaged. The higher the tentative end value of the purpose, the more people with an elastic conscience tend to detached themselves from their sound ethical principles.

In general, the pharmaceutical industries have the stronger financial position that enables them to dictate in which area of research they want to carry on clinical trials and invest their money. Much of these types of research activities are performed primarily in the interest of the sponsor, clinical investigators and in some cases the participating university. As a consequence, most preclinical and clinical research activities and consulting are financed by funds provided by for-profit organizations. These organizations have a special interest, and in most cases they will also conduct data management and analyses. In some of these cases they may also write the reports on behalf of the clinical investigators. Unfortunately, these circumstances increase the risk that the clinical importance of the findings becomes overemphasized (9,10). Systematic examinations of the relation between funding and conclusions in 370 clinical trials have found that the odds of recommending an experimental drug as treatment of choice increases fivefold with for-profit funding compared with not-for-profit funding (11). In 62% of these clinical trials the finally performed analyses, including subgroup analyses and composite measures, deviated from the primary analysis plan. Of overriding importance is the need for each clinical trial to define a clear and coherent policy for such uses of baseline data in the context of an overall predefined statistical analysis plan. Thus, the risk of post hoc exaggerated emphases across a multiplicity of possible analyses can be reduced, and readers can have greater confidence in the validity of authors’ conclusions (12).

An additional unethical mode of procedure is when for-profit organizations fail to report findings that indicate their experimental drug performs no better or less favorably than the comparator. An example of this type of publication bias was addressed by the American Congress in 2004 when it was revealed that 12 out of 15 clinical studies that demonstrated treatment with selective serotonin reuptake inhibitors (SSRIs) in children is ineffective had not been published (13). Another example of under-reporting is demonstrated by a study from Spain that shows that the results of only 21% (26/123) of finished clinical trials were published in peer-reviewed journals three years later (14). In contrast to under-reporting, a positive finding may be reported as covert duplicate publications with different authors and with no reference to the original trial. A survey in British Medical Journal demonstrated that 17% of the published studies were duplicates without referring to the original study (15).

Most scientists and clinical investigators depend on funding from for-profit organizations in order to fulfill the requirements for making an academic success. Under such circumstances, these clinical investigators and consults are kept on a short leash by the for-profit organizations, which pose a risk of selection of yes-people among members in advisory boards, funded research groups, etc. Not infrequently, these individuals run the risk of acting as chaperones for the organization in a process with a hidden agenda, creating an unpleasant situation where one can be held responsible despite having acted in good faith. The unwholesome financial dependence on for-profit organizations may influence scientists and clinical investigators, like the worship of the golden calf, to endorse clinical trials even if it can be predicted that the results will be of very limited scientific and clinical value. Obviously, this means losing financial funding that could be put to much better use.

A conflict of interest has been defined as a situation in which a person has a private or personal interest sufficient to appear to influence the objective exercise of his or her official duties as, say, a public official, an employee, or a professional (16). Readers benefit from transparency. To meet their responsibility to readers and to the public to provide clear and unbiased scientific results and analyses, most medical journals currently demand that manuscripts should be accompanied by clear disclosures from all authors of the nature and level of their contribution to the article, their understanding regarding the obligation to share data and materials, and any affiliations, funding sources, or financial holdings that might raise questions about possible sources of bias. Before manuscript acceptance, therefore, authors will be asked to sign an authorship/conflict-of-interest form. Specific information will be sent to most authors at the time of manuscript revision.

It is not wrong to have a conflict of interest but the ethical issues are in what you do with it! In generalizing the theme on conflicts of interest, I have come across two attitudes that are poles apart. One is the very conservative position that can be described by the proverbial principle of the three wise monkeys to “see no evil, hear no evil and speak no evil,” to which I would add one more: “Do no evil.” The diametrically opposed approach is recognized by a person who seems to be involved in everything and collaborating with everyone. The unadventurous clinician will be able to write no conflicts of interest on his or her disclosure form whereas the omnipresent colleague will have to write down any factors that a reasonable person might think is likely to bias his or her decision-making judgment. Which of these two attitudes is better when it comes to trust and credibility? My personal view is that the conservative positioning is the timid way of behavior that often restricts professional learning ability and thus one’s capability to give sound judgments on, for example, medical issues. The omnipotent collaborators, however, who are in attendance here and everywhere, are most likely the people who run the highest risk of undermining their impartiality and thus, limit their ability to discharge their responsibility to a third party.

I have been following the scientific field of headache for more than 30 years and over that time span, almost every other year, someone has come up with the “ultimate answer” to intriguing questions with respect to management of migraine or the pathophysiological mechanisms involved. In most cases, the answers have been so clear and self-explanatory that the rest of us in the headache community have accepted them as facts without any serious examination. The new findings have been broadcast and been given plenty of space in scientific sessions and journals, and awards have been given out. Although I strongly believe that the intention behind this whole process has been good, in most of the cases I also think that sometimes the new “trends” have been driven by other, obscure reasons.

Some years later, the interest has cooled down due to the fact that it has been difficult for other groups to demonstrate similar findings, or in their attempts to do so, have come up with conflicting results. Unfortunately, the latter contradictory results are given little publicity and may even have a hard time getting published. Still, even in the absence of enough evidence, we will have to take a stand and say publicly that the presented hypothesis is most likely false. I would go as far as to say that this is one of the International Headache Society (IHS's) responsibilities. I believe so for several reasons. One is that the myths may impinge on clinical management of headache diseases for many years and may, in a worst-case scenario, put patients at risk. In addition, the longer it takes to put false theories to rest, the longer we have to wait for the final solution.

Furthermore, it would also work as an eye-opener for those of us who easily get carried away and are willing to accept new good ideas without any greater skepticism.

Where do we go from here?

I believe that each and every one of us should scrutinize our own liability in order to find out where we find ourselves in the process of sliding ethical valuing and try to regain sound fundamental ethical principles, flavored by increased personal integrity and less dependence on for-profit organizations. We should devote ourselves to supporting any action plan to redirect future research funding via not-for-profit institutions that distribute their financial support to research activities that primarily are performed in the interest of the patients. We should create independent committees that follow up the validity of clinical research in a longer perspective. The benefit of this would be to find out if interesting research findings have been confirmed by other independent research groups and that treatment recommendations based on these findings still prove to be true when used in clinical practice in a longer, e.g. five-year, perspective. If not, it would be the responsibility of such a committee to inform the parties concerned. These individually driven ambitions, together with national and international regulatory demands, would help us to create a platform where research activities are performed under improved ethical principles and promote a better outcome in terms of value for invested research money. In practice, the higher goals should be to discover true innovative drugs/treatments that add new therapeutic value to the individual patient.