Towards Trans-cultural Process Based Ethics: Silencing critics of clinical trials in developing countries

PROPOSITION

As things now stand, Ethical Pluralism and the avoidance of a modern ethical imperialism of sorts, allows for exploitation or at a minimum the appearance of exploitation to persist, and has been taken off the table concerning acceptable strategies in dealing with developing countries, making its acceptability something of a moot point. If taken stringently, in practice it would undue years of work towards universalising ethical codes for research involving human subjects. Moral universalism has intrinsic and inescapable problems tied to imperialism of values and cultural norms. It offers a totalitarian stance on how things ought to be and all but ignores important differences between cultures. Procedural pluralism an approach not discussed in depth herein is on the right track but is only just beginning to come to some structured definition. Although it is arguably currently allowing for exploitation to persist with large variances in the capacity of local institutions to properly assess clinical trials and a remaining difficulty with what to take as “standard of care”, these can be overcome with capacity building clauses and reviews from developing world taken as universal decisions.

The position being proposed is for a new push towards a trans-cultural process based ethics. Trans-cultural process based ethics hopes to take the procedural necessity from ethical pluralism but aims to shape it into a more stringent universal form with standards. Questions then diverge from whether ethical committees merely exist, to whether they meet universalized standards of what is required to function unbiased and in a manner which could silence the criticism. With a new look at the role capacity plays in claims of exploitation, criticism of pharmaceutical companies which say that the absence or malfunction in many instances of local ethics committees is what is making developing countries so attractive to large pharmaceutical companies may be silenced.

ARE CLINICAL TRIALS EXPLOITATIVE?

Large pharmaceutical companies are increasingly moving into international markets to develop therapies, making clinical trials in the developing world a core component of their business models. Looking at the United States, one third of their trials are being conducted outside the country, many in countries which are still developing. Pushing this move is the desire to help local health care concerns, lower costs, and expedite the time taken to conduct these trials. Reasons for these trials are there contribution to the development of national economies and health care systems, along with enabling higher standards of quality. They offer global access to academic expertise and patient populations.

In countries which have healthcare budgets of less than ten dollars per person per year, clinical research can benefit entire communities. Backed with large funding budgets a country can benefit greatly by maintaining an environment ideal for clinical research through which entire healthcare systems can be developed and capacity built. For pharmaceutical companies developing nations offer pools of patients not otherwise found in the developed world, allowing for research on drugs to take place which would otherwise be impossible.

With the increase of clinical trials in the developing world there has been increased concern after several well known instances, one of which involving HIV trials in Africa, have fed the fires of criticism over these trials. The criticism largely revolves around the double standard of care which can be found in developing countries that allow for these trials to exist and increase in popularity because of savings associated with cost and time.

Declarations such as that of the Declaration of Helsinki, adopted virtually universally in the world, show a trend which aims at making ethical considerations more explicit when determining ethical acceptability of humans in research. However, with these declarations providing minimum recommendations to what is acceptable there are radical differences between how they are interpreted in practice. High standards which are espoused in these declarations critics say, are not being espoused in practice and questions such as “Is it ethically acceptable to confine subjects in the control arm to treatments which are considered substandard in the sponsoring country of the study?” persist in delivering heated debate in the medical community.

Serious questions about which standard of care to use in a control arm of a study remain and are compounded with questions of the ability of ethics committees in developing countries to function properly. On one side we can find proponents of a position which would push for ethical pluralism, allowing for local ethics committees and standards to trump positions and therapies found in developed countries. The other side can be summarized within a moral universalism ideology. They push for universal standards and weighting of principles, uphold opinions coming from ethical committees and review boards from developed nations, and demand standard of care requirements to be defined as that of best globally rather than locally. Depending on which of the two camps one finds themselves in changes the entire appearance of the debate.

As with all debates that have been around for some time, there is a third camp which takes a sort of middle ground. They can be said to fall within procedural pluralism which can be taken to mean that the declarations which are been agreed upon are universal in some sense, although they are goals rather than principles and which in their attainment, can be ethically allowed to differ from differing cultural contexts. They place tremendous importance to local ethics committees and their autonomy to make decisions for the communities for which they serve. It is perhaps within this arm of the debate that progress can be made at turning what appear to be exploitative practices into clear examples of ethical research.

This proposal looks at the current disparity between international and local standards, what it means to the existing debate, implicitly shows a need for a new approach for approval of international clinical trials, and states what that approach could be.

EXPLOITATION (Universalism vs. Pluralism)

Due to less stringent regulatory constraints and income disparities, trials can be carried out quicker and cheaper in a developing country rather than developed. A core criticism to international clinical trials is that the level of income found in developing countries means that people are often more willing to participate. They are, it is argued, more vulnerable than participants in wealthier nations.

Problems for ethical research in a developing country include 1) a health system which may function inadequately, leaving patients to join trials mistakenly in search of treatment, 2) troubles offering well informed participants able to make informed consent due to poverty, illiteracy, a hierarchical doctor-patient relationship, and lack of access to treatment, and 3) a lack of training needed to conduct trials according to ethical standards. These problems pose serious questions to the ethical nature of any trial being conducted in such a setting.

There is such a discrepancy between clinical environments that many have even ventured to ask if fair participant selection, a core tenant of ethical research, is even possible. This is attributed to the fact that participants could very well be coerced through economic reasons or because they cannot receive treatment otherwise. In instances found in India where physicians are paid large sums to recruit participants, it is difficult to ensure that procedures meant to provide consent are genuine and legitimate. Again those who argue for an ethical pluralism stance for administrating clinical trials, sway opponents by noting that clinical research in these communities is necessary and that it meets their standards, that is the local standards, for what is ethically permissible. Similarly, with informed consent difficulties surrounding its acquisition are usually excused with claims that the guidance of universal declarations do not take into account local circumstances where Western consent procedures may conflict with cultural norms and notions of autonomy.

Despite the shortcomings of local capacity to adhere to international standards, ethical pluralist side with a position that would have local ethics committees and their outputs trump that of developed nations on the position that their autonomy and standards should be recognized. Moral Universalists however, claim that it is precisely the low standards at the local level which allow for exploitation to occur. If universal standards were used, such exploitation would not exist. The disagreement on whether to use universal standards or a pluralistic stance on what is to be acceptable is precisely what has led to criticisms of exploitation.

STANDARD OF CARE Developed vs. Developing

The question of whether exploitation exists in clinical trials which are conducted in developing countries is unresolved. This is largely dependent on how existing universal principles found in declarations such as the Declaration of Helsinki are interpreted at the local level. For example, withholding in a control arm a therapy known to be effective albeit in an intensive and expensive form for the common local therapy is construed as ethical relativism. Moral Universalists would argue that you cannot withhold the better Western treatment or therapy. What should be taken as the “standard of care” whether local or global is of crucial importance and is far from being resolved.

Standard of care, or the best standard of care is meant to protect vulnerable participants from being unjustly harmed through deprivation of standard medical treatment while in an experiment. In essence no patient in a trial funded by the United States should be denied the ‘standard of care’ available in the United States. Problems arise though when one examines the reaction to changes made to the Declaration of Helsinki which stated it is a worldwide best standard which should be used in a control arm. The reaction was a rejection by every national and international committee that reviewed it. This rejection however, leaves the benchmark for control arms arguably far too low. Moral Universalists would claim that we cannot waiver on a global standard of care which ought to be provided while ethical pluralists would claim a more context based answer involving the local treatments which are commonly provided can be sufficient. The claim that all research subjects are entitled to minimum guarantees that are transnational and non-negotiable is widely accepted although realisation of these entitlements often falls far short in practice. There is another double standard at play though which complicates the debate and that is of the quality and capacity of ethics committees in developing countries to participate at international standards.

There have been incidences of ethics committees in wealthy countries approving studies that would not be allowed in their own country to be conducted in poor countries. Critics, Moral Universalists, claim that different standards of research ethics are being applied, one for developed countries, the other for the developing ones. Cultural differences are being used to validate clinical trials with the primary responsibility for assessing proposals left with the relevant ethical review committees in the developing countries. This is problematic because it is often more difficult to conduct scientifically sound research in countries where basic healthcare is not widely available and research ethics committees are underdeveloped or absent.

A major concern is the ability of regulatory agencies and ethics committees to function properly, without their functioning, declarations and the principles found within cannot be upheld as intended. With wide disparities in terms of economic, social standing, and their health care systems, the fear is that the lack of capacity in developing countries jeopardizes the rights of research patients by bringing in trials which should not be approved. One study for example showed that only 56% of the 670 researchers surveyed in developing countries stated that their research had been reviewed by a local institution review board or health ministry. In another study 90% of published clinical trials conducted in China in 2004 did not report ethical review of protocol.

Those who would continue clinical trials in countries where a lack of proper oversight is abundantly clear, highlight the need for a different balance to be met between risks and benefits where there are differences between resources and health conditions. This leads again to their falling under an ethical pluralist stance which shows that from their side, a study may be acceptable in one country but not in another because of differences in wealth or burdens of disease. The very fact of a discrepancy of acceptability does not warrant a claim of exploitation it is said. Those who continue to defend such trials associate a great deal with the process requirements of a trial. From the fact that the trials are being supported by local governments and approved by ethics committee, it should be seen as a trial which is not exploiting the local population but rather one which builds the local healthcare system and capacity of participating healthcare practitioners.

International conventions have little practical guidance for when local ethics committees show a lack of capacity. More worrisome is that although guidelines advise investigators to submit proposals for ethical review in both the funding and receiving country, they are silent on the question of primacy concerning differing opinions on acceptability and other matters. If we look to the Council for International Organizations of Medical Sciences than the problem can be said to be exacerbated when it states “the host country’s ethics committee has a ‘special responsibility’ on matters of detail of a trail, such as acceptability of plans to obtain informed consent, while committees in the sponsoring body need only to be satisfied that the trial conforms broadly to the ethical standards prevailing in their own country.” This gives an almost trumping status to ethical review committees which may have major shortcomings concerning expertise. Only a handful of African nations currently have the capacity for growing international requirements. They along with non-African nations tend to have under-developed mechanisms and procedures. The countries which have the most vulnerable populations to clinical trials have the least developed systems to review such research.

As questions such as whether the ‘best proven diagnostic and therapeutic method’ refers to international standards or should we take local resources into consideration, and whether healthcare needs and budgets justify ethical standards in developed countries to differ from the developing, the debate on whether these trials are exploitative will continue. Although there is already a recognized need for universal guidelines and regulatory requirements to minimize conflicting reports, these guidelines can often led to two very different answers. Agreements must be made further on the weighting of principles and exactly how the more detailed aspects of clinical trials in the local context can universally be handled. An additional ‘layer’ of guidance between the universal and contextual is clearly needed. Similarly harmonisation is needed between existing research ethics guidelines.

While there has been considerable work done on what makes clinical research ethical, with the development of principles and benchmarks to guide ethics committees, there has been considerably less research done on overcoming differences in views of exploitative research or claims made thereof. As claims of exploitation can severely damage the reputation of a pharmaceutical company which is conducting clinical trials in developing countries in what is considered by them ethical and non-exploitative there must be a method developed to deal with resolving claims of exploitation. We should go further than consensus building on what is deemed ethical. We should aim to develop a method whereby existing principles are untangled from one another and whereby through, an as of yet developed structure for analysis, clinical trials which involve multiple cultures may realize their benefits without facing what some times appear as inherent criticisms of exploitation.

REFERENCES

David M. Studdert and Troyen A. Brennan “Clinical trials in developing countries: scientific and ethical issues”. The Medical Journal of Australia 1998 Vol 169 pg.545-548

Ezekiel J. Emanuel et al. “What Makes Clinical Research in Developing Countries Ethical? The Benchmarks of Ethical Research”. JID March 1, 2004 Vol 189 pg. 930-937

Francis P. Crawley “Developing Clinical Trials in Africa: Building the Scientific, Regulatory and Ethical Frameworks”. Journal for Clinical Studies Nov. 2008 pg.16-17

Greg Koski et al. “Research Involving Human Subjects in Developing Countries”. The New England Journal of Medicine July 12 2001 Vol 345;2 pg. 136-138

Michael J. Selgelid “Module Four: Standards of Care and Clinical Trials”. Developing World Bioethics 2005 Vol. 5;1 pg. 55-72

National Bioethics Advisory Commission “Ethical and Policy Issues in International Research: Clinical Trials in Developing Countries”. Report and Recommendations of the National Bioethics Advisory Commission April 2001 pg. 1-12

P.K. Julka “Clinical Trials in India: Dilemmas for Developing Countries”. Issues in Clinical Research April 2007 pg. 69-71

Yousefi- Nooraie et al. “Registration of Clinical Trials: How Developing Countries Could Prepare for the Upcoming Storm”. Archives of Iranian Medicine July 2008 Vol 11;4 pg. 361-363

Seth W. Glickman et al. “Ethical and Scientific Implications of Globalization of Clinical Research”. The New England Journal of Medicine Feb. 19 2009 Vol 306;8 pg. 816-823

Soren Holm “Moral pluralism”. The ethical aspects of biomedical research in developing countries, Proceedings of the Round Table Debate Oct. 1 2002 pg. 9-10

Wemos Foundation “Call for Ethical Clinical Trials in Developing Countries”. Fair Drugs Feb. 2009 pg. 1-7

Wemos Foundation “Do European registration authorities ascertain whether clinical trials in developing countires have been conducted in an ethical manner?” Fair Drugs June 2007 pg. 1-8

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