The Demand for Human Trials in Biologicals Research

The Demand for Human Trials in Biologicals Research FREDERICK C ROBBINS Today we are enjoying the benefits of steady progress since the late 19th century in the development of effective biological products; within the past 20 years there has been a burst of activity with the introduction of new vac- cines against poliomyelitis, measles, mumps, and rubella. Vaccines against meningococcus types A and C have just been licensed. Much yet needs to be leamed, however, and at present a considerable number of prophylac- tic agents are in various stages of development. To cite a few examples: An inactivated vaccine against hepatitis B is in the earliest phase of testing in man; live temperature-sensitive mutant strains of influ- enza and respiratory synctial virus vaccines are just beginning to be tried in humans; vaccines prepared from hemophilus influenza-type B polysaccharide are being tested in small groups of children. Other vaccines in the very early experimental stage are those directed against the herpes family of viruses such as varicella- zoster and cytomegalovirus. Further along are polyvalent pneumococcal polysaccharide prepa- rations, which are now undergoing large scale field trials. Efforts are being made to treat cancer with biological products such as Freund's adjuvant and anti-cell antibodies. (If it is ever demon- strated that a virus or viruses are the cause of any human cancers we wil then be faced with the necessity of developing prophylactic mea- sures that will present entirely different prob- lems from those we encountered with infec- tious diseases; this follows from the presump- tion that the interval between infection and the appearance of canoer will be measured in years, rather than in the days or weeks involved in infectious diseases.) In addition to the new biologicals some of the old familiar ones such as the toxoids, pertussis, cholera and typhoid vaccines are now under intense scrutiny. At this point It miight be well to comment briefly on the steps required in order to develop a biological product for general use in man. The two features of any product that must be established are its safety and efficacy. The rigor of the proof required to substantiate these attributes varies in different parts of the world. Indeed, in the United States, only 30 or 40 years ago no proof of efficacy was required for licensure of a biological; it is even more recently that such a requirement has been placed on drugs. Assuming that a need can be documented, the first step is to establish that it is theoreti- cally feasible to develop the product. This involves the demonstration in the laboratory and in experimental animals that a vaccine, for example, can be prepared in an appropriate form in adequate quantity, that it is free of known contaminants, has no adverse effects and is protective in animals. Once the laboratory studies are complete, trials in man become necessary. These are begun with small numbers under conditions that permit close observation. The purposes of such limited trials is to determine whether or not the product produces the anticipated effect, such as antibody production, and whether there are any short-term untoward Dean, School of Medicine and Professor of Pediatncs and Community Health, Case Western Reserve University, 2119 Abington Road, Cleveland, Ohio 44106. U S.A. 73 74 F. C tobbins reactions. Increasingly larger populations are employed in order to detect less frequent complications. Durin the course of these trials it may be possible to accumulate statistically valid data of efficacy. However, it is probable that a field triala of considerable size will be required in order to secure adequate evidence of effectivenmUia, size of the trial will be determined primarily by the frequency of the disease in questipn, the efflcacy of the product, and epidemlologc consideratlons such as the number of susceptibles in the population, the ease of spread ;of the causative agent, and the ability to recognie the disease. In some field trils one may be jaterested in such considera- tions as the ability of a vaccine vixus to spread from vaccineos to normal contacts, or the effect of immunization-upon the spread of the wild agent. A desired but seldom realized goal is to identify some attribute that can be determined in the laboratory that correlates with the desired result in man: e.g. the presence of the temperature senmitity marker in an influenza virus mutant with lack of virulence for man or the ability of & aince to induce antibodies in an experimental animal with its protective effect in man, I should like now to elaborate further upon some of the principles that I consider important in the development of a biological product even though none of thm will be new to you. 1. The pieduct Should be tested for safety and efficacy to the fufleat extent possible in the laboratory and i animal models before any trials in man ae attempted. This statement expresses an important prin- ciple that no one would argue with, for much of value can be learned in the laboratory. However, it must be recognized that there are few instances n which there are models that are fully comparable to the situation in man. In the lat analysis it is .nly after tests have been conducted in a significant number of people that one can be.assWred of safety and efficacy. Thus it follows that a product is never of assured safety and efficacy when first tried in man. An area for research of critical importance is the search for laboratory models that will predict reably what is to be expected in humns. 2. The firt trias in man of a new product should be conducted on a snall scale, under caefully controled conditions and in a popula- tion theoretically leat at isk, or in whom a reacdon would be the leat injurious. The implications of this statement are self- evident but in practice it is not always easy to select appropriate subjects, particularly since the potential hazards are not known. Not infrequently the investigators and their associ- ates are the first test subjects, which seems reasonable enough, but this is a small popula- tion at best and not necessaily one which meets the various criteria of suitability. One procedure to which I do objet is the use of young dildren of investigators as test subjects. In such situations there is a peculiar problem both in respect to the objectivity of the investigator and the capability of the subjects to refuse participation. In the past, persons in institutions, such as prisons or homes for the retarded, have been utilized frequently to con- duct early trials. However, as will be discussed later, this is beooming increasingly more diffi. cult to do and presents investigators with a major problem. 3. The population or populations in whom the product is to be used must be employed eventualy as test subjects. It nay well be desirable to do the early testing in adults of a product that is to be used in children on the theory that any possible reactions would be less serious in the older persons. However, there is no escaping, at some point, the conduct of trials in the age group for which the product is intended, since just as there are significant differences in response amongst species, so are there differences asoci- Since I hsave not bui ible to find an official derinition of field trial, I have chown to consider it to be any designed test of a product conducted in persons living under reasonably normal circumstances for the purpose of evaluating its safety and/or 0escy. (The word reaonably is used delibetely so as to include persons in the military or ininstitutions such as prisons, schools, or those for the mentally retarded.) Ihe Demand for Human Trials on Biologicals Resach ated with age. An important consideration in selecting the appropriate population in which to conduct efficacy trials wil be the prevalence of the disease in questlon since the more widespread the condition, the more quickly and reliably will the answer be obtained. 4. The experiental desi shoud be such that an uequivocal anse wE be obtained. It would be my contention that one of the most grievous sins that an investigator can commit is to subject persons to even the slightest risk or inconvenience as participants in a poorly planned experiment that fails to provide an answer. In view of the importance of this issue, it is desirable to obtain expert advice, as a rule, when planning a trial, even though the experimenter may consider himself a compe- tent judge. It may not be possible to conduct the trial in the preferred manner because of ethical or other practical considerations. When such b the case appropriate adjustments should be made, bearing in nd the ultimate validity of the experinment. If it does not prove possible to accommodate to the ethical issues and still perform an adequate experiment, then the experiment should not be done. Although it is imperative to conduct the experiment so as to obtain an answer, it is also important to do so with the least inconvenience or risk to the participants. One useful method ofreducing the time and number of subjects required is that of sequential analysis. This permits termination of the experiment as soon as the data become statistically significant. The riss of a trial should never exceed the potentil benefit. Klthough easy to state, this principle is not al ays so simple to apply, since the risk can drely be anticipated. Whot Sould have pra r lybthefading of the SV40wl rusav a contaminant of the poliovirus vaccine and who could asess the risk when it was discovered? Many other such examples could be cited, but in the last analysis it is only after a product has had widespread use that a reasonably accurate estimate of the complications associated with its use can be made. This kind of risk-benefit analysis has been attenpted since time immemorial. Examination of the history of the attempts to control smalpox provides an excellent illustration of how our behavior has been modified by chang- ing risk-benefit ratios. In many parts of the world before the advent of Jennerian vaccina- tion, substantial numbers of people were willing to subject themelves and their children to the considerable hazard of inoculation with small. pox virus because the risks associated with naturl infection were so much greater. Jurin in London (1) in 1723 collected statistics on the complications of inoculation and showed how it compared most favorably with the risks of the disease and Benjamin Frankihn (2) 20 years later in the United States made a simlar study. Vaccination against snallpox, although much safer than inoculation, still carried a siht but measurable risk of encephalitis, eczema vaccina- tum, vaccina gangrenosa and other less serious conditions. Again, this risk was accepted with- out question as long as smallpox remained a real threat. However, in recent years the likeli- hood of acquiring smallpox has become so remote in much of the world that even this slit risk is no longer acceptable and snullpox vaccination has ceased to be a routine proce- dure in many countries. 6. A significant sanmple of persons who are participants in the safety and efficacy tests of a vaccine or other biologial product should be obsrved on a continuing bsis for petence of immunity and any late effects. I realize how difficult it is to follow a population over a period of time, much less to correlate anything seen after a long interval with the initial event. Some small groups have been observed for persistence of antibody to measles and rubella for 5 to 10 years but as a rule such longitudinal follow-ups are not made. When complications have been recognized, eitier they have been those that occurred promptly or a chance obseation has stimu- lated curiosity concering a possible relation- ship which upon retrospective analysis has proved to be valid. A classic example of this 75 F. C Robbins process would be the recognition of the rubella syndrom by Gueg (3) and Swann (4). In the light of what we now know about the long incubation period of viral induced malignancies, slow virus infections such as SSPE and experi- ences such as those with the killed measles and RSV vaccines, I would suggest that in spite of the obvious difliculties of the task, such an effort should be made and provided for as part of the cost of introducing a new product, particularly virus vaccines. 7. Once a product such as a vaccine is accepted for general ue, some means of surveil- lance should be adopted that wil be capable of recognizing failure of efficacy and untoward reactions. This statement follows and amplifles the previous one. In the United States, the Center for Disease Control ha developed reasonably effective surveillance systems for certain vac- cines. However, their efforts are limited in extent and are seriously handicapped by the rather primitive data systems available. One serious problem is that of obtaining on a regular basis accurate data from the field. Even so it has been possible to monitor with some reliabil- ity the safety and efficacy of certain vaccines, such as polio and measles. For instance, para- lytic disease due to residual live virus in lots of inactivated poliovirms produced by one com- pany (the Cutter episode) was promptly recog- nized and brought under control. A localized outbreak of measl in vaccinated children was recognized and found to be due to inproper storage of vaccine by a single physician. Contin- uing surveillance should be of particular value in recognizing waning immunity due to a vaccine, a matter of great importance, since we have no way of predicting with any certainty how long protection will last. 8. The conduct of all trials must adhere to acceptable ethiol standards that recognize and protect the rights of each participant. Here is the wcm of the entire enterprise and the area of greatest controversy. Attitudes towards this subject are influenced by cultural backgrounds, religous beliefs, personal philoso- phy and even politics. Thus, it becomes extremely difficult if not impossible to set down gneral principles that are acceptable under all conditions. Nonetheless, I will attempt to present what seem to me to be principles that are widely accepted and point out some of the special problem areas for which we urgently need a meeting of the minds. The so-called Nuremberg Code (5) (Appendix A) and the statement of the World Medical Associ- ation (6) (Appendix B) do represent inter- national opinion, and I have drawn upon them heavily. As I will attempt to point out, each one has shortcomings from our point of view. a. Full disclosure and informed consent. Most people would agree that participants in field trials, or those legally responsible for them, should be fully informed concerning the purpose of the trial, how it is to be conducted and any anticipated risks or inconveniences. Such disclosure should include a description of how the controls will be dealt with, including the use of placebos. Only following full dis- closure can truly informed consent be obtained. However, it must be recognized that there are certain populations that, because of age, limited mental capacity, or special circunutances that place them under unusual constraints, cannot give consent for themselves. These situations will be discussed more fully later. It is impor- tant that investigators inform subjects in terms that they can understand, which is not always easy to do. Records should be kept indicating the methods used to inform subjects. It is cdearly not enough to provide them with a written statement and ask them to sign it. The issue of informed consent and full disclosure is one about which much has been written and about which there is still a great deal of debate. Nonetheless, it remains the cornerstone of properly conducted human trials. b. The issue of controls. The ethical issues that arise over the use of controls can be perplexing indeed. If one adheres to the World Medical Association code which states that no child shall participate in an experiment from which he derives no personal benefit, the 76 The Demand for Human Trials on Biologicals Research alternatives become considerably lmited. The problem does not arise so acutely when an entirely new product is being tested, since the subjects stand to gain, and untreated or placebo controls are at no disadvantage when compared to the population at large. When a substitute or improved product is beimg tested and there is an existing one of limited or uncertain value that has been widely used, the usual procedure is to compare the newer product to the accepted one and not include untreated controls. This meth- od is satisfactory, providing one has some knowledge of the effectiveness of the estab- lished product. If this is not known, one may end up with the unsatisfactory answer that the two substances are either equally effective or equally ineffective. It is especially difficult to conduct tests on products that have been widely used but have never been tested prop- erly for efficacy. They invariably have strong proponents and the fact that their use has become accepted practice makes it almost impossible to deny them to the control groups. I have not said much about placebo oontrols as such but considered them along with untreated controls. Some people single out the placebo as particularly undesirable (7). This may be true in experiments where it is necessary to conceal the fact that placebos are being used. However, in field trials of biologicals such disclosure should present no problem. Under these conditions I see no ethical problem with the use of placebo controls. c. The issue of providing inducements for participation in trials. Sometimes subjects in trials are rewarded for their participation; for example, prisoner volunteers may be given special privileges or early consideration for parole or student volunteers may receive pay. On the face of it, this practice seems distasteful and coercive. If done solely in order to entice subjects to participate, it probably is ethically suspect. On the other hand, an argument could be made that participation does inconvenience the individual and may, indeed, cost something. It would seem reasonable to pay for inconven- ience and/or any costs such as those for transportation, or for a mother to pay for a babysitter while she brings her child to a clinic. Another issue conerning compensation arises where a subject sustains an injury as a result of participation in an experiment. I would suggest that any person who serves as a subject in any experiment should be adequately insured against injury, either by the sponsor of the experiment, or by some governmental agency, and I believe that in some countries, such as Denmark, this is done. Although it is rare that subjects do suffer reactions of any significance, it would be a relief both to the investigator and to the subjects to know that in the case of an untoward event appropriate assistance would be available. d. External review. In recent years, in the United States at least, it has become mandatory for any experiment involving human beings and funded by the Federal govemment to be reviewed by a panel of persons not directly involved in the conduct of the experiment. These panels usually review the protocol for its scientific soundness, but most particularly from the ethical point of view. Considered are such questions as: Is there evidence of properly obtained informed consent? What is the risk- benefit estimate? Will there be proper super- vision? And so forth. When this system was originally introduced, many investigators were concerned that it would prove to be unduly cunbersome and would inhibit experimenta. tion, and sonm felt that it was an infringement upon their independence. After a number of years experience, I believe most investigators have come to accept external review as useful rather than a hindrance. It has led to more red tape, it takes longer to initiate and carry out an experiment, and it unquestionably increases the cost of expenmentation. However, the necessity to justify the protocol to others has increased the attention that is paid to ethical considerations and even to experimental design. Onginally these panels were limited to scientific peers but lately other persons such as lawyers and even non-professional lay persons have been asked to sit with these bodies. The 77 F. C. Robbhs experience with *ii has proved to be in some instances highly satiefactory, in others less to, but data are to limited for any accurate generalizations to be made. The Presidential Commission on the Protection of Human Subjects is conducti a natiowide study to analyze the way in which such human experimentation r'^ew bodies operate. In a few months thd data may be available and should be helpfl itn underadming how better to conduct externl review. There is much yet to be leaned but it would m that the principle of extenal review is futly in accord with good sience and has geeral applicability. e. Peculiar problm of special popuIatom.s In conducting trial ofbilogical products there are pcial p Ukans that have been most vluable, but wh presnt peculiar prob- lems. One didsigshing feature of these groups is that they canot sive informed consent, either because of their imbility to undersand or because of sei constraints under which they suffer. In the. flist oategory are mentally retarded perow , young en, and, of course, the fetuswhich presnts a unique problemh with which I wfil not attempt to cope in this presntation. In the second category are prsoner., miay personnd, students, and perons who rdependent upon public or other organized avices and thus become pecu- liarly available for eVplotaon. I wil not atto v pt to deal with the unique features of each of the special populations. Thes matters have been dealt with at great length elsewhere. It is important, however, to reconize the sulrability to exploita- tion of these popuats and to approach their indusion in field tiab with grat snsitivity to this fact. On the other hand, I would be reluctant to prohibit fth conduct of studies in any populatic, peovided It is not Innately suscptible to undue uisk. The two popuations that have been uniquy auable in the early testing of biola are the institutionalized mently retarded and p r volunteers. The advantages of lmAtutkaized perons are sev- eral: They can be observed carefully without disruption of their lives, their environment can be controled to some degree, and they are likely to be available for long-tenn follow up. In spte of the obvious advantages that these populations offer, the prevailing cimate of public opinion in many countries discourages their use. We are all fair with the sevre criticisn to which Dr. Saul Krugman and his associates wnre subjected for their experiments at the Wilowbrook State School for the Mentaly Retarded. (This was in spite of the fact that these experiments were conducted with great attention to the ethical issues and may well have laid the groundwork for the eventual control of hepatitis.) Thus, it is prudent to consider carefully all alternative means of testing before turning to the mentally retarded or prisoners. One approach is that employed at the Common Cold Center in Salisry, Eigland. Couples were offered accommodations and a holiday in return for allowing themselves to be inoculated with experimental materials. In some parts of the world there is a tendency to select preferentially as experi- mental subjects persons of low socio-economic status. Thes persons are often poorly educated and dependert upon publc services. The vul- nerability of this population to exploitation is not generally appreciated. To the extent posd- ble, large sle field tials of vaccine and other biologicals should include al segments of the population. Since the population generally will benefit, it seem. appropriate that all clases of perons be asked to participate and share in whatever risk may be entailed. A related matter of considerable concem to the World Health Organiation is that of trials conducted in countries other than those In which the biologi- cals are produced. When populations are diffi- cult to obtain in a particular country, either because of the attitudes of the population or the restaints placed upon eperimentation, investigators may look to other countries where, for resons of poverty, ignorance, ava- rice, or lack of legislative restraints, they can fnd popuations avalable for experimentation. I am aware that tis happens but have little idea 78 The Demand for Human Tull on BioloScals Research as to how frequently. However, one must recogze that not all such experiments are unethical. Not infrequently experiments may have to be done in certain countries where the disease in question is sufficiently prevalent that an adequate field trial can be conducted. An experiment which raised some ethical questions and was debated at great length before it was undertaken is the field trial of the pneumococ- cal polysaccharide vaccines, which have been developed recently in the United States. In looking for suitable populations in which to do efficacy trials, it was clear that there were relatively few populations at sufficiently high risk that one could get significant data within a reasonable length of time. One population that seemed peculiarly appropriate was a group of miners in South Africa. For reasons that are not clear, but undoubtedly relate to the environ- mental conditions under which they work, they are highly susceptible to pneumococcal pneu- monia. The rate of disease in this population is extraordinarily high in comparison to any other group that could be identified. These experi- ments have now been under way for a year or more and I understand that they are proving to be quite successful. On the face of it this might be looked upon as exploitation but, on the other hand, the miners are being greatly bene- fited. Another excellent example would be the testing of measles vaccines in children in Africa where mortality rates are very high as compared to those in much of the rest of the world. In the preceding discussion I have given some of the reasons why in the development of new biological products it has been and will continue to be necessary to conduct trials in man. An important area of research is to attempt to develop better laboratory criteria for safety and efficacy in man. As we learn more in both man and animals about the pathogenesis and epidemiology of disease, the intricacies of the imune response, and the biochenmcal and physical nature of microbial agents, it may one day be possible to predict with some accuracy the outcome mnan on the basis of the laboratory data alone. We are a long way from this goal. A point that can never be emphasized enough is that no matter how many data have been secured, the first trial in man is aociated with an unknown risk. Nothing is totally safe! Although we all recognize this fact, we are sometimes reluctant to express it in public for fear that awareness of risk would lead to rejection of the product. I tend to believe that candor is the better policy in the long run, as it provides a basis for trust. In discussing the ethical issues, I have relied greatly upon the two documents of intemation- al nature: the Nuremberg Code and the World Medical Association's statement of ethical prin- ciples. Fine as they are, they do not satisfy fully the needs of those concerned with the conduct of field trials of biological products. Neither one deals adequately with the problems of children or other special populations. They do not provide adequately for surrogate con- sent or for the use of controls. I would suggest that the WHO consider assumnng the responsibility for developing a new international code for human experimenta- tion that specifically addresses the issues of controlled field trials and the use of special populations. Such a move seems appropriate since, no natter where a product is developed,. it will benefit people throughout the world. A set of international standards would also help to ameliorate the possible problem of exploit- ing populations in foreign lands. I have two other suggestions of possible roles that the WHO night play in the field of biologicals testing. The organization might serve as an international registry and clearing house of information on all trials being conducted. This might include a registry of participants for long-term follow-up. I realize that this would not be easy to do but it does seem an appropriate role for an international body. Finally, it would seem highly desrable to explore in considerable detail the problems associated with programs for oDmpensation of persons injured as the result of participation in experimentation directed to the benefit of the larger oommunity. Should some method seem feasible and desirable, then I would urge that 79 80 F. C. Robbins senous consideration be given to administering it through an international body such as the WHO. References 1. Miller, G.: The Adoption of Inoculation for Smallpox in England and France. Philadelphia, University of Pennsylvania Press, 1957. 2. Franklin, B.: Some Account of the Success of Inoculation for the Smallpox in England and America. Together with Plain Instructions by Which Any Person May be Enabled to Perform the Operation and Cond4ct the Patient Through the Distemper. London, 1759. 3. Gregg, N. M.: Congenital Cataract Following German Measle in the Mother. Trans. Ophth. Soc. Australia, 3:3546, 1941. 4. Swann, C.: Rubella in Pregnancy as an Aetiological Factor in Congenital Malformation, Stillbirth, Miscarriage and Abortion. J. Obst. Gynaec. Brit. Empire, 56:341-363, 1949. 5. Katz, J.: Experimentation With Human Beings. New York. Russell Sage Foundation, 1972, pp. 305-306. 6. Draft Code of Ethics on Human Experinentation. Presented to the General Assembly of the World Medical Associaton, September, 1961. Brit. Med. Jml., p. 1119, October 27, 1962. 7. Bok, S.. The Ethics of Giving Placebos. Scientific Amencan, 231:17-23, 1974. General References Pollack, T. M.: Trials of Prophylactic Agents for the Control of Communicable Disease. A Guide to their Organization and Evaluation. W.H.O., Geneva, 1966. Hfill, A.B.: Medical Ethics and Controlled Trials. Brit. Med. Jrnl., pp. 1043-1049, Apr. 20, 1963. Ethical Aspects of Experimentation with Hurman Subjects: Daedalus, 98, 1969. Amer. Acad. of Arts & Sci., Boston, Mass. Experiments and Research with Humans: Values in Conflict, National Academy of Sciences, Washing- ton, D.C., 1975. Fried, C : Medical Experimentation. Personal Integrity and Social Policy. Clinical Studies, Vol. 5, 1974. North Holland-Amsterdam, Oxford. American Elsevier, New York. Curran, W. J., Beecher, H. H: Experimentation in Children. A re-examination of legal ethical principles. Jrni. Amer. Med. Assoc., 10:77-83, 1969. The Demand for Human Trials in Biologicals Researchl APPENDIX A NUREMBERG CODE 1. The voluntary consent of the human subject is absolutely essential. This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, over reaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment. The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs, or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity. 2. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature. 3. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under study that the anticipated results [wilt] justify the performance of the experiment. 4. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury. 5. No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects. 6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment. 7. Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death. 8. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment. 9. During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible. 10. During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, in the exercise of the good faith, superior skill, and careful judgment required of him that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject. 81 F. C. Robbbu APPENDIX B DRAFT CODE OF ETHICS ON HUMAN EXPERIMENTATION WORLD MEDICAL ASSOCIATION General Principles and Definitions 1. An experiment on a human being is an act whereby the investigator deliberately changes the internal or external environment in order to observe the effects of such a change. 2. Such change in the environment as defined should be made only if the following conditions are observed: (a) that the nature, the reason, and the risks of the experiment are fully explained to the subject of it, who should have complete freedom to decide whether or not to take part in the experiment; (b) that whefe children are to be the subject of an experiment the nature, the reason, and risks of it should be fully explained to their parents or lawful guardians, who should have complete freedom to make a decision on behalf of the children; (c) that children in institutions and not under the care of relatives should not be the subject of human experiment; (d) that the experiment should be conducted onty by scientifically qualified persons and under the suporvieon of a qualified medical man; Ce) that during the course of the experiment tihe subject of it should be free to withdraw from it at any time; (f) that the invesgator, or investigating committee, or any scientifically or medically qualified person asiodated with him or the committee should be free to discontinue the experinent if in his or their Judgment it may, if continued, be harmful to the subject of the experiment; (g) that any risk to which the subject of an experiment may be exposed should be carefully assessed In terms of direct benefit to himself or indirect benefit to others, on the assumption that the risks have been explained to, and freely accepted by, the subject of the experiment. Experiments for the Benefit of the Patient 1. A doctor performing an experiment for the possible benefit of his patient should not extend -his experiment beyond this without the full and previous consent of the patient. 2. A doctor combining clinical research with the personal care of patients should never abuse the trust of the patient in him as a doctor by conducting experiments solely for the acquisition of knowledge, unless the full consent of the patient has been previously obtained. 3. Experiments on a human being for the prevention of disease should be based on laboratory and animal experiments, or other scientific data. 4. Controlled tKfls In therapeutic and preventive medicine should be conducted according to the general and -*eat ethical rules concerning experiments on the individual. 5. Special caution should be exercised in performing experiments in which the personality of the subject may be altered by drugs or experimental procedures. 82 'Me Demuand for Humn Trial in Biolosicals Research 6. In the treatnmnt of the sick person the doctor should be free to perform an experiment for the first time if in his judgment it offers the only hope of saving life or alleviating pain or suffering, the consent of the patient or his legal reprentative having been obtained. Experiments Conducted Solely for the Acquisition of Knowledg Experiments not done for the benefit of the subject (whether healthy or ill) of the experiment, but solely for acquiring knowledge, should be conducted under the most stringent safeguards, as follows: (a) The subject of the experiment should be in such a mental, physical, and legal state as to be able to exercise fully his power of choice. (b) No doctor should lightly experiment on a human being when the subject of the experiment is in a dependent relationship to the investigator, such as a medical student to his teacher, a patient to his doctor, a technician in a laboratory to the head of his department. (c) Prisoners of war, military or civilian, should never be used as subjects of experiment. (d) Civilians detained in any place as a result of military invasion or occupation, or for administrative or political reasons, should never be used for human experimentation. (e) Persons retained in prisons, penitentiaries, or reformatories - being "captive groups" - should not be used as subjects of an experiment; nor persons incapable of giving consent because of age, mental incapacity, or of being in a position in which they are incapable of exercising the power of free choice. (f) Persons retained in mental hospitals or hospitals for mental defectives should not be used for human experimentation. 83