Ethical issues in clinical trial collaborations with developing countries - with special reference to preventive HIV vaccine trials with secondary endpoints

Ethical issues in clinical trial collaborations with developing countries - with special
reference to preventive HIV vaccine trials with secondary endpoints
Reidar K. Lie, M.D., Ph.D.
Department of Philosophy
University of Bergen
Sydnesplassen 7
N-5007 Bergen, Norway
Fax. + 47 55 58 96 51
Tel. + 47 55 58 24 37
Email: Reidar.Lie@fil.uib.no

---

TABLE OF CONTENTS
1. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Existing research ethics guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
The issue of HIV vaccine efficacy trials with secondary endpoints . . . . . . . . . . . . . . . . . 5
2. PROBLEMS WITH THE GUIDELINES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
The CIOMS notion of “Underdeveloped communities” . . . . . . . . . . . . . . . . . . . . . . . . . 6
Different opinions among experts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
The notion of different levels of risk in different countries . . . . . . . . . . . . . . . . . . . . . . . 8
Previous trials in developing countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
3.DIFFERENT ECONOMIC CONDITIONS IN DIFFERENT COUNTRIES . . . . . . . . . . . . . 13
The perinatal transmission studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
The criticism by Angell, Lurie and Wolf . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Arguments for and against the trials with placebo controls . . . . . . . . . . . . . . . . . . . . . . 16
Can useful results be obtained with a non-placebo controlled trial? . . . . . . . . . . . . . . . . 21
Concluding discussion of the perinatal transmission studies . . . . . . . . . . . . . . . . . . . . . 23
The debate in South Africa about whether a pharmaceutical company is obligated to
provide treatment after the trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
4. PREVENTIVE HIV VACCINE TRIALS WITH SECONDARY ENDPOINTS . . . . . . . . . 25
5. THE ROLE OF RESEARCH ETHICS GUIDELINES AND RESEARCH ETHICS REVIEW
PROCEDURES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
6. CONCLUSION AND SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
7. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

---

1. INTRODUCTION
Existing research ethics guidelines
One central ethical concern when conducting research on human subjects which involves a
collaboration between research groups in different countries is to avoid research which has been
rejected as unethical in one of the countries. It is not difficult to point to examples of such
research in the past (Kiatboonsri & Richter, 1988). In order to ensure that cases such as these do
not happen, it has become generally accepted that collaborative research should be approved by
the relevant bodies (regulatory authorities, ethics committees) in both countries (see CIOMS
guideline 15) . If the research protocol is rejected in one country, the research should not be
carried out.
Some of the wording in the CIOMS guidelines represents a stronger version of this
principle. Fundamental to the CIOMS guidelines is the notion that some groups or countries are
more vulnerable than others and need special protection. A vulnerable group could be an
underdeveloped community in a developed or a developing country, or could be a developing
country in relation to a developed country. According to these guidelines, if research can be
carried out in the developed community, then it should not be carried out at all in an
underdeveloped community. If the research needs to be carried out in an underdeveloped
community, not only should it be approved in both places, but it actually needs to be carried out in
both places simultaneously. This is reflected in the following guideline 8:
Before undertaking research involving subjects in underdeveloped communities, whether
in developed or developing countries, the investigator must ensure that persons in
underdeveloped communities will not ordinarily be involved in research that could be
carried out reasonably in developed communities.
In the commentary to this guideline, it is stated even more precisely:
Phase I drug studies and Phase I and II vaccine studies should be conducted only in
developed communities of the country of the sponsor. In general, phase III vaccine trials
and phase II and III drug trials should be conducted simultaneously in the host community
and the sponsoring country; they may be omitted in the sponsoring country on condition
only that the drug or vaccine is designed to treat or prevent a disease or other condition
that rarely or never occurs in the sponsoring country.
It is not difficult to see the attraction of wanting to adhere to such a principle. By following this
principle, one would not only avoid the obvious cases of abuse, but, by requiring that the
sponsoring country actually carries out the research at home, one would ensure that there are no
reasons which may not be immediately obvious to outsiders for not wanting to carry out the
research in one’s home country.
The principle has received widespread support from some developing countries and from a
number of commentators. The Indian Council of Medical Research recently refused to fund
3

---

research by foreign organizations if they are only carried out in India (Mudur, 1997). The
National HIV/AIDS Vaccine Trial and Evaluation Plan of Thailand required that preventive HIV
vaccine candidates should be tested in the sponsoring country before phase I/II trials are initiated
in Thailand, in agreement with the CIOMS guidelines, although this policy has recently been
changed (see below). The same is the case with the guidelines approved by the Brazilian AIDS
Vaccine Committee (Greco, 1997).
Some commentators have expressed a general distrust in the intentions of foreign
scientists wishing to do research in developing countries, because of past examples of abuse
(Gbolade, 1997). Garner et al for example have pointed out that researchers sometimes conduct a
trial in a developing country, build the necessary infrastructure to do the research, but then when
the research has been carried out and shown a positive effect of an intervention, leave the country
behind without any benefits at all (Garner et al., 1994). If the research is carried out in this way is
of primary benefit to the sponsoring country, and in addition is regarded to be unethical in that
country, it is a particularly blatant example of exploitation of developing countries. One of the
primary motivations behind the CIOMS guidelines is to avoid such cases of exploitation and
abuse, which is reflected in the following subsection of guideline 8:
the research is responsive to the health needs and the priorities of the community in which
it is to be carried out
And in the commentary to this guideline, as well as in the commentary to guideline 15, it is stated:
As a general rule, the sponsoring agent should ensure that, at the completion of successful
testing, any product developed will be made reasonably available to inhabitants of the
underdeveloped community in which the research is carried out; exceptions to this general
requirement should be justified and agreed to by all concerned parties before the research
is begun.
Relevant to the issue of the ethics of collaborative research are also some passages from
the Declaration of Helsinki (latest version, October 1996):
I.5. Concern for the interests of the subjects must always prevail over the interests of
science and society
II.3 In any medical study, every patient - including those of a control group, if any -
should be assured of the best proven diagnostic and therapeutic method. This does not
exclude the use of inert placebo in studies where no proven diagnostic or therapeutic
method exits.
II.6 The physician can combine medical research with professional care, the objective
being the acquisition of new medical knowledge, only to the extent that medical research
is justified by its potential diagnostic or therapeutic value to the patient.
4

---

These principles of the Helsinki declaration are also endorsed by the CIOMS guidelines. The
commentary to guideline 14 states that the ethical review committee must ensure that “the
provisions of the Declaration of Helsinki are applied in all biomedical research involving human
subjects.”. Furthermore, the commentary of this guideline 14 quotes section II.3 of the Helsinki
declaration, and adds that “if there is already an approved and accepted drug for the condition
that a candidate drug is designed to treat, placebo for controls usually cannot be justified”. It
continues, “no other interventions must be known to be superior to those being compared in the
clinical trial, unless eligibility to participate is limited to persons who have been unsuccessfully
treated with the other superior intervention or to persons who are aware of the other intervention
and its superiority and have chosen not to accept it”.
Principle I.5 of the Helsinki declaration seems to say that one cannot justify endangering
individuals for the sake of acquiring knowledge that may benefit society in general or future
patients. The reason for wanting to accept such a principle is obviously to avoid repeating the past
examples of misuse of research where dangerous research projects were justified for precisely this
reason. The principle is, however, problematic, if, as some have argued, all clinical trials involve a
certain amount of risk for the research subjects which is justified in terms of possible future
benefit (I have discussed this elsewhere Lie, In press, and see below). The Helsinki declaration
explicitly demands that participants in clinical trials should receive the best proven therapy.
Neither the Helsinki declaration nor the CIOMS guidelines refer to restrictions on this principle
because of different circumstances. Language such as “there is .. an approved ... drug” and “no
other interventions must be known to be superior” does not place limits on what should be
provided to what is common practice in the place where the trial is conducted, although this
interpretation may not in fact be what is intended by those who wrote the guidelines. It is this
principle which seems to be violated in some of the recent controversial clinical trials.
The issue of HIV vaccine efficacy trials with secondary endpoints
A number of recent cases have raised the issue of the appropriateness of the guidelines. One such
case is HIV vaccine trials with secondary endpoints. The ethical dilemma with regard to HIV
vaccine trials with secondary endpoints is the following. An effective preventive AIDS vaccine
need not only prevent infection, a primary endpoint, but could also be of value if it modified
disease progression, a secondary endpoint. It would for example be of interest to see if a vaccine,
although it did not prevent infection, reduced a person’s viral load. A reduced viral load would be
associated with a better prognosis. This way of making a distinction between primary and
secondary endpoints may not be the way it is usually done, but it follows the way the distinction is
drawn in UNAIDS documents on this matter. If standard therapy in industrialized nations,
however, is to treat patients immediately following infection with currently available combinations
of drugs that are highly effective in reducing viral load, it would be impossible to carry out such
secondary endpoint trials in these countries. Such trials could of course be carried out in countries
where the drug therapies are not available for economic reasons. If, however, as the guidelines
mentioned above seem to require, trials have to be carried out simultaneously in both host and
sponsoring country, all participants have to receive the best proven therapy, then these trials
5

---

cannot be carried out in any country. The consequence of this would be that it is impossible to
find out whether a vaccine candidate is effective with regard to secondary endpoints and whether
it could possibly save a large number of lives.
This particular case is not the only one, and it raises the more general question under what
circumstances, if any, is it ethical to conduct a study in one country that cannot be ethically
conducted in another. This background paper will examine that question. I will do so by
examining the current guidelines in relation to a number of recent cases that have shown that the
guidelines need revision. I will also discuss the recent controversy over the perinatal transmission
studies as we can draw some important lessons from this controversy. Based on this discussion, I
will return to the issue of HIV vaccine trials with secondary endpoints.
2. PROBLEMS WITH THE GUIDELINES
Although, as has been mentioned above, there are obvious reasons why one would want to adhere
to the existing guidelines, a number of recent cases have indicated that some of the wording may
need modification. There are basically five issues that need discussion:
C
The notion of ‘underdeveloped communities’ that are ‘vulnerable’ and may need special
protection
C
What one should do when there is legitimate disagreement among experts concerning the
possible benefits of a particular treatment
C
The relevance of different evaluations of risks versus benefit because a particular disease is
a much greater problem in one country, or the urgency of developing a treatment is much
higher
C
The appropriateness of the general prohibition against carrying out phase III trials in
developing countries but not in developed countries
C
How one should deal with the fact that, because of economic conditions, some treatments
are not available in one country, but available in another country

In this section I shall discuss the first four issues as they are the easiest to deal with. I shall argue
that one should reject a general notion of ‘underdeveloped communities’; that one can carry out a
trial in one country that is not carried out in another if the reason for this is genuine disagreements
among experts; that one should be skeptical about justifying trials in one country because of
different risk-benefit evaluations; and that the general prohibition against carrying out phase III
trials in developing countries is not defensible. I shall in the next major session examine the issue
of different economic conditions.
The CIOMS notion of “Underdeveloped communities”
The CIOMS guidelines introduces the notion of an “underdeveloped community” that needs
special protection because it is vulnerable to exploitation. There is a long tradition in research
6

---

ethics for identifying certain populations as vulnerable, such as prisoners, children or psychiatric
patients. Special care needs to be taken when doing research among these populations. For
example, it is a generally accepted principle that one should not do research on children that can
just as well be done on adults. In the CIOMS declaration this is reflected in the notion that one
should not do research in ‘underdeveloped communities’ if that research can be done elsewhere.
Specifically, this means that one should not do phase I and phase II vaccine studies in
‘underdeveloped communities’. The rationale for this is, that since phase I and phase II studies are
designed to test safety and immunogenicity, and there is not reason to expect that this would
differ among different populations, there is no need to do these studies in underdeveloped
communities.
The notion of ‘underdeveloped communities’ differs from other types of populations, such
as prisoners, children, and psychiatric patients. It is relatively ease to give precise criteria for who
belongs to these populations, but this is not the case for what should count as an underdeveloped
community. Clearly it has to be a relative term. Communities may be ‘underdeveloped’ in one
sense, such as economically, and developed in another sense, such as having a well functioning
research review procedure. It would for example be wrong to lump all those countries together
who are called ‘developing countries’ in an economic sense and identify them as ‘underdeveloped’
for research ethics purposes. For this reason, it might be preferable to drop this term altogether,
and concentrate on principles that should govern all collaborative research between countries
where conditions differ. This may be differences in economic conditions, it may be differences in
research ethics review procedures, and it may be differences in basic values. If this approach is
taken, one would have to evaluate each situation separately and ask if a particular research project
can be carried out in one country if it is not carried out in another country.
This recommendation to drop the general term ‘underdeveloped communities’ should,
however, not mean that some of the substantial reasons for wanting to adopt such a term are
rejected. There is a real issue of wanting to avoid exploitation of one group by a more powerful
group. My scepticism against the term ‘underdeveloped communities’ merely questions whether
this term is the best to capture our desire of wanting to identify situations where exploitations are
likely to occur.
Different opinions among experts
Several recent cases have shown that there is another reason why the general prohibition of
carrying out trials in one a host country, but not in the sponsoring country, is problematic. These
are cases where there are genuine differences of opinions among experts about what should be
regarded as standard of care.
The first example is the tuberculosis case mentioned by Marcia Angell in her recent
editorial commented on more fully below (Angell, 1997b). In Uganda a clinical trial was carried
out to ascertain the effects of various regimens of prophylaxis against tuberculosis among HIV
positive adults. One group in the trial received a placebo. Angell makes the point that this trial
could not have been carried out in the US, as various advisory bodies had previously issued
recommendations that all HIV positive persons with a positive tuberculin test should receive
7

---

preventive therapy (Msamanga & Fawzi, 1997; Whalen et al., 1997). Angell also notes, however,
that there was no universal agreement as to whether this recommendation should constitute
standard of care. She concedes that under these circumstances a trial that could not have been
carried out in the US, nevertheless can be justifiably carried out in another country.
If this is accepted, we admit of an exception to the CIOMS rules in cases where there are
legitimate differences of opinion about what constitutes standard of care. I have elsewhere
discussed two similar cases: the decision of WHO to go ahead with trials of preventive AIDS
vaccines in developing countries despite the decision by US authorities to put these trials on hold,
and the acellular pertussis vaccine trials in Sweden (Lie, Forthcoming). In both of these cases I
think a case can be made that there are legitimate disagreements among experts, although I
believe a stronger case can be made for legitimate disagreements in the HIV vaccine case
compared with the pertussis case. After all, the US decision concerning HIV vaccine trials was
controversial even among US experts, whereas a vast majority of experts would agree that the
Swedish and Italian pertussis vaccination policies could not be defended as standard of care.
One should, however, note that these cases are not in violation of the principles of the
Helsinki declaration. The Helsinki declaration demands that all participants should receive the best
proven therapy; if there is disagreement among experts there simply is no single best proven
therapy. Even in cases of disagreements about standards of care, however, there may be
agreement among experts that some other treatments are inferior. In such cases, although one
cannot identify one unique treatment, one can rule out those treatments considered inferior by all
experts. The situation where there is disagreements among experts about what is the best therapy,
is precisely the situation where there is clinical equipoise, and when the initiation of clinical trials
can be justified.
The notion of different levels of risk in different countries
A common argument in the discussion about the ethics of collaborative research is that different
levels of risk in different countries may mean that a trial that cannot justifiably carried out in one
country, nevertheless can be carried out in another. For example, it is pointed out that AIDS is
much bigger problem in many developing countries; therefore it may be ethically acceptable to
carry out trials in these countries which may not be acceptable in industrialized nations where the
AIDS problem is much less of a problem. Often when this argument is presented one simply
points to the number of AIDS cases in different countries, and leaves the rest of the risk-benefit
calculation unspecified. Let us therefore try to flesh out the argument.
The benefit we are talking about here is benefit to society, or benefit to future vaccine
recipients. For an excellent discussion of the various types of benefits and risks in clinical trials,
see (Levine, 1986). If an effective vaccine is developed, people in the future would have access to
this vaccine and avoid infection. In developing countries a much larger population is at risk of
infection; therefore the potential benefits of an effective vaccine is much greater in developing
countries. There are also some ‘societal’ risks: if the vaccine turns out to be ineffective, resources
will have been wasted, or a general scepticism towards the development of new vaccines may
arise in the country where the trial has taken place. Clearly, different countries may make different
8

---

judgements with regard to how to balance these types of risks against the possible benefits of a
vaccine candidate, and may legitimately reach different conclusions depending on how much of a
health problem AIDS is in the country. One country may for example conclude that the expense
of a phase III trial is justified in light of current science because of the expected benefits if the
vaccine turns out to be effective, whereas another country may decide that the expenses are not
justified. If this is what is meant by different levels of risks in different countries, a case can be
made for carrying out a trial in one country, but not in another.
There may, however, also be risks to the participants, such as possible side-effects of the
vaccine, social discrimination as a result of taking part in the vaccine trial, or the possibility that
future, more effective vaccines, will not be as effective to the trial participants. One might be
tempted to weigh these types of risks against the possible benefits, and then also conclude that
one may accept a higher level of these individual risks in a country where the potential benefits of
a vaccine are greater. The problem with this position is that it seems to violate the Declaration of
Helsinki’s principle I.5: Concern for the interests of the subjects must always prevail over the
interests of science and society. If the reason for wanting to carry out a trial in one country, but
not another, is that the benefits to society is much greater in the first country, then it would seem
that the interests of society do prevail over the interests of the subjects.
There is a line of argument, however, that, if valid, would entail that under some
circumstances it would nevertheless be justifiable to carry out trials in one country on the basis of
an estimate of the individual risk vs. societal benefit ratio. This line of argument does, however,
depend on what is currently a controversial position among commentators on research ethics. For
a discussion see (Lie, In press). Many, including, Benjamin Freedman, have argued that one
should never admit arguments in terms of individual risks vs. societal benefits:
Proponents of clinical trials ... often ... argue that there is a need to balance the rights of
subjects against the needs of society. By this tactic, the proponents of clinical trials have
implicitly surrendered, for to admit that something is a right is to admit that it represents a
domain of action protected from the claims and interests of other individuals or of society
itself”(Freedman, 1992).
Others such as Robert Levine has at least voiced caution when weighing benefits to society versus
risks to research subjects (Levine, 1986, p. 62). Still others have pointed out that all clinical trials
assume some type of altruistic motive among trial participants, and that one will always have to
weigh the possible risks to the participants against the possible benefit to society. This means that
it is never possible to fulfill a strict interpretation of principle I.5 of the Helsinki-declaration in any
country. An ethics committee has the obligation to weigh these individual risks against the
possible benefits to society, but in addition there has to be a real disclosure of the inherent risks in
the research proposal. Each potential trial participant has to decide for himself or herself whether
the possible individual risks are outweighed by the possible benefits to future patients, and then
decide if he or she wants to take part in the trial on the basis of a motive of wanting to assume
these individual risks for the possible benefit of future patients. If that is the case, it is again
reasonable to expect that different people may evaluate these types of risk vs. benefits differently,
both as members of regulatory committees and as individual potential trial participants. If one
9

---

wishes to use this argument, one should recognize its controversial nature, and recognize that it
depends on an informed consent process that is probably never realized in most trials in any
country. Margaret A. Somerville has emphasized the problems of proper informed consent in this
context (Somerville, 1997). Finally, in the context of HIV vaccine trials, investigators involved in
these trials, such as Dirceu B. Greco, have also warned against accepting a higher individual risk
for participants in these trials with the justification that there will be a greater social benefit in
developing countries: “The consideration that ‘the AIDS epidemic is out of control, that the
preventive measures do not work and that any vaccine independent of its efficacy is better than
nothing’ may put out of focus all the reasonable ethical and scientific evaluations, especially when
we know that much of the knowledge needed is still lacking”(Greco, 1997).
Previous trials in developing countries
The discussion above indicates that there is a problem with a general prohibition against carrying
out phase III trials in developing countries but not in developed countries. An examination of a
number of previous trials in developing countries further supports this position.
During the May 8th Congressional hearings, CDC's David Satcher emphasized the principle
of the CIOMS guidelines that requires research to meet the needs and interests of the host country
and is going to result in benefits for the host country. As an example of such research he
mentioned the hepatitis B studies that were done in China in the early 1980s. The studies on oral
rehydration therapy for Cholera in Bangladesh were also mentioned as examples of such research.
It may be instructive to examine these examples.
In the mid 1960s standard treatment of cholera was replacement of lost water and
electrolytes by intravenous fluids, which was a highly effective treatment. This treatment could
not be used as a widely available treatment in developing countries, for both economic and
logistic reasons, and it would be desirable to study alternative treatments more suitable to the
conditions in developing countries. One such alternative treatment was to give electrolyte
solutions by mouth. We now of course know that oral rehydration has saved hundreds of
thousands of lives. The situation at the end of the 1960s with regard to treatment of diarrhea in
developing countries is therefore very similar to the current situation with regard to prevention of
HIV transmission.
Studies published in 1968 had shown that cholera patients did absorb fluids infused to
their stomachs (see for example Hirschhorn et al., 1968; Pierce et al., 1968). In 1968-1969 several
clinical trials were published showing that oral rehydration was just as effective as treatment for
cholera. Interestingly enough these are not placebo controlled trials. The control groups received
the then standard therapy of intravenous fluids. This is the case both for the two studies carried
out in Calcutta, India (Pierce et al., 1969; Sack et al., 1970), and the one in Dacca, Bangladesh
(then East Pakistan) (Nalin et al., 1968).
Mabey et al (1996) mentions several trials carried out in developing countries which have
changed therapies. One is a trial showing that chloramphenicol is effective against meningitis
(Whittle et al., 1973). The standard treatment was intramuscular penicillin, which was also not
used much in the area because for reasons of economics and logistics. In this trial also, the newly
10

---