CONSIDERATIONS FOR INTRODUCTORY TRIALS
Ethical issuesThe first, systematic approach to public sector introduction of a contraceptive method was under taken by the Population Council with the introduction of Norplant subdermal implants. No contraceptive method until that time had undergone so many years of safety and efficacy research prior to introduction. Introductory trials of Norplant began in 1983 following 15 years of clinical research on safety and efficacy. Norplant has been approved in 18 countries. More than 55,000 women have used it in 46 developed and developing countries. The objective of the introductory trials has been to establish adequate clinical conditions, including training in insertion and removal, counseling, and clinical follow-up, in addition to post-introductory surveillance. The Council made this substantial investment for several reasons. Previous experience with IUDs had often been very negative, partly because neither providers nor users were adequately informed and trained. Norplant requires minor surgery for insertion and removal and has side effects for which women and providers need to be prepared. As a high-technology, provider-dependent method, Norplant can potentially be abused and a careful introduction process is one way to reduce that risk.
Drawing on the experience with Nor plant, the presentations and discussions on introductory trials considered ethical issues, the process of introduction, evaluation of such trials, and cost.
It was agreed that there have been and can be a number of ethical problems with the introduction of fertility regulation methods. It is therefore essential to formulate and follow clear ethical principles at each stage of the process.
Although guidelines exist for research on human subjects (the Special Programme uses them in all of its clinical research), these guidelines are often not followed completely or meaningfully at either national or clinic levels. For example, participants in the trial may sign informed consent forms without fully understanding that the fertility regulation method is under development, or that the method may have as yet undetermined risks or side effects. Scientists, at both national and international levels, in collaboration with women's health advocates, could, it was agreed, undertake to improve approaches to and standards for informed consent as well as to ensure consistent and effective use of the procedure.
Freedom to participate or not in a trial depends on the client's access to alternative methods. For instance, if the clinic has only the trial method, an oral contraceptive and surgical sterilization, many clients who are tired of the pill and do not want to be surgically sterilized may accept the trial method. This acceptance would not, however, reflect freedom of choice. Poor, illiterate women especially may often have little or no choice among clinics or methods and therefore no real freedom to decide whether to participate in a trial. While participants in the meeting agreed in principle that availability of alternative methods and services is important and that trials should not be conducted only with poor women, they did not discuss how to achieve these standards.
Participants generally agreed that methods should not be selected for introduction unless minimum standards of quality of care can be assured, but those minimum standards remain to be defined.
"Method introduction requires that as much attention be paid to the service delivery requirements of the method as to the characteristics and properties of the method itself. Methods are not introduced in isolation of existing service conditions; if conditions are not appropriate, it must be determined whether they can be strengthened, or whether it would be better not to offer the method in that locale but instead use referral mechanisms to another centre". - Joanne Spicehandler
Full and accurate information, sympathetic and respectful provider-client interaction, continuity of care, and availability of other basic reproductive health services, are essential for informed consent and freedom of choice.
These qualities are not very often present, and it was suggested that the introduction process can be used to stimulate improvements in quality of care, at least in clinics or programmes where the trials are under taken.
Women's health advocates were skeptical, however, and pointed out that improvements in the few sites used for introductory trials could not ensure improvements throughout a national programme. They questioned whether the experience with an introductory trial would be generalizable to a national programme. There was some discussion on how to achieve a reasonable balance between optimal and realistic conditions for introductory trials, and it was agreed that progress could best be made through collaboration and dialogue between scientists, women's health advocates and programme managers at national and local levels.
The basic purpose of an introductory trial, whether of a new fertility regulation method or of an existing one not used previously in the particular place, is to evaluate the method in an actual service delivery setting. In the past, the focus has been on how best to deliver the method. How should staff be trained? What are the logistical challenges? What changes need to be made in the delivery system? More recently, partly as a result of concerns raised by women's health groups, it has been recognized that introductory trials should be used to determine whether a method should be introduced. Women's health advocates, therefore, made a number of suggestions about the design of introductory trials. It was agreed that the design of a trial should allow for the possibility of deciding not to proceed with full scale introduction if the method seems unacceptable or inappropriate to many women.
Women's health advocates suggested that ethnographic studies should be done to help ensure that method selection and trial design are appropriate to local patterns of sexuality, reproductive health, and other considerations. Ethnoanatomy (how people view their own bodies) and ethnoterminology (the language people use to describe various organs, functions and symptoms) are important tools which can be used to design trials and to educate providers and users. Scientists agreed that such studies could be very useful not only for the design of introductory trials but also for their basic work on method development.
Some participants also pointed out that community participation and sensitivity to community needs will be key factors in the success of an introductory trial. Informing and involving various segments of the community, including the media, should help create a positive environment for a trial and for later expansion.
Size of the trial and relationship to the health care system
Women's health advocates from India and Indonesia who have had direct experience with contraceptive introduction urged that introductory trials be done on a small scale and be carried out only in areas where there are adequate health personnel, training, and equipment. Most participants agreed that introductory trials should begin on a small scale and should test whether facilities and personnel are adequate, after which they could be expanded to get a broader base of information to understand the needs of both urban and rural populations. However, women's health advocates felt that such phasing has not usually been done and that, while it should be possible to design trials for rural areas, this may be appropriate for some methods and not others.
All agreed that the weaknesses of an existing health or family planning system can be magnified by introductory trials. Scientists and women's health activists with experience of introductory trials stressed that a trial must therefore include assessment of the limitations of the health service, and identification of means to improve the system and the quality of care offered.
"Even introduction of one item like Norplant means that a clinic which previously did not need to use local anesthesia has to find local anesthetics. So you are dealing with introduction of consequences to the health care system and there should always be provision for this in introduction". - Joseph Kasonde
In particular, women's health advocates suggested that providers taking part in a trial should receive training in counseling, be taught how to discuss sexuality and gender issues, and be trained in the diagnosis and treatment of gynecological diseases such as reproductive tract infections. The risk of pregnancy should be explained clearly to the women taking part in the trial, and where allowed, providers should be prepared to provide safe abortion services as a back-up.
Women's health advocates suggested that monitoring be concerned not only with the number of women who accept and continue the method but also with the recruitment process itself- how women are recruited, whether they are aware that they are taking part in a trial, whether their partners know about it, in what language information is provided, whether they understand it, who signs the consent form (woman or partner), whether she or he understands what she or he is signing, and what other choices of contraception women are given. Provider-client interaction should be documented to determine whether risks, side effects and benefits were properly explained, whether an examination was performed, whether follow-up instructions were given, whether guidelines for use were followed and whether women were aware of their right to stop participating in the trial if they so wished. It was suggested that women's groups can play a major role in collecting data on all of these, through direct and indirect observation, and through interviewing users on their experiences, including those who discontinue.
An example of such collaboration has occurred in Peru. The Peruvian Ministry of Health consulted with women's groups and scientists on whether to begin an introductory trial of Norplant. Women's groups were then invited to participate in an advisory role for the duration of the study. One example of their contribution in this role is that they advised that illiterate women should be excluded from the study since the educational materials had been prepared for a literate population. The main constraint for the women's groups was a lack of funds for broader participation in the trial. It was agreed that women's groups should be encouraged to develop and submit research projects for funding on issues related to introduction that could be coordinated with the introductory trial.
Participants agreed that follow-up is a complex issue which requires much more attention and investment, particularly with provider-dependent methods such as IUDs and implants, both of which should be removed after a recommended period. Many women may not return for routine follow-up visits and special outreach efforts will be needed. But, very often, clients do not have addresses, or they may move frequently. Can women be found five years later for removal of the implants? Will those who remember that removal is necessary be able to find a properly trained and experienced provider to remove it? What constitutes an acceptable percentage of loss-to-follow-up in such a case?
Evaluation of introductory trials
The discussion focused on the divergence of views regarding the overall goals of trials. If the goal is to find out how best to make a method widely available, on the assumption that the method should be made available, then evaluators will be primarily concerned with operational issues. If the goal is to determine whether a method should be more widely distributed in a country, then the evaluation must assess the acceptability and appropriateness of the method for that country.
"Introductory trials have provided us with the opportunity to establish dialogue between health providers, scientists and user's groups and women's health activists. However, it seems to me for the future it will be extremely important to establish this dialogue at an earlier point...". - Gregorio Perez-Palacios
Concern was expressed that introductory trials to date have focused on how a method can be introduced and have had a built-in momentum that made nation wide introduction inevitable. Women's health advocates argued strongly for a "pause" in the introduction process to allow for analysis of data and lessons learned from the introductory trials. For example, it was argued that the trial period for a long-acting method like Norplant, which requires removal at the end of five years, should be the full duration of efficacy of the method, so that all stages of use of the method can be assessed before a decision is taken to expand provision. Otherwise, large numbers of new users may begin the method, generally under less controlled conditions, before major lessons can be learned from the introductory trial.
A number of scientists responded that the appropriate time for a pause is not after introductory trials but rather after toxicology testing and clinical trials. Dialogue and collaboration with women's health advocates and other concerned groups at these earlier stages would prevent costly mistakes in later selection of methods for introduction. They were concerned that a "pause" following the introductory trial would be extremely expensive and would cause the service providers and the women taking part in the trial to unduly conclude that the trial had produced negative findings. It was agreed, that, if women are fully informed about the nature of the research at the outset and are kept informed as the trial proceeds, their fears of being used as guinea-pigs will be reduced.
"There was a political pause in the case of Norplant in Brazil. As uncomfortable, bad-mannered, and controversial as this episode has been, I think...that, in the historical process of contraceptive research, it might have been a landmark that makes us now think about pausing in the process of introduction". - Sonia Correa
It was suggested that the need for a pause could be satisfied if introductory trials were started on a small scale and expanded very gradually. Some methods, such as surgical sterilization, implants and IUDs for instance, might be provided at levels of a health care system where more sophisticated facilities exist, while diaphragms, pills and condoms might be introduced at the community level.
While the meeting came to no clear position on the need for a "pause" at the conclusion of an introductory trial prior to wide-scale expansion, there emerged from the discussion an understanding that an introductory trial is a trial as well as an introduction process. Its results must there fore be carefully evaluated. The trial should include time for reflection and consultation at every stage of the process and should allow for decisions that might curtail country-wide introduction of a fertility regulation method.
Whatever the results of a trial might be, it was suggested that full, impartial information on benefits and side effects, obtained from clients (both users and discontinuers) as well as from medical records, should be made rapidly and widely available. This information should be published in national and international journals and presented in such a way that it is accessible to the general public as well as to the scientific community.
The cost of some modern methods may be prohibitive for countries burdened by international debt and multiple demands on their meagre foreign exchange earnings. In these same countries, the costs of service delivery by highly skilled personnel may also be prohibitive. Scientists and women's health advocates urged that every effort be made to estimate the likely costs of introducing a method before a trial starts. Estimates should include not only the costs of services and supplies, but also the costs of changes needed in existing health infrastructure and of technology transfer for local production.
One participant noted that, even at a late stage in the method development process, it is not always possible to estimate with any accuracy the cost of introducing some methods, particularly those which depend on drug delivery systems. However, methods such as pills, injections, condoms and other lower technology methods can be adequately costed. Continuing efforts are being made by the Special Programme and others to negotiate lower public sector prices with pharmaceutical companies.
Given these issues, participants recommended that all parties involved, including policy-makers, industry and donors, should be better informed on women's and scientists' views, and should work towards an approach which would cover all the concerns expressed in this section .
- Develop guidelines collaboratively to specify under what circumstances particular methods should be introduced and to clarify the criteria by which introductory trials determine whether a method is appropriate for widespread introduction.
- Include women's groups and women's health advocates in all parts of the introductory trial process, including ethical and scientific committees that design, monitor and evaluate introductory trials.
- Broaden the evaluation team to include service providers, social scientists, and representatives of women's groups, women's health advocacy groups and community groups.
- Disseminate the results of evaluation widely.
- Provide for long-term follow-up studies.
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