Criteria for Guidelines on the Role of the Individual and the Community in the Research, Development, and Use of Biologicals

Criteria for Guidelines on the Role of the Individual and the Communit in the Research, Development, and Use of Biologicals Biologicals differ from drugs and other therapeutic agents in that they have commonly been developed for the prevention of com- municable diseases; they are generally used in healthy people, frequently infants and young children; and they usually provide long-term protection for communities as well as indivi- duals. A special characteristic of biologicals is the need in most instances for large-scale field tests of safety and effectiveness before the pro- duct is licensed. Continuing sureiUance at local, national, and intemational levels of the benefits and risks of biologicals in use is also essential. Both developed and developing countries have need for biologicals and mutually benefi- cial collaboration and partnership could lead to substantive advances. In addition, such colla- boration would help to strengthen the scientific and technical competency of the developing countries. Ihe ethical principles governing all bio-b medical research apply generally to research on biologicals. However, field trials and other tests and evaluations of biologicals pose special con- ditions that contemporary ethical codes for clinical research may not cover adequately. Criteria have therefore been developed to pro- vide guidance for the suitable involvement of human subjects in biologicals research. These criteria are based in principle on the Declaration off Helsinkdi which needs to be aAs revisd by the 29th World Medical Assmbly, Tokyo, Japan, 1975. See abo "Selected Bibliogrphy," page 177. amplified to encompass research in the biologi- cals field, particularly when groups and com- munities are involved. As in all research an es- sential prerequisite is the moral integrity and scientific skill of the investigators. These criteria are desiged to assist govem- ments, agencies, or investigators in developing their own codes of practice when undertaking research in biologicals including field trials. Ihey should also be useful in developing educa- tional and orientation programmes for subjects in field trials and for the community. GENERAL CRITERIA A. National and international bodies, in recog- ning the special characteristics of biologicals research, development, and use, should take in- to account: 1. Procedures to identify systematically the needs for biologicals and the scientific and technical possibilities for their development. This is of particular importance as regards the needs of developing countries and of some special populations at high risk for certain di- seases. 2. Economic and social strategies for sup- porting the research, development, and use of biologicals including the required skilled nmn- power and other essential resources. 3. Social and legislative action to be taken to provide for the needs of subjects involved in biologicals research and recipients of biologicals in eneral use who suffer disabling adverse ef- fects. 173 174 cirita for Guidelines on the Role of e Individubl and the Community in the Resach, Developmant, and Use of Bido,cals B. To enhance progress in research, develop- ment, and u,W.jf., bidogicals, collaboration between nati .#and intemational bodies should be imp $ extend knowledge and experience iZ th elicening field trials of new biologicals and in the continuing surveil- lance of safety and efficacy of products in routine use. Information obtained from these activities should be widely shared. C. National and international bodies should seek to increase public awareness of both the individual and the community benefits that ac- crue from systic use of safe and effective vaccines. They should stress the Importance of public support of, and involvement in, biologi- cals research, developinent, and use as a demon- stration of social respotsibility in health protec- tion. D. Field trials in one country proposed by in- vestigators an.O,popsors from another should be initiated only ofter there has been mutual agreement on the technical details, the ap- propriateness of the tnral in the selected popula- tion of the ho4t'omtry, and the provision of adequate surveWlJweo and evaluation. It is the responsibility of soapvis of field trials, in- vestigators, an4 the authorities of the host country to deal with ethical issues in accord- ance with accepted intemational standards based on the Declartion of Helsinki and the particular ethical concerns of the host country and the communities in which the tnral will take place. Provision sloidd be made for an inter- national body to oifer assistance in technical and ethical review of protocols on request from countries engaged in international trials. SPECI .CRITERIA The following eriteTia require interpretation based on the p-- r needs of countries or bodies planning to use them. No biologcal should be used i himans until it has been judged by evidence from laboratory and animal tests to be safe. CInudance in assuring essential safety can be founa in Appendix I to this Memorandum ("The development of a biologi- cal product before marketiq')jwd in he. "dSelected Bibliography." ' 4 1.Desip of fildtials ; 1. Field trials must be designed toprovide definitive results with regprd' to s&iy and ef-: fectivenessof biologcals. 2. A subgrouip of the eatly-phse partici- pants should be evaluated periodically over many years for evidence of long-term safety and effectiveness. 3. Protocols for field trials must be re- viewed critically by an independbnt review group for evidence of scientific 4uility, as- surances of safety, and full respect for the dipity and integrity of hurnan beings. 4. Protocol review for the protection of the rights of participants at local, national, and in- ternational levels should involve technical and non-technical persons who are competent and responsible members of the community. 5. A sufficient amount of data on safety, potency, and effectiveness must be derived from trials in communities or population groups that in age, sex, and other characteristics are comparable to those expected to be the principal recipients when the product becomes generally available. 6. Field trials should be continuously eval- uated and should be terminated as soon as the results are conclusive. If the product is effec- tive, control groups should receive it as a matter of priority. Results of-trials should be made available to the review committee and, bnce meaningful studies have been comnpleted, made available upon request to interestea persons. l.Humn invovment in fidtd I. Ethical selection of resarch subjects must be made on the basis of their ftee choice amhe organization, execution and evaluation of field trials has been the subject of nunrws publica- tions. See "Sdected Bibliography-BiCklcals docu- ments." Crieia for Guina on the Role of the Indid and the Community 175 in the Research, Dveopment, and Use of Biolocs to participate in studies that offer possible per- sonal and public benefit, and this consent should be recorded before the studies begin. 2. The first administration to human beings should be carried out under careful observation on a small number of persons presumed to be least at risk from the vaccine and in whom a reaction might reasonably be expected to be the least injurious. 3. Consent to participate in biologicals re- search must also be consistent with existing national legal requirements, sociocultural atti- tudes, and professional codes of conduct. Special care must be used in obtaining consent for emotionally or intellectually handicapped individuals living in institutions or other cus- todial environments as well as for prisoners, military personnel, students, and other similar groups whose general freedom of choice to par- ticipate may be questioned.a Parents or legal guardians may give the researchers consent for their minor children to take part if the biologi- cal to be studied is intended for these children's benefit; special care must be used in obtaining consent for children living in institutions or other custodial environments. All these points should receive the particular attention of the review committee. 4. Potential research subjects (or their legal guardians) should be informed of the objectives of the study, including full and clearly intelligi- ble disclosure of the risks of the procedure and the individual and communuty benefits that may be reasonably expected. Since large field trials pose special problems of communication, appropriate information should be disseminated to communities and individuals in a variety of ways and well in advance of, as well as during, the trials. The results should be made available quickly. S. Review of multinational trials should take into account the ethical principles con- tained in accepted international standards based on the Declaration of Helsinki and the parti- cular ethical concerns of the host country and the communities in which the trial will take place. 6. Individuals in any sector of a population should not be excluded from being involved in well conceived field trials of biologicals which are designed for their benefit, unless this is con- trary to existing local statute, regulation, or social custom". m. Surveiance of safety and effectivene I. There must be assurance of a high degree of quality control in the production, distribu- tion, and use of biologicals. 2. There should be continuing assessment of the safety, effectiveness, and patterns of the use of biologicals based on balancing their bene- fits and risks and the alternatives that may have become available. The collection, analysis, and dissemination of data, particularly on safety, on a local, national, and international basis, is es- sential for confdence in recommending their continued use. 3. Efforts should regularly be made to im- prove biologicals. It is recognized that substan- tially modified products may need to be eval- uated in studies in which they are compared with the previous product to determine safety and effectiveness. 4. In order to minimize misuse, health workers involved in immunization programmes should be fully informed of the characteristics of, and contraindications to, the biologicals they are using. aOne participant did not find it possible to subscribe to the statements in these sentences, which he thought were not sufficiently restrictive. 176 Cf ow Gudin on de Role of the Individual and the Community in di Reearch, Dedopment, and Use of BioloCSca Apendix I THE DEVELOPMENT OF A BIOLOGICAL PRODUCT BEFORE MARKETING There are twr4tages for the testing of a new vaccine. stage 1. The development of the "seed" As soon as t*e. etiological agent of an infectious disease has been identified and grown in vitro, the possibility of producing a vacie may be considered. The first stage in development, however, is the production of a "seel" from which future batches of vaccine will be prepared. Frequently a process of attenuation is necessary but eventually a stage is reached when all laboratory tests have been completed and there' has not been evidence of any untoward reaction. At this stage, however, the potential "seed" must be administered to small groups of subjects, including representatives of those in whom the vaccine is most likely to be used. When such tr4als have shown that the "seed" is satisfactory the production of vaccine may be considered and tE pt6duction and testing passes on to Stage 2. Stage 2. The d.i'cprment and testing of the vaccine before larg-scale tuias and mauketi Before a vaccine is subjected to trials in volunteers, the following criteria for the production and testing of the vaccine should be satisfied: 1. The vaccn. sl be produced in premises and by staff in compliance with "The general requirements for the manufacturing establishments and control laboratories."" 2. The vacciwalmall have been made from a seed approved by the national control authority in the country in whidalt is produced. 3. The method of production shall have been approved by the national control aulthority. Tests on the substrate used for the growth of the microorganism, together with any added excipient, shall have shown them to be safe and free from any kind of toxicity. The results of such tests shall be made available. 4. Each batch'bf'the vaccine, identified by batch number, shall have been shown by appropriate in tvo and In'vt'o tests approved by the national control authority to be free from detectable extraneous agents ad' toxiLity.t 5. Whenever posible an animal model should be developed and used for the asay of potency. Where such a model exits the vaccine shall have been shown to protect against challenge or induce a specific antibody rense or state of sensitivity, whichever is appropriate. 6. The maEW shall show consistency of production from tests on serial batches of vaccine. The results of ah4tsts shafull be made available. 7. In those boutAos in which a safety committee exists the vaccine shall have been approved for trial in human beings by that committee. Written approval to this effect shall be made available. Countries without such a committee should establish one as soon as their resources permit. SWHO Technical Report Series, No. 323, 1966, pp. 11-22. tWHO Requirements for the manufacture and control of many vaccines are available upon request to Chief, Biologicals, World Health Organization, 1211 Geneva 27, Switzerland. critenk for Guidelines on the Role of dIe Individual and the Community 177 in the Research, Development, and Us of Didogcal Selctd Bibliography HEALTH CODES AND DECLARATIONS Hippocratic Oath: Dorland's Medical Dictionary, Twenty-fifth edition, Philadelphia, Saunders, 1974. Nuremberg Code: The code was devloped for the medical case at the Nuremberg Trials. United States Adjutant General's Department, Thala of swr crim- nais before Nuremberg Miitary Tribunals under Con- trol Counci Law No. 10 (October 1946-April 1949). T7he medica case Washington DC, US Government Printing Office, 1947, voL 2, pp. 181-183. See dio Ladimer, L & Newman, R.W. Clicl invstlgaptions in mediine: lept, etdical and moral aspects. Boston University, Law-Medicine Research Institute, 1963, p. 116. Declaration of Helsinki: Recommendations guiding nwdical doctors in biomedical research involving hu- man subjects, adopted by the 18th World Medical As- sembly, Helsinki Finland, 1964, and revised by the 29th World Medical Assembly, Tokyo, Japan, 1975. HEALTH AND HUMAN RIGHTS Health aspects of human rights with special reference to developments in biology and medicine: Geneva, World Health Orgnization, 1976. Health aspects of human nghts and scientific and tech- nological developments (preliminary memorandum by the World Health Organization): United Nations Docu- ment A/8055/add. 1, 30 November 1970. International covenant on civil and political rights, adopted by the UN General Assembly Resolution 2200A (XX1), 16 December 1966. Official Records: Twenty-first session, supplement No. 16(A/6316), New York, United Nations, 1967. Science in the contemporary world: the human impli- cations of scientific advance: Repost of meeting of experts on the ethical problems posed by recent pro- gress in biology, Varna, Bulgaria, 1975, Paris, United Nations Educational, Scientific and Cultural Organiza- tion (in press). Recent progress in biology and medicine: its social and ethical implications: 7th CIOMS Round Table Con- ference, Geneva, Council for Intemational OrFniza- tions of Medical Sciences, 1972. Protection of human rights in the light of scientific and technological progress in biology and medicine: 8th CIOMS Round Table Conference, Geneva, World Health Organization, 1974. TESTING AND DEVELOPMENT OF NEW DRUGS Guidelines for evaluation of drugs for use in man: WHO Technical Report Series, No. 563, 1975. Principles for the clinical evaluation of drugs: WHO Technial Report Series, No. 403, 1968. Principles for pre-clinical testing of drug safety: WHO Technical Report Series, No. 341, 1967. Responsibility in investigations on human subjects: Report of the Medical Research CouncDi, 1962-63, London, Her Majesty's Stationery Offce, 1964, pp. 21-25 (Cmnd. 2382). Biomedical science and the dilemma of human experi- mentation: Proceeding of a CIOMS Round Table Conference, Liege, Belgium, Desoer, 1967. BIOLOGICALS DOCUMENTS Pollock, T.M., ed.: Trils of prophylactic agents for the control of communicable diseas. A guide to their organization and evaluation, Geneva, World Health Organization, 1966 (WHO Monograph Seri, No. 52). General requirements for the sterility of biological substances (Requirements for biological substances, No. 6): WVHO Technical report Seris, No. 530, 1973, Annex 4. Requirements for biological substances and other sets of recommendationsl: WHO Technical Report Series, No. 530, 1973, Annex S (including on pages 62-63 a list ofWHO Technical Reports giving specifications for manufacture of specific biologicals). Development of a national control laboratory for bio- logical substances: WHO Technical Report Series, No. 444, 1970, Annex 3. Requirements for biological substances: manui- facturing establishments and control laboratories: WHO Technical Report Series, No. 323, 1966. A 'Code of Conduct' for clinical trials: In: Interna- tional Symposium on Vaccination against Communica- ble Disease, Monaco, 1973, Baslc, Karger, page 392 (Symposia Series in Immunobiological Standardiza- tion, Vol. 22). Study group on randomized trials in preventive medi- cine and health service research-summary report: Copenhagen, WHO Regional Office for Europe, 1975. ISccao Lists ofintemrtional biologicastandards; intenatil bilosical references preparations and in- tenational biological reference reagents, 1977, World Health Organization, 1977.