Section 4. Reading
Title: Continuing Unethical Conduct of Underpowered
Clinical Trials
Authors: Scott D. Halpern, Jason T. Karlawish, and Jesse
A. Berlin
Publication Information: JAMA, Vol 288, no.3 (2002),
pp.358-362.
Summary:
A long-standing understanding among the investigators is
that the
statistically underpowered clinical trials are
“scientifically useless”.
These Random Clinical Trials (RCTs) fail to test the
underlying
hypothesis adequately. Hence, they expose individuals to
risks and
burden of human testing through such unethical trials.
Nevertheless,
RCTs are widespread. Some recent publications support such
underpowered
RCTs. Authors of these publications argue that by combining
the results
of similar small studies, the investigators can estimate the
efficacy of
an intervention. Secondly, even though the small studies may
not test
the hypothesis, they still provide valuable estimates of
treatment
effects using confidence intervals. Halpern, Karlawish, and
Berlin
assess these arguments in the light of ethical and moral
issues and
conclude that underpowered trials can be ethical only in the
following
circumstances:
(1) If the trials are for a rare disease and
investigators document
explicit plans for combining the results with similar trails
in a
prospective meta-analysis
(2) Early-phase trials in the development of drugs,
devices, or other
interventions can be underpowered
The trio-authors also stress that the researchers must
inform the
prospective participants that their participation may only
indirectly
contribute to future health care benefits.
In the world of null hypothesis testing, there are two
types of errors –
type I and type II. Type I error occurs when the experiment
data
incorrectly rejects the null hypothesis and type II happens
when the
experiment data fails to reject a false null hypothesis.
Investigators
would like to minimize both of such errors in their trials.
They would
normally consider an experiment statistically powered if
there is at
least 80% chance of detecting a clinically significant effect
when one
exists. The number of individuals enrolled in a trial and
variability of
their outcomes are the factors used by investigators to
calculate the
power of a study. RCTs lacking enough participants are hence
statistically underpowered.
The authors of other publications supporting underpowered
small studies
argue that prohibiting such studies means diminishing of
knowledge.
Halpern, Karlawish and Berlin, however, find practical and
ethical
problems with this argument. It is not practical to become
too
optimistic about the usefulness of small studies. It is also
not
practical to synthesize the results from various such studies
all the
time. Furthermore, the underpowered trials are more likely to
produce
negative results and consequently the investigators may not
publish the
results. This practice makes the meta-analysis incomplete and
useless.
Then there are ethical problems when for different reasons,
the
investigators do not inform the participants about the
limited value of
the underpowered studies. Normally people participate in such
studies to
help the humanity. However, if they are not fully aware of
the value of
the studies they are about to participate in, their ability
to decide
autonomously diminishes. Due to these practical and ethical
issues, the
trio-authors do not approve underpowered studies across the
board.
The two exceptions when investigators can consider
underpowered studies
are in the case of rare diseases and early-phase studies of
experimental
intervention with certain restrictions. It is understandable
that it is
difficult for investigators to have a large number of
participants in
cases of rare diseases. A mere argument that having some
evidence is
better than none, is not enough for approving underpowered
studies for
rare diseases. The investigators must explicitly plan to make
the
results of a small trial available for inclusion in a
prospective
meta-analysis. Only then, it provides sufficient assurance to
the
participants that a study’s results will eventually
contribute to
valuable or important knowledge. The prospective
meta-analysis has
innovation and organization that will enable the synthesizing
of various
results. Similarly, plans for large, comparative trials of
experimental
interventions can justify the conduct of small studies in
earlier phases
of drug or device development. Each phase of trial must aim
adequately
for the next phase and the investigators must inform the
participants
that their participation will guide only the future studies.
Summary: Hita Gurung (QCC,2003) |