Ethical considerations of clinical trials in the developing world

Joseph R. Fitchett
Joseph.fitchett@doctors.org.uk

Published in the Transactions of the Royal Society of Tropical Medicine and Hygiene,
doi:10.1016/j.trstmh.2009.02.021

Summary
The developing world is entering new territory with rapid advancements in biomedical
research and science. In order to ensure the protection of those most vulnerable, bioethics
must experience a similar expansion and progression worldwide. Inequalities in healthcare
remain an influential issue to redress on a global scale, and may provide an opportunity to
induce a paradigm shift in the worldwide approach to medical research. In particular, clinical
trials performed in a nation different to that of the sponsoring institution must appreciate any
underlying ethical conflict and ensure that the volunteers involved are treated with the best
attainable and sustainable standards.

1. Healthcare ethics and global health inequalities

Inequality in healthcare provision, medical research and infrastructure investment are
alarmingly apparent worldwide. Healthcare expenditure in developing countries corresponds
to less than 1% of that of OECD countries (members of the Organisation for Economic Co-
operation and Development).1 Healthcare ethics on a global scale is central to redressing the
inequalities in global health through improvements in medical research, healthcare provision
and resource allocation. Such reform is crucial when historically so little of the global burden
of disease has attracted so much of global expenditure for biomedical research.[2] and [3]
Globalisation is bringing to the surface new, complex ethical dilemmas with regards to
international health and healthcare research.4 Although it is unrealistic to expect today's
clinical care in sub-Saharan Africa to be similar to that in developed countries, when
approximately 50% of the population live on less than 1 dollar a day,5 protection of patients
and determination to prevent the persisting burden of neglected tropical diseases (NTDs) are
essential to improve a world that has become so interconnected.

2. International declarations: the old and the new

Subsequent to the Nuremberg Code at the end of World War II, the World Medical
Association Declaration of Helsinki provided a set of “ethical principles to provide guidance
to physicians and other participants in medical research involving human subjects”.6 The
Declaration of Helsinki forbids coercion, demands that volunteers fully understand the risks of
the respective study, and requires written or verbal consent (the latter being fully documented
and witnessed). Notably, the declaration is not legally binding7 and was developed to protect
vulnerable patients involved in new and unproven studies as well as to uphold the ethical
duties of the medical profession.
The sixth revision of the Declaration of Helsinki reaffirms the international standards
for conducting medical research with human participants. It further states the requirement for
new treatments to be tested against the “best current” treatment, as opposed to the local
treatment. However, this may not allow testing against drugs such as aspirin for coronary
heart disease, which would yield great health benefits in developing countries but would not
necessarily be the “best current” treatment available worldwide. Bloom advocated for the
adoption of “highest attainable” standards with regards to international clinical trials.8
Acceptance of the use of best local treatment as opposed to the best available treatment may,
however, lead to great exploitation of the vulnerable in developing countries by research
programmes which would otherwise not be carried out in the sponsoring country.9 A
systematic review by Kent et al. indicated the tendency for adherence of clinical trials to “best
current standards” to be largely disease-specific and variable.10 Explanations for such results
include trial design on a local level of care rather than international standard of care (for
example, highly active antiretroviral therapy was not widely available to sub-Saharan Africans
at the time of the respective studies, whereas with tuberculosis standards were similar
internationally). Thus a fine line demarcates whether the “best current” or “highest
attainable” standards should be the basis of interventions in clinical trial research.
Further declarations and guidelines have since been outlined in an attempt to bridge
the gap between the developed and developing world. For instance, the Council for
International Organizations of Medical Sciences (CIOMS) collaborated in 2002 with the
World Health Organisation (WHO) to revise the ‘International Ethical Guidelines for
Biomedical Research Involving Human Subjects’, offering an alternative set of guidelines,
highlighting the great care required for dealing with medical research in the developing
world.11 The Commission for Research Partnership with Developing Countries (KPFE)
similarly studied and published their analyses of joint research ventures to assist with
guidance.12

3. The duty for a global approach to bioethics

Dilemmas surrounding clinical trials in the developing world are abundant and include
practical complexities with informed consent (particularly in an illiterate subpopulation),
choice of placebo group, publication bias of results and variation in standards of clinical care.
In addition, economic or academic interests may not benefit the host country directly, and
there is the issue of continuing the interventions should the treatment prove a success.
While Phase I and Phase II trials require few human participants, the impact is felt
most seriously in the Phase III trials, which often require several thousand volunteers to
provide the evidence and research quality expected for final regulation of an intervention.
With volunteer numbers in the Western world limited, numerous regulatory bodies and high
demand for innovative treatment, clinical trial research is relocating to the developing world,
where such regulatory bodies have not previously existed and numerous patients may have
little choice other than to attempt a new and unproven treatment.
A notable weakness was the lack of adequate ethics centres in the developing world.
Much activity has been promoted in recent years to rectify this situation, such as by the
Strategic Initiative for Developing Capacity in Ethical Review (SIDCER), the Pan-African
Bioethics Initiative (PABIN) and Assisting Bioethics Committees (ABC) at UNESCO. All aim
to strengthen awareness of bioethics and discuss its applications.
An ethical model for research and training partnerships between developed and
developing countries is further required. Singer and Benatar suggested a model based on the
International Clinical Epidemiology Network (INCLEN) that created a network of clinical
epidemiology units worldwide for bioethics.13 The creation of an alliance or forum for global
healthcare ethics would create the future leaders in current opinion. The global network
would be able to provide the WHO and governments with clearer direction regarding policy.
Such direction could in turn ensure a redistribution of healthcare and medical research
expenditure across the globe. The Nuffield Council on Bioethics report, ‘The Ethics of
Research Related to Healthcare in Developing Countries’,14 provides an ethical framework
based on four principles of duty:

1. duty to alleviate suffering

2. duty to show respect for human beings
3. duty to be sensitive to cultural differences
4. duty not to exploit the vulnerable.
In the application of these four principles, the social, cultural, political and economic context
of the respective country must be taken into account when undertaking clinical trial research.
The report advocates that countries set national priorities related to provision of healthcare
and to enhance their capacity to conduct research relevant to their needs, and that all
countries should establish an effective system for the ethical review of research, which includes
the establishment and maintenance of research ethics committees. When externally sponsored
research falling oustide the national priorities is proposed, its relevance must also be justified
to the appropriate research ethics committees, and national and international sponsors of
research should ensure that adequate provision is made for training in the ethics of research
for professionals involved in research related to healthcare. Finally, the development of local
expertise and ethical relativism in healthcare research should be an integral component of any
proposed project.
Medical researchers appear to have recognised the need for clinical trial design to be
sensitive and relevant to local levels of care based on the subpopulation from which
participants are recruited, and the concept of an irreducible set of ethical standards
transcending borders appeals on a moral level.15
Costello and Zumla underline a key flaw of clinical trials in developing countries as
being the overemphasis of results, leading to a neglect of issues including development of
national research capacity, sustainable research and ownership.16 They stress the pivotal
importance of national academic leaders and institutions being involved in the research to
translate findings into practice for the respective country. ‘Postal research’ and ‘parachute
research’, whereby samples are sent to the developed sponsoring country for analysis or
researchers travel for short periods to the developing country, respectively, reiterate the need
for a stronger national involvement on a local level – decentralised from the sponsoring
developed country. Such a system of merging ‘annexed sites’ abroad, or partnership model as
advocated by Costello and Zumla,16 could lead to substantial mutual gain through shared
knowledge. With ethical norms differing from country to country, visiting researchers require
a broader and deeper understanding of the social, economic, and political context of trials in
the respective developing state.

4. Controversy and clinical trials abroad

Pfizer was at the centre of a controversial dispute in Kano, Northern Nigeria (1996), when
testing a promising new antibiotic Trovan (trovafloxacin). Many children who were
administered the drug died, and more were left with lasting injuries from their meningitis
infection. Was the outcome a result of poor global regulation?
In developed countries, ethics boards would not allow doctors to withhold treatment
during experimentation – i.e. researchers must administer the best existing treatment at that
time to the control group. In developing countries, as patients would often receive no
treatment outside the clinical trial, new drugs may be tested against a placebo (for instance
Surfaxin in Latin America). Today, according to the reformed Declaration of Helsinki in
2008, ethics committees may approve a placebo treatment for “compelling and scientifically
sound methodological reasons”, reiterating the conflicts defining “best standards”. The
updated version seeks to advocate a public health approach to medical research and
addressed the importance of research benefiting the local population.
The 1994 ACTG 076 clinical trial demonstrated a reduced risk of transmission of
HIV from pregnant mothers to their infants following an intensive zidovudine course.17
Subsequently, clinical trials conducted globally looked into the effectiveness of less intensive
zidovudine courses with the aim of providing more affordable treatment regimes.[18] and [19]
The trials, sponsored by the National Institutes of Health (NIH) and Centers for Disease
Control and Prevention (CDC), induced intense criticism, with some believing that they
violated international guidelines.20 The clinical trials were thought not to fulfil the
requirement to ensure participants receive the “best proven” therapeutic method as control
patients were not administered any active treatment. It was emphasised that investigators are
responsible for all clinical trial participants, not a select few.
 Others argue that the criticism does not take into account the purpose and complexity
of such clinical trials, or the needs of their respective host country. In particular, it is argued
that their criticism inappropriately alluded to the Tuskegee Experiment – a study which in
fact did not test an intervention but instead deprived individuals of a “known, effective and
affordable intervention”.21 The Tuskegee Experiment unarguably violated the tenth principle
of the Nuremberg Code, requiring termination of the experiment if it is deemed “likely to
result in injury, disability, or death to the experimental subject”. The 1994 ACTG 076 clinical
trial case is more complicated, as the outcome of the patients administered a placebo would
have been hypothesised – any “injury, disability or death to the experimental subject” would
not be due to the intervention itself but more accurately due to their pre-existing condition.
The fifth principle of the Nuremberg Code states that “no experiment should be conducted
where there is an a priori reason to believe that death or disabling injury will occur”. The
principle is similarly complex in its application to the 1994 ACTG 076 clinical trial as the “a
priori reason to believe death or a disabling injury” will occur is not related to the intervention
itself but to the pre-existing condition. Finally, the fourth principle of the Nuremberg Code
dictates that an “experiment should be so conducted as to avoid all unnecessary physical and
mental suffering and injury”. It is the fourth principle that ultimately stirs ethical concern in
the 1994 ACTG 076 clinical trial, as the healthcare professionals, whose duty is to protect the
patients with no possibility to delegate to another “with impunity”, were aware of the most
probable outcome of administering a placebo as opposed to the “best current” treatment.
The importance of traditional declarations such as the Nuremberg Code and the
Declaration of Helsinki, although created years ago, form the basis of subsequent guidelines.
The fact that certain trials cannot adhere to simple directing principles exposes the flaw of
certain trials in the developing world, particularly when referring to “best standards”.
A strength for the promotion of the “best attainable and sustainable” standard of care
is the fact that it allows for the study into inexpensive “intermediate” interventions that are
practical, despite being considered less effective than the “best standard” intervention.22 With
regards to the 1994 NIH and CDC clinical trials, the principal issue was whether it would be
ethical to test a new treatment against a placebo control when an existing, known and
effective (whether affordable or not) treatment was available elsewhere in the world. Reasons
for using a placebo-controlled trial in countries where there is no current intervention divide
academics and their views. It may be argued that the assignment of a placebo carries no risk
higher than current, albeit poor, standard practice in the respective country and that it
provides a more definitive answer with fewer participants. It may further provide decisive
answers to questions about safety and the value of the treatment (particularly in an area where
the disease is found), and becomes the primary ethical obligation as the results may improve
future care of many patients.
Should a new intervention be tested against an intervention known to provide the best
care, it may not actually provide the host country with useful information, as the best care
may be out of range in financial terms. Morally, healthcare professionals should consider
comparison of a potential new treatment with a placebo only when there is no known,
effective and available intervention, in particular when the availability (or affordability) of a
drug or treatment may be determined by pharmaceutical pricing policies.

5. The changing of an industry

The pharmaceutical industry often has a poor image, with only a few divergent perceptions
by various industry names.23 As the industry changes, questions are raised as to the ethical
responsibility and role of pharmaceuticals. Does the pharmaceutical industry have an ethical
obligation to contribute to the promotion of global health? How far does the role of the
pharmaceutical industry extend? What types of contribution (for instance training,
medication, distribution networks) should be expected from the pharmaceutical industry?
With a particular lack of focus on the poor-return NTDs, institutions often question the lack
of the pharmaceutical industry's clinical trials into local conditions. With great power,
knowledge and resources comes great expectation.
 With India and China leading the transformation of the Asian and worldwide
pharmaceutical industry (particularly the supply market) the worldwide pharmaceutical
industry launched Global Health Progress in 2008. The initiative aims to bring together
research-based pharmaceutical companies, global health leaders and policymakers to improve
global health, with particular emphasis on the developing world. The initiative is also
intended to share research and build partnerships, although sceptics argue the initiative is a
means to improve the reputation of the industry. However, as the regulatory structure in
developing pharmaceutical markets is weak compared with those of the OECD countries, the
pharmaceutical industry has an ethical obligation to contribute to the promotion of global
health while undertaking its research and business initiatives in order to protect society's most
vulnerable.

6. Best ethical standards

On reflection, clinical trials undertaken in the developing world present intricate ethical
dilemmas to an already controversial issue: scientific experimentation on human subjects.
Ethical considerations must always be taken into account, and particular care employed when
a decision focuses on a culture often vastly different to that of the sponsoring institution. With
the inequality of global health in terms of infrastructure, provision, access and research, today
more than ever before there is an ethical duty and responsibility towards education and
progression in medical science in the developing world – particularly when the developing
world plays a pivotal role in clinical trial research benefiting the developed world. As Angell
argues, “our ethical standards should not depend on where the research is performed”.24 To
ensure this, the globalisation of clinical trials requires a proportional globalisation of legal and
ethical regulation. With the Nuremberg Code and the Declaration of Helsinki providing only
limited and varying international guidelines on experimentation on human subjects, reliance
on a more recent and clearer set of principles and regulations, such as from CIOMS and the
Nuffield Council, are proving vital to provide protection to the world's most vulnerable.
Clinical trial research demands a strict balance between the normative ethical
theories, with a particular focus on duty-based ethics to ensure that participants in clinical
trials are treated “never simply as a means, but always as the same as an end”, reinforcing the
notion of a duty to protect. With the consideration that the wellbeing of human participants
must take precedence over the interests of science and society, clinical trials must never lose
sight of the fundamental aim to stand by the principle outlined by the World Medical
Association that the “health of my patient will be my first consideration”.

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