Ethical Dilemmas in Drug Evaluation Professor K. O'Malley (Royal College of Surgeons in Ireland)
Early on in the evaluation of new drugs one has to study their effects in humans, often both volunters and patients, and it is at this stage that one encounters many ethical difficulties. In addition to the subject who will receive the drugs the investigator and employer or sponsor, other medical staff, nursing staff or other relevant paramedical staff are all in- volved in this process. Before a study is started the local ethic-~ committee is involved as is the government department which regulates the introduction of and monitors the safety of drugs.
One naturally concentrates on the competence of the inves- tigators, not only with regard to their scientific skill, but also to their profesional background which must be adequate to "care" for the patient and deal adequately with any untoward reactions which may occur. The Declaration of Helsinki, which is the most helpful guide to such matters, states clearly (1.3) that "Biomedical research involving human subjects should be conducted only by scientifically qualified persons and under the supervision of a competent medical person. The responsibility for the human subject must always rest with a medically qualified person". The competence of the investi- gator involves their ability to design a study which could yield meaningful data, and to get appropriate advice from statisti- cians etc. not only with regard to design but also on recording of data. They must also include steps to get "informed consent" in so far as this is possible. This can produce prob- lems, as no drug is "100% safe" and one must consider the balance of harm and good which could be caused by the drug under study. The ability to fully explain both aspects of drug action play a part in selection of subjects, and a competent investigator will ensure that compensation has been arranged in the event of an untoward happening. Recent experience of the death of a volunteer following a new benzodiazepine has shown that on occasion such events may not be related to the study.
Honesty, at all stages of a trial, is a requisite for every investigator. Regretfully there have been occasions when there was fraudulent recording of data, or dishonest evalu- ation of results - sometimes showing a bias towards the sponsor. More difficult to assess is honesty in stopping a trial at an appropriate stage and even more difficult at a very early stage. No one likes to "get beaten" or "give up" yet the Nuremberg Code states clearly "During the course of the experiment, the scientist in charge must be prepared to termi- nate.., at any stage ... if he has probably cause to believe.., that
a continuation.., is likely to result in injury, disability or death to the experimental subject". The United States Department of Health Education and Welfare (DHEW) expresses the same guidance in a different way: "The risks to the subject (must be) so outweighed by the sum of the benefit to the subject and the importance of the knowledge to be gained as to allow the subject to accept these risks". If the investigator has reason to suspect that this is not proving so, then the trial must be stopped. One of the more difficult ethical decisions of an enthusiastic investigator is to stop a drug trial.
"Research may not be INITIATED unless the consequence of conducting it is judged likely to produce more good than harm, and it must be TERMINATED if certain harm appears likely".
Good research design is an ethical requirement for any drug trial. It must be sufficiently well designed to achieve its stated purpose and must be scientifically sound. Biomedical re- search involving human subjects must conform to generally accepted scientific principles and should be based on ade- quately performed laboratory and animal experimentation and on a thorough knowledge of the scientific literature. Consideration and approval of the design by a properly con- stituted research ethical committee is now standard practice. They should consider not only the design of the experiment, but its justification in what new information will it produce? The committee should be capable of distinguishing a clinical trial from clinical practice, and be aware of such guiding principles asrandomisation, consent, "double blind admini- stration" as well as adequacy of recording and appropriate analyses of data.
A National Ethics (Medical Research) Committee in Ire- land would have an important role in multicentre trials, would be available for "orphan investigators" (i.e. investigators with no local ethics committee) and would be particularly useful where expertise is limited. Furthermore such a committee would ensure that the public are being protected and that the rights of the individual patients participating in drug trials is fully considered.
Selected References Relman, A. S., Publish or perish - or both. New England Journal of Medicine
1977; 297:724-725 Hamilton, M. T. Invited remarks. Clinical Pharmacology and Therapeutics
1979; 25: 647-648. Levine, R. J., Lebaeqz, K. Some ethical considerations in clinical trials.
Clinical Pharmacology and Therapeutics 1979; 25: 728-741.