Class 1 DQ 8

Exportation of unethical practices to low and middle income countries in biomedical research - Germán Novoa-Heckel, Rosemarie Bernabe, Jorge Linares Rev Bio y Der. 2017; 40: 167-177

* Germán Novoa-Heckel. MD PhD, National Autonomous University of Mexico (UNAM). Bioethics Universitary Program. México City. E-mail: [email protected]. * Rosemarie Bernabe: MA PhD, Julius Center for Health Sciences and Primary Care, University Medical Center U trecht (Netherlands). E-mail: [email protected]. * Jorge Linares: PhD, National Autonomous University of Mexico (UNAM). Bioethics Universitary Program. México City. E-mail: [email protected].

Revista de Bioética y Derecho Perspectivas Bioéticas

www.bioeticayderecho.ub.edu - ISSN 1886-5887

ARTICLE

Exportation of unethical practices to low and middle income

countries in biomedical research

Exportación de prácticas éticas deficientes de investigación

biomédica hacia países con menor grado de desarrollo

GERMÁN NOVOA-HECKEL, ROSEMARIE BERNABE, JORGE LINARES *

OBSERVATORI DE BIOÈTICA I DRET DE LA UNIVERSITAT DE BARCELONA

Revista de Bioética y Derecho was established in 2004 at the initiative of the Bioethics and Law Observatory (OBD, initials in Spanish) with the support of the Master in Bioethics and Law at the University of Barcelona: www.bioethicsandlaw.es/master. In 2016 the journal Perspectivas Bioéticas from the Bioethics’ Program at the Latin American Faculty of Social Sciences (FLACSO, initials in Spanish) merged with Revista de Bioética y Derecho.

This is an electronic open access journal which means that all content is freely available at no cost to the user or his/her institution. Users can read, download, copy, distribute, print or link to the full texts of the articles in this journal without previous permission of the publisher or the author, provided there is no profit in such transactions, and provided that the source is always cited. This is consistent with the BOAI definition of open access.

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Abstract

Substandard ethical practices in biomedical research have been exported from more developed

countries to less developed countries worldwide. The term for this practice is called ethics

dumping, which can be described as exporting, in clinical research, sensitive ethical practices from

more developed to less developed countries, with subpar requirements and other economic or

operational advantages that would be inadmissible in developed countries. Examples for this

practice are described, as well as its origin, receptivity, and perpetuation, together with some

preliminary guidance and advice in order to work towards possible solutions for this ethically

sensitive issue in the future.

Keywords: clinical research; ethics; ethics dumping; research ethics; research bioethics.

Resumen

En la investigación biomédica se han exportado prácticas éticas deficientes desde los países con

mayor grado de desarrollo hacia países con menor grado de desarrollo a nivel mundial. El término

para esta práctica es el de deposición de prácticas éticas (“Ethics Dumping”), que puede

describirse como el hecho de exportar, en la realización de investigación clínica, prácticas éticas

sensibles del tipo de exigencia disminuida y otras ventajas de índole operativa y económica no

aceptables en países desarrollados, hacia países no desarrollados. Se describen ejemplos de esta

práctica, así como su origen, receptividad, y perpetuación, junto con algunas guías preliminares y

recomendaciones, con el fin de trabajar hacia el futuro en busca de posibles soluciones para este

asunto éticamente sensible.

Palabras clave: investigación clínica; ética; deposición ética; ética de la investigación; bioética de

la investigación.

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1. Introduction

Exporting substandard ethics to developing countries

That substandard ethical practices in biomedical research are continuously exported to the

developing world have been the topic of discussion in the research ethics literature for some time

now.1, 2, 3, 4, 5 It is only recently, however, that the concept of “ethics dumping” has received regulatory

attention.6 The term “dumping” seems to have been borrowed from the realm of commerce and

economics referring to the practice of exporting goods at prices lower than the home -market prices.

It is used in the context of international commerce law where a company fixes for its export goods a

price lower than the cost of producing them in the importing country, thus driving loc al competitors

out of business.7 Even though the term has negative connotations, free-market supporters consider

the practice beneficial for consumers.

In clinical research, “ethics dumping” designates the risk of sensitive ethical issues being

exported from more developed countries (MDCs) to less developed countries (LDCs) in pursuit of

potential economic and operational advantages under conditions deemed unacceptable in MDCs. The

European Commission defines it as “the exportation of research practices that would not be accepted

in Europe on ethical grounds”.6 For more than two decades, some research organizations have been

seeking to conduct their work in LDCs, regardless of whether the drugs tested can be marketed under

local economic and organizational conditions.8, 10 One of the advantages researchers see in these

countries, precisely, are large numbers of patients who are completely new to treatment and

significantly easier to recruit.11

A clearer definition is needed in order to understand what we mean by “ethics dumping”. We

can begin by expanding the definition “exporting ethically unacceptable practices to developing

countries”: in clinical research, this refers to the practice of exporting to developing countries research

practices that may be ethically unacceptable in developed countries. The motivation for this

exportation are usually economic and/or operational advantages.12, 13

What would constitute examples of unethical practices being exported by countries who

commission clinical research abroad? Relatively well-known instances of this would be exerting

undue pressure by offering researchers incentives to recruit patients faster, or individual c ases in

which legal, economic, operational or competitive standards are lowered to the advantage of MDC

organizations dominant in LDCs. Another example would be working with payment rates that fail to

match first-world rates or compensate for the cost of operation for LDC researchers and facilities. Yet

another instance of these practices is the adoption of double standards, as discussed by Macklin, for

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example.14 What the term implies here is that, with the intention of avoiding the pitfalls associated

with the differences in clinical research between MDCs and LDCs, certain practice standards are

applied in the former, while entirely different standards are applied in the latter. Table 1 shows some

examples of ethics dumping and its consequences. Note that we are not claiming that all practices are

“unethical”. To do so, we would need to make a case for each of these examples. In the table below, we

simply wish to demonstrate the undesirable consequences of the various ethics dumping practices.

Ethics dumping practice

Examples (ethical and unethical)

Undesirable consequences

1. Patient recruitment issues Recruiting babies for epilepsy studies and taking advantage of mothers' commitment to watch over their children for the 24 to 48 hours needed to complete the study.

Abusing parents' and guardians' availability, good faith and mistaken beliefs about potential treatment benefits.

2. Methodological issues Using placebos in cases where lower treatment standards in LDCs seem to justify it. The argument is that patients are not being exploited: since their condition does not actually worsen, it is not necessary to administer active medication. (8)*)

Abusing the good faith of patients; denying patient -participants of a proven intervention even when such exists.

3. Advantages in dealing with authorities and Research and Ethics Committees (RECs)

Studies with varying degrees of risk can be difficult to carry out in MDCs due to tighter restrictions. RECs in LDCs might be less rigorous.

This practice entails increased risk to participants from LDCs.

4. Recruitment advantages Studies deemed burdensome or problematic in other countries because of increased patient discomfort/burden (e.g. complex laboratory testing or use of IV markers).

Abusing patients who often are unaware of the absence of benefits and the increase in risks.

5. Advantages due to increased prevalence of certain diseases

Studies of the antibiotic treatment of diarrhea conducted in the North of Mexico. (e.g. Studies in the 90s).

Some diseases are more prevalent in LDCs. The availability of subjects is abused, with little compensation or for LDCs.

6. Economic advantages Studies are less costly in LDCs, though the burden of work is the same.

Taking advantage of the lack of negotiating power and the availability of local research teams.

7. Logistical advantages (e.g. implementation times)

Shorter implementation times, accelerated patient recruitment achieved by offering questionable incentives to researchers, which may be unacceptable in MDCs.

Inadequate compensation, unethical in MDCs.

Table 1. Ethics dumping practices and examples of practices.

* The use of placebos has to do with using or not the best methods available worldwide as control treatment. In the Nevirapine

controversy it is shown that the rule of best methods available worldwide and, as a result, the limitation of using placebos to conditions

in which there is no medical alternative under no circumstances are good rules, but there are some exceptions in which research may

be carried out while at the same time participants are not exposed to exploitation” (15).

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An additional manifestation of ethics dumping emerges as a more subtle issue when it

comes to recruiting patients for research. In MDCs, participating in research may be seen as a

moral obligation, a commitment by subjects to help find more and better treatments.16 In the less

developed world, by contrast, the agreement to take part in a study is often predicated on patients'

hope of solving their medical problems or improving their health. This issue has been detailed in

a very comprehensive study17 (See also: International Conference on Harmonization, ICH-E6,

specifically the definition in 1.61: Vulnerable subjects).18 Clinical studies thus make “therapeutic

promises” they may not actually fulfill, but participants may not be fully aware of this when they

sign the informed consent.19 It is the nature of clinical research to not claim expected therapeutic

benefits for the present or future health of patients, with the exception of phase IV clinical trials.20

The phenomenon wherein therapeutic benefit is expected in clinical trials has been described in

the medical literature as “therapeutic misconception”: study participants believe that their

individual therapeutic needs will be considered during clinical trials, a faulty understanding of the

nature of clinical trials coupled with the unreasonable expectation of receiving medical benefits.21

It is worth noting that the many unsolved issues in clinical research (such as the use of placebos,

or justifications unconvincingly rooted in the principle of equipoise)22 only add to the problems

raised by the exportation of substandard ethical practices. This in turn only deepens rifts of

misunderstanding and abuse.

The moral obligation to take part in a trial, as may be understood in MDCs (i.e. the

importance of contributing in the search for more and better treatments23 is invalidated by the

fact that these new therapies might not be available, at least in the short term, to LDCs population.

When they do become available, it is likely that their market price will continue to make them

unavailable for as long as patents are valid. Generic versions, though less expensive, will still be

unaffordable for some. Informed consent requirements and therapeutic promises are thus

unequal, insufficient and surely unjust.

2. Origins of ethics dumping

With the aim of arriving at a viable solution, we must first investigate the causes of ethics dumping.

The answer is many-sided. First, there is an increased demand for clinical services in MDCs. This

puts pressure on existing research capacities to grow, in a context of research saturation and

patient shortage.23 Second, strict requirements and regulations in MDCs are subject to additional

pressure from other, equally urgent factors as are economic and marketing factors. There follows

pressure to conduct research with simpler regulatory requirements and at lower cost.24

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Next, we should consider the effects of a certain automaticity in southbound exportation.

Together with the exported research, countries where requirements tend to be more flexible and

authorities more lenient also receive the pressure and demands typical of MDCs if LDCs wish to

be competitive hosts of clinical trials.25 The demand for research services in LDCs are increased,

along with the possibility that sponsors or their intermediaries may act unfairly characterized by

uneven commercial interactions between countries and unequal negotiations. The risk is that this

kind of interaction will result in exploitation, i.e.

…when wealthy or powerful individuals or agencies take advantage of the poverty,

powerlessness, or dependency of others by using the latter to serve their own ends (those

of the wealthy and the powerful) without adequate compensating benefits for the less

powerful or disadvantaged individuals or groups.26

To sum up, the context of research is subject to pressure from authorities and corporations.

Many of these demands can be traced back to economic interests, as the term “time-to-market”

denotes. Such pressure can move international clinical researchers to apply double standards

(moral and otherwise) and resort to ethics dumping, a phenomenon in which unequal ethical

practices inadmissible in MDCs are offshored to the developing world. The consequences include

a sense of disappointment, frustration and lack of empathy, and misunderstandings in

transnational clinical research, with a loss of prestige and moral credibility for both sides of the

equation.

Also at the root of ethics dumping are faulty negotiations. LDCs might not be familiar with

the standard of rights and obligations to be observed in specialized transnational research

negotiations. Other issues which perpetuate the exportation of substandard ethical practices will

be discussed in the following sections.

Finally, an allegory extracted from family dynamics might help explain the “natural” course

MDCs follow in the attempt to deal with increased pressure. In some families, one parent is less

strict than the other when it comes to demands like pressure to succeed in school and restrictions

placed on the children's behavior. The natural course of action for a child seeking to obtain special

permissions or approval will thus be to appeal to the parent that offers less resistance. Though

both parents are equivalent as authority figures, their authority is exercised differently, with one

of them offering less resistance. It can be understood in this same sense that the search for new

research territory “naturally” (also) looks to developing countries.

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3. Receptivity of LDCs to ethics dumping

LDCs become receptive to ethics dumping for a number of reasons. Some of the most widely

acknowledged include the need for growth and international recognition, economic needs, the

quest for scientific and technological development, and a duty to stay in line with parent

corporations. Other less studied motivations have to do with cultural nuances, such as the

perception of flattery combined with feelings of inferiority, and the resulting pressure to

demonstrate ability, worth and equality.

Receptivity in LDC regions is reinforced by the relaxed regulations we have mentioned, plus

some operational advantages. An undeniable fact is that patient availability is greater in these

regions, together with accommodating management, reduced costs, and qualified, efficient

personnel with unmet economic needs.

We can group all these factors under “LDC receptivity”. Together with “reduced regulatory

and economic demands,” this preserves a relationship that can lead to the exportation of

unacceptable ethical practices. In summary, the pursuit of clinical research shifts from its origins

in the direction of LDCs seeking increased speed, reduced costs and advantages in implementing

and carrying out studies as far as ability (and goodwill) will allow it.

4. Perpetuation of ethics dumping

We will now attempt to surmise on the possible contributing factors to the long-term prevalence

of these practices. Note that a systematic approach to look into the causes for the perpetuation of

ethics dumping would have yet to be done in future research.

Ethics dumping subsists and even change shape over time mainly because the ethics that

MDCs apply outwardly are seldom revised by LDCs. This depends on the perception that practices

of varying acceptability on both sides should be geared towards fulfilling the demands and

priorities of the sponsoring agents. In other words, the idea is to solve a host of different and

varying problems of conducting clinical research. An additional complication is that LDCs often

approach negotiations with little knowledge of accepted and acceptable practices, guidelines and

valid premises in MDCs. Also, there is much to be desired with regard to community engagement

or participant consultation27 in global research. LDCs are thus unable to identify ethics dumping,

its origins and its forms. LDCs place a blind trust on MDCs and adapt to their precepts easily.

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5. Working out our differences

We have seen that there are various issues related to the installment by receptivity of LDCs and

how this leads further to the perpetuation of ethics dumping.

We think that there is a need to intervene on existing norms, both in procedural and tangible

matters (the former being conflict resolution, changes in terms, etc., and the latter compensations,

duties, and performance). Requirements should be regulated to harmonize with the developing

world, encouraging openness and transparency in negotiations, and eliminating the unfair

exportation of ethical practices such as double standards.

We could start by harmonizing our understanding of patient involvement, supporting the

conditions of moral obligation to participate in studies. Though it seems complicated, this is not

impossible. The search for homogenous visions and regulations (as part of a proposed

harmonization conference) could include negotiating the terms of participation by LDCs, as well

as establishing clear guidelines for solving issues of ethics dumping. Additionally, we should

commit to sharing study results and benefits more equitably, so as to ensure fair conditions for

LDCs.

In the recent CIOMS Guidelines28 of mid-2016, in GUIDELINE 2: “Research conducted in low-

resource settings”, there are recommendations in order to tackle different issues partially

discussed already; for instance, the use of comparators provided in our table. In the comments

section “Responsiveness of research to health needs or priorities”, it states: “a question about

responsiveness might arise if a study of a new intervention is planned for a community in which

established effective interventions for a health condition are not locally available and the new

Intervention has features that would make it difficult to implement in that community. In

such cases, researchers and sponsors must consider whether the study could be made more

relevant to local health needs.” It further states: “If the knowledge to be gained from the research

is intended for use primarily for the benefit of populations other than those involved in the

research, the responsiveness requirement is violated”. Further, this last sentence would address

the compliance that is necessary with community interests, brought about in general form

originally by the Declaration of Helsinki. In general, the valuable recommendations brought about

by this last review should help to tackle ethics dumping further in some of its most salient features.

Other recommendations in Guideline 2, as is the building of local research capacity or to ensure

an overall fair distribution of the benefits and burdens of the research, should well serve the

purpose of preventing this phenomenon.

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The issue of informed consent should also be on our agenda. Informed consent needs to be

justified and culturally sensitive to the conditions of LDCs. A “showtime” approach, in which

patients are called upon and dismissed as needed, leaves a community's real needs unaddressed

when the study concludes. In LDCs, this might be interpreted as abandonment, creating a sense of

emptiness or alienation, with no perceived gain. Such issues could be eliminated with clear

guidelines as to personal and community benefits, in accordance with the latest version of the

Declaration of Helsinki.29

Most importantly, we should endeavor to eradicate ethics dumping to the best of our ability,

through a clear discussion and understanding of existing differences. Practices such as offering

payments to expedite recruitment, for example, might prove too complex to solve in the short

term, but we could outline feasible solutions to correct imbalances wherever possible, without

resorting to unacceptable practices, always seeking to eliminate abusive, unfair or exploitative

behavior.

Technical and methodological aspects should also be on our agenda. In a provocative

review, Contopoulos-Ioannidis30 examines the differences between MDCs and LDCs in relation to

the over or underestimation of risks. The study concludes that there is a need to prioritize and

standardize the documentation and reporting of harms in all randomized trials, both in MDCs and

LDCs.

Our first priority should be instituting a negotiating table guided by a bilaterally established

agenda, with the goal of harmonizing differences. We must keep in mind the need for open, honest

and transparent discussion of the existing differences that have so far been the cause of many

misunderstandings and obstacles (or even disrepute). Such difficulties, however, can and should

be overcome. The ongoing practice of ethics dumping is, undoubtedly, in need of being addressed

and solved as soon as possible. The advice and rules expressed in many ways through different

channels at present should make it more difficult in the future to trespass the desired limits,

getting closer to the ideal of complying with what is feasible, and at the same time what is decent,

fair and just in biomedical research as it is practiced in developing countries.

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Received for publication: 28 September 2016

Accepted for publication: 6 March 2017