Commentary: The Possibility of Uniform Statutes and Regulations

Commentary: The Possibility of Uniform Statutes and Regulations J. DE MOERLOOSE I was requested to study the possibility of uniform statutes and/or regulations relating to biological products. However, as one of the main purposes of the Conference will be to frame guidelines for experimentation involving human subjects, the present study has ob- viously had to focus on this aspect, the source material consisting essentially of statute law. In order to draw conclusions which might prove useful for framing guidelines, the legisla- tion existing in the following selected countries was reviewed: Austria; Belgium; Colombia; France; Federal Republic of Germany; Hungary; Sweden; Switzerland; United King- dom; and United States of America.a Obvious- ly, additional information is available from a great number of other countries, the most re- cent text issued in this connexion being the Danish Law on medicaments of 26 June 1975. The main aspects of the review deal with the registration and/or licensing of biological pro- ducts, including trials involving human subjects. The principal conclusions which emerge from the review are not only the striking dif- ferences from country to country in the legisla- tion on biological products but also the general absence of ethical elements in the legislation relating to experimentation on human subjects. As will be noted from the study, the chief ex- ception to this latter statement relates to the United States of America. Because of the absence of specific ethical provisions relating to the use of human subjects m the legislation, it was deemed necessary to try to find out if ethical rules could be traced in specific or general codes of medical ethics. Rules of ethical conduct do, in fact, exist in some countries, but again, as Sir William Refshauge has stated, their provisions are in most cases based on the Declaration of Helsinki (which has now been revised [Tokyo, 1975]). Therefore, reaching uniform statutes covering the two elements, namely licensing and ethical rules, would seem to be a difficult task. Summarizing the present situation, one may state- 1. In the past, most countries have promul- gated legislation on biological products separate from the legal provisions relating to drugs or medicine. As is well known, a number of countries are still in this parti- cular situation, the Netherlands, for in- stance. 2. There is at present a tendency to incor- porate licensing and/or registration of biological products under the legal provi- sions relating to medicines. A good ex- ample is the United Kingdom Medicines Act of 1968, which, insofar as it covers biological products, will entail the repeal in the near future of the Therapeutic Sub- stances Act of 1956 (which deals with biological products only). 3. In some countries, a more complex legal system obtains whereby the statutory provisions are different in cases where biological products are manufactured by the State and where they are produced by Chief, Health Legislation, World Health Organization, Geneva, Switzerland aAn appendix summarizing legislation existing in these countnes is available from the author on request. 147 14 de Moedoom industrial firms; this Is, for instance, the case in France, where distinctive legal provisions apply to the Pasteur Institute. The recent Danish Law which has been mentioned shows that the registration proced mmpisd ts do not apply to biow1 d uts which are prepared by the State Serum Institute. 4. As might be expected, wherever the li- censln dures are similar for medi- cines and or biological products, the law- maker hb'u'4' nile concentrated on the requiroeMntO If medicines rather than for biol0tgcalproducts, and therefore the clinical tlrLwquirements for medicines are not nmoesaly adapted to biological products. Aqu, of oourse, from general requir.*miti; such as those concerming safety or innoculty, speciflc provisions re- lating to *tthe testing and licensing of biolosical" prbducts and, in particular, trias invohkg human subjects are largely non-existent. 5. A perual'dof*he commonly known ethi- cal codes" alowed that these, too, are framed In wpty-gendrl terms; while some of them sW. afpplicable to biological pro- ducts, rmnppeofic elements are missing. Obviouslyygtol statements concerning risk, benefit, or consent apply to both medicknand biologicals, but for the conduow atMals on human subjects spe l ave mising. It appoesrs;,e*=Otht the hope of achieving uniformity ofsoWtuoty instruments is rather re- mote. As to trialhon human subjects, again the Declaration of liH nki ems to be the only genral intemrtolnd instrument available. The possibility of 'tw eitence of regional rules needs to be explored, atd, In this respect, the directives of tho lBuropean Economic Com- munity should be *hor studied. We conclude 'tIht -very few common ele- ments exist Inhtb. lgislation of the different countries cosidered which might permit de- velopment of uniform statutes and regulations and that the absence of provisions dealing with the ethical aspects of research on biologicals makes the drawing.up of uniform statutes an impossible task. In trying to find the relevant provisions dealing more specfficaily with the testing of biologicals and the ethical problems which may aris when human subjects are In- volved, the same comment applies to the dif- ferent codes of ethics relating to the use of hu- man subjects, I.e., with reference to biologicas. In spite of the present deficiencies in legisa- tion and codes, we attempted to determine if at least some positive elements could be identified which could serve as a basis for drawing up guidelines relating to biological. This sems possible in a few countries such as the Federal Republic of Germany, Hunpry, Sweden, Switzerland, the United Kingdom, and the United States of America. In the proposed new Division 6 of the draft of the new German Act for instance, Section 8 provides that the neces- sary financial cover to compensate for any harm incurred by the subject during the con- duct of the clinical trial must have been ar- ranged by the investiptor. In relation to the consent which the human subject has to formu- late, it is stated that consent will only be valid if, among other conditions, compenseatory cover is asured by means of insurance or by a finan- cial commitment or signed guarantee by a third party. The cover must be commensurate with the risks entailed by the clinical trial. Where the cover Is provided by insurance, the minimum amount payable in the event of death or per- manent disablement Is 100 000 DM. TIhe Federal Rpublic of GetrAay is one of the countries (others are Hungry, France, Austria, Denmark, and the Gennan Democratic Republic) wich provides compensation in the event of injury resulting from the enforcement of compulsory vaccination schemes. However, again, this does not concern compensation in cases of research, as provided by the new Medi- cines Act. In Hungary, under the provisions of the 1972 Health Law, it is specified that if as a result of a compulsory vaccination or other compulsory epidemliological masure, a citizen 148 Comnmentay: lhe Possibility of Unifoon Statutes and Regulations has suffered damage to his health or physical well-being, has acquired a disability, or has died, the State pays compensation to him or, as the case may be, to his relatives. Compensation for injuries also applies, under the terms of the Health Law, to health measures taken by the health authority; the same provision applies in the German Democratic Republic. One might, perhaps, conclude that the same provisions are applicable to research involving new vaccines if compulsory measures exist. In Sweden, a physician employed at a medi- cal care establishment which has a local ethical comnmttee has to submit the research protocol to that committee for approval. In the absence of a local committee, he must apply to the regional committee. The director of the investi- gation must ensure that the subjects of the cli- nical trials are suitably insured against adverse effects that may occur in connexion with the trials, irrespective of whether the physician or any other person may be made legally responsi- ble for the occurrence of adverse effects. Again it is obvious that the decisions to be taken ap- ply more specifically to problems other than those raised by biologicals under clinical trials. In the Guidelines for Experimental Research on Human Subjects, drawn up by the Swiss Academy of Medical Sciences, Section 6 pro- vides that in the case of experimental studies not primarily undertaken in the interests of the patient, it must be ensured that adequate com- pensation is guaranteed in the event of injury, irrespective of any third party liability coverage of the investigator. The positive elements found in regulations or codes of ethics concern compensation for damages or injuries as a consequence of im- munization or research. In the United Kingdom and in the United States of America, some important elements can be traced in the legisla- tion or codes of ethics which might be used for drawing up guidelines. In the United Kingdom, a sub-committee of the Committee on Safety of Medicines is responsible for giving advice on the safety, quality, and efficacy of biological pro- ducts. In the clinical trial certificate which is prescribed by the 1968 Medicines Act, there are no specific elements relating to the ethical as- pects of the clinical trial. However, in 1964 the Medical Research Council issued a statement re- lating to the responsibility in investipations on human subjects. This contained important ele- ments, some of them relatmg to biological pro- ducts. In fact, in the Section dealing with the "procedures contributing to the benefit of the individual," the following is stated: A category of mnestigtion that has occasionally raised questions in the minds of investigtors is that in which a new preventive, such as a vaccine, is tried. Neces- sarily, preventives are given to people who are not, at the momnent, suffering from the relevant iLness 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 pro- fessional judgment whether the procedure in question offers a better chance of doing so than previously existing measures. In the same document, with regard to con- trolled trials, which are so important in the field of biologicals, there is the following state- ment which obviously applies more to specific clinical tnals on patients but which all the same presents some interest: Such controled 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 co- operation invited. Occasionally, however, to do so is contraindicated. For example, to awaken patients with posibly 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. Be- cause 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. In the USA, the requirements for the li- censing of biological products are the same as those applicable to the licensing of new drugs. These requirements also apply to research generated outside the United States. Of impor- tance in this connexion is information on pre- 149 J.d Moedoome clinical and clinical data which has to be pro- vided in accordance with Part 312 of Sub- chapter D of Title 21 of the Code ofFederal Reguktions. Particular importance is given to the Institutiond Review Committee; two im- portant forms he" been issued relating to this Committee, namely, Form FD-1571 and Form FD-1573. The review by the Institutional Re- view Committee, In accordlance with Part 46 of Title 45 of the Code of Federat Regulations, provides that if the oubjects are exposed to risks, the followiq points have to be con- sidered: 1. The risks to the subject are so outweighed by the sum of the benefit to the subject and the importance of the knowledge to be gained as to warrant a decision to al- low the subject to accept these risks; 2. The rights and welfare of any such sub- jects will be adequately protected; 3. Legally effective infonned consent will be obtained by adequate and appropriate methods in accordance with the provi- sions of this Part; and 4. The conduct of the activity will be re- viewed at timely intervals. In relation to clinical investigations outside the United States, regulations published in the Federal Register of 9 April 1975 specifically refer to the Declaration of Helsinki. 150