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RESPONSIBILITY IN INVESTIGATIONS ON

HUMAN SUBJECTS

Medical Research Council, 

Great Britain

1963

Ten years prior to the appearance of this document on 16 October 1953, the British Medical Research Council issued its Memorandum on Clinical Investigations (Memorandum MRC 53/649). (See Irving Ladimer and Roger W. Newman, eds. Clinical Investigation in Medicine. Boston: Boston University Law-Medicine Research Institute, 1963, pp. 152-154.) The following, more extensive statement was published in 1963.

During the last fifty years, medical knowledge has advanced more rapidly than at any other period in history. New understandings, new treatments, new diagnostic procedures and new methods of prevention have been, and are being, introduced at an ever-increasing rate; and if the benefits that are now becoming possible are to be gained, these developments must continue.

Undoubtedly the new era in medicine upon which we have now entered is largely due to the marriage of the methods of science with the traditional methods of medicine. Until the turn of the century, the advancement of clini­cal knowledge was in general confined to that which could be gained by observation, and means for the analysis in depth of the phenomena of health and disease were seldom available. Now, however, procedures that can safely, and conscientiously, be applied to both sick and healthy human beings are being devised in profusion, with the result that certainty and understanding in medicine are increasing apace.

Yet these innovations have brought their own problems to the clinical investigator. In the past, the introduction of new treatments or investigations was infrequent and only rarely did they go beyond a marginal variation on estab­lished practice. Today, far-ranging new procedures are commonplace and such are their potentialities that their em­ployment is no negligible consideration. As a result, investigators are frequently faced with ethical and sometimes even legal problems of great difficulty. It is in the hope of giving some guidance in this difficult matter that the Medical Research Council issues this statement.

A distinction may legitimately be drawn between procedures undertaken as part of patient-care which are intended to contribute to the benefit of the individual patient, by treatment, prevention or assessment, and those procedures which are undertaken either on patients or on healthy subjects solely for the purpose of contributing to medical knowledge and are not themselves designed to benefit the particular individual on whom they are performed. The former fall within the ambit of patient-care and are governed by the ordinary rules of professional conduct in medicine; the latter fall within the ambit of investigations on volunteers.

Important considerations flow from this distinction.

Procedures Contributing to the benefit of the Individual

In the case of procedures directly connected with the management of the condition in the particular individual, the relationship is essentially that between doctor and patient. Implicit in this relationship is the willingness on the part of the subject to be guided by the judgment of his medical attendant. Provided, therefore, that the medical atten­dant is satisfied that there are reasonable grounds for believing that a particular new procedure will contribute to the benefit of that particular patient, either by treatment, prevention or increased understanding of his case, he may as­sume the patient's consent to the same extent as he would were the procedure entirely established practice. It is ax­iomatic that no two patients are alike and that the medical attendant must be at liberty to vary his procedures accord­ing to his judgment of what is in his patients' best interests. The question of novelty is only relevant to the extent that in reaching a decision to use a novel procedure the doctor, being unable to fortify his judgment by previous ex­perience, must exercise special care. That it is both considerate and prudent to obtain the patient's agreement before using a novel procedure is no more than a requirement of good medical practice.

The second important consideration that follows from this distinction is that it is clearly within the competence of a parent or guardian of a child to give permission for procedures intended to benefit that child when he is not old or intelligent enough to be able himself to give a valid consent.

A category of investigation that has occasionally raised questions in the minds of investigators is that in which a new preventive, such as a vaccine, is tried. Necessarily, preventives are given to people who are not, at the mo­ment, suffering from the relevant illness. But the ethical and legal considerations are the same as those that govern the introduction of a new treatment. The intention is to benefit an individual by protecting him against a future haz­ard; and it is a matter of professional judgment whether the procedure in question offers a better chance of doing so than previously existing measures.

In general, therefore, the propriety of procedures intended to benefit the individual whether these are directed to treatment, to prevention or to assessment—are determined by the same considerations as govern the care of patients. At the frontiers of knowledge, however, where not only are many procedures novel but their value in the particular instance may be debatable, it is wise, if any doubt exists, to obtain the opinion of experienced colleagues on the de­sirability of the projected procedure.

Control Subjects in Investigations of Treatment or Prevention

Over recent years, the development of treatment and prevention has been greatly advanced by the method of the controlled clinical trial. Instead of waiting, as in the past, on the slow accumulation of general experience to deter­mine the relative advantages and disadvantages of any particular measure, it is now often possible to put the question to the test under conditions which will not only yield a speedy and more precise answer, but also limit the risk of untoward effects remaining undetected. Such trials are, however, only feasible when it is possible to compare suit­able groups of patients and only permissible when there is a genuine doubt within the profession as to which of two treatments or preventive regimes is the better. In these circumstances it is justifiable to give to a proportion of the patients the novel procedure on the understanding that the remainder receive the procedure previously accepted as the best. In the case when no effective treatment has previously been devised then the situation should be fully explained to the participants and their true consent obtained.

Such controlled trials may raise ethical points which may be of some difficulty. In general, the patients partici­pating in them should be told frankly that two different procedures are being assessed and their cooperation invited. Occasionally, however, to do so is contra-indicated. For example, to awaken patients with a possibly fatal illness to the existence of such doubts about effective treatment may not always be in their best interest; or suspicion may have arisen as to whether a particular treatment has any effect apart from suggestion and it may be necessary to intro­duce a placebo into part of the trial to determine this. Because of these and similar difficulties, it is the firm opinion of the Council that controlled clinical trials should always be planned and supervised by a group of investigators and never by an individual alone. It goes without question that any doctor taking part in such a collective controlled trial is under an obligation to withdraw a patient from the trial, and to institute any treatment he considers necessary, should this, in his personal opinion, be in the better interests of his patient.

Procedures Not of Direct Benefit to the Individual

The preceding considerations cover the majority of clinical investigations. There remains, however, a large and important field of investigations on human subjects which aims to provide normal values and their variations so that abnormal values can be recognized. This involves both ill persons and "healthy" persons, whether the latter are en­tirely healthy or patients suffering from a condition that has no relevance to the investigation. In regard to persons with a particular illness, such as metabolic defect, it may be necessary to know the range of abnormality compatible with the activities of normal life or the reaction of such persons to some change in circumstances such as an alter­ation in diet. Similarly it may be necessary to have a clear understanding of the range of a normal function and its re­action to changes in circumstances in entirely healthy persons. The common feature of this type of investigation is that it is of no direct benefit to the particular individual and that, in consequence, if he is to submit to it he must volunteer in the full sense of the word.

It should be clearly understood that the possibility or probability that a particular investigation will be of bene­fit to humanity or to posterity would afford no defence in the event of legal proceedings. The individual has rights that the law protects and nobody can infringe those rights for the public good. In investigations of this type it is, there­fore, always necessary to ensure that the true consent of the subject is explicitly obtained.

By true consent is meant consent freely given with proper understanding of the nature and consequences of what is proposed. Assumed consent or consent obtained by undue influence is valueless and, in this latter respect, particu­lar care is necessary when the volunteer stands in special relationship to the investigator as in the case of a patient to his doctor, or a student to his teacher.

The need for obtaining evidence of consent in this type of investigation has been generally recognized, but there are some misunderstandings as to what constitutes such evidence. In general, the investigator should obtain the con­sent himself in the presence of another person. Written consent unaccompanied by other evidence that an explanation has been given, understood and accepted is of little value.

The situation in respect of minors and mentally subnormal or mentally disordered persons is of particular diffi­culty. In the strict view of the law parents and guardians of minors cannot give consent on their behalf to any proce­dures which are of no particular benefit to them and which may carry some risk of harm. Whilst English law does not fix any arbitrary age in this context, it may safely be assumed that the Courts will not regard a child of 12 years or under (or fourteen years or under for boys in Scotland) as having the capacity to consent to any procedure which may involve him in an injury. Above this age the reality of any purported consent which may have been obtained is a question of fact and as with an adult the evidence would, if necessary, have to show that irrespective of age the per­son concerned fully understood the implications to himself of the procedures to which he was consenting.

In the case of those who are mentally subnormal or mentally disordered the reality of the consent given will fall to be judged by similar criteria to those which apply to the making of a will, contracting a marriage or otherwise taking decisions which have legal force as well as moral and social implications. When true consent in this sense cannot be obtained, procedures which are of no direct benefit and which might carry a risk of harm to the subject should not be undertaken.

Even when true consent has been given by a minor or a mentally subnormal or mentally disordered person, con­siderations of ethics and prudence still require that, if possible, the assent of parents or guardians or relatives, as the case may be, should be obtained.

Investigations that are of no direct benefit to the individual require, therefore, that his true consent to them shall be explicitly obtained. After adequate explanation, the consent of an adult of sound mind and understanding can be re­lied upon to be true consent. In the case of children and young persons the question whether purported consent was true consent would in each case depend upon facts such as the age, intelligence, situation and character of the subject and the nature of the investigation. When the subject is below the age of 12 years, information requiring the perfor­mance of any procedure involving his body would need to be obtained incidentally to and without altering the nature of a procedure intended for his individual benefit.

Professional Discipline

All who have been concerned with medical research are aware of the impossibility of formulating any detailed code of rules which will ensure that irreproachability of practice which alone will suffice where investigations on human beings are concerned. The law lays down a minimum code in matters of professional negligence and the doc­trine of assault. But this is not enough. Owing to the special relationship of trust that exists between a patient and his doctor, most patients will consent to any proposal that is made. Further, the considerations involved in a novel procedure are nearly always so technical as to prevent their being adequately understood by one who is not himself an expert. It must, therefore, be frankly recognized that, for practical purposes, an inescapable moral responsibility rests with the doctor concerned for determining what investigations are, or are not, proposed to a particular patient or vol­unteer. Nevertheless, moral codes are formulated by man and if, in the ever changing circumstances of medical ad­vance, their relevance is to be maintained, it is to the profession itself that we must look, and in particular to the heads of departments, the specialized Societies and the editors of medical and scientific journals.

In the opinion of the Council, the head of a department where investigations on human subjects take place has an inescapable responsibility for ensuring that practice by those under his direction is irreproachable.

In the same way the Council feel that, as a matter of policy, bodies like themselves that support medical re­search should do everything in their power to ensure that the practice of all workers whom they support shall be unexceptionable and known to be so.

So specialized has medical knowledge now become that the profession in general can rarely deal adequately with individual problems. In regard to any particular type of investigation, only a small group of experienced men who have specialized in this branch of knowledge are likely to be competent to pass an opinion on the justification for undertaking any particular procedure. But in every branch of medicine specialized scientific societies exist. It is upon these that the profession in general must mainly rely for the creation and maintenance of that body of precedents which shall guide individual investigators in case of doubt, and for the critical discussion of the communications pre­sented to them on which the formation of the necessary climate of opinion depends.

Finally, it is the Council's opinion that any account of investigations on human subjects should make clear that the appropriate requirements have been fulfilled and, further, that no paper should be accepted for publication if there are any doubts that such is the case.

The progress of medical knowledge has depended, and will continue to depend, in no small measure upon the confidence which the public has in those who carry out investigations on human subjects, be these healthy or sick. Only insofar as it is known that such investigations are submitted to the highest ethical scrutiny and self-discipline will this confidence be maintained. Mistaken, or misunderstood, investigations could do incalculable harm to medical progress. It is our collective duty as a profession to see that this does not happen and so to continue to deserve the confidence that we now enjoy.

[Reprinted with the permission of the Medical Research Council.]

EXPERIMENTAL RESEARCH ON HUMAN BEINGS

British Medical Association

1963

1. New drugs or other therapy should not be prescribed unless prior investigation as to the possible effects upon the human body has been fully adequate.

2. Before a new drug is used in treatment, the clinician should ensure that the distributors of the drug are rep­utable and the claims made for the products include reference to independent evidence of its effects.

3. No new technique or investigation shall be undertaken on a patient unless it is strictly necessary for the treatment of the patient, or, alternatively, that following a full explanation the doctor has obtained the patient's free and valid consent to his actions, preferably in writing.

4. A doctor wholly engaged in clinical research must be at special pains to remember the responsibility to the individual patient when his experimental work is conducted through the medium of a consultant who has clinical re­sponsibility for the patient.

5. The patient must never take second place to a research project nor should he be given any such impression. Before embarking upon any research the doctor should ask himself these questions:

a.     Does the patient know what it is I propose to do? 

b.     Have I explained fully and honestly to him the risks I am asking him to run? 

c.     Am I satisfied that his consent has been freely given and is legally valid?

d.     Is this procedure one which I would not hesitate to advise, or in which I would readily acquiesce, if it were to be undertaken upon my own wife or children?

[British Medical Journal Supplement 2 (1963): 57. Reprinted with the permission of the British Medical Association.]