The inaugural training conference for Research Ethics Committees dealing with Phase I volunteer studies took place in November 1996; the second conference in 1997, and looks set to become a popular annual event. The catalyst for this initiative was the ABPI under whose auspices a working party was set up under the chairmanship of Professor Tony Birmingham, Emeritus Professor of Pharmacology, University of Nottingham. A research ethics committee has the dual function of preventing unethical exposure of the subject to either hazard or invasion of privacy and also to approve ethical attempts to identify improved treatments. The purpose of the venture was to address certain ethical issues which had emerged as giving cause for concern in the work done by ethics committees and to provide a much needed opportunity to share the considerable expertise within the same, given that they work in isolation in different parts of the country. A training programme for new members was also identified as a need. The main themes on which the organisers have focused are legal and ethical issues, the recruitment and treatment of volunteers and toxicology and drug development.
The inaugural training conference for Research Ethics Committees dealing with Phase I volunteer studies took place in November 1996; the second conference in 1997, and looks set to become a popular annual event. The catalyst for this initiative was the ABPI under whose auspices a working party was set up under the chairmanship of Professor Tony Birmingham, Emeritus Professor of Pharmacology, University of Nottingham. A research ethics committee has the dual function of preventing unethical exposure of the subject to either hazard or invasion of privacy and also to approve ethical attempts to identify improved treatments. The purpose of the venture was to address certain ethical issues which had emerged as giving cause for concern in the work done by ethics committees and to provide a much needed opportunity to share the considerable expertise within the same, given that they work in isolation in different parts of the country. A training programme for new members was also identified as a need. The main themes on which the organisers have focused are legal and ethical issues, the recruitment and treatment of volunteers and toxicology and drug development.
Professor Laurie Prescott, (Chairman, SmithKline Beecham Committee) opened the inaugural conference by giving a short discourse on the history of clinical research ethics. This ranged from the inhuman practices of Nazi Germany to more recent instances of fraud and misconduct in clinical trials. Unethical practices cannot be said to have been relegated to antiquity, they can and have tarnished modern research initiatives. The tenor of his argument was that ethics committees provide a vital safeguard in ensuring that research is open to scrutiny, thereby protecting the interests of the volunteer.
This theme was further developed by Ms Anne Somerville (BMA, London) when she dealt with major ethical problems which arise in the context of research studies, giving examples of fraud and misconduct in research which ranged from radiation experiments in America which took place without patients’ knowledge or consent, to more recent instances of GPs forging patients’ signatures on consent forms and prescribing drugs without telling them. She argued that the volunteer’s consent is an ethical prerequisite. In order to act ethically in obtaining that consent the clinician must impart adequate information regarding:
the nature, duration and purpose of the study
the method and means by which it is to be carried out and
the effects on health to be expected.
Recent research suggests that questions of knowledge and consent are not adequately addressed by researchers as 25% of the subjects interviewed did not know that they were participating in a clinical trial whereas 18% mistakenly believed that they were. The subject’s consent may also be compromised by financial inducements which may encourage the volunteer either to be less than frank about their health or to volunteer for multiple studies simultaneously which would be likely both to endanger their health and invalidate the studies in question.
The subject of ethics was revisited in 1997 when the main meeting began with a plenary lecture by Professor John Harris, the Sir David Alliance Professor of Bioethics at the University of Manchester, on the subject ‘The Principles of Medical Ethics—Medical Research on Healthy Volunteers’. Professor Harris defined the first principle of research ethics as an individual’s entitlement to the concern, respect and protection of the community and this should not be affected by his/her status as a research subject. This principle is an application of a more general principle, the equality principle, whereby each person is entitled to the same concern, respect and protection of society as is accorded to any other person in the community. He continued by suggesting that research ethics committees need training in ethics and thus supported the concept behind the conference.
The first principle of ethics previously outlined is an expression of respect for persons which involves four important elements:
Concern for the welfare of others
Respect for their wishes
Respect for the intrinsic value of their lives
Respect for their interests
However, it is important that these four elements are understood and prioritised. Professor Harris concluded by indicating that we all benefit from living in a society in which medical research is carried out and which utilises the benefits of past research. The practicalities of dealing with volunteers were discussed by Ms Penny Thorne, (SmithKline Beecham), who spoke on the ‘Principles of Recruitment—the Reward and Registration of Volunteers’. Her ideal volunteer would be 18–45 years old with no previous medical or family history; s/he would be available on any study day offered, have a pleasant personality, and be quick to understand instructions. Ms Thorne continued by considering the frequently debated pros and cons of using internal company volunteers or external ones. Internal volunteers provide a stable population with a longer medical history, and it is often easier for them to make return visits, but the numbers may be restricted and they could be biased towards the company. External volunteers can be selected from a larger population but may be lost to follow up and are more likely to be members of other panels.
Important information that needs to be considered when taking on a healthy volunteer for a trial includes the distance they live from the unit, how long they have been registered with their GP, what their time commitments are and whether they take recreational drugs. With regard to payment of volunteers, factors that need to be considered include the inconvenience and number of investigations, time spent in the unit, and restrictions on driving and exercise. Other issues regarding payment include payment for volunteers who knowingly violate the protocol and payment of a retainer if the unit runs a panel of volunteers. It was an overriding principle, which was strongly endorsed by delegates, that payment should never be made on a risk basis but should, as is presently the case, be calculated on the number of procedures involved in the study and the inconvenience or discomfort to which the subject is exposed. Future issues that need to be considered are whether a central register of volunteers should be developed in the UK. This would only be useful if all units carrying out Phase I trials were involved but there would be difficulties in maintaining and administering such a database. Data protection issues would need to be considered and it was thought that such a database should have ABPI approval.
Mrs Christine Bendall (McKenna and Co., London) addressed the legal issues which arise from the standpoint of the investigator, the sponsor and other interested parties such as ethics committees, regulators, research sites and society as a whole. The main legal issues in research concern the protection of the human subject, regulatory compliance and ownership and protection of discoveries. Her paper concentrated on the protection of the human subject in respect of consent, confidentiality and compensation. The ABPI guidelines insist that compensation for volunteers in Phase I trials should be on a ‘no fault’ basis.
Drug development has been a recurring theme at these conferences. An interesting insight into the critical path of drug development was provided by Dr Nigel Baber (Glaxo Wellcome, Greenford). A series of detailed flow charts gave delegates a clearer understanding of the manner in which drug development is managed. Research and development are integrated but normally managed separately. The goal of drug development is to achieve swift and safe registration and marketing of a novel drug substance. The objective of drug development is to evaluate safety, efficacy and value of a novel drug substance. Development is not linear because there is often overlap between several phases of development. The animal and human trials are proceeding in tandem so that each satisfactorily completed stage of the animal trials enables a further stage to take place in the human volunteer trials. From the initial idea for a compound to putting a drug on the market takes 10–12 years and costs over £200 million.
Professor Anthony Dayan (St Bartholomew’s Hospital, London), in an elegant and succinct paper entitled, ‘The Purpose, Design and Interpretation of Toxicology Studies’, succeeded in reducing a complex and technical subject to one which was comprehensible even by the non-scientific members of the audience. He outlined the main aims of toxicity testing, which are to detect toxic effects in vivo and in vitro, to identify the circumstances of occurrence and from this to predict whether the effect would occur in human beings, its severity or importance and whether it is reversible and/or treatable. He then dwelt on the interpretation of the toxicity test data by the toxicologist and enumerated five instances when he considered that independent toxicological advice should be sought by an ethics committee:
where there is the danger of harm which is irreversible, for example, genetic or cancer
where there are low dose effects
where there are serious unanticipated effects in animals which are not explained, such as, a scatter of deaths not related to the known properties of the substance
where there is a sensitising potential from a single or small number of doses which could potentially produce a lifelong effect and
first in man studies.
This guidance will prove invaluable to members of ethics committees dealing with Phase I studies and will give them renewed confidence and security in dealing with these extremely difficult issues.
The final lecture at the 1997 conference was given by Dr Trevor Jones, the Director-General of the ABPI on the topic ‘Biotechnology and New Drug Development’. This was a tour de force covering the likely innovations in drug development over the next 5–10 years, but particularly in the field of genomics. Clearly these new developments present novel issues for ethics committees to consider and the first ones to consider them will be those committees involved with Phase I work. In particular, the lay members of committees present found Dr Jones’s presentation stimulating and there have been a number of requests for this pioneering work in new drug development to be deliberated at future meetings.
One of the most interesting and valuable aspects of the conferences have been the workshops attended by all delegates in rotation at which participants were able to share their expertise and debate areas of common difficulty. The 1996 workshops were coordinated by Dr Malcolm Eve (Pfizer), Dr Andrew Williams (Zeneca Pharmaceuticals), Dr Frank Wells (former Medical Director, ABPI), Mrs Claire Foster (Centre of Medical Law and Ethics, Kings College, London), Miss Kathy Doyle (Chairman, Zeneca Committee) and Professor Laurie Prescott. The topics covered, all of which gave rise to lively debate, included: selection and screening of volunteers; protocol content: are there special issues for Phase I studies; informed consent: what are the important elements.
Two developments of major importance which came out of the conferences were the Handbook for new members and the training session designed specifically for new members provided in the morning session before the start of the main conference.
A Handbook for new members of ethics committees, prepared by Dr Michael Goggin (Canterbury LREC), was debated in a workshop during the inaugural conference. The purpose of the document, which has now been published as a booklet by the ABPI [1], is to provide fundamental information for new members of ethics committees about the structure and workings of the committees and the more common problems which arise. Previously new members have had little or no initial training and this was seen as a matter which required urgent attention. The document was well received by delegates whose suggestions shaped the final form of the booklet.
Further provision for new members consists of the introductory seminar which will precede all future conferences covering the following topics: being a member of a research ethics committee, a structured review of a protocol, an introduction to toxicology and some likely areas of difficulty.
An important issue which was considered by the delegates concerned the constitution and administration of ethics committees. The groups felt that Phase I research ethics committees should consider themselves accountable to the volunteers, the general public, the pharmaceutical company or the health authority, the good name of the institution, and their own personal and professional standards. It was vital to guarantee that these committees were totally independent, irrespective of their servicing arrangements, and steps should be taken to ensure that their independence is not compromised in any way.
With regard to the composition of the committees, a number of professions are at present represented. The health professionals included hospital consultants, GPs, nurses, pharmacologists and/or pharmacists. The lay professions included teachers, lawyers, the clergy, architects and policemen. It was agreed that a volunteer would be a useful addition to membership. The method of selecting members for ethics committees varies widely between companies. The most popular was by the committee itself with accreditation coming from the sponsor. Certainly committees should not feel hidebound by company proposals. As far as payment of members of committees was concerned it was clear that there was wide variation. Some members are paid directly, the figure ranging from £500–£2700 per annum when other committees receive a sum to be donated to charities of the committee’s choosing.
For 1997 a workshop session was devoted to consideration of problem protocols which had been developed from real examples by Professor Laurie Prescott and Dr Jim Milledge, the Chairman of the GlaxoWellcome committee. Four protocols were considered by the workshops. Issues that the groups considered included:
– Does the drug have a future?
– Concern about the size of the dose
– Was the protocol practical?
– Was it really a Phase II study?
– Could the volunteers be adequately counselled?
In conclusion the groups felt that the protocols had highlighted differences between the procedures adopted by the committees represented and it was mooted that some form of audit of committees in the future could be instructive. The protocols had highlighted the difficulties inherent in the procedure adopted by some committees where one member of a committee considers a protocol in detail and presents it to the committee for a decision.
The latest conference was rounded off by a ‘Question Time’ session, with a panel of experts drawn together to answer questions posed by the audience. Delegates had been asked to submit questions beforehand and the Chairman of the conference, Professor Tony Birmingham, had selected ten for the session. The issues ranged from contraception for volunteers, through payment for volunteers, gene testing, animal welfare, risk assessment and should the protocol proposer be present at the ethics committee meeting? In the end only eight of the questions could be addressed and the session overran with debate being very lively.
An informal conference dinner was held. The feedback from the end of conference questionnaire indicated that 100% of respondents would like further conferences preferably on an annual basis. 100% felt that the format and venue were right. Therefore, the organising committee is now planning for the 1998 conference to be held at Sopwell House Hotel, St Albans on November 19/20th.
References
- 1.Introduction to the Work of Research Ethics Committees: what is involved in being on a research ethics committee for Phase I studies—ABPI booklet [Google Scholar]