For and againstDeclaration of Helsinki should be strengthenedForAGAINSTRothman and Michels' riposte
BMJ 2000; 321 doi: https://doi.org/10.1136/bmj.321.7258.442 (Published 12 August 2000) Cite this as: BMJ 2000;321:442All rapid responses
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We would like to join the ongoing debate regarding the next revision
of the Declaration of Helsinki, and address some "for and against
"arguments eloquently put by Rohtman and Michels and by Baum in the recent
issue of the BMJ1.
We agree with Rothman and Michels that "equipoise" (or,
"the uncertainty principle"2) is an essential ingredient of an ethical
human experiment and that the declaration should be amended to say so. In
fact, more recently, we argued that extraordinary care should be given to
understand and protect this fundamental principle on which nearly the
entire system of human experimentation stands3. However, Baum writes of
"tensions between conduct of a trial and the autonomy of the individual"1.
This involves the notion that patients who participate in trials are asked
to make a sacrifice for the good of others 4. However, this concern is
alleviated by explicitly invoking equipoise as the principle upon which
randomized controlled trials (RCTs) are based. The uncertainty principle,
or equipoise, states that the patient should be enrolled in a RCT only if
uncertainty about which of the trial treatments would benefit a patient
most is so substantial that they are in "equipoise" or "indifferent"
between treatment options5 6. It follows that so long as we are
substantially uncertain which treatment is superior, patients do not loose
out prospectively and are not required to sacrifice themselves for the
benefit of others5. Thus, ethically, RCTs should be acceptable to both
utilitarians (who seek to bring the greatest good to the greatest number
of patients by ensuring scientifically robust results) and Kantians (who
seek to protect and preserve autonomy of individual patients)5. The same
principle applies to any randomised trial, whether it is placebo-
controlled or not. It is just that in the case of placebo-controlled
trials we should be particularly vigilant about applying the uncertainty
principle3.
In our opinion, the ethical dilemma expressed in the BMJ
article is false - it has already been resolved. The question is now a
technical one - how do we improve communication so that patients can
really find out whether or not they are indifferent between treatment
options?
Literature:
1. Rohtman KJ, Michels KB, Baum M. Declaration of Helsinki should be
strengthened. For and against. BMJ 2000;321:442-5.
2. Peto R. Trials:the next 50 years. BMJ 1998;317:1170-1171.
3. Djulbegovic B, Lacevic M, Cantor A, Fields K, Bennett C, Adams J, et
al. The uncertainty principle and industry-sponsored research. Lancet
2000;356:635-638.
4. Mathe G, Brienza S. From methodology to ethics and from ethics to
methodology. Biomed & Pharmacother 1988;42:143-153.
5. Edwards SJL, Lilford RJ, Braunholtz DA, Jackson JC, Hewison J, Thornton
J. Ethical issues in the design and conduct of randomized controlled
trials. Health Technol Assessment 1998;2(15):1-130.
6. Lilford RJ, Jackson J. Equipoise and the ethics of randomization. J R
Soc Med 1995;88:552-559.
Competing interests: No competing interests
As I understand it placebos are usually given in addition to the
standard treatment. Thus patients are randomised into two groups:
1. Standard treatment plus placebo and
2. Standard treatment plus new treatment.
This seems to offer no ethical problems unless the placebo is onerous
in some way (e.g. it involves injection). The problem would be where the
new treatment will be given instead of some aspect of standard treatment.
For example, standard treatment might include drug B instead of A. In
such a case, a placebo trial might result in standard treatment being
defined as everything normally given but absenting A. Then you would have
groups:
1. Standard treatment plus placebo.
2. Standard treatment plus A.
3. Standard treatment plus B.
It seems that it is this type of trial which is of concern. My
thought is that such trials would rarely be justified except where there
was equipoise over whether A is effective or not. The key point is that
it is not the fact of whether or not a placebo is used that makes a trial
unethical, it is whether or not standard treatment is defined in such a
way that patients as research participants/subjects are deprived of a
treatment known to be effective.
Competing interests: No competing interests
The current debate over changes to the Declaration of Heklsinki is
disappointing, because it has in many ways muddled the waters instead of
clearing debris in order to improved international research ethics
standards. What we see at the moment is a very clear faltline between the
US and UK medical associations, for instance, both of which support lower
standards of care for people living in developing countries and
continental European, Latin American, but also some Asian medical
associations who reject such a double standard. In the UK the private
Wellcome Foundation sponsors currently a research project designed to
bolster the case of the anglosaxon medical associations, while it saw
itself unable to sponsor a project critical of this campaign.
One of the crucial questions one has to face in this context is this:
do we want to see more clinical research undertaken the primary objective
of which are solutions to economic rather than medical problems. If the
answer to this question is affirmative, it is only logical to demand lower
standards of care, because they come cheaper. If, on the other hand, we
are serious about tackling the health problems of people in developing
countries, and this includes access to affordable medication, surely the
point should be to question the economic frameworks that give rise to the
purported necessity to develop 'cheaper drugs'. Anglosaxon pragmatism, in
this case, readily accepts the economic frameworks and tries to make the
best out of the situation.
Is it really unreasonable then, to ask of them a bit more honesty in
their campaign. They ought to state unequivocally, that they think it is
ethically acceptable that Thai subjects (or soon African subjects) die as
a consequence of an HIV infection acquired during preventive HIV vaccine
trials. This is what the lower standards of care both associations deem
ethically acceptable will mean practically for the impoverished and
otherwise vulnerable subjects in these trials.[1]Reasons for this position
can be found. They are not even unintelligent reasons. I find them
unconvincing. A first step to improve the debate, could surely be to be
frank about what one does and what one doesn't consider acceptable with
regard to for instance standards of care in preventive vaccine trials.
We should also be concerned about attempts to manufacture what is
likely to be billed as an international 'consensus' on this matter.
International research ethics meetings take place currently all over the
world, but developing country based scholars and treatment access
activists have more often than not only access if they know a generous
Western sponsor who pays for their airfare, and accommodation. This itself
renders these meetings, of course, unrepresentative in any meaning of the
word.
[1] U Schuklenk, R Ashcroft. International Research Ethics. BIOETHICS
2000; 14: 158-172.
Competing interests: None
Competing interests: No competing interests
Editor - Michael Baum’s attitude makes depressing reading. (1) He
would have no problem with placebo controlled trials in some
circumstances. He perceives nothing wrong with depriving patients of
currently best available treatment for the benefit of medical research.
This is a classic conflict of interest disguised by the profession’s
mantra: everything is done “in the patient’s best interests”.
Unfortunately medical advances depend on the use of patients as
guinea pigs. Placebo controlled trials can easily lead to viewing
experiments on people unable to give informed consent as ethically
acceptable. “A disciplined search for an objective reality” is liable to
mean sacrificing the interests of the already disadvantaged “in the
service of mankind”.
The Declaration of Helsinki aims to protect the vulnerable from
attempts by over-enthusiastic seekers of new treatments to short cut
ethical practice. Consumers for Ethical Research (CERES) has produced a
comprehensive guide for patients contemplating participation in trials. It
is sad to learn that the BMJ declined to publish this excellent document.
In the new era of a patient-centred NHS, perhaps it should re-consider
this decision as a public service to both doctors and patients. We must
respect and cultivate the inherent altruism of many patients, rather than
allow tunnel vision researchers to undermine it.
Roger M. Goss
Director - Patient Concern
P.O. Box 23732,
London SW5 9FY
1 Rothman K, Michels K, and Baum M. Declaration of Helsinki should be
strengthened BMJ 2000; 321: 442-445. (12 August)
Competing interests: No competing interests
Dr. Anderson's example is fallacious: if side effects make a
treatment unacceptable to some patients, for them the best treatment may
be nothing. In that case a placebo control for them is completely
ethical, and would not violate the Declaration of Helsinki.
Competing interests: No competing interests
Placebos are used in trials both to facilitate blinding and to
control for the psychosomatic effects of offering treatment. Dr. Senn is
wrong to suggest that placebo is necessary for blinding. In most
situations blinding can be achieved with an active control as well as with
placebo, at least for outcome assessment. Dr. Senn has seriously misread
our paper if he thinks we are advocating "no-treatment" as an alternative
to placebo, and he seriously misunderstands modern medicine if he thinks
that only newly developed treatments are effective.
Furthermore, he is in
sparse company in thinking that equipoise is irrelevant. What is his
justification for deliberately denying effective treatment to a portion of
his patients? –Kenneth J. Rothman and Karin B. Michels
Competing interests: No competing interests
Editor - Richard Smith seeks questions. I have one: "Is a `for and
against` presentation by health professionals an adequate format to
present this issue in the 21st century?"[1]
The involvement of non-health professionals as `participants* in research`
now has two meanings: firstly, as invited trial participants; secondly, as
participants in research teams and in the whole research process from
choosing the question through to interpreting, publishing, disseminating
and utilisation of resultant research data.
(*Not "subjects" please, Robert Temple and Michael Baum!) [1]
The second group of participants would query the implied homogenous
passivity of patients [2] in need of "suggestions to strengthen
protection of patients" and the "ethical choice of patients rights over
the good of society". What about consideration of their responsibilities
as citizens, hand-in-hand with their rights? [3]
Inclusion of `patients` in trial steering committees and data monitoring
committees provides lay members of society with a direct voice to balance
researchers` aims with patients` desires and measures of outcome. This
partly addresses their need for protection "from rogue investigators" by
providing a stabilising component to redress the excesses of commercial
and medical zeal and power over their "subjects". Achievement of
democratic rather than dictatorial research should, I believe, be the
perceived goal of those who are addressing the very difficult issues that
revision of the Declaration of Helsinki exposes.
I would agree with Professor Baum that flexibility is required, also a re-
establishment and strengthening of trust, rather than going further down
the road to absolutism and more stringent rules. The "tensions between the
conduct of a trial and the autonomy of the individual" are better jointly
considered within joint working groups of health professionals and
`consumers`, such as the Consumers` Advisory Group for Clinical Trials
(CAG-CT), jointly founded by Professor Michael Baum and the undersigned in
September 1994. [4]
Professor Baum has thus actively supported and encouraged consumer
involvement in the research process. I believe he could have strengthened
his argument by mentioning that the trial of clinical breast examination
versus mammographic screening that he is proposing with Professor
Indraneel Mittra has benefited from lay involvement and scrutiny by the
undersigned; her contribution in the paper presenting a case for this [5];
and from the involvement and comment of the CAG-CT at an early stage of
its consideration. It is hoped that he has retained his enthusiasm for lay
involvement during his "transubstantiation" from "poacher to gamekeeper"!
Hazel Thornton (Mrs.)
Founding Chairman of the Consumers Advisory Group for Clinical Trials.
REFERENCES:
1. Rothman KJ, Michels KB, Baum M. For and against. Declaration of
Helsinki should be strengthened, BMJ 12 August 2000 321:442-445.
2. Thornton H. Today`s patient: passive or involved? Lancet 2000;
siv/48
3. Thornton H. Patients` understanding of clinical trials. Lancet.
1998; 352:72
4. Baum M. The whole population must be mobilised in the war against
cancer. BMJ 1997; 314: 1482
5. Mittra I, Baum B, Thornton H, Houghton J. Is Clinical Breast
Examination an Acceptable Alternative to Mammographic Screening for Women
and for the Health Service? BMJ 2000 In press.
Competing interests: No competing interests
Sometimes it's unethical to prohibit placebo control.
Scenario:
A sub-population of depressed patients are best treated with
antidepressant drugs, and a sub-population within that sub-population has
forgone such treatment because they do not want to risk any "sexual side
effects."
A researcher would like to use patients from this "sub-sub-
population" in a placebo controlled trial, comparing an aromatherapy
treatment to a placebo treatment.
An IRB, citing the Helsinki Agreement, prohibits use of the placebo
group, even though subjects in that group have already made independent
decisions not to subject themselves to any of the standard treatments for
depression.
--
RICHARD B. ANDERSON
Bowling Green State University
randers@bgnet.bgsu.edu
http://personal.bgsu.edu/~randers
Competing interests: No competing interests
The paper by Rothman and Michels1 will only serve to confuse the
issues. A placebo is always specific to a given treatment. Its purpose is
to blind that treatment, since for any other purpose it would be
sufficient simply to have a control group in which the experimental
treatment was withheld. The issue as to whether a placebo is given is
logically independent of the decision as to whether a standard "effective"
treatment is withheld. Placebo-controlled trials are frequently run as
"add-on" trials. Indeed, when we consider that the list of effective
treatments for all diseases includes, food, water, air and nursing care,
all trials are (or should be!) add-on trials. The pure "no-treatment"
group is a myth. The question is, how much of standard care to maintain
when running a placebo controlled trial: frequently the answer has to be
"all".
In running a trial, the ethical issue is whether it is acceptable to
withhold a standard available effective treatment. In the context of drug
development, the experimental treatment is not generally available.
Society has mandated the regulator to withhold treatments, until proved
efficacious, except under the special circumstances of a clinical trial.
This can be justified in terms of John Rawls's Theory of Justice2 as being
a choice we would make in "the original position" regarding the sort of
society we want to live in.
Equipoise is an irrelevance3. Patients are entered onto the trial
because the trialists believe that the experimental treatment is better.
The control group treatment should be as good as that available outside
the trial. Experimentation continues until either the trialists are
convinced they are wrong (equipoise is reached) or they convince Society
they are right.
This is not to say that placebos are not sometimes used in ways in
drug development that are unethical. One such use is in placebo run-
ins3,4. These violate consent and should be abandoned.
Declaration of interest: the author is a consultant to the
pharmaceutical industry
References
1 Rothman KJ, Michels, KB. Declaration of Helsinki should be
strengthened: for. BMJ 2000;321:442-5
2 Rawls, JA Theory of Justice. Oxford: Oxford University Press, 1972
3 Senn SJ. Statistical Issues in Drug Development. Chichester: Wiley,
1997.
4 Senn SJ. (1997) Are placebo run ins justified? BMJ 2000; 314:
1191-3.
Competing interests: No competing interests
Equipoise: Analogies must have it.
Dear Sir:
In arguing for randomized trials, Dr. Baum uses an attractive but flawed
analogy. He states that there is an anlogy between demanding the best
evidence to convict a criminal of a capital offense and the need to demand
the absolute knowledge of the best treatment for a fatal illness. There is
an ironic lack of correspondence(equipoise)in the manner that Dr. Baum
uses this analogy. The correct use of this analogy should mantain a
correspondence between the terms of comparison as follows:
The best evidence to convict is the disease since it will result in the
death of the accused. The remedy is the slightest doubt that the accused
is guilty,since its use can lead to the survival of the accussed. In the
case of the therapy of a fatal illness, the correspondence is that the
illness is the equivalent of the best evidence to convict, since it will
lead to the death of the patient. The evidence of therapeutic efficacy of
a known remedy is the equivalent of doubt about the guilt of the
accused,since its use can lead to the survival of the patient. Demanding
the best evidence to convict has no correspondence with demanding to know
the best treatment for a fatal illness, and thus invalidate the use of Dr.
Baum analogy.
Adan Rios M.D.
Competing interests: No competing interests