Biological aspects of experimentation on humans
Gonzalo Herranz, Bioethics work group . School of Medicine. University of Navarra
VI Summer Courses in San Sebastian - Donostiako Udako VI Ikastaroak
University of the Basque Country - Euskal Herriko Unibersitatea
Cycle: Law and Social Sciences
A-4. Biology in the face of Ethics and Law
San Sebastian,1987
I. Human biology: a very demanding science
The ethical quality of the academic publication
II. Biology of man: aspects relevant to human experimentation.
Biologically vulnerable populations
Pharmacological experimentation and gestation
III. The new way of thinking in medicine
First of all, I would like to thank Professors Francisco Javier Caballero Harriet and Begoña Ochoa Olascoaga for inviting me to participate in this course. The reasons for this gratitude are partly personal and do not need to be detailed in public.
Other reasons are more public and I must briefly mention them. In recent years my interest in the Ethics of Medicine and consequently my dedication to it has been growing. I suffer when I see the rudimentary status in Spain of the study, research and, especially, the internship application of medical ethics. There are beginning to be people among us who are becoming interested in it, but few are the bold ones who do it seriously and risk taking. There are some Bioethics centers modestly equipped with people and documentation: but they are still very few. Among physicians and biologists there are some with great ethical sensitivity, but the general attitude of our society oscillates between the disdain of most professionals and the occasional outbursts of a journalist driven by the "I accuse" complex. In contrast to what is happening out there, almost all our Universities have deserted their duty to educate students in Biomedical Ethics, which is very modern discipline and very internship.
For all these reasons, I would like to thank the organizers of these summer courses for including the topic "Biology versus Ethics and Law" in their program. The fact that a School of Law pays attention to these problems could not be more flattering, since it makes it possible for the legal aspects of bioethical problems to be studied in the critical calm of academic research and not only legislated with the haste, sometimes frivolous, of parliamentary discussions.
These are the reasons why I am grateful to the organizers of this Summer Course for the inclusion in the Law and Social Sciences cycle of the Conferences and Round Tables on "Biology versus Ethics and Law".
I have been asked to speak on "Biological aspects of experimentation on human beings". Before I go any further, I must outline the limits of my assignment.
I am not going to analyze - it would be out of place - the notion of human experimentation. Suffice it for our needs today to consider as such the subject of research requiring an intentional biomedical manipulation of the human being. It is this spontaneous intervention modifying natural reality that distinguishes experimentation from simple observation. It involves the use of invasive procedures, both in the physical sense (such as, for example, the application of different substances or forms of energy, modification of the environment, instrumental measurement of responses) and in the psychological sense (intrusion into privacy, provoked changes in mood). The purposes of this deliberate and controlled manipulation are very different in biomedical science, since they are aimed, among other things, at understanding the structure and function of the human organism, perfecting or validating diagnostic, prophylactic or therapeutic procedures, and clarifying the causes or mechanisms of diseases.
Once biomedical experimentation on human beings is understood in this way, we must ask ourselves what are the relevant biological aspects for an ethical and legal reflection on experimentation on human beings. This question allows many answers. In order to reduce the topic to the dimensions of a Summer School lesson, I will limit myself to consider it from two different perspectives: one considers some requirements that Biology as a science demands of experimentation on human beings for it to be recognized as genuinely biological; the other considers certain features of the biological structure of the human being that are of particular ethical significance.
That is: the first will allow us to observe human experimentation from the perspective of biology as a science. Biological experimentation has its own methods and techniques: rules for the construction of hypotheses, a manipulative and observational technology, an analytical approach for the critical assessment of the bibliography. These are the features, technical or epistemological, that biology as a science demands of us when we experiment on the human being. And all of them have a very rich ethical content.
From the second point of view, we will examine how certain biological aspects of man, such as his biological development , i.e. his different ages, his sex and race, his being healthy or sick, have particular bioethical significance. These biological categories, many of them also and inevitably biographical, present important ethical implications related to experimentation on human beings.
I. Human biology: a very demanding science
There is constant talk of the enormous acceleration of progress in biomedical sciences in recent years. It is now commonplace to say that our knowledge is aging very quickly, that in a few years a large part of the scientific data and explanations are renewed. The scientific information sections of newspapers, magazines and television tend to give us an optimistic image of achievements and promises, leading us to believe that for modern biomedical science there are no insurmountable obstacles, that what matters is to formulate the problems skill , because solving them is a matter of a few months or years and more or less money.
But the day-to-day reality of human biology is quite different from the rose-colored version offered by popularizers. Human biology is very demanding, since its techniques have benefited from formidable progress and, at the same time, have been raising the bar in terms of intellectual and ethical quality.
For every scientific finding that becomes news that reaches the general public, there are hundreds of published papers that hardly anyone talks about or that have not even been published. Behind every finding that deserves the fleeting honor of appearing on the television screen or in the Science section of a newspaper there are countless hours of effort to analyze the bibliography, discuss the methods, refine the techniques, validate the results. Once the work is finished, it has to be published. In recent years, the publication process of biomedical research has become increasingly demanding in terms of originality, methodological rigor, formal quality and ethical finesse. Many papers do not meet the standards required by the editors of established journals. To publish in them, you have to do things very well. research in laboratories and hospitals no longer tolerates defects in design or execution of experimental protocols. The highest quality demanded makes it necessary to discard as unusable experimental material that not many years ago was considered decent. Many works that are started are aborted, die without remedy, because they were based on brilliant hypotheses but do not pass the test of experimental verification or their defects are exposed by the evaluators of scientific journals.
The ethical quality of the academic publication
That we are advancing in ethical sensitivity is demonstrated by the public denunciations that, in recent years, have been made of researchers lacking scientific integrity. Today we live in the confidence of all members of the academic community who wish above all else to seek objectivity in their research and to publish only true data . But this trust is violently shaken by some sporadic cases of cheating scientists publishing fabricated papers, fudging data or stealing ideas from others. The names of Absati, Soman, Darsee, Long, Burt have achieved the deplorable notoriety of those who have betrayed the rules of intellectual honesty that govern the world of natural science.
The analysis of these cases has made it possible to distinguish some basic types of academic misconduct that we should all be aware of in order to avoid them. Thus, Broad and Wade have typified fraud, which is the deliberate presentation of unsubstantiated statements as if they were facts; plagiarism, which is the presentation of other people's ideas and data as if they were one's own. The cosmetics of data is when observations that do not fit with the results that one wishes beforehand are eliminated or data are "fixed" to agree with the preconceived average . We speak of "shaved publication" when one hides one's own or other people's data that could erode the firmness of one's own conclusions.
The contamination of the bibliography with technically deficient or deliberately manipulated papers is not only an offense to science itself, but is also an affront to the academic community. Publications are today a factor, I believe too decisive, in the professional degree program . The publication of articles or collaborations in journals of recognized scientific solvency considerably increases the prestige of the researcher 's staff and improves his or her possibilities of academic, professional and economic promotion. There are many temptations that lie in wait for the researcher and that can lead him/her to break the ethical rules accepted by the academic community in his/her desire to publish a lot and immediately in order to compete for a work space that satisfies his/her ambitions. There are sins that come from the immoderate desire to swell the publication list. Some ambitious authors get together in co-authorship cooperatives and grant each other a place in the list of signatories of the articles that each one of them produces, without actually having participated in a significant way in the realization of the work. Others resort to the subterfuge of repeated publication, albeit with slight variations, of the same material in different journals.
The academic community has reacted vigorously against such "traitors of truth". The editorial boards of the journals have strengthened their vigilance and have established some disciplinary measures for the repression of academic misconduct. May the optimistic promise of the saying that every cloud has a silver lining come true among us!
What good can we derive from these evils? It is very proper of Ethics to wisely apply the principle of beneficence. It seems to me that the state of alert created by the delinquents of science will contribute to eliminate not only the major delinquency but also the small faults that steal decorum from biomedical experimentation. I am referring to imprecision of language, carelessness of style, deficiencies of method, statistical sloppiness, second-hand citation, exaggeration of the significance of findings, irrelevant discussions, inflated bibliographies, which so often mar the articles produced in our laboratories and hospitals.
We now have a great opportunity. The internship of the new University Reform Law can be used to give a strong impulse to the programs of study of the third cycle, enriching their methodological and ethical contents. The doctorate programs of study must be very demanding in those points that provide the foundation of the scientific mentality. Our graduates must learn to write the language of science, they must know how to handle those essential instruments of the scientist's work and mind which are the statistical methods. They must be convinced of the very close relationship between thought and writing, and thus become fond of using the concise, clear, univocal scientific essay as an instrument to refine and give precision to their descriptions and their thinking. They must be familiar with the specific problems of experimental design and its statistical implications in order to validate the results: it is not enough to learn how to use laboratory instruments, but they must also learn to read critically the biomedical bibliography Only then is it possible to understand the close relationship between skill and integrity, between science and ethics.
In recent years I have made a particular effort to highlight the ethical aspects of academic publication. Publication is the final, decisively important phase of the entire researcher process. The publishing house process, in its task of selecting the articles to be published, can be an immensely effective written request raise the technical and ethical level of research. In this respect, we still have a long way to go. In the recent past in Spain we have taken a good step forward in the quality of what is published in Medicine. Some journals can compete in presentation and content with the good journals of other European countries. However, when we dig a little deeper, we find that we still have a lot of room for improvement. Let us look at an example. An excellent Spanish medical journal, Medicina Clínica, from Barcelona, has adhered to the Uniform Standards for original submissions to biomedical journals promulgated by the International committee of Medical Journal Editors, commonly known as the Vancouver group . Among the requirements imposed by the current edition of the 1982 Guidelines is the following: "When reporting experiments on human subjects, indicate whether the protocols used followed the ethical standards of the clinical research committee of the institution where the experiments were performed or the guidelines of the 1975 Declaration of Helsinki. When reporting animal experiments, state whether the standards for the care and employment of laboratory animals established by the institution or by the corresponding national research committee were followed". I did a review of Clinical Medicine last year to see how faithfully this rule was followed: in the second semester 1985, out of a total of 38 original articles published on human experimentation, none made reference letter to the above requirement. Only five articles stated that informed consent had been obtained from the experimental subjects. I hear that the Clinical Trials Committees that must oversee research on pharmaceutical or medicinal products, as established by Royal Decree 944/78 and the Ministerial Order of August 3, 1982, function somewhat ataxic, which is logical in view of their composition and structure. We can see how far we still have to go. Biomedicine is a very demanding science that ethically improves those who profess it with skill.
This is very clearly sample in the statistical approach to experiments on human beings: professional skill is a source moral rectitude and a fine-tuned staff ethic has an immediate influence on a more correct experimental design . It is unethical to carry out statistically poorly planned experiments. However desirable the objectives may be, if the statistical apparatus of these works is deficient, the research will be immoral, because its conclusions will be misleading; the economic and instrumental resources invested in them, a waste; the animals sacrificed or the patients used, victims of an irresponsible abuse. Before starting his research, the human experimenter has, for example, a serious technical and ethical responsibility to determine the precise issue of patients or volunteers needed to reach statistically significant conclusions, since it is unfair to subject his patients to risks of injury or discomfort in experiments in which the subjects are too few to obtain valid results or exceed the issue necessary to establish the conclusion sought, or are distributed inappropriately in the groups of a double-blinded test protocol .
As we can see, and this is one of the major attractions of Bioethics, there is a very close relationship between technical skill and ethical requirements. One and the other require each other. Among the biological aspects of experimentation on human beings are those I have just mentioned, which basically consist in the fact that human experimentation is first and foremost required to be good biology. I always repeat that the physician's first ethical requirement is his duty as a scientist.
II. Biology of man: aspects relevant to human experimentation.
When one reads the fundamental documents that offer precepts or recommendations to guide or inspire the ethics of experimentation on human beings, one is struck by the emphasis given to certain biological characteristics.
With the Nuremberg Code of 1947, the ethical regulation of human experimentation was born. Its imprint has been accentuated with the passage of time. Its doctrine, accepted and perfected in the Declaration of Helsinki of the World Medical association , has been developed in the regulations and guidelines of the vast majority of agencies, public or otherwise, that promote and finance biomedical experimentation and has inspired a large issue of programs of study by contemporary bioethicists. The Nuremberg Code made informed consent a touchstone for the ethical quality of biomedical research .
Since then, a fundamental difference has been established between human beings on the basis of their ability or inability to consent - or dissent - freely and with knowledge to research. This creates a particular obligation for researchers and institutional research committees to protect the incompetent and particularly vulnerable. Most of the particularly vulnerable populations of research subjects are defined by a so to speak "legal" feature: their inability to give free and informed consent. They are, for example, persons deprived of their liberty (prisoners of war, convicts) or lacking the capacity to understand or to give reasonable consent (mentally ill, young children).
Biologically vulnerable populations
But not all particularly vulnerable populations are defined by this legal label. Let's look at an example. The color of the skin of certain individuals or groups may condition their selection or exclusion as experimental subjects. There are investigations in which all or most of the subjects belonged to an ethnic or cultural minority or social class , not because the interest of the human experiment was focused on some characteristic of that specific population, but because it was a poorly protected or underprivileged population. Well known examples of experiments of this subject are the Tuskegee observation of untreated syphilitics, Willowbrook's study on gamma globulin protection against infectious hepatitis, the essay on oral contraceptives on Puerto Rican or Chicano women. Episodes of this subject occur, fortunately, less and less frequently. They continue to occur, however, in the form of "export of risks": some pharmaceutical industries prefer to carry out the preliminary phases of the essay of new drugs or vaccines, not on the educated population of advanced countries, but on that of less developed countries which, in exchange for the eventual benefit of the new treatment, accept, it seems, voluntarily, its as yet undefined risks. There has recently been a vigorous protest against the essay of an anti-AIDS vaccine being carried out in Zaire, which has not been subjected to the required prior experiments on laboratory animals, nor have the potential dangers been thoroughly discussed. Faced with the danger of this kind of neocolonialism of human guinea pigs, the International committee of International Organizations of Medical Sciences (CIOMS) reacted, whose XV lecture on "Human Experimentation and Medical Ethics" held in Manila in 1981 was intended to provide countries with limited resources for biomedical research with guidelines for drawing up their own laws or regulations on the subject and thus prevent their population from being used in unethically controlled experimentation.
All major modern ethical documents contain a non-discrimination clause enshrining the medical tradition of inquiring not about the patient's race, religion or origins, but only about his or her condition. According to this clause, the physician is obliged not to allow his relationship with his patient to be interfered with by considerations extraneous to his official document of healing. All must be treated with the same professional skill , none may be mistreated or despised. The lists of non-discrimination factors vary from one code to another, but in the Western world it is understood that it is unethical to discriminate on the basis of race, religion, social rank, political militancy, economic level, age, sex, illness, lifestyle, etc.
We see that among these criteria of non-discrimination there are some (sex, age, illness suffered) which, although inextricably linked to metabiological values, are in themselves primarily biological realities. There is much to be said about the ethical resonance of biological realities such as being male or female, embryo, fetus or child, adult or elderly, suffering from diabetes or AIDS. I will limit myself to offering a sample button: that of the problems posed by pharmacological experimentation on pregnant women.
Pharmacological experimentation and gestation
The ethical problems of the pharmacology of pregnant women are very interesting because, among other things, they show us how excessive control in the name of ethics can have unfavorable effects. We must not forget that medical ethics can sometimes be used unethically, and it seems to me that the pharmacology of the maternal-fetal unit is an example of this.
Being a woman and being pregnant or being an embryo are primarily biological issues that are fraught with ethical consequences for biomedical research . It is obvious, on the one hand, that the biology of the pregnant woman is profoundly changed. The physiology of gestation describes many profound adaptations of the mother's apparatus and systems to the stimuli coming from the embryofetal organism. This, in turn, presents, in the course of the nine months of its intrauterine development , a particular reactivity that changes continuously. We already know a lot about maternal-fetal physiology, but we do not know proportionally as much about pharmacology. Twenty years ago Shirkey called the pregnant woman and her child "the orphans of an expanding therapeutic" and today they still deserve this degree scroll, because they still constitute a considerable part of the "special populations" to which I referred earlier. The need to defend them from potential risks and abuses has kept them out of clinical trials. Safety has, to some extent, been paid for with ignorance.
This status is largely due to the extremely harsh experience of the thalidomide tragedy, the memory of which is still vivid in everyone's report . Governments and international health and drug control agencies realized then that such a catastrophe should never be repeated and took appropriate measures to prevent it. One of these measures is public information. Drug manufacturers must indicate the risks that each drug entails for the pregnant woman and for embryo-fetal development . The consequence is this: in the package inserts of almost all drugs there are warnings of the subject "There is no data on its possible effects on pregnancy, so it should not be administered to pregnant women". The results of this safety policy are clear: people live in peace, knowing that tragedies of global proportions will not happen again. But this precaution has brought research to a screeching halt. Our ignorance about the pharmacology of pregnancy is growing with each passing day, and the pregnant woman and her child are the orphans of an expanding therapeutic approach.
But fear has not been the only factor in this status. Women of childbearing age are not ideal subjects for pharmacological research . Any experimentation on drugs, while involving risks, demands great scientific precision. Women are not ideal subjects. That is why fewer pharmacological experiments are carried out on women. Many years ago, women were excluded for reasons of chivalry: it was ungentlemanly to cause any kind subject discomfort to the "weaker sex". This argument is no longer receipt in times of egalitarian feminism. But researchers have always tried to eliminate the methodological problems arising from the changing metabolic status conditioned by the cyclical changes of the female organism. It is not easy to evaluate the actions of certain types of drugs on a continuously changing biological and psychological background.
In addition to these drawbacks, there are others. On the one hand, the fear of drug iatrogenesis. The fear of drug-induced teratogenesis triggered by thalidomide was rekindled when, years later, the carcinogenic effect of diethylstilbestrol, administered precisely to avert the threat of miscarriage in the early stages of pregnancy, became known. This synthetic estrogen turned out to be the cause of the vaginal cancer that appeared years later in the daughters of the women treated. It is understandable, on the other hand, that the reluctance to carry out pharmacological experimentation on women who could become mothers has not waned, because things have become even more complicated due to the fear of the physician of being the victim of a lawsuit for bad internship if he is accused of having induced a development disorder and due to the panic of the pharmaceutical industry in the face of the moral and economic catastrophe caused by a massive lawsuit for damages attributed to one of its products.
All this has created a defensive atmosphere among physicians, researchers and industrialists. It is understood that it is a general rule to avoid, during pregnancy, the consumption of drugs except in cases of absolute necessity. This is the current rule : "If possible, no medication should be taken during the first trimester of pregnancy. In addition, the benefits and risks of taking medication throughout pregnancy and delivery should be carefully weighed". So begins the guidelines of the December 1986 Update of the Committee on Safety of Medicines.
If this is the status with respect to drugs that have been approved for public consumption, we can deduce that it takes a great deal of boldness to carry out new pharmacological trials in pregnant women. But deserting this field is very serious, since it means condemning the pregnant woman to be a victim of therapeutic nihilism.
I believe that this is a very interesting topic for interdisciplinary discussion, because it involves biological, ethical, legal and human aspects quotation are highly significant. In certain environments, under the influence of the abortionist mentality, a diffuse awareness is being created that pregnancy is a disease and the fetus is an enemy. And it would be an even greater misfortune to add to this pessimistic impression another one consisting in suspecting that the pregnant woman is deprived of the benefits of pharmacological treatment.
Fortunately, things are not so black. Because to fill in data of the problem, it is useful to know that, faced with the restrictions imposed by the managers of pharmacovigilance, women pay little attention to their alarmist recommendations. Research in the 1970s showed that 80 percent of pregnant women not only did not abstain from taking drugs, but took an average of four drugs during their pregnancy. Two-thirds of the total were taking medications not prescribed by the doctor. And the staff experience of physicians is full of anecdotal experiences in which mother and fetus have happily emerged unscathed from treatments that, according to the forecasts of some, should have ended with abortion or with serious malformations. It seems to me that it is an urgent task, both ethically and scientifically, to accumulate these scattered data , to analyze them critically as a whole and to draw scientifically founded consequences from them. There is a growing appreciation in certain areas of clinical research for these scattered observations that can be reconverted into valid conclusions: with these crumbs one can make a good loaf of bread.
III. The new way of thinking in medicine
The experimenter, but especially the physician who sees his profession as an indissoluble mixture of science and ethics, cannot forget that, when planning his experiments or reasoning his clinical decisions, he must move on a double plane.
On the one hand, biomedical research , both that of the Basic Sciences and the controlled clinical programs of study of new therapeutic remedies or the latest diagnostic techniques, is research that belongs to the realm of natural science. Modern biological science demands, as we have seen, a high level of methodological and critical quality, which, among other things, makes it necessary to develop statistical vision in order to critically evaluate the works that are read or projected.
Moreover, in the last few years, the instructions is being laid for what will be a very radical innovation in physician thinking. Some clinicians have begun to apply the statistical theory of decision making to medical internship problems and have already laid the instructions for some new ways of programming clinical research and patient care.
And, curiously enough, this new way of facing problems and solving them has made it clear that practically all the physician's decisions contain both a scientific judgment (statistical probability) and a value judgment (ethical beneficence). It is true that good physicians of all times have been sensitive to the human values of their patients. What is really new is that, as a result of the continuous and inspiring presence of ethics in the business of medicine, there is now a widespread conviction in hospitals and laboratories that it is no longer legitimate to exclude the ethical element, the consideration of moral values, from research .
In the same way that the physician always needs more and more precise instruments to diagnose his patients, molecules with increasingly specific and controllable actions to treat them, a mind capable of perceiving statistical relationships to formalize his prognoses more rigorously, he has an inexcusable need to exercise himself in the application of certain ethical principles.
I will end now. And in case what I have said so far has not provided adequate subject for this afternoon's discussion, I would like to add one more point.
The biological aspect of man plays a fundamental role in medical ethics. It is becoming fashionable to say that, in the midst of the inevitable discord of contemporary ethical pluralism, it is possible to establish certain principles (of justice, beneficence, non-maleficence, autonomy) that can serve as a common basis for physicians and patients, legislators and ethicists. If only this were true! I hold these principles in the highest esteem and think that they can go a long way. But inevitably we will fall short, we will not be able to reach the end of our ethical commitments. Medical ethics must inevitably be based on a principle of specific respect for the patient, it must definitively accept the biological reality of weakness. This is what it is all about, this is the official document of the physician. Physicians necessarily deal with human beings who are weakened in body and mind, incapable, lacking in strength, sometimes degraded to the extreme. The genuine medical vocation is realized in the attention those who suffer a more or less intense diminution of their humanity, without discrimination. The embryo is as radically human as the adult. So is the deficient as well as the wise. There has been a loss of this sense of biological family in recent times, which can infect medicine and rot its humanitarian roots. Lewis Thomas in his Night Thoughts listening to Mahler's Ninth Symphony says, speaking of the need for asylums: "A society may be judged by the way it treats its most deficient, its least beloved members, its insane. As it is, we are going to be judged badly enough. It's time to straighten our ways."
I think that by reflecting on the biological aspects of Medicine we will find many incitements to straighten the crooked paths.
Thank you very much.