Role of Ethical Guidance Committees in Clinical Research

H. Breuer and F. W. Fischer

From the Institut fti'r Klinische Biochemie der Universitdt Bonn, and the Deutsche Forschungsgemeinschaft, Bonn, Federal Republic of Germany

INTRODUCTION

Problems of medical ethics and ethics in medical research are, insofar as they are reflected by public opinion, symptoms of contradictory social tensions and a widespread uneasiness as to "progress." Everyone considers advances in the prevention and treatment of illness desirable and necessary. The citizen's attitude toward research is, therefore, positive in an abstract sense. His or her attitude is also positive in the concrete instance if a sickness touches him or her personally. This attitude changes, however, when the discussion turns to the implementation. Then distrust, reserva- tions, doubts, and fears are often articulated. Politicians react to this uneasy public opinion. They appoint committees and organize hearings. Experience shows that in the end there are always the same demands: improvement of the protection of the individual and his rights by more visibility and mechanisms for more self-control, as well as by increased control from outside the medical profession.

The declarations of Helsinki (1964) and Tokyo (1975) are a reflection of this development. The declaration of Helsinki was an appeal for ethical behavior in research. In Tokyo the attempt was made to regulate and to control ethical behavior. This trend has cont inued--at least in Europe--and has led chiefly to discussions of the strengthening of control mechanisms already in existence.

LEGAL GUIDELINES P R E D A T I N G THE FEDERAL REPUBLIC

Discussions of ethics that are underway in the Federal Republic of Germany are being conducted against a specific background. This background has been provided by history. Here the visitor from abroad is apt to think of the events between 1933 and 1945 that led directly to the Nuremberg Code (1947) and essentially influenced the Declaration of Helsinki (1964). In these discussions, the German observer includes the years before 1933, a period

Address requests for reprints to Professor H. Breuer, Institut fl& Klinische Biochemie der Universitat Bonn, 5300 Bonn 1, Federal Republic of Germany.

Controlled Clinical Trials 1, 421-427 (1981) 421 © 1981 Elsevier North Holland, Inc., 52 Vanderbilt Avenue, New York, NY 1 0 0 1 7 0197-2456/81/040421007502.50

422 H. Breuer and F. W. Fischer

governed by a h igh ethical tradit ion. He also thinks of those physic ians and scientists who cont inued the t radi t ion u n d e r the 1933-1945 dictatorship.

H.-J. Wagner [1] has recently po in ted out that as early as 1931 the then Minis ter of the Interior issued guidel ines for new forms of medical t reatment and for carrying out scientific exper iments wi th h u m a n beings. These guidel ines were publ i shed in the Reichsgesundheitsblatt (National Heal th Gazette). The guidel ines are clearer, more concrete, and more far-reaching than both the Nuremberg Code and the recommenda t ions decided on in Helsinki.

In examining the in ternat ional s i tuat ion today, it may be informative first to take a br ief look at the most impor t an t of these ethical guidel ines s temming from the Germany of 1931:

1. Every new form of t rea tment must in its justification and its implemen- tat ion be in ha rmony with the principles of medical ethics and the rules of medical art and science. This ques t ion mus t always be carefully examined and weighed: Are the ill effects that might be caused in an appropr ia te relat ionship to the expected benefit? A new kind of t reatment may only be under taken if previously, as far as possible, it has been tested in exper iments with animals.

2. A new kind of t rea tment may only be under taken , moreover , if the person in ques t ion, or his legal representat ive, after previous per t inent instruct ion has unequivoca l ly declared his or her agreement with the under taking.

3. Medical ethics reject any exploi tat ion of social d isadvantage in reaching a decision about a new k ind of t reatment.

4. In clinics, including those for outpat ients and hospitals or other insti tu- tions for the t reatment or care of the ill, a new t reatment may only be carried out by the senior phys ic ian himself or by another physic ian on the senior doctor 's express order and on his full responsibil i ty.

5. About every new kind of t rea tment there is to be a record, showing the purpose of the measure , the reason for it, and the way of carrying it out.

For pure ly scientific exper iments wi thou t special benefi t for the individual undergo ing tests the following addit ional guidel ines were valid:

6. a. No expe r imen t may be u n d e r t a k e n w i th o u t the existence of an agreement . b. No exper iment on h u m a n beings may be made if instead it can be conducted w i t h animals. An exper iment with a person or persons may only be under t aken if first there has been p rocurement of all available data regard ing labora tory tes~ts and exper iments wi th animals. The r equ i r emen t rules out any r edund an t or nonessent ia l exper iments on h u m a n beings. c. Exper iments wi th chi ldren or persons unde r 18 years of age are inadmiss ible if they would even only slightly endanger the child or the

young person. d. Exper iments with dying persons are incompat ible with the principle of medical ethics and for that reason are inadmissible.

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These guidelines were valid up to 1945. They could not, of course, prevent all that happened in Germany after 1933. Even today the possibility of such wayward developments cannot be automatically excluded everywhere.

In th,e years after World War II there was a strong movement to return to ethical traditions in Germany. The generation that was studying in those first postwar years occupies the leading clinical and scientific positions in today's Germany. Within the professional scientific associations it is repre- sentatives of this generation who decide which research should receive financial support. The high degree of this generation's sensitivity toward ethical problems has been preserved up to the present day.

LEGAL GUIDELINES OF THE FEDERAL REPUBLIC

The German legal conception, pertaining to medical ethics, is based on articles 1, 2, and 5 of the Constitution and on general legal norms. It is true that freedom of science and research is guaranteed--in article 5, paragraph 3, of the Constitution. But this freedom is qualified: It does not extend to possible interference with the human rights of the persons on whom experiments are being performed, in particular as far as safeguarding their human dignity is concerned (article 1, paragraph 1) and their right to life, inviolability of the person, and individual freedom (article 2). Further details are regulated by professional rules of the Chambers of Physicians of the states. Laws, professional rules, or other written regulations of procedure in matters of clinical research did not exist until recently. This restraint, practiced for three decades, stemmed from the conviction that in civil and penal laws there existed sufficient stipulations with which experiments with human beings would need to be in harmony.

On January 1, 1978, a new drug law (Law for the Reorganization of Pharmaceutical Legislation) came into force. Its sections 40 and 41 contain detailed rules for the protection of human beings in clinical drug testing.

Many recommendations of the declarations of Helsinki and Tokyo have entered into the new law: limitation of the risk, informed consent, direction of the investigation by an experienced physician, legal competency of the test persons. New and indicative is a key regulation pertaining to itlsurance law (section 40, paragraph 1, no. 8, along with section 40, paragraph 3); according to it, insurance protection will be granted in case of harm even if otherwise nobody is responsible for the harm ("accidental harm").

It may be expected that in the future the principles formulated in the new drug law will also influence the legal norms in other fields of clinical research. The Tokyo recommendation of introducing controls by ethical review committees has not been embodied in the present version of the drug law.

ROLE OF THE DEUTSCHE F O R S C H U N G S G E M E I N S C H A F T

The Deutsche Forschungsgemeinschaft (DFG), which is the central research- promoting organization in the Federal Republic of Germany, has gotten

424 H. Breuer and F. W. Fischer

along wi thou t the existence of ethical review commit tees since its founda- tion. Every appl icant is asked to present his test p rogram in detail and to c o m m e n t on ethical and legal aspects. Every appl ica t ion is submi t t ed to several referees. In this conjunct ion it may be men t ioned that the DFG has its evaluat ing experts elected for 4 years each by the scientific c o m m u n i t y in direct, secret vot ing. Apar t f rom the elected referees, the DFG can hear as an expert any qualified scientist . This a r r angemen t results in a suprare- gional and i n d e p e n d e n t sys tem of evaluat ing experts wi th the h ighes t poss ib le degree of special ized knowledge .

All referees are expressly asked to take a pos i t ion in regard to not only the scientific bu t also the ethical and legal aspect of research projects. Appl ica t ions that raise ethical p rob l ems are cons idered orally in the grants commi t tee that decides abou t the approva l and f inancing of appl icat ions. If even the sl ightest doub t s as to the ethical admiss ib i l i ty of a p lanned project r ema in dur ing the d iscuss ion, then suppor t is refused. Grants can be l inked with condi t ions. Not rarely the condi t ion is set that a superv i sor of the

~applicant takes full respons ib i l i ty for tests wi th h u m a n subjects , along with the selection of test pe r sons and their en l igh tenmen t as to the project.

In 1973 the DFG asked that in a n u m b e r of Special Col laborat ive Programs ~ local ethical r ev iew commit tees be es tabl i shed in order to gain exper ience wi th this i n s t rumen t of control. As of n o w the advan tages and d i sadvan tages of local commit tees can be assayed only in part .

An advan tage of local examina t ions is doubt less ly that there the clinical exper ience of the researcher , for example in pract ic ing invas ive me thods , his special work ing condi t ions , and certain technical details of an exper imen t can be bet ter judged than by an evaluat ing expert at a distance.

A certain d i sadvan tage s tems f rom the s t rong special izat ion of clinical research. At a g iven location often only the project leader himself can really judge the r isk-benef i t ratio of a p l anned exper iment . The m e m b e r s of a local commit tee , by reason of the subject , m a y be over taxed if asked to evaluate a risk. A fur ther p r o b l e m m a y result f rom local personal relat ions and dependenc ies that are b o u n d to exist everywhere~

For the reasons just men t ioned , the DFG concentrates on keep ing its o w n wel l - func t ion ing rev iew sys t em opera t ive . The respec t ive supra reg iona l evaluat ing repor ts m a y be s u p p l e m e n t e d b y r e c o m m e n d a t i o n s of local commit tees , bu t the local com m en t s m a y by no means obvia te the evaluat ing reports . So the DFG repea ted ly poin ts out to its evaluat ing experts that the existence of local commit tees does not release the evaluators f rom their du ty to examine critically the ethical and legal admiss ib i l i ty of exper imenta l p rograms . The DFG expressly reserves the r ight to reject research projects for ethical reasons alone even if they have been a p p r o v e d by local commi t - tees.

1Special Collaborative Programs at selected universities involve institutionalized groups ot researchers of various disciplines for carrying out long-term coordinated work in a specific field of research. Although the program covers all disciplines, up to now emphasis has been placed on medicine, but there are increasing developments in other fields of science and technology.

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ESTABLISHMENT OF LOCAL COMMITTEES

Clinical research in the Federal Republic of Germany is f inanced not only by research-promot ing organizat ions but also from funds of the clinics themselves. In the latter case, no external procedure for obta in ing expert evaluations exists. Here an examinat ion of clinical research projects by local committees appears to be bet ter than no examinat ion at all. Not least for this reason, the DFG asked the Federal Chamber of Physicians (Bundesdrz- tekammer) to plan for the es tabl ishment of local committees.

It is being r ecommended to the various state chambers of physic ians that they establish commit tees for advis ing on and evaluating ethical and legal aspects of research on human beings. These commit tees are to consist of three researchers , of whom two have clinical and one has theoret ical experience, along with a lawyer and a representa t ive of the chamber of phys ic ians . The m e m b e r s of the ethical r ev iew commit tees are to be appoin ted on the recommenda t ion of the scientific society and the local medical faculty for a 4-year term of office. The commit tee is to operate on the basis of the existing law and of the declaration of Helsinki , as revised by the World Medical Assoc-ation in Tokyo. The commit tee is to consider a specific s i tua t ion or, a wr i t t en appl ica t ion of the phys ic i an w h o is responsible for the respective research project. It is to reach a decision by a s imple majori ty vote. If the decision is negative, the applicant must be offered a hear ing before final rejection. In any case, the applicant is in formed in wri t ing about the result of the hearing. If the commit tee has objections to a research project or its me thod of implementa t ion , the mot ivat ion is to be explained in writing.

The commit tees are to restrict themselves to the evaluation of ethical and legal aspects of research projects; they are expected to advise and not to decide. However , the practical significance of this l iberali ty ought not to be overest imated. The mere existence of these ethical rev iew committees will exert a - - to our minds , thoroughly w h o l e s o m e - - p r e s s u r e to appeal to them, especially in those cases where there is any doub t about the ethical or legal founda t ion of the research project. If so m eb o d y relies solely on his own judgment in a difficult and complex matter , a l though he has at his disposal the capable advice and evaluat ion of a commit tee that has been establ ished by the state chamber of physicians, then he cannot plead that his error was unavoidable .

Nei ther the DFG nor the Bundesdrztekammer is at present th inking of establishing a national advisory board. Impor tant problems that can be resolved by a general rule, as for instance examinat ion of pharmaceuticals and x-ray protect ion, have recently been regulated by laws and ordinances. Most ethical problems do not at all lend themselves to considerat ion on general principles, bu t require , instead, individual discussion and decision.

REMAINING PROBLEMS

In the preceding sections we have largely dealt with control mechanisms. A thoughtful considerat ion of the ethical aspects of medical research also

426 H. Breuer and F. W. Fischm

extends, however , into quite other d imensions . For instance, there is the ques t ion of what degree of risk a society considers it can ask of its members . For compar ison, other risks, for instance in industr ial work or in sports , would have to be considered. Eve rybody should be free, at the same risk, to contr ibute to the progress of science.

A basic mot ive of authors of all pharmaceutical laws and all orders on procedure in matters of ethics has been and is the protect ion of children and of minor i t ies . Al though this e n d e a v o r a lways finds b road publ ic agreement , it has, however , not only posi t ive consequences . The restrictions at the same t ime result in our knowing part icularly little about m a n y therapies in pedia t r ics and in pregnancy. These therapies are the reby bu rdened by special uncertaint ies and a comparable h igh rate of unexpec ted incidents. The strong emphasis on individual protect ion in h u m a n experi- ments reduces individual dangers but brings about , at the same time, new collective dangers. It can be unethical to examine a therapy scientifically; but it can also be unethical to apply a scientifically unexamined therapy. The researcher in his day- to-day practice is confronted here by contradic- tions that are hard to resolve.

Nor do existing laws and procedural regulat ions take into specific consid- erat ion the wishes of the ill and the motives of volunteers w h o are in normal health. In the latter group, financial and idealistic motives may be inter- twined; an addi t ional factor is, however , often the pleasure of taking a calculated risk.

If we weigh the pros_and cons then, in my opin ion , the arguments speak p redominan t ly for the es tabl ishment of ethical review committees. But it will of course depend on the individuals on these commit tees whe ther they will be a valuable suppor t or a bureaucrat ic i m p e d i m e n t for the phys ic ian doing research. Everyone cooperat ing here is facing a hard task. He must be ready to acknowledge that there is no progress wi thou t risk and he must also be ready to pu t up with the fact that for himself, too, there will be the risks of error.

CONCLUSIONS

The tension be tween ethics and science can in its last analysis be resolved nei ther by declarations nor by control mechanisms. This is true, similarly, of the tension be tween science and medical practice or that be tween the t ra in ing of s tudents and the we l l - founded interes ts of the ill. In the guidel ines of ~931, men t ioned earlier, the conclusion states:

As early as in academic instruction there shall be reference at every suitable opportunity to the special duties that are incumbent on a physician in undertaking a new treatment of a scientific experiment, as well as when publishing its results.

With that, what is p robab ly the most crucial po in t emerges: namely, the avoidance of unethical behavior . Here we may well find that a runn ing dia logue is the best form of p reven t ion . That is: It can pay us more exper ienced scientists, and benefi t society as a whole, if we avoid too much

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dependence on rules for checking on the extent to which the younger generation of physicians and researchers are in fact conducting themselves ethically. Instead, we have the opportunity to talk more often and more freely with science's oncoming generation about ethics and ethical behav- i o r - s e e k i n g to harmonize our experience, these younger scientists' sense of dedication, and the evolving needs of the community we all serve.

REFERENCES

1. Wagner H-J: Heilversuche und Experiment aus rechtsmedizinischer Sicht. Beitrdge zur gerichtlichen Medizin 33:24-32, 1975.