The concept of protection of the human rights of
patients involved in clinical research studies by the use of informed
consent and institutional review of test protocols is not new to
these pages. We have, in the past, presented editorial opinion and
policy, as well as a review of the subject in our Current Concepts
Review section1. The process of
protection of the human rights of experimental subjects continues
to evolve through the mechanism of the Declaration of Helsinki as
adopted by the World Medical Association. This international group
met in October 2000 to clarify some issues concerning the allowable
structure of experimental protocols when human research is combined
with medical care. At issue was the acceptability of a classic study protocol
that involves use of a placebo as a control in an experiment that
is being performed to determine the safety and efficacy of an experimental
treatment. Often such a test protocol is used to examine new drugs
that are the subject of review by the United States Food and Drug
Administration. That agency has been charged by Congress with the
responsibility of determining the safety and efficacy of a drug
before granting the drug manufacturer permission to market the drug.
At the October 2000 meeting of the participants of the Helsinki
World Congress, the use of a placebo as a control was severely restricted,
as is evident in paragraph 29 of the agreement, which states:
The benefits, risks, burdens and effectiveness of a new method
should be tested against those of the best current prophylactic,
diagnostic, and therapeutic methods. This does not exclude the use
of placebo, or no treatment, in studies where no proven prophylactic,
diagnostic or therapeutic method exists2.
Thus, the signers of this accord, including the United States,
Canada, and the United Kingdom, have clearly stated that in any
study, including blinded and double-blinded studies, the subjects
shall not be treated with a placebo if an effective, clinically
acceptable treatment currently exists. If that is the case, then
the experiment should be structured so that the control treatment
is that currently acceptable treatment and not a placebo.
Some publications have expressed concern about the effect that
such experimental protocol limitations might have on the development
of new medical treatments. They point out that most new drugs are
tested against a placebo when regulatory approval from the Food
and Drug Administration is being sought for the marketing of the
drug. We at The Journal of Bone and Joint Surgery cannot
share such concerns. We support, without reservation, the right
of subjects involved in clinical research to receive the best possible
medical care consistent with their diagnosis and the availability of
acceptable treatment modalities. If there is no clinically acceptable
treatment for the problem, and the investigators are seeking to
determine whether a proposed experimental treatment is safe and
effective, then no treatment, or a placebo treatment, is a morally
acceptable control. However, patients who might otherwise receive
a therapy that has a clinically acceptable level of safety and efficacy
certainly should not be denied such treatment simply because they
have been asked to enroll in an experimental study.
In a study in which a currently available and clinically acceptable
treatment is used as a control treatment, the null hypothesis is
that the new treatment is as safe and as effective as the existing
treatment. Proving the null hypothesis allows a choice of treatments
based on other factors, such as cost, ease of use, and duration
of treatment. Rejecting the null hypothesis results in abandonment
of the new treatment, if it was not as safe and effective as the
existing treatment, or in favoring of the new treatment, if it was
safer and more effective. It may well be that, in marketing new
treatments, the manufacturer's legal obligation is only to show
that the new treatment is both safe and effective without absolute definition
of those terms. Such arbitrary limits of safety and efficacy will
now be justified only for the newest treatments of a clinical problem.
Subsequent investigators will be obliged to conduct experiments
that will provide both comparative and absolute data for regulatory
agencies.
How will this affect orthopaedic research? We believe that following
the guidelines of the Helsinki accord will have no negative impact
whatsoever. We believe that researchers already appreciate both the
ethical position and the clinical advantage of using acceptable
existing treatments as a control when such treatments are available.
There is another paragraph of the October 2000 Declaration of
Helsinki that applies to many of the studies submitted to The
Journal. This new guideline is intended to provide "absolute
transparency regarding economic incentives involving in research."
Paragraph 22 states, in part:
In any research on human beings, each potential subject must
be adequately informed of the aims, methods, sources of funding,
any possible conflicts of interest, institutional affiliations of
the researcher, the anticipated benefits and potential risks of
the study and the discomfort it may entail2.
We support this provision for giving the subject information
concerning the sources of financial support and the financial interest
of the institution and the investigator in the treatment used in
the study. Providing more information in the informed-consent process
will allow the subject to better understand the motivation for the
study.
The policy of The Journal of Bone and Joint Surgery has
been to publish manuscripts resulting from studies that conform
to the principles of the Helsinki accord. In order to further support
this policy, The Journal's Instructions to Authors
now contain the request to include, with submission of a manuscript
concerning a study involving human subjects, a statement that the
study has been approved by an institutional review board or its
equivalent.
Albert H. Burstein, PhD
Deputy Editor for Research
Marc F. Swiontkowski, MD
Deputy Editor for Outcome Studies