Research Ethics

Kenneth D. Pimple, Kenneth D. Pimple

• Publisher: Routledge
• Year: 2017
• ISBN:
  9781351904001
• Edition: 1
• Topic: Philosophy
• Subtopic: Philosophy History & Theory

This volume includes more than 40 important articles on integrity and misconduct, biomedical research, the social and disciplinary contexts of science, research in the social sciences, the social responsibility of science and scientists, and other core issues in research ethics. A new introduction by the editor places these articles in their historical and conceptual context. The volume provides a rich library of resources, ideas and challenges in the ethics of research for any scholar concerned with such issues.

Part I
Foundations

[1]
ETHICS AND CLINICAL RESEARCH*

HENRY K. BEECHER, M.D.†

BOSTON

HUMAN experimentation since World War II has created some difficult problems with the increasing employment of patients as experimental subjects when it must be apparent that they would not have been available if they had been truly aware of the uses that would be made of them. Evidence is at hand that many of the patients in the examples to follow never had the risk satisfactorily explained to them, and it seems obvious that further hundreds have not known that they were the subjects of an experiment although grave consequences have been suffered as a direct result of experiments described here. There is a belief prevalent in some sophisticated circles that attention to these matters would “block progress.” But, according to Pope Pius XII,¹ “… science is not the highest value to which all other orders of values… should be subordinated.”

I am aware that these are troubling charges. They have grown out of troubling practices. They can be documented, as I propose to do, by examples from leading medical schools, university hospitals, private hospitals, governmental military departments (the Army, the Navy and the Air Force), governmental institutes (the National Institutes of Health), Veterans Administration hospitals and industry. The basis for the charges is broad.^‡

I should like to affirm that American medicine is sound, and most progress in it soundly attained. There is, however, a reason for concern in certain areas, and I believe the type of activities to be mentioned will do great harm to medicine unless soon corrected. It will certainly be charged that any mention of these matters does a disservice to medicine, but not one so great, I believe, as a continuation of the practices to be cited.

Experimentation in man takes place in several areas: in self-experimentation; in patient volunteers and normal subjects; in therapy; and in the different areas of experimentation on a patient not for his benefit but for that, at least in theory, of patients in general. The present study is limited to this last category.

REASONS FOR URGENCY OF STUDY

Ethical errors are increasing not only in numbers but in variety – for example, in the recently added problems arising in transplantation of organs.

There are a number of reasons why serious attention to the general problem is urgent.

Of transcendent importance is the enormous and continuing increase in available funds, as shown below.

MONEY AVAILABLE FOR RESEARCH EACH YEAR

MASSACHUSETTS GENERAL HOSPITAL		NATIONAL INSTITUTES OF HEALTH*
1945	$ 500,000†	$ 701,800
1955	2,222,816	36,063,200
1965	8,384,342	436,600,000

* National Institutes of Health figures based upon decade averages, excluding funds for construction, kindly supplied by Dr. John Sherman, of National Institutes of Health.

† Approximation, supplied by Mr. David C. Crockett, of Massachusetts General Hospital.

Since World War II the annual expenditure for research (in large part in man) in the Massachusetts General Hospital has increased a remarkable 17-fold. At the National Institutes of Health, the increase has been a gigantic 624-fold. This “national” rate of increase is over 36 times that of the Massachusetts General Hospital. These data, rough as they are, illustrate vast opportunities and concomitantly expanded responsibilities.

Taking into account the sound and increasing emphasis of recent years that experimentation in man must precede general application of new procedures in therapy, plus the great sums of money available, there is reason to fear that these requirements and these resources may be greater than the supply of responsible investigators. All this heightens the problems under discussion.

Medical schools and university hospitals are increasingly dominated by investigators. Every young man knows that he will never be promoted to a tenure post, to a professorship in a major medical school, unless he has proved himself as an investigator. If the ready availability of money for conducting research is added to this fact, one can see how great the pressures are on ambitious young physicians.

Implementation of the recommendations of the President’s Commission on Heart Disease, Cancer and Stroke means that further astronomical sums of money will become available for research in man.

In addition to the foregoing three practical points there are others that Sir Robert Piatt² has pointed out: a general awakening of social conscience; greater power for good or harm in new remedies, new operations and new investigative procedures than was formerly the case; new methods of preventive treatment with their advantages and dangers that are now applied to communities as a whole as well as to individuals, with multiplication of the possibilities for injury; medical science has shown how valuable human experimentation can be in solving problems of disease and its treatment; one can therefore anticipate an increase in experimentation; and the newly developed concept of clinical research as a profession (for example, clinical pharmacology) – and this, of course, can lead to unfortunate separation between the interests of science and the interests of the patient.

FREQUENCY OF UNETHICAL OR QUESTIONABLY ETHICAL PROCEDURES

Nearly everyone agrees that ethical violations do occur. The practical question is, how often? A preliminary examination of the matter was based on 17 examples, which were easily increased to 50. These 50 studies contained references to 186 further likely examples, on the average 3.7 leads per study; they at times overlapped from paper to paper, but this figure indicates how conveniently one can proceed in a search for such material. The data are suggestive of widespread problems, but there is need for another kind of information, which was obtained by examination of 100 consecutive human studies published in 1964, in an excellent journal; 12 of these seemed to be unethical. If only one quarter of them is truly unethical, this still indicates the existence of a serious situation. Pappworth,³ in England, has collected, he says, more than 500 papers based upon unethical experimentation. It is evident from such observations that unethical or questionably ethical procedures are not uncommon.

THE PROBLEM OF CONSENT

All so-called codes are based on the bland assumption that meaningful or informed consent is readily available for the asking. As pointed out elsewhere,⁴ this is very often not the case. Consent in any fully informed sense may not be obtainable. Nevertheless, except, possibly, in the most trivial situations, it remains a goal toward which one must strive for sociologic, ethical and clear-cut legal reasons. There is no choice in the matter.

If suitably approached, patients will accede, on the basis of trust, to about any request their physician may make. At the same time, every experienced clinician investigator knows that patients will often submit to inconvenience and some discomfort, if they do not last very long, but the usual patient will never agree to jeopardize seriously his health or his life for the sake of “science.”

In only 2 of the 50* examples originally compiled for this study was consent mentioned. Actually, it should be emphasized in all cases for obvious moral and legal reasons, but it would be unrealistic to place much dependence on it. In any precise sense statements regarding consent are meaningless unless one knows how fully the patient was informed of all risks, and if these are not known, that fact should also be made clear. A far more dependable safeguard than consent is the presence of a truly responsible investigator.

EXAMPLES OF UNETHICAL OR QUESTIONABLY ETHICAL STUDIES

These examples are not cited for the condemnation of individuals; they are recorded to call attention to a variety of ethical problems found in experimental medicine, for it is hoped that calling attention to them will help to correct abuses present. During ten years of study of these matters it has become apparent that thoughtlessness and carelessness, not a willful disregard of the patient’s rights, account for most of the cases encountered. Nonetheless, it is evident that in many of the examples presented, the investigators have risked the health or the life of their subjects. No attempt has been made to present the “worst” possible examples; rather, the aim has been to show the variety of problems encountered.

References to the examples presented are not given, for there is no intention of pointing to individuals, but rather, a wish to call attention to widespread practices. All, however, are documented to the satisfaction of the editors of the Journal.

Known Effective Treatment Withheld

Example 1. It is known that rheumatic fever can usually be prevented by adequate treatment of streptococcal respiratory infections by the parenteral administration of penicillin. Nevertheless, definitive treatment was withheld, and placebos were given to a group of 109 men in service, while benzathine penicillin G was given to others.

The therapy that each patient received was determined automatically by his military serial number arranged so that more men received penicillin than received placebo. In the small group of patients studied 2 cases of acute rheumatic fever and 1 of acute nephritis developed in the control patients, whereas these complications did not occur among those who received the benzathine penicillin G.

Example 2. The sulfonamides were for many years the only antibacterial drugs effective in shortening the duration of acute streptococcal pharyngitis and in reducing its suppurative complications. The investigators in this study undertook to determine if the occurrence of the serious nonsuppurative complications, rheumatic fever and acute glomerulonephritis, would be reduced by this treatment. This study was made despite the general experience that certain antibiotics, including penicillin, will prevent the development of rheumatic fever.

The subjects were a large group of hospital patients; a control group of approximately the same size, also with exudative Group A streptococcus, was included. The latter group received only nonspecific therapy (no sulfadiazine). The total group denied the effective penicillin comprised over 500 men.

Rheumatic fever was diagnosed in 5.4 per cent of those treated with sulfadiazine. In the control group rheumatic fever developed in 4.2 per cent.

In reference to this study a medical officer stated in writing that the subjects were not informed, did not consent and were not aware that they had been involved in an experiment, and yet admittedly 25 acquired rheumatic fever. According to this same medicaL officer more than 70 who had had known definitive treatment withheld were on the wards with rheumatic fever when he was there.

Example 3. This involved a study of the relapse rate in typhoid fever treated in two ways. In an earlier study by the present investigators chloramphenicol had been recognized as an effective treatment for typhoid fever, being attended by half the mortality that was experienced when this agent was not used. Others had made the same observations, indicating that to withhold this effective remedy can be a life-or-death decision. The present study was carried out to determine the relapse rate under the two methods of treatment; of 408 charity patients 251 were treated with chloramphenicol, of whom 20, or 7.97 per cent, died. Symptomatic treatment was given, but chloramphenicol was withheld in 157, of whom 36, or 22.9 per cent, died. According to the data presented, 23 patients died in the course of this study who would not have been expected to succumb if they had received specific therapy.

Study of Therapy

Example 4. TriA (triacetyloleandomycin) was originally introduced for the treatment of infection with gram-positive organisms. Spotty evidence of hepatic dysfunction emerged, especially in children, and so the present study was undertaken on 50 patients, including mental defectives or juvenile delinquents who were inmates of a children’s center. No disease other than acne was present; the drug was given for treatment of this. The ages of the subjects ranged from thirteen to thirty-nine years. “By the time half the patients had received the drug for four weeks, the high incidence of significant hepatic dysfunction… led to the discontinuation of administration to the remainder of the group at three weeks.” (However, only two weeks after the start of the administration of the drug, 54 per cent of the patients showed abnormal excretion of bromsulfalein.) Eight patients with marked hepatic dysfunction were transferred to the hospital “for more intensive study.” Liver biopsy was carried out in these 8 patients and repeated in 4 of them. Liver damage was evident. Four of these hospitalized patients, after their liver-function tests returned to normal limits, received a “challenge” dose of the drug. Within two days hepatic dysfunction was evident in 3 of the 4 patients. In 1 patient a second challenge dose was given after the first challenge and again led to evidence of abnormal liver function. Flocculation tests remained abnormal in some patients as long as five weeks after discontinuance of the drug.

Physiologic Studies

Example 5. In this controlled, double-blind study of the hematologic toxicity of chloramphenicol, it was recognized that chloramphenicol is “well known as a cause of aplastic anemia” and that there is a “prolonged morbidity and high mortality of aplastic anemia” and that “… chloramphenicol-induced aplastic anemia can be related to dose…” The aim of the study was “further definition of the toxicology of the drug. …”

Forty-one randomly chosen parents were given either 2 or 6 gm. of chloramphenicol per day; 12 control patients were used. “Toxic bone-marrow depression, predominantly affecting erythropoiesis, developed in 2 of 20 patient...