Science & Society
`
`The ethics of global clinical trials
`
`In developing countries, participation in clinical trials is sometimes the only way to access medical
`treatment. What should be done to avoid exploitation of disadvantaged populations?
`
`Katrin Weigmann
`
`C linical research by academic institu-
`
`tions and pharmaceutical companies
`has followed the general
`trend of
`globalization and has moved inexorably
`towards low- and middle-income countries
`(LMIC). This
`trend has
`raised various
`concerns,
`including whether the research
`being conducted is of value to public health
`in these countries or whether economically
`disadvantaged
`populations
`are
`being
`exploited for the benefit of patients in rich
`countries. Nevertheless, clinical trials and
`the research and health care that accompany
`them can directly benefit patients, in particu-
`lar those who would otherwise have no or
`only little access to health care services. It is
`therefore a matter of striking a fine-tuned
`balance between the economic and research
`interests of pharmaceutical companies and
`academia and the needs of patients in LMIC
`to make sure that all sides benefit.
`......................................................
`“. . . clinical research also helps
`to build research and health
`care capacity and can improve
`local infrastructure and boost
`the economy”
`......................................................
`
`Clinical trials are a necessary step in drug
`development and are conducted throughout
`the world, both in developed and in develop-
`ing countries. Trials themselves are thus
`not per se immoral, and there are a variety
`of reasons to conduct responsible clinical
`trials in LMIC. Doing so, for example,
`is
`often the only way to test drugs and
`vaccines for diseases that predominantly
`afflict people in these countries; trying to
`test
`the safety and efficacy of a malaria
`
`vaccine in Europe or North America would
`be relatively futile given the lack of patients.
`Beyond the obvious and direct public health
`benefits—in terms of both new knowledge
`and new treatments—clinical research also
`helps to build research and health care
`capacity and can improve local infrastructure
`and boost
`the economy.
`In fact, many
`developing countries have been actively
`trying to attract clinical research for these
`reasons.
`From the perspective of those conducting
`the trials, a major benefit of LMIC is that it
`is easy to enrol patients who are willing to
`participate, particularly if they are poor. For
`many of these patients, clinical trials are
`their only access to medical care. However,
`it is precisely this unmet medical need that
`poses a risk for exploitation. “You want to
`make sure that you don’t take advantage of
`deprivation and that you don’t see the world
`as a convenient population of sick people
`where you can go and get the data that you
`need to make more robust health systems in
`high income countries”, commented Alex
`John London, Professor of Philosophy and
`Director of The Center for Ethics and Policy
`at Carnegie Mellon University in the USA.
`Indeed, human subjects research in LMIC
`has often been criticized for exporting the
`risk of research to those who will, in the
`end, not be able to afford the resulting medi-
`cal products. Clinical trials can pose real
`health risks to participants, as the safety and
`side effects of the drugs or vaccines being
`tested are not yet fully known.
`
`T he history of clinical trials and their
`
`globalization can be
`subsequent
`to
`the
`thalidomide
`traced back
`scandal
`in Germany in the early 1960s.
`Many children were born with severe
`
`deformations of their extremities; it subse-
`quently became clear that
`thalidomide, a
`sedative developed by the German company
`Gru¨ nenthal, caused birth defects in babies
`whose mothers had been taking the drug
`during pregnancy. Public outrage over the
`devastating effects of the drug and the fact
`that it had not been sufficiently tested for
`safety fuelled discussion within the US Food
`and Drug Administration (FDA) and quickly
`led to legislation to improve the safety test-
`ing of new drugs. The so-called Kefauver-
`Harris Amendments were passed to prevent
`another thalidomide disaster and—although
`not directly related to the drug scandal—
`introduced the requirement for drug manu-
`facturers to prove drug effectiveness in
`addition to safety.
`......................................................
`“From the perspective of those
`conducting the trials, a major
`benefit of LMIC is that it is
`easy to enroll patients who are
`willing to participate,
`particularly if they are poor”
`......................................................
`
`As the standards for safety and efficacy
`developed over the decades, so did research
`ethics principles. Again, it was medical scan-
`dals that spawned today’s human subjects
`regulations in the USA, most notably the so-
`called Tuskegee Syphilis study. In this infa-
`mous experiment, conducted from 1932 to
`1972, US physicians denied penicillin, a
`known treatment for syphilis since the late
`1940s, to a cohort of syphilis-infected Afri-
`can American sharecroppers to study the
`natural course of advanced syphilis. Outrage
`over these practices led to the passage of the
`
`Freelance journalist in Oldenburg, Germany. E-mail: mail@k-weigmann.de
`DOI 10.15252/embr.201540398 | Published online 7 April 2015
`
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`ARGENTUM
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`

`Katrin Weigmann
`
`Clinical trials in developing countries
`
`EMBO reports
`
`National Research Act in 1974 and eventu-
`ally to the Belmont report, which forms the
`basis
`for any human subject
`research
`conducted in the USA. As a result, the regu-
`latory process for drug development and
`testing in the USA has very high standards,
`but at a price: the US Food and Drug Admin-
`istration (FDA) has been regularly criticized
`for being disproportionately strict and for
`requesting too much data. Clinical
`trials
`have thus become increasingly complex and
`time-consuming in the USA, leading to what
`has been termed “drug lag”: prior to the
`Kefauver-Harris Amendments, an average of
`40 new drugs were introduced each year,
`whereas the number dropped to 16 there-
`after.
`
`T he FDA is in a difficult position: being
`
`too strict ensures safety, but it slows
`down the approval process and can
`delay new drugs from benefiting patients. If
`this
`affects
`drugs
`for
`life-threatening
`diseases, delays can cost lives if there are no
`other treatment options. By way of example,
`during the early 1990s, activists in the US
`lobbied the FDA to ease its rules and expe-
`dite approval for the first generation of anti-
`HIV drugs because so many AIDS/HIV
`patients were dying each year. On the other
`hand, not being strict enough can lead to
`public health problems if unsafe drugs enter
`the market. Prominent examples are Rezulin
`(troglitazone) and Vioxx (rofecoxib), both of
`which turned out to have unacceptable side
`effects.
`......................................................
`“Research began to leave the
`USA, first to Scandinavia and
`the UK, then to Eastern Europe
`and Latin America, and now
`to China and India”
`......................................................
`
`Yet, the FDA has an incentive to err on
`the side of caution: lives lost owing to drug
`delays usually results in fewer negative
`headlines than lives lost to dangerous drugs
`approved too soon. In addition, some of the
`FDA’s regulations make clinical research
`more burdensome and costly even without
`improving human subjects protection or
`drug safety. It has been argued, for example,
`that requiring continued annual review by
`Institutional Review Boards (IRBs) even for
`minimal risk studies is simply not necessary.
`
`In addition, multicentre studies are often
`reviewed by multiple local IRBs, a costly but
`redundant procedure. When clinical
`trials
`started to move abroad in the 1980s, strin-
`gent FDA regulations were a major factor,
`and still are today.
`FDA regulation is not the only reason
`that so many clinical trials have moved to
`LMIC [1]. Because many new drugs confer
`only a small benefit over existing treat-
`ments, ever larger trials with increasing
`numbers of human subjects are required to
`measure
`improvements with
`statistical
`significance. This has become particularly
`relevant for so-called me-too drugs that are
`chemically very similar to those already on
`the market. Recruiting a sufficient number
`of patients therefore remains a major bottle-
`neck for medical research, and companies
`have turned to LMIC to conduct
`trials
`because it is easier to find participants there.
`Moreover, operational costs in developing
`countries are low and there are large pools
`of “treatment-naive” patients, whereas in
`traditional research areas, the use of too
`much medication generates the risk of drug–
`drug interactions. Research began to leave
`the USA, first to Scandinavia and the UK,
`then to Eastern Europe and Latin America,
`and now to China and India (Fig 1). A recent
`investigation found that the 20 largest US-
`based
`pharmaceutical
`companies were
`conducting one-third of their clinical trials
`solely at foreign sites, while the majority of
`study sites are outside the USA [2].
`
`W hen research by US companies is
`
`in other countries,
`carried out
`the FDA still has some responsi-
`bilities to ensure that
`these comply with
`ethical standards. But
`there are doubts
`whether all
`the US rules and regulations
`should be exported to other countries. “The
`US regulatory system is far from perfect, it
`has been criticized as being overworked and
`inefficient. Some would argue that it is not
`the best model to bring to lower income
`countries that don’t have the resources we
`have”, said Sandra Alfano, Research Scien-
`tist at Yale School of Medicine and Chair of
`Yale’s Institutional Review Board (IRB).
`Moreover, not all ethical principles have
`cross-cultural validity. Informed consent, for
`example,
`is a central concept
`for any
`research with human subjects. However, as
`Alfano remarked, “the principle of informed
`consent flows out of a Western philosophy
`of
`individual autonomy. That does not
`
`always translate well to other countries”. An
`Eastern philosophy, she explained, may
`rather rely on community or family decision.
`“Individualism is not a universally embraced
`idea”, she said. She therefore thinks that
`Western researchers “should be strongly
`encouraged to involve the local community
`in setting the agenda—deciding whether this
`is a good project to be done—and then help-
`ing to design the research protocol and
`addressing the question about who is the
`right body to give consent”. This principle is
`referred to as “community-based participa-
`tory research”, or CBPR. “CBPR is really the
`focus on everyone’s mind, but it is very diffi-
`cult to achieve”, Alfano said.
`......................................................
`“. . . the primary goal of
`conducting clinical trials in
`developing countries should be
`to address the health needs of
`the host population”
`......................................................
`
`cultural differences and the
`Despite
`need to collaborate with local communi-
`ties,
`there are guidelines for conducting
`research in international settings, notably
`the Declaration of Helsinki (DoH) by the
`World Medical Association (WMA), and
`the international guidelines for biomedical
`research involving human subjects by the
`International Organisation
`for Medical
`Sciences (CIOMS). They are not
`legally
`binding, but set out
`important standards
`nonetheless. “Many countries refer to the
`DoH in their legislation. But what is more
`important is that it is a document written
`by physicians and for physicians. There is
`a moral obligation for physicians to stick
`to these rules”, said Ramin Parsa-Parsi,
`Head of the Department for International
`Affairs of the German Medical Association.
`The DoH was adopted in 1964 and has
`since undergone
`seven revisions, most
`recently in October 2013. A major revision
`was made in 2000 in response to studies
`performed with US federal funds of mother–
`child transmission of HIV in developing
`countries, which denied effective medication
`to participants in the placebo control arm.
`The DoH, in its 2000 revision, accordingly
`greatly limited the use of placebos. However,
`some argued that this would restrict research
`too much and that long-term benefits would
`justify the use of placebos [3]. The FDA,
`
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`EMBO reports
`
`Clinical trials in developing countries
`
`Katrin Weigmann
`
`CANADA
`13555
`
`UNITED
`STATES
`83689
`
`EUROPE
`51990
`
`MEXICO
`2309
`
`CENTRAL
`AMERICA
`2163
`
`AFRICA
`4375
`
`NORTH ASIA
`3463
`
`MIDDLE
`EAST
`7775
`
`EAST ASIA
`17010
`
`JAPAN
`3589
`
`SOUTH
`ASIA
`3097
`
`SOUTH
`AMERICA
`6334
`
`SOUTHEAST ASIA
`3835
`
`PACIFICA
`4914
`
`Source: http://ClinicalTrials.gov
`
`Colours indicate number of studies in clinical trials
`with locations in that region
`
`LEAST
`
`MOST
`
`Labels give exact study count
`
`Figure 1. Distribution of study locations of all trials registered with ClinicalTrials.gov.
`
`when regulating studies outside the USA,
`kept referring to older versions of the DoH
`and,
`in 2008, abandoned referring to it
`altogether at the expense of the “Harmoni-
`sation of Technical Requirements for Regis-
`tration of Pharmaceuticals for Human Use
`Good Clinical Practice” (ICH-GCP) guide-
`lines. “The ICH-GCP has been created by
`European, Japanese and US regulators in
`collaboration with
`the
`pharmaceutical
`industry. There are large differences in
`ethical standards between the DoH and
`ICH-GCP, particularly in the
`areas of
`placebo use and post-trial access”, Parsa-
`Parsi explained.
`The newest revision of the DoH, issued
`in late 2013, leaves the placebo paragraph
`essentially unchanged. The ICH-GCP regula-
`tion, on the other hand,
`is much more
`permissive: it explicitly states that the stan-
`dard of care required to be provided to the
`control group depends on the population,
`meaning that control group subjects are only
`entitled to the standard of care they would
`
`otherwise receive locally. This is morally
`ambiguous. According to London, “you
`can’t use the mere fact that people don’t
`have access to an intervention that works to
`say that you don’t have an obligation to
`provide them with something that works”.
`
`T he ongoing debate shows just how
`
`difficult it is to define ethical stan-
`dards for research in international
`settings, to walk the narrow line between
`protecting research subjects and enabling
`research that contributes to the social good.
`According to London,
`the question of
`placebo-controlled trials should be viewed in
`the context of the research question studied.
`In his view, the primary goal of conducting
`clinical trials in developing countries should
`be to address the health needs of the host
`population. “In general, we should provide a
`high standard of care”, he said, but main-
`tained that there could be rare exceptions.
`Such exceptions might be in cases where
`placebo-controlled trials are particularly
`
`important to developing countries: for exam-
`ple, when testing a new intervention that is
`similar to but cheaper than existing drugs, or
`one that has some other characteristic that
`conveys particular advantages in LMIC. One
`such feature would be heat resistance, which
`would make it easier to transport medication
`to remote locations in tropical areas. In such
`cases,
`it would be reasonable to use a
`placebo control
`in the trial, as it will be
`difficult to compare the efficiency of the new
`product to the existing one.
`A crucial aspect in the DoH and CIOMS
`guidelines concerns research on vulnerable
`groups. If people in developing countries
`belong to severely socio-economically disad-
`vantaged populations, this would impact on
`their
`freedom to consent, making them
`susceptible to undue influence and there-
`fore vulnerable. According to the DoH,
`research in vulnerable groups is only justi-
`fied, “if the research is responsive to the
`health needs or priorities of this group and
`the research cannot be carried out
`in a
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`Clinical trials in developing countries
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`
`this
`In addition,
`non-vulnerable group.
`group should stand to benefit
`from the
`knowledge, practices or interventions that
`result from the research”.
`......................................................
`“. . . taking advantage of
`people’s deprivation to impose
`on them the risk of health
`research can be exploitive if it
`is not carefully planned and
`regulated”
`......................................................
`
`“We have discussed including, in addition
`to the current requirements which reflect
`the ‘reasonable availability’ approach, a
`wording on fair benefits”, Parsa-Parsi said.
`Indeed, “fair benefits” is a hotly debated
`topic. Whereas the DoH and CIOMS base
`ethical acceptability mainly on responsive-
`ness to health needs of the host commu-
`nity, others maintain that
`research is
`justified as long as the host community
`receives “fair benefits” in a more broadly
`defined sense. Such benefits would not
`have to be directly related to the research
`projects and might include employment and
`training for community members or the
`building of
`infrastructure [4]. However,
`after long debates and consultations with
`developing countries, a fair benefits option
`was not included in the current version of
`the DoH. “The possibility of exploitation—
`that you buy consent with money or other
`benefits—was considered too high by the
`WMA”, Parsa-Parsi explained. London takes
`a similar view: “Ancillary benefits are
`important, but I don’t think they can make
`up for lack of relevance of the science to
`local health needs”, he said. For him,
`addressing the local health needs is the key
`issue. But ethical commitment should not
`stop there. “Just because I know the answer
`doesn’t make you better off. That informa-
`tion then has to be translated into some-
`thing from which you benefit concretely”,
`he said. “You start by studying the health
`needs, you build up an information base
`needed to discover interventions that work
`and then you close the cycle of translation
`by making those interventions and that
`knowledge available to their communities.”
`Availability of
`the drugs developed
`remains another major issue. Medication is
`often far too costly people in LMIC to afford,
`but with time, that too can change. “People
`
`were worried that HIV studies carried out in
`LMIC were not relevant to local health needs
`because the drugs were too expensive”,
`London recalled. “Ten years later, many
`more people have access than what was
`originally expected.” According to the WHO,
`the number of patients taking antiretroviral
`therapy has increased rapidly in LMIC since
`2003 from just 400,000 to 11.7 million by
`the end of 2013 (http://www.who.int/gho/
`hiv/epidemic_response/ART_text/en/).
`
`I n the meantime, other diseases are taking a
`
`terrible toll in LMIC, and it is not clear
`when new drugs will be cheap enough for
`wide use by their citizens. Hepatitis C, an
`infectious disease that can lead to liver cirrho-
`sis, is on the rise globally, and developing
`countries carry the highest burden with infec-
`tion rates as high as 11% in Egypt, 4.8% in
`Pakistan and 3.2% in China. During the past
`decade, research has led to the development of
`new drugs that work more effectively, in less
`time and with fewer side effects. Moreover, in
`contrast to the previous treatment regimens,
`these all-oral medications do not require regu-
`lar interferon injections, making them ideal for
`use in remote settings. The drugs are just start-
`ing to come to market, with more in the pipe-
`line, but their cost at the outset puts them out
`of reach for most people in developing coun-
`tries. It is likely that, as in the case of AIDS
`medication, it will take long until they become
`available to most LMIC.
`In many cases, therefore, studying local
`health needs will not necessarily generate
`immediate benefits for poorer communities.
`Nonetheless, studies that are responsive to
`local health needs will generate information
`that is necessary to improve public health in
`the long run. “When you ensure that the
`information is relevant to the local popula-
`tion, you build the foundation of knowledge
`necessary to generate beneficial
`interven-
`tions and policies, and this is a kind of bene-
`fit
`itself”, London commented. Making
`important new treatments available in LMIC
`should be considered a health priority, but
`this might take years or even decades at the
`current rate of progress. For participants in
`clinical trials, it will therefore be important
`to help them to bridge the gap between the
`end of
`the trial and the time the drug
`becomes available in their country.
`
`B oth the CIOMS and the DoH require
`
`to
`groups
`studies on vulnerable
`address their health needs. But does
`
`research in LMIC address local health needs
`in reality? According to the 2014 report by
`the Access to Medicine Foundation, an inter-
`national not-for-profit organization that
`ranks the top 20 research-based pharmaceu-
`tical companies with respect to their efforts
`to improve global access
`to medicine
`(http://www.accesstomedicineindex.org/),
`there is some promising development, but
`there is still a long way to go. “There is
`evidence of sustained commitment to R&D
`for relevant diseases, with most companies
`having an R&D strategy in place that explic-
`itly takes patients in developing countries
`into account”,
`the
`report
`says. More
`precisely,
`the index investigated research
`activities on 47 diseases that were regarded
`as most relevant to LMIC according to the
`WHO. Although a number of studies tackle
`these diseases, the research activities can
`mainly be attributed to only five of the 20
`companies, and they concentrate on only
`five of the 47 diseases: diabetes, lower respi-
`ratory infections, hepatitis, HIV/AIDS and
`malaria. Neglected tropical diseases, as the
`report shows, remain neglected. In addition,
`the report criticises companies’ lack of effort
`to make their products available to people in
`LMIC: “On average, products are registered
`in only [. . .] 8% of low-income countries
`covered by the Index.”
`Conducting clinical trials in LMIC is not
`intrinsically immoral. Indeed, trials some-
`times represent the only medical treatment
`that patients in deprived settings can hope
`to receive, and can also provide other
`advantages at the personal, community and
`national levels. Nonetheless, taking advan-
`tage of people’s deprivation to impose on
`them the risk of health research can be
`exploitive if it is not carefully planned and
`regulated. At the moment, there is such a
`variety of
`legislation that
`the conduct of
`trials differs widely, often depending on why
`a company decided to use a developing
`country in the first place. Trials that address
`locally relevant diseases and that will deliver
`affordable drugs and care for the local popu-
`lation are certainly to be lauded. Ones that
`do not provide immediate or obvious bene-
`fits locally are less laudable and must be
`assessed on a case-by-case basis.
`
`References
`1. Petryna A (2009) When Experiments Travel:
`Clinical Trials and the Global Search for Human
`Subjects. Princeton, NJ: Princeton University
`Press
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`Clinical trials in developing countries
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`Katrin Weigmann
`
`2. Glickman SW, McHutchison JG, Peterson ED,
`Cairns CB, Harrington RA, Califf RM, Schulman
`KA (2009) Ethical and scientific implications of
`the globalization of clinical research. N Engl J
`Med 360: 816 – 823
`
`3. Wolinsky H (2006) The battle of Helsinki:
`two troublesome paragraphs in the Declara-
`tion of Helsinki are causing a furore over
`medical research ethics. EMBO Rep 7:
`670 – 672
`
`4.
`
`Schulz-Baldes A1, Vayena E, Biller-Andorno N
`(2007) Sharing benefits in international health
`research. Research-capacity building as an
`example of an indirect collective benefit.
`EMBO Rep 8: 8 – 13
`
`570
`
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