http://bmj.com/cgi/content/full/324/7331/239
BMJ 2002;324:239 ( 26 January )
Letters
Quinacrine in possible or probable CJD
If
you had suspected CJD would you be indifferent between placebo and quinacrine?
It
is blinded investigators, not patients, who must be in equipoise over treatment
If you had suspected CJD would you be
indifferent between placebo and quinacrine?
After
the apparent recovery of a patient with suspected variant Creutzfeldt-Jakob
disease when she was treated with quinacrine, the Department of
Health is reported as planning a clinical trial to evaluate the
drug's effectiveness as a potential treatment for the disease.1 Should an
ethics committee approve such a trial?
There is clearly considerable uncertainty about the effect of quinacrine in
variant Creutzfeldt-Jakob disease and other prion diseases,2 but we find
it almost inconceivable that a rational patient with suspected prion
disease would be in equipoisethat
is, indifferentbetween
quinacrine and placebo. The side effects of quinacrine are well
known and are comparatively minor over a wide dose range; the drug
penetrates the blood-brain barrier moderately well and has high
activity against prions in vitro and in some animal studies.3
Prion diseases are invariably fatal when untreated. The balance of risks and
benefits is clearly in favour of taking quinacrine (which is cheap
and easily available). Any patient prepared to be randomised in a
trial of quinacrine versus placebo is likely not to have understood
properly what the implications are. Such a trial should not,
therefore, be sponsored at present, or be approved by ethics committees.
It has already been recognised that recruiting patients would be
difficult, if not impossible.4
The alternative to a randomised trial is a "historically controlled
trial." Although diagnosis is tricky, patients classified by
the National Creutzfeldt-Jakob Disease Surveillance Unit in Edinburgh
as having possible Creutzfeldt-Jakob disease are thought to have a
50-60% chance of having the disease. Those classified as having
probable Creutzfeldt-Jakob disease are thought to have a 95% or
greater chance of having the disease (R Knight, National Creutzfeldt-Jakob
Disease Surveillance Unit, personal communication).
An ethically acceptable approach would be to offer quinacrine to all patients
classified as having possible or probable Creutzfeldt-Jakob disease.
It will quickly become apparent, even allowing for the potential
biases that can arise from using historical controls, whether
quinacrine is preventing the deaths of a large proportion of
patients with the disease.
If quinacrine is preventing deaths then trials comparing doses, or
combinations of quinacrine and other drugs, could proceed. If,
however, it is clearly not saving a majority of patientsfor
example, if the first 50 patients treated follow courses only a
little better than those of historical controlsthen
the balance of risks and benefits for patients becomes much more
equal. Only when an ethics committee judges that fully informed,
rational patients would be prepared to enter a trial is it
reasonable to allow a trial to proceed.5
David Braunholtz
D.A.Braunholtz@Bham.ac.uk
Judith Harris
Department of Public Health and Epidemiology, University of Birmingham,
Birmingham B15 2TT
|
1. |
In Brief: Treatment trial for Creutzfeldt-Jakob disease
announced. BMJ 2001; 323: 650 |
|
2. |
Lilford RJ, Djulbegovic B. Equipoise and uncertainty
principle are not mutually exclusive. BMJ 2001; 322: 795 |
|
3. |
Korth C, May BCH, Cohen FE, Prusiner SB. Acridine and phenothiazine
derivatives as pharmacotherapeutics for prion disease. Proc Natl Acad Sci
2001; 98: 9836-9841 |
|
4. |
Young E. First vCJD clinical trial to begin.
NewScientist.com News Archive. (www.newscientist.com/news/news.jsp?id=ns99991307.)
|
|
5. |
Edwards SJL, Lilford RJ, Braunholtz DA, Thornton J,
Jackson J, Hewison J. Ethical issues in the design and conduct of randomised
controlled trials. Health Technology Assessment 1998; 2: 1-96 |
It is blinded
investigators, not patients, who must be in equipoise over treatment
Is
there not a fundamental misunderstanding about double blind trials in the title
of Braunholtz et al's letter about Creutzfeldt-Jakob disease (bmj.com/cgi/eletters/323/7314/650
and printed here, above)? And a misunderstanding about the meaning
of "equipoise"? The authors say, "We find it almost
inconceivable that a rational patient with suspected prion disease
would be in equipoise . . . between quinacrine and
placebo."
What one agrees to is not to take a placebo but to take a treatment with a
50% chance of containing an active ingredient that might be of
value. In this way one submits to an unknown fate, but not without
hope; one trusts that the blinded investigators are in equipoise as
to the risk of alternative fates for your life. A proposed trial of
quinacrine seems to meet that criterion.
Ed Cooper
Newham General Hospital, London E13 8SL Ed.Cooper@nhspeople.net
|
Other related articles in
BMJ:
NEWS
In brief.
BMJ 2001 323: 650.
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