For some reason, the most interesting discussion always happens when I am
on (extremely busy) clinical service. Neverthless, let me try to highlight
some of the issues that I think have been forgotten over the years (some of
this, has been summarized in my recent article entitled "Acknowledgment of
Uncertainty: A Fundamental Means to Ensure Scientific and Ethical Validity
in Clinical Research" Current Oncology Reports 2001, 3 (5):389-95; will be
happy to forward a copy to those who are interested). (I appologize if what
follows sounds too didactic).

1. Why do we do (clinical) research?

Clinical research is done to resolve existing uncertainty (say, about
relative effects of two competing treatment alternatives). Thus, a clinical
trial is only justified if the patient (and clinician) are uncertain about
which treatment to choose from the available options. If we are not
uncertain, scientifically, nothing new would be learned, and ethically, we
would administer an inferior treatment (in at least half of our patients).

2. What are tools that are available to resolve the existing uncertainty?

It may come to surprise, but the best technique that has ever been developed
to resolve uncertainty about effects of health care interventions is- the
flip of coin. It should be remebered that randomization is just a technique
for resolution of the uncertainty-nothing more, nothing less. This is the
main difference between RCTs and Non-RCTs; in the former, it is chance that
decides for us, in the latter it was us that made decision about
treatment(s).

3. Our state of ignorance can range from not knowing, to uncertainty to
equipoise (which is equal to maximum uncertainty). The fact that we do not
know something does not justify experimental testing. Only if we are
uncertain ("indifferent") about the relative value of the treatments, it is
time for a trial. Equipoise is in our minds.  When there is "clash" (either
on collective or individual level) in interpretation of existing evidence,
tension is created that requires its resolution by undertaking a clinical
trial. [I should also mention that we have a model (unpublished at this
time), which shows that randomization is the best recourse for the
resolution of uncertainty under vast majority of circumstances].

4. Remember, the question of treatment is the question of comparison. The
key issue always relates to a choice of the control group. Practical
importance of acknowledgement of equipoise (or uncertainty) is that it is
only known mechanism that we have to ensure the choice of an adequate
control group. Studies can meet all other quality criteria regarding conduct
and design and still be biased if the control group is inferior or
inadequate. Randomization deals with selection bias, acknowledgment of
uncertainty deals with a choice of the control group.

I think I will stop now. Sorry for this long message. Looking forward to an
interesting debate.

ben djulbegovic
--

-----Original Message-----
From: Simon, Steve, PhD
To: [log in to unmask]
Sent: 8/17/01 9:00 PM
Subject: Re: Randomized versus non-randomized studies

David Doggett writes:

>This raises a point that has always puzzled me.  RCTs are
>only considered ethical if there is equipoise.  But what can the
>evidence be for equipoise? EBM only recognizes RCTs as valid
>evidence.  As far as I know, EBM is silent on what the evidence
>must be for equipoise.  Any thoughts anyone?

I addressed this topic (indirectly) in an email to the
Evidence-Based-Health
group and Jeanne Lenzer. I am working on this issue on a web page:

http://www.childrens-mercy.org/stats/plan/placebo.asp

that discusses the ethics of placebo controlled trials. As in the other
email, I want to encourage any of the readers of this group to provide
me
feedback. The page is still an early draft.

In the other email, I talked about lung reduction surgery for patients
with
severe emphysema. Many doctors embraced a 1996 study that compared 150
consecutive surgeries to a historical control group. They apparently
felt
that this non-randomized study was sufficient to upset equipoise in
favor of
the surgery, although a randomized trial has shown that the opposite was
true, at least for some patients.

Weijer, Shapiro, and Glass (2000) have argued that information "on
personal
experience, on anecdote, on tacit understanding, or rules of thumb" is
sufficient to upset equipoise but that a "hunch" is not sufficient.

That same article highlights the debate between the uncertainty
principle
(which I would call individual equipoise) and community equipoise. An
interesting argument would be that equipoise exists until a randomized
study
has been done. I have not heard anyone make that argument directly, but
is
appears to be implied by some arguments in favor of community equipoise.

Others have argued (see some of the arguments in William Silverman's
book)
that you need to randomize from the very first patient, before there is
a
chance for non-randomized data to upset equipoise. This strikes me as a
bit
naive. Some therapies require a bit of preliminary data before they can
even
be considered equivalent to placebo, because they have serious side
effects.
Furthermore, some therapies like surgery require some training and
experience before they can be incorporated into the context of a
clinical
trial. Besides, if equipoise is such a fragile thing that a few
preliminary
non-randomized patients can upset it, then why wouldn't promising
results in
an animal model also upset equipoise?

The issue is further clouded when a regulatory agency, such as the
United
States Food and Drug Administration, requires a strong level of evidence
(typically two randomized trials) before a new drug is approved.
Wouldn't
equipoise be violated in the replication study (the second study)?

And Stephen Senn has argued in an eLetter to the BMJ that equipoise is
not
required for an ethical trial.

Placebo confusion Stephen Senn,  BMJ eletters. 15 August 2000
www.bmj.com/cgi/eletters/321/7258/442

Where's the Evidence? : Debates in Modern Medicine by William A.
Silverman
(1999) Oxford Univ Press; ISBN: 0192630881.

For and against: Clinical equipoise and not the uncertainty principle is
the
moral underpinning of the randomised controlled trial * FOR * AGAINST
Charles Weijer, Stanley H Shapiro, Kathleen Cranley Glass, and Murray W
Enkin. BMJ 2000; 321: 756-758.

You can get the full text of this article from the bmj.com web site.

Steve Simon, [log in to unmask], Standard Disclaimer.
STATS: STeve's Attempt to Teach Statistics. http://www.cmh.edu/stats
Watch for a change in servers. On or around June 2001, this page will
move to http://www.childrens-mercy.org/stats