Br. J. clin. Pharmac. (1977), 4, 73-76
ETHICAL REVIEW IN THE PHARMACEUTICAL INDUSTRY L.E. RAMSAY,* M.J. TIDDt, J.K. BUTLER & G.R. VENNING Division of Scientific Affairs, G.D. Searle & Co. Ltd, Lane End Road, High Wycombe, Buckinghamshire, HP12 4HL
1 There seems no reason why clinical pharmacology studies conducted within the pharmaceutical industry should be exempt from the requirement of ethical review, and independent review in this situation reduces the vulnerability of the company and its employees, in addition to serving its primary function of protecting the volunteer subjects. 2 Experience within one company has shown that independent ethical review need not seriously influence the pace of research. 3 It is important that such committees should be seen to be independent and competent.
Introduction An increasing number of clinical pharmacology studies have been conducted in healthy subjects, and many are performed within the pharmaceutical industry under the supervision of workers who are in the full-time employ of drug manufacturers. Recognizing potential problems in this situation, the Association of the British Pharmaceutical Industry (ABPI) appointed an expert committee to advise on the conduct of experiments in staff volunteers within the industry. The report of this committee (ABPI, 1971) provides useful guidance for clinical pharmacologists within the industry and an account of the practice of clinical pharmacology within this framework has been published (Munro-Faure, 1973).
The case for independent protocol review The ABPI expert committee (1971) had to consider as one of its terms of reference 'the advisability of seeking clearance from an independent body (such as the Toxicity Sub-Committee of the Committee on Safety of Drugs)' for tests on staff volunteers. The only reference to this question in the committee's report is found in its conclusion: 'It is felt that control of the pace of research might be seriously affected by the delay which would occur if prior approval of the Committee on Safety of Drugs was soug}t Providing that the safeguards outlined in Section 4 * Present address: Gardiner Institute of Medicine, Western
Inflrmary, Glasgow, G 1 6NT. t Present address: Syntex Research Centre, Research Park, Heriot-Watt University, Riccarton, Edinburgh, EH14 4AS.
are adopted the Committee sees no reason for reference of the protocol of the initial experiments on man to the Committee on Safety of Drugs'. In the report there is no indication that the expert committee considered the advisability of seeking clearance from an independent body other than the Committee on Safety of Drugs. The chairman of the expert committee later wrote that 'outside industry, tests on volunteers or on patients must have been considered by a responsible local ethical committee' (Stuart-Harris, 1973), but gave no reason why experiments within industry should be exempt. In the United States the Food and Drug Administration have stated that clinical pharmacology units on the premises of a pharmaceutical firm 'are not considered institutions, (and) committee review is not required' (F.D.A., 1975), although emphasis was placed on the desirability of ethical review, whether or not required. Again it is not clear why the authors did not make specific recommendations or define the requirements in detail. Views to the contrary have been expressed. Laurence (1964) implied that some check on experimentation within the pharmaceutical industry was needed in his statements that 'the necessity for an industrial promoter to convince an independent worker of the need for such trials acts as a desirable safeguard' and 'for at least one investigator the chief motives should be neither commercial profit or academic interest'. More recently Feldmann (1972) suggested that 'Pharmaceutical manufacturers may need to consider the possibility of setting up ethics review committees analogous to those suggested for hospitals.... A
74
L.E. RAMSAY, M.J. TIDD, J.K. BUTLER & G.R. VENNING
group of medical and non-medical personnel, representing both the organization and the outside public, might ensure continued public support of research activities which require volunteers, as well as provide an additional check on the methods and techniques being employed in these studies'. There are additional reasons for seeking indepe-ndent ethical review of protocols. Review may be necessary to ensure acceptance of the experiments not only by the general public (Feldman, 1972), but also by the volunteers themselves, and by the editors of medical or scientific journals should the clinical pharmacologist in industry wish to publish his results. Although the primary function of ethical review is protection of the subjects participating in the studies, it would also serve to reduce the vulnerability of the investigator, who is well aware that 'the consequences of any mishap will be visited with especial severity on a drug firm undertaking clinical experimentation' (Laurence, 1964). Although the experiment remains fully the responsibility of the investigator regardless of peer group approval (Tyrrell, 1973) it seems clear that such approval would be to the investigator's advantage in the event of a mishap, provided of course that the nature and risks of the experiment had not been misrepresented to the ethical review committee. Finally, the existence of an independent ethical review procedure may be of value when considering the difficult problem of payment to volunteers. Such payment has generally been considered ethically justifiable (ABPI, 1971;
Munro-Faure, 1973; Stuart-Harris, 1973; Laurence, 1964; Tyrrell, 1973). However, it is difficult in practice to reconcile one recommendation, that the amount paid should be reasonably related to the effort and discomfort anticipated (ABPI, 1971), with another, that the material rewards should not constitute an inducement to participate in the studies (Stuart-Harris, 1973; Tyrrell, 1973). It is obvious that a very small sum of money may constitute an inducement to those potential volunteers who need it badly, and conversely that much larger sums of money may be necessary to adequately compensate volunteers participating in some studies, for example those involving prolonged dietary restriction, numerous venepunctures, or frequent attendance outside normal working hours. A realistic approach to this problem was offered in a report of a WHO Scientific Group (1968): 'In some places, subjects may be rewarded for participation in research, sometimes to encourage participation and at other times as an incidental reward. To ensure that rewards do not induce subjects to submit to unreasonable hazards, persons not involved in the research should review the protocol and decide the
advisability of the study independently of considerations of reward'. In this view the investigator can offer financial rewards which relate realistically to the efforts involved, provided that the protocol has first been approved by an independent ethical review committee.
Practical aspects In view of these considerations it was decided that independent review of protocols would be desirable for clinical pharmacology studies conducted in the Division of Scientific Affairs of G.D. Searle and Co. Ltd, High Wycombe, U.K. A senior consultant physician in a nearby hospital agreed to act as chairman and the composition of an ethical review committee was agreed. As far as possible in the circumstances the principles outlined by the Royal College of Physicians (1973) were followed. The committee has medical, non-medical scientific and lay representation. Half of the members have some connection with the Company, although not with the division conducting the studies, but in the event of disagreement the final decision would rest with the independent committee chairman. After reviewing the current standards of practice of clinical pharmacology within the company the committee agreed to undertake ethical review of protocols, and has now done so for over 1 year. Protocols are channelled to the committee through the physician in charge of the Department, after he has given his own approval. The same physician arranges committee meetings as required (rather than at regular intervals) and attends the meetings to respond to queries. The investigator who is responsible for the proposed study may also attend if required. During the first year, the committee met five times and reviewed fourteen protocols. Williams (1973) has questioned how one may judge the value of the work of an ethical committee, and concern has also been expressed that such committees may perform their duties in a perfunctory manner (F.D.A., 1975). To date, no protocol has been rejected by the committee, but this is a poor yardstick since the experimental proposals, like those described by Munro-Faure (1973), would generally be considered suitable. Modifications to protocols have been requested, and the committee has also been responsible for changes in general procedures such as that for obtaining informed consent. Beyond these general observations we have no way of judging the performance of the committee or of comparin4it with that of ethical committees in other
ETHICAL REVIEW IN THE PHARMACEUTICAL INDUSTRY
institutions. From the point of view of the company the committee has adopted a flexible approach and has proved willing to review at short notice any protocol which was considered urgent. Protocol review has not seriously affected the pace of research, a concern expressed by the ABPI Expert Committee (1971). Discussion
Ethical review of protocols for experimental studies with drugs satisfies the need for an investigator to ask whether his assessment of all the possible toxic as well as beneficial effects is shared by others with competence and experience (Williams, 1972), and such review is now recommended in medical institutions in Britain. The Royal College of Physicians (1973) suggested that an Ethical Committee should be small, should contain a lay member, should not hinder the advance of medical knowledge unreasonably and should be responsible to the institution conducting the research. The question of independence of the Ethical Committee from the department or institution was not considered. The practice in medical schools and hospitals at the present time is quite variable. The Ethical Committee may consist of the head of the department or institution, or of other physicians from the same department, may or may not contain a layman and may or may not be truly independe t of the institution conducting the research. The College included non-therapeutic experiments but did not consider it necessary for Ethical Committees to review new experimental treatments involving surgery, radiotherapy or the use of isotopes, but only drugs. We see no reason to exclude such forms of experimentation from our Ethical Committee which will review protocols, if the occasion arises, for experiments with new devices such as invasive monitoring equipment.
In the pharmaceutical industry there are additional problems related to the financial interest of the institution in the conduct of the experiments. We consider this unlikely to lead to any more bias than, for instance, the vested interests of institutional investigators in furthering academic knowledge and their own careers, but quite apart from this physicians in industry have a special need to ensure that experiments on employees are scientifically and ethically justifiable and are clearly seen to be justifiable. The synonym 'peer review' implies that an ethical committee should include members who have experience and knowledge in the field of investigation being considered. The types of study conducted within the pharmaceutical industry tend to be highly specialized, and the competence
75
of the committee described might be questioned on the grounds that no member has specialist knowledge of clinical pharmacology. Addition of an academic clinical pharmacologist to the committee could possibly enhance its competence to undertake ethical review. Unfortunately true 'peers' outside the industry are not plentiful in Britain, and they might not be able to devote the time required to perform this task. In addition to competence an ethical committee needs to have both independence and authority (Williams, 1973). From a practical point of view we feel that the committee described above satisfies these criteria, but we are also aware that this system of protocol review might be criticized theoretically on each of these grounds. Half of the committee have some link with the Company, and it may be argued that the deliberations of the committee could be biased by their inclusion. In practice those members of the committee connected with the Company have proved at least as critical as the independent members, and have also contributed through their knowledge of conditions within the Company. In addition, the final decision in the event of a conflict lies with the independent chairman. It has been considered that 'involvement of manufacturers in the formation and financing of review committees may lead to lack of objectivity in selection of committee members and possibly in evaluations of individual protocols. It would be preferable . . . that such committees be formed by local branches of medical societies' (F.D.A., 1975). The committee described above was formed through direct approach to an individual with a known reputation for integrity, commonsense and good medical judgement. If we had approached a local medical society or hospital committee the likelihood of correctly identifying an appropriate individual would have been lessened, and we might well have finished up with a committee lacking the right type of leadership or the necessary technical competence. Perhaps in years to come, when more physicians have had experience of this type of work a direct approach to recruitment will no longer be necessary. The question of financing the review committee has not arisen since the members have generously performed the task without any form of recompense. The authority of the committee stems entirely from an assurance given by the company that all research proposals would be submitted for review and that all recommendations of the committee would be heeded. We wish to express our gratitude to the members of the ethical committee, who have voluntarily and conscientiously devoted their time to reviewing protocols.
76
L.E. RAMSAY, M.J. TIDD, J.K. BUTLER & G.R. VENNING
References ASSOCIATION OF THE BRITISH PHARMACEUTICAL INDUSTRY (1971). The report of the committee to investigate medical experiments on staff volunteers. FELDMAN, E.S. (1972). Ethics and morality in drug
research. J. pharm. Sci., 61, 1. FOOD & DRUG ADMINISTRATION, Department of Health Education, and Welfare (1975). New drugs for investigational use. Federal Regiter, 40, (69), 16053-16057. LAURENCE, D.R. (1964). First clinical trials of potential drugs. In Evaluation of Drug Activities: Pharnnacometrics., I, ed. Laurence, D.R. & Bacharach, A.L., pp. 3-22. Academic Press: London & New York. MUNRO-FAURE, A.D. (1973). Relationship between industry and clinical pharmacology departments. In International Aspects of Drug Evaluation and Usage, ed. Jouhar, A.J. & Grayson, M.F., pp. 79-84. Churchill Livingstone: Edinburgh & London. ROYAL COLLEGE OF PHYSICIANS (1973). Committee
on the Supervision of the Ethics of Clinical Research Investigations in Institutions. H.M.S.O. STUART-HARRIS, C. (1973). Medicolegal aspects of the evaluation of new drugs. In International Aspect of Drug Evaluations and Usage, ed. Jouhar, A.J. & Grayson, M.F., pp. 205-210. Churchill Livingstone: Edinburgh & London. TYRRELL, D.A.J. (1973). Some ethical and other aspects of the use of volunteers in pharmaceutical research. In Intemational Aspects of Drug Evaluation and Usage, ed. Jouhar, A.J. & Grayson, M.F., pp. 211-215. Churchill Livingstone: Edinburgh & London. WILLIAMS, R. (1973). Research investigations in adults. Br. med. J., 2, 220-224. WORLD HEALTH ORGANISATION SCItNTIFIC GROUP. (1968). Principles for the clinical evaluation of drugs. Wld. Hlth. Orgn. techn. Rep. Ser. No. 403.
(Received April 1, 1976)
ETHICAL REVIEW IN THE PHARMACEUTICAL INDUSTRY L.E. RAMSAY,* M.J. TIDDt, J.K. BUTLER & G.R. VENNING Division of Scientific Affairs, G.D. Searle & Co. Ltd, Lane End Road, High Wycombe, Buckinghamshire, HP12 4HL
1 There seems no reason why clinical pharmacology studies conducted within the pharmaceutical industry should be exempt from the requirement of ethical review, and independent review in this situation reduces the vulnerability of the company and its employees, in addition to serving its primary function of protecting the volunteer subjects. 2 Experience within one company has shown that independent ethical review need not seriously influence the pace of research. 3 It is important that such committees should be seen to be independent and competent.
Introduction An increasing number of clinical pharmacology studies have been conducted in healthy subjects, and many are performed within the pharmaceutical industry under the supervision of workers who are in the full-time employ of drug manufacturers. Recognizing potential problems in this situation, the Association of the British Pharmaceutical Industry (ABPI) appointed an expert committee to advise on the conduct of experiments in staff volunteers within the industry. The report of this committee (ABPI, 1971) provides useful guidance for clinical pharmacologists within the industry and an account of the practice of clinical pharmacology within this framework has been published (Munro-Faure, 1973).
The case for independent protocol review The ABPI expert committee (1971) had to consider as one of its terms of reference 'the advisability of seeking clearance from an independent body (such as the Toxicity Sub-Committee of the Committee on Safety of Drugs)' for tests on staff volunteers. The only reference to this question in the committee's report is found in its conclusion: 'It is felt that control of the pace of research might be seriously affected by the delay which would occur if prior approval of the Committee on Safety of Drugs was soug}t Providing that the safeguards outlined in Section 4 * Present address: Gardiner Institute of Medicine, Western
Inflrmary, Glasgow, G 1 6NT. t Present address: Syntex Research Centre, Research Park, Heriot-Watt University, Riccarton, Edinburgh, EH14 4AS.
are adopted the Committee sees no reason for reference of the protocol of the initial experiments on man to the Committee on Safety of Drugs'. In the report there is no indication that the expert committee considered the advisability of seeking clearance from an independent body other than the Committee on Safety of Drugs. The chairman of the expert committee later wrote that 'outside industry, tests on volunteers or on patients must have been considered by a responsible local ethical committee' (Stuart-Harris, 1973), but gave no reason why experiments within industry should be exempt. In the United States the Food and Drug Administration have stated that clinical pharmacology units on the premises of a pharmaceutical firm 'are not considered institutions, (and) committee review is not required' (F.D.A., 1975), although emphasis was placed on the desirability of ethical review, whether or not required. Again it is not clear why the authors did not make specific recommendations or define the requirements in detail. Views to the contrary have been expressed. Laurence (1964) implied that some check on experimentation within the pharmaceutical industry was needed in his statements that 'the necessity for an industrial promoter to convince an independent worker of the need for such trials acts as a desirable safeguard' and 'for at least one investigator the chief motives should be neither commercial profit or academic interest'. More recently Feldmann (1972) suggested that 'Pharmaceutical manufacturers may need to consider the possibility of setting up ethics review committees analogous to those suggested for hospitals.... A
74
L.E. RAMSAY, M.J. TIDD, J.K. BUTLER & G.R. VENNING
group of medical and non-medical personnel, representing both the organization and the outside public, might ensure continued public support of research activities which require volunteers, as well as provide an additional check on the methods and techniques being employed in these studies'. There are additional reasons for seeking indepe-ndent ethical review of protocols. Review may be necessary to ensure acceptance of the experiments not only by the general public (Feldman, 1972), but also by the volunteers themselves, and by the editors of medical or scientific journals should the clinical pharmacologist in industry wish to publish his results. Although the primary function of ethical review is protection of the subjects participating in the studies, it would also serve to reduce the vulnerability of the investigator, who is well aware that 'the consequences of any mishap will be visited with especial severity on a drug firm undertaking clinical experimentation' (Laurence, 1964). Although the experiment remains fully the responsibility of the investigator regardless of peer group approval (Tyrrell, 1973) it seems clear that such approval would be to the investigator's advantage in the event of a mishap, provided of course that the nature and risks of the experiment had not been misrepresented to the ethical review committee. Finally, the existence of an independent ethical review procedure may be of value when considering the difficult problem of payment to volunteers. Such payment has generally been considered ethically justifiable (ABPI, 1971;
Munro-Faure, 1973; Stuart-Harris, 1973; Laurence, 1964; Tyrrell, 1973). However, it is difficult in practice to reconcile one recommendation, that the amount paid should be reasonably related to the effort and discomfort anticipated (ABPI, 1971), with another, that the material rewards should not constitute an inducement to participate in the studies (Stuart-Harris, 1973; Tyrrell, 1973). It is obvious that a very small sum of money may constitute an inducement to those potential volunteers who need it badly, and conversely that much larger sums of money may be necessary to adequately compensate volunteers participating in some studies, for example those involving prolonged dietary restriction, numerous venepunctures, or frequent attendance outside normal working hours. A realistic approach to this problem was offered in a report of a WHO Scientific Group (1968): 'In some places, subjects may be rewarded for participation in research, sometimes to encourage participation and at other times as an incidental reward. To ensure that rewards do not induce subjects to submit to unreasonable hazards, persons not involved in the research should review the protocol and decide the
advisability of the study independently of considerations of reward'. In this view the investigator can offer financial rewards which relate realistically to the efforts involved, provided that the protocol has first been approved by an independent ethical review committee.
Practical aspects In view of these considerations it was decided that independent review of protocols would be desirable for clinical pharmacology studies conducted in the Division of Scientific Affairs of G.D. Searle and Co. Ltd, High Wycombe, U.K. A senior consultant physician in a nearby hospital agreed to act as chairman and the composition of an ethical review committee was agreed. As far as possible in the circumstances the principles outlined by the Royal College of Physicians (1973) were followed. The committee has medical, non-medical scientific and lay representation. Half of the members have some connection with the Company, although not with the division conducting the studies, but in the event of disagreement the final decision would rest with the independent committee chairman. After reviewing the current standards of practice of clinical pharmacology within the company the committee agreed to undertake ethical review of protocols, and has now done so for over 1 year. Protocols are channelled to the committee through the physician in charge of the Department, after he has given his own approval. The same physician arranges committee meetings as required (rather than at regular intervals) and attends the meetings to respond to queries. The investigator who is responsible for the proposed study may also attend if required. During the first year, the committee met five times and reviewed fourteen protocols. Williams (1973) has questioned how one may judge the value of the work of an ethical committee, and concern has also been expressed that such committees may perform their duties in a perfunctory manner (F.D.A., 1975). To date, no protocol has been rejected by the committee, but this is a poor yardstick since the experimental proposals, like those described by Munro-Faure (1973), would generally be considered suitable. Modifications to protocols have been requested, and the committee has also been responsible for changes in general procedures such as that for obtaining informed consent. Beyond these general observations we have no way of judging the performance of the committee or of comparin4it with that of ethical committees in other
ETHICAL REVIEW IN THE PHARMACEUTICAL INDUSTRY
institutions. From the point of view of the company the committee has adopted a flexible approach and has proved willing to review at short notice any protocol which was considered urgent. Protocol review has not seriously affected the pace of research, a concern expressed by the ABPI Expert Committee (1971). Discussion
Ethical review of protocols for experimental studies with drugs satisfies the need for an investigator to ask whether his assessment of all the possible toxic as well as beneficial effects is shared by others with competence and experience (Williams, 1972), and such review is now recommended in medical institutions in Britain. The Royal College of Physicians (1973) suggested that an Ethical Committee should be small, should contain a lay member, should not hinder the advance of medical knowledge unreasonably and should be responsible to the institution conducting the research. The question of independence of the Ethical Committee from the department or institution was not considered. The practice in medical schools and hospitals at the present time is quite variable. The Ethical Committee may consist of the head of the department or institution, or of other physicians from the same department, may or may not contain a layman and may or may not be truly independe t of the institution conducting the research. The College included non-therapeutic experiments but did not consider it necessary for Ethical Committees to review new experimental treatments involving surgery, radiotherapy or the use of isotopes, but only drugs. We see no reason to exclude such forms of experimentation from our Ethical Committee which will review protocols, if the occasion arises, for experiments with new devices such as invasive monitoring equipment.
In the pharmaceutical industry there are additional problems related to the financial interest of the institution in the conduct of the experiments. We consider this unlikely to lead to any more bias than, for instance, the vested interests of institutional investigators in furthering academic knowledge and their own careers, but quite apart from this physicians in industry have a special need to ensure that experiments on employees are scientifically and ethically justifiable and are clearly seen to be justifiable. The synonym 'peer review' implies that an ethical committee should include members who have experience and knowledge in the field of investigation being considered. The types of study conducted within the pharmaceutical industry tend to be highly specialized, and the competence
75
of the committee described might be questioned on the grounds that no member has specialist knowledge of clinical pharmacology. Addition of an academic clinical pharmacologist to the committee could possibly enhance its competence to undertake ethical review. Unfortunately true 'peers' outside the industry are not plentiful in Britain, and they might not be able to devote the time required to perform this task. In addition to competence an ethical committee needs to have both independence and authority (Williams, 1973). From a practical point of view we feel that the committee described above satisfies these criteria, but we are also aware that this system of protocol review might be criticized theoretically on each of these grounds. Half of the committee have some link with the Company, and it may be argued that the deliberations of the committee could be biased by their inclusion. In practice those members of the committee connected with the Company have proved at least as critical as the independent members, and have also contributed through their knowledge of conditions within the Company. In addition, the final decision in the event of a conflict lies with the independent chairman. It has been considered that 'involvement of manufacturers in the formation and financing of review committees may lead to lack of objectivity in selection of committee members and possibly in evaluations of individual protocols. It would be preferable . . . that such committees be formed by local branches of medical societies' (F.D.A., 1975). The committee described above was formed through direct approach to an individual with a known reputation for integrity, commonsense and good medical judgement. If we had approached a local medical society or hospital committee the likelihood of correctly identifying an appropriate individual would have been lessened, and we might well have finished up with a committee lacking the right type of leadership or the necessary technical competence. Perhaps in years to come, when more physicians have had experience of this type of work a direct approach to recruitment will no longer be necessary. The question of financing the review committee has not arisen since the members have generously performed the task without any form of recompense. The authority of the committee stems entirely from an assurance given by the company that all research proposals would be submitted for review and that all recommendations of the committee would be heeded. We wish to express our gratitude to the members of the ethical committee, who have voluntarily and conscientiously devoted their time to reviewing protocols.
76
L.E. RAMSAY, M.J. TIDD, J.K. BUTLER & G.R. VENNING
References ASSOCIATION OF THE BRITISH PHARMACEUTICAL INDUSTRY (1971). The report of the committee to investigate medical experiments on staff volunteers. FELDMAN, E.S. (1972). Ethics and morality in drug
research. J. pharm. Sci., 61, 1. FOOD & DRUG ADMINISTRATION, Department of Health Education, and Welfare (1975). New drugs for investigational use. Federal Regiter, 40, (69), 16053-16057. LAURENCE, D.R. (1964). First clinical trials of potential drugs. In Evaluation of Drug Activities: Pharnnacometrics., I, ed. Laurence, D.R. & Bacharach, A.L., pp. 3-22. Academic Press: London & New York. MUNRO-FAURE, A.D. (1973). Relationship between industry and clinical pharmacology departments. In International Aspects of Drug Evaluation and Usage, ed. Jouhar, A.J. & Grayson, M.F., pp. 79-84. Churchill Livingstone: Edinburgh & London. ROYAL COLLEGE OF PHYSICIANS (1973). Committee
on the Supervision of the Ethics of Clinical Research Investigations in Institutions. H.M.S.O. STUART-HARRIS, C. (1973). Medicolegal aspects of the evaluation of new drugs. In International Aspect of Drug Evaluations and Usage, ed. Jouhar, A.J. & Grayson, M.F., pp. 205-210. Churchill Livingstone: Edinburgh & London. TYRRELL, D.A.J. (1973). Some ethical and other aspects of the use of volunteers in pharmaceutical research. In Intemational Aspects of Drug Evaluation and Usage, ed. Jouhar, A.J. & Grayson, M.F., pp. 211-215. Churchill Livingstone: Edinburgh & London. WILLIAMS, R. (1973). Research investigations in adults. Br. med. J., 2, 220-224. WORLD HEALTH ORGANISATION SCItNTIFIC GROUP. (1968). Principles for the clinical evaluation of drugs. Wld. Hlth. Orgn. techn. Rep. Ser. No. 403.
(Received April 1, 1976)
