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After committing itself to researching poverty-linked diseases, the EU is working to decide what responsibilities it has to EU-funded research activities in developing nations.
While Europe is refining its own rules on clinical trialsit still awaits detailed guidelines for the European Unions clinical trials directiveit is already planning how the rules should be applied to clinical trials in developing countries. The ongoing international controversy over access to treatments for AIDS in Africa triggered these reflections. Because the EU recently committed itself to support research into poverty-linked diseases (View from Brussels, November 2002), it recognizes the need for some special controls on what sort of clinical trials it might find itself sponsoring in developing countries.
The European Group on Ethics in Science and New Technologies, which advises the President of the European Commission, has just delivered a lengthy opinion on the ethical strategy the Commission should adopt. The opinions starting point is that in industrialized countries there is a rather homogeneous conception of what is good scientific method based on a logical and rational approach. In other cultures, however, other medical traditions may exist, and our approach concerning scientific research may have no equivalent. Because research activities have a cultural as well as a scientific dimension, this may have consequences, especially during ethical evaluation of a clinical trial.
The opinion is aimed at providing help to the Commission in the exercise of its responsibility regarding the implementation of EU-funded research activities in countries which culturally or economically differ from the West European context, it intones. But it also claims that it could have relevance for some aspects of trials in the EU. It may also be applicable to research involving cultural minorities or vulnerable groups within industrialized countries.
It also comes out firmly in favor of the highest ethical standards. The fundamental ethical rules applied to clinical trials in industrialized countries are to be applicable everywhere. Even if some difficulties may arise in their implementation, a weakening of the standards would be in contradiction to fundamental principles, it says. In the case of conflicting views between parties, every effort should be made to negotiate solutions, but without compromising fundamental principles. Human rights standards are to be respected explicitly in all these countries, it insists.
All trials that the EU funds in developing countries must meet certain basic criteria: respect for human dignity, nonexploitation, nondiscrimination, noninstrumentalization, and individual autonomy. That entails free and informed consent from the subjects and respect for their privacy and the confidentiality of personal data, justice, the principle of beneficence and nonmaleficence, and proportionality. In short, that means that research methods should be necessary to the aims pursued and that no more acceptable alternative methods are available.
It isnt just a matter of making sure the trial meets high standards. Demanding criteria are also suggested to determine whether a trial should be mounted at all in such circumstances. Optimal protection of the participant must be a priority no matter where a clinical trial is performed: thus, only if very strict justification can be given should it be carried out in countries with a less adequate healthcare environment. And it goes on to offer some of the limited range of justifications that might be advanced. One of the more evident ones, it says, would be where the trial aims at addressing specific health conditions of the countries involvedfor instance, tropical diseases. Equally, it could be valid if the trial aims at addressing diseases also existing in industrialized countries but with a specifically high incidence in developing countries. Another justification could be that the trial aims at developing treatments having a specific interest for the country, such as a new treatment that would be cheaper than those already available.
It acknowledges that clinical trials have become increasingly a private-sector exercise over the last 20 yearsClinical trials are set up also for commercial goals and can be done to promote marketing, it explicitly recognizes. Nevertheless, the group of experts insists, Research activities involving human subjects cannot exclusively be assimilated to an economic activity subject to market rules. And to define the context within which trials can be satisfactorily conducted, it offers some detailed assessment of the dilemmas that are bound to emerge as the EU starts to put money behind trials in Africa and Asia.
The central problem, the opinion suggests, arises from the fact that the comprehensive legislative and ethical background that is routinely taken into account in clinical trials in many developed countries is often lacking in the host countries. This may jeopardize protection of the participants in clinical trials. The problem is complex, the EUs ethics experts recognize. Globalization occurs in a very heterogeneous world, extreme wealth and poverty coexist, and injustice is a fact, so the relationship between parties is not per se fair and rules must be defined to avoid exploitation and increasing injustice.
Different cultures may have different values, it points outleading to potential problems whichever approach is taken, if care is not exercised. In a paternalistic or imperialistic approach, the sponsor of the research tends to impose his own values on the host country. In contrast, when the respect for local tradition leads to relativism and non-respect of values considered as fundamental in Europe, this implies a risk of double standards.
Consequently, carrying out research in a developing country implies additional responsibility of the sponsor towards the subjects, and also towards the local community where the trials take place. Private or public investigators who do their research in developing countries have a moral duty to make a concrete contribution to overcome inequalities, the opinion says. And the additional responsibility does not end with the end of the clinical trial. Notably, The protocol cannot ignore the context where the clinical trial will take place, and in a context of poverty and absence of healthcare, the fact of participating in a clinical trial may constitute for the patient the only opportunity to have access to healthcare.
The differences in culture can have a significant influence on the validity of the approach to the trial, the opinion warns. The way information is given to patients and the procedure of obtaining consent may vary according to the specific situation of the country where a clinical trial takes place, regarding the level of literacy, the level of scientific understanding, or the organization of the community,
it remarksadding, That may influence the consent procedures regarding the involvement of persons, in particular women, in a clinical trial. Similarly, different cultures may have different views regarding privacy and personal data. This may have consequences for the acceptability of certain aspects of research protocols, namely regarding data collection, and the data subjects right of access and right to object.
In addition, the involvement of all partners, from the funding institutions to the host countries or communities, is essential at each phase of the research activities, from the definition of the program and of the research priorities, to the follow-up after the end of the trials, the opinion asserts.
And the scientific and ethical evaluation of the research protocol should be carried out by ethical committees from all countries involved. So host countries need to have a legal and ethical framework in order to take part in the clinical trial evaluation effectively and independently. Building local ethical committees in the host countries should be considered as a priority. If it is not possible to involve, at the very least, an independent local representative in the evaluation, then no clinical trial should be implemented in the country.
Some consensus exists, some doesnt
Not everything will have to be re-invented to find a modus operandi, the group says. Broad consensus exists on ethical questions like the publication of results (even negative ones), or the need to address orphan diseases and poverty-linked diseases, which are found only in developing countries. But other issues remain controversial, the experts say, including the conditions under which the use of placebo is acceptable, whether to use the best proven treatment as a comparatoreven when this is usually not available in the country where the trial takes placeand whether there are universal values which are applicable whatever the sociocultural context.
Dilemmas of this sort are all the more pressing, the group suggests, because clinical trials carried out in developing countries often contribute to developing new drugs, which will be used in industrialized countries but will remain unavailable to developing countries. Clinical trials carried out to develop new drugs for exclusive use in developing countries, like treatment for tropical diseases, are comparatively rare, the opinion points out.
Placebo or not placebo?
Much of the opinion is devoted to the vexed question of the use of placebo in trials. The group of experts comes out strongly with a defense of the use of placebo in certain circumstancesbut the tortuous discussion the opinion provides of the subject, and its frank admission of internal divisions on the subject, indicate how seriously the question presents itself in EU circles.
To belong to a placebo group in a clinical trial does not necessarily mean that this group does not receive any treatment, the opinion states boldly. In the case where another treatment already exists, the use of a placebo can also be a way to test more quickly and with a limited number of participants if a new drug has a specific effect to treat a disease.
But, it admits, such a placebo-controlled trial will not answer the question whether this new drug is more or less efficient than the other existing treatments.
Generally, the opinion says, the use of placebos should be regulated in developing countries by the same rules as in European countries. Any exception must be justified. But it does offer some examples:
An obvious one is when the primary goal of the clinical trial is to try to simplify or to decrease the costs of treatment for countries where the standard treatment is not available for logistic reasons or inaccessible because of the cost. It may thus be justified to derogate from the rule of best proven treatment.
Nevertheless, the onus of proof lies with the sponsor, the experts make clear. The justification of using a placebo must be clearly demonstrated in the research protocol submitted to the ethical committees and especially approved by the local committee, it says. And it recognizes that even with these constraints, not all anxieties can be fully met. Two members of the group, the opinion notes, consider that the use of a placebo for the purpose of developing low-cost treatment could mean accepting a double standard for poor and rich countries, and research in developing countries could lead to a vicious circle: On the one hand, clinical trials in developing countries contribute to developing new treatments which can be patented in rich countries and are then unaffordable for poor countries, and on the other hand the non-availability of treatment in the poorest countries is due partly to the patent costs, it cites them as saying.
Care of the elderly in Europe
While the EUs group of experts on ethics has been reflecting on the particular challenges of conducting trials in poor countries, the European clinical trials community has been reflecting on another special casethe needs of the growing elderly population in Europe. The European Forum for Good Clinical Practice held a meeting in Brussels in Januarythe 10th anniversary of the Forums foundationto promote thinking on how to cater for this large minority. The challenge here is analogous to the challenge the EU is already taking on (again with EFGCPs stimulus) in trying to develop systems that promote trials for pediatric medicines. There is not space here to report on the first European move in this new area of debatebut it is important enough to merit some extended coverage, so watch this space.