How does unethical research come about

Bioethics

Prof. Dr. Bert Heinrichs

is Professor of Ethics and Applied Ethics at the Institute for Science and Ethics (IWE) at the University of Bonn. He is head of the "Representation and Model" working group at the Institute for Ethics in Neurosciences (INM-8) at Forschungszentrum Jülich.

Due to the atrocities committed by the National Socialists, the word "human experiment" has a negative connotation to this day. But research on humans is important - but in Germany it has to meet certain ethical and legal requirements. Following the principle of dignity of the GG, people should never be seen as a means, but always as an end as well.

After extensive preliminary examinations, every drug must also be tested on humans. (& copy picture-alliance, PhotoAlto)

The development of drugs and medical devices is a complex and lengthy process. After extensive preliminary investigations, a new substance must be tested on living organisms (individual cells, animals) and ultimately also on humans. Testing on humans is called a "human experiment" or a "clinical study". A distinction is made between four phases: In phase I, the tolerability of an active ingredient is first examined on a small number of healthy test subjects. Phase II is then about testing the effectiveness (e.g. against a disease). This, in turn, only takes place on a small group of test persons. If phases I and II have been successfully completed, the effectiveness and tolerance tests are carried out on a large group of test persons in phase III. The number of test subjects must be large enough that statistically reliable results can be achieved. To confirm the results, there are control groups in phases II and III that do not receive the new substance but an established active ingredient or a placebo. Phase IV is used to further investigate a new drug or medical product after its approval, for example to identify rare side effects. Human experiments exist not only in drug research, but also in other areas of medicine. In surgery, for example, new surgical techniques must be compared with old ones and tested.

In addition, there are other disciplines that human subjects use to answer scientific questions. Human experiments are particularly common in psychology. The ethical discussion of human experiments begins in the middle of the 19th century. Since then, attempts have been made to formulate conditions under which human medical experiments are ethically justifiable. The 'Corpus Hippocraticum' (originating between the 4th century BC and the 1st century AD) already contains an important contribution to medical ethics with the 'Hippocratic Oath'. However, the development of a specific ethics of research on humans in medicine did not begin until much later. This is mainly due to the fact that the scientific-experimental methodology, which was developed by Galileo Galilei, Francis Bacon and others from the 16th century, received little attention in medicine for a long time. Unlike in physics, for example, the controlled experiment to test research hypotheses remains largely meaningless in medicine in the 18th century. It was not until the 19th century that it became established as a methodological standard (Bernard 1961). However, the adoption of the experimental method is not developing without problems. Doubtful and sometimes criminal experiments have repeatedly burdened medical research on humans and in some cases permanently discredited it. Especially because of the atrocities in German concentration camps during the Nazi era, the term "human experiment" still has a deterrent and threatening undertone (Mitscherlich and Mielke 2004).

Today, research ethics is mostly based on a few abstract principles, the validity of which is considered to be guaranteed. This approach can be found in the Belmont Report, which is influential for the ethics of biomedical research in humans, and, following on from this, in the Principles of Biomedical Ethics by Tom Beauchamp and James Childress (2013). There four basic ethical principles are formulated, namely "respect for persons" or "respect for autonomy", "beneficence", "nonmaleficence" and " Justice "(" justice "). Based on these principles, more concrete rules and norms are gradually established. The first important step in the transfer of these "principles of medium range" to the field of human experiments consists in the informed consent, the risk-benefit analysis ("assessment of risks and benefits") and the fair selection of test subjects ("Selection of subjects") to be named as concrete rules of action. Further content-related provisions and context-dependent specifications then follow in further application steps.

In contrast to the Belmont Report or the Principles, the validity of these principles can be developed from the idea of ​​human dignity (Heinrichs 2006). According to this view, we should never use other people solely as a means to achieve our own ends. The idea of ​​personal dignity, which Immanuel Kant (1785) decisively developed in his moral philosophy, has found its way into national constitutions, such as the Basic Law, Article 1, Paragraph 1, and in international documents, not least in the Charter of Human Rights United Nations. It can serve as a widely accepted normative foundation for more specific rules and norms. The prohibition of instrumentalization can be understood as an operationalized form of the principle of dignity, which says that people should never be viewed as just a means, but always as an end as well.

This has direct consequences for dealing with people in the context of human experiments. Human experiments are characterized precisely by the fact that the test subjects involved are used as a means of gaining knowledge. According to the previous considerations, this is morally unobjectionable - and only then - if the test subjects involved are not completely reduced to being means in the experimental implementation, i.e. not being fully instrumentalized. The test persons are used in a certain way as a means, but they should always be respected as a person and always remain part of the intended purpose. The decisive question of the ethics of research on humans can therefore also be formulated as follows: What must be done so that test subjects are not completely instrumentalized in the context of medical human experiments? The four principles mentioned by Beauchamp and Childress can be understood as the first answer to this question. However, they are not specific enough to clarify which specific rules and norms have to be observed in human experiments if they are used in accordance with the dignity of the test subjects. Even if you choose this justification approach, a further application step must follow, which leads to the more specific rules of research ethics already mentioned: (1) informed consent, (2) careful weighing of harms and benefits, and (3) fair selection of test subjects. These rules are directly important in the practical implementation of human experiments. They will be presented in more detail below.

(1) The informed consent

The principle of self-determination requires that everyone can make free decisions in a core area. It thus ties in with the ability of humans to set goals for themselves and to actively pursue them. However, the right to self-determination of the one finds its limit at the right to self-determination of the other. The principle of self-determination thus has both a freedom-enabling and a freedom-limiting dimension. If a researcher were to accept a person as a participant in a research project without their knowledge, then this would violate the right to self-determination. The decision about participation must, after the deliberations just made, be left to the person himself. The researcher has to ask the person in question whether they want to make themselves available as a participant or not. But that alone is not enough. It must also be ensured that a negative answer is accepted by the researcher and does not have any negative consequences. In other words: Consent must be voluntary in order to really be considered as realizing the right to self-determination. There is, however, another aspect to consider: even if the person agrees of their own free will, there is still insufficient assurance that it is really their will to participate in the study. She may not have realized that participating is associated with certain risks and burdens. She may have refused to participate on the basis of a fuller understanding of the experiment in question. The immediate consent would accordingly not be understood as an actual realization of the right to self-determination. A further condition is therefore that the consent is informed. The prerequisite for such informed consent is that potential participants are informed in advance about the "nature, meaning and scope" of an experiment - this formulation was coined by the Federal Court of Justice in various decisions on the subject of drug research. Particular emphasis should be placed on (i) voluntariness, (ii) the right of revocation and (iii) dealing with persons incapable of consent:

(i) Voluntariness
In addition to being informed, as already briefly mentioned, there is a second important component of fully valid consent in voluntariness. Now it should seldom happen (under the protection of a free democratic social order) that a person is directly forced to participate in a research project. More subtle forms of pressure that could influence the person's decision are entirely realistic. For example, a potential test person is often also a patient. As a patient, he could fear that he would not be treated more or at least with less commitment if he refused to participate in the research project that was proposed to him. In this way the patient might feel compelled to participate. In the context of the education, it must be clearly conveyed that a refusal to participate will not have any negative consequences. The voluntary nature of participation can also be impaired by positive incentives, for example through a high financial allowance or even payment.

(ii) Right of withdrawal
A person who has given their informed consent to take part in a research project is by no means irrevocably committed. The consent is not a contract that obliges researchers and test subjects to provide mutual services. Consent can be withdrawn accordingly, at any time and without giving reasons. The right to self-determination therefore also includes the right to withdraw consent once given at any time. The respondent must be made expressly aware of this right in the course of the explanation. It must again be explicitly made clear that an early departure does not have any negative consequences.

(iii) Persons unable to give consent
A problem with regard to informed consent arises with potential test subjects who are unable to give fully informed consent to participate in a human experiment, such as the mentally disabled, dementia patients or minors. While a minority argues that for this reason (purely beneficial for others) research with minors is fundamentally not ethically justifiable, the overwhelming majority now assume that there are ways to compensate for the lack of consent. Above all, the consent of a legal representative can take on such a compensatory function. Under certain conditions, prior consent can take the place of normal consent, for example if the progressive course of the disease leads to the ability to consent being lost at a later point in time.

(2) The harm-benefit balance

In addition to the principle of self-determination, the non-damage principle has been named above as a particularly important ethical principle. On closer inspection, both principles are in a tense relationship with one another, since the right to self-determination can also extend to self-damaging behavior. And in fact, participating in a human experiment, which is associated with risks to the health of the test subjects, is an act in which the agent accepts at least possible damage to his or her psychophysical integrity in a self-determined manner. Nevertheless, it would be wrong to prohibit such actions in principle on the basis of the principle of non-damage. This is because such an approach would mean that the principle of non-harm is generally superordinated to the principle of self-determination and that the aforementioned tension is unilaterally resolved. A more differentiated approach consists in recognizing both principles in their validity at the same time, which in practice means that both principles limit each other. Research projects with human subjects are generally not ethically questionable if the subjects have given their informed consent, but it must be ensured that the possible damage associated with the research methods is "appropriate". But what does "appropriate" mean here? First of all, it will be demanded that experiments with the participation of human test persons have no alternative to the scientific question as a method, i.e. that there are no alternative research methods that can produce comparable results. In addition, the scientific design of an experiment, such as the choice of statistical evaluation methods and, depending on this, the specified number of test subjects, must be flawless. If this is not the case, the gain in knowledge for the purpose of which an experiment is carried out is not guaranteed. As a result, you will have to reject even a minor risk to the test subjects. Ultimately, it will be required that the experiments will in all probability not lead to serious or permanent damage to the test subjects or even to their death. In a sense, all three conditions are absolute limits that apply regardless of the nature of a specific experiment.

Against the background of the principle of no harm, there is also a relative limit to be observed: the expected benefit associated with an experiment must be in a balanced relationship with the possible harm to the test subjects involved. Here, both the general gain in knowledge and the direct benefit for the test person must be taken into account. However, a clear distinction must be made between the two. If there is a significant direct medical benefit in prospect for the test persons - for example because no standard therapy is available for their condition - then one will certainly consider a higher risk risk to be acceptable than for healthy test persons who are used as a comparison group in basic research . Not only the type of benefit to be expected must be taken into account here, but also the status of the test subjects involved. If, for example, it is a question of minors or dementia patients, then you have to set significantly narrower limits. It is difficult to determine exactly where these limits are. Here, the careful judgment of researchers and experts in the ethics committees is required, who have to decide on a case-by-case basis whether the risks can be ethically justified.

An important distinction has not yet been made, namely that between damage and stress. While the term "damage" includes (rather "objective") negative effects on the health of a test person, the term "stress" describes (rather "subjective") disorders of the overall condition. These must be invoiced separately when evaluating a human experiment. It is possible that there are little or no dangers associated with an experiment, but that the burden for the test participants is quite considerable. For example, lengthy examinations can be perceived as extremely uncomfortable. Focusing solely on possible "objective" damage is therefore insufficient.

(3) The fair selection of subjects

The principle of justice demands that benefits and burdens have to be distributed "fairly" within a community. With reference to human experiments, this means first of all that here, too, benefits and burdens must not be unilaterally distributed. For a further specification of this requirement with regard to medical human experiments, it makes sense to differentiate between two levels: On an "individual" level, the principle of justice requires that only factual considerations (and not the researcher's sympathy considerations) come into play when selecting the test subjects.The decision may be made solely on the basis of inclusion and exclusion criteria, which must be recorded in the study protocol before the start of recruitment. Specification is more difficult on a "social" level: it is questionable whether there are certain social groups that should preferably be involved in human experiments or that generally have to be disregarded.

An answer to this question can be given using the following rule: Subjects who are under special protection, such as children or pregnant women, i.e. subjects from so-called "vulnerable groups", should only be involved in human experiments if the experimental design makes this absolutely necessary makes. Children should only be used in experiments that are specifically dedicated to teething or developmental disorders in childhood and that can only be researched in this group. If, on the other hand, it is an experiment that can just as easily be carried out with adults who are capable of giving consent, then it is ethically advisable to carry out the human experiment with adults. In this context, one also speaks of the principle of subsidiarity. The aim is that the burdens of biomedical research are borne as far as possible by the resilient members of a society and only in the event that such burden sharing is impossible for scientific reasons, the recruitment of test persons from vulnerable groups of people.

The research ethical principles and specifications described form the broadly accepted framework today for the ethical evaluation of research projects with people. It can be found in a number of international documents, e.g. B. the "Declaration of Helsinki" of the World Medical Association or the "Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Biomedical Research" of the Council of Europe. Many countries have also implemented legal regulations for research on humans. In Germany, corresponding regulations can be found primarily in the Medicines Act (Sections 40-42b) and in the Medical Devices Act (Sections 20-22). Despite these regulations, there are still problems for which adequate solutions are being sought, especially with regard to research with people from vulnerable groups.

Even outside of medicine, research on humans essentially follows the principles described. Scientific professional associations, such as the Professional Association of German Psychologists e.V., have drawn up guidelines in which the specifics of the respective subject are dealt with.


literature

Beauchamp, Tom L., Childress, James F. (2013): Principles of Biomedical Ethics. 7th ed. Oxford: Oxford University Press.

Bernard, Claude (1961): Introduction to the Study of Experimental Medicine. Leipzig: Johann Ambrosius Barth.

Heinrichs, Bert (2006). Research on humans. Elements of an ethical theory of biomedical human experiments. Berlin: De Gruyter.

Kant, Immanuel (1785). Basis on the metaphysics of ethics. Hamburg: Meiner, 1999.

Mitscherlich, Alexander / Mielke, Fred (eds.) (2004): Medicine without humanity. Documents of the Nuremberg Doctors Trial. 16th edition. Frankfurt am Main: S. Fischer.

Documents, guidelines and laws

Medicines Act.

Professional Association of German Psychologists / German Society for Psychology (2016): Professional ethical guidelines.

Council of Europe (2005): Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Biomedical Research.

Medical Devices Act.

World Medical Association (2013): Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects.