Avoiding Wishful Thinking Over New Drugs - More Trials Should Be
Double-Blinded Say Cancer Experts
Source: Mario Negri Institute, Milan
Italian researchers have urged that doctors should, wherever possible, be
'blinded' to which drug a patient is receiving in a trial when the endpoint
involves subjective judgments by the investigators.
They believe it would lessen the risk of wishful thinking - an unconscious
tendency by doctors to expect new drugs to perform better than the older
ones they are being tested against.
This perception of a drug's effectiveness was named 'wish bias', when it
was first reported more than a decade ago. In a report published in the
March 2002 issue of Annals of Oncology, the research team says it may help
to explain why the response rate of tumors to a new drug decreased over time.
Dr Roldano Fossati and colleagues from the Mario Negri Institute in Milan
combed through the results of 29 randomized trials that took place between
1975 and 1999. They analyzed the response rate of 2,234 women with advanced
breast cancer who had been in the arms of the trials using the anti-cancer
drug, doxorubicin (Adriamycin). They extracted the global (i.e. complete
plus partial) response rate from all the trials.
"We found that every five years there was a 11 percent relative decrease in
the odds of a global response and most of this decrease was in the partial
response rate, where evaluation involves more subjective judgment than is
involved in determining complete response," said Dr Fossati.
Of the 29 studies they investigated, only one had used a double blind**
approach, and in two studies patients' records were just externally audited.
"In these situations a bias due to financial and academic conflicts of
interest or more subtle forms of 'wish bias' could easily arise and account
for an impression that when a drug is new it does better," said Dr Fossati.
The team carried out the assessment of the 29 studies to test their
hypothesis that doctors' unconscious favorable attitudes to new treatments
may result in a tendency to overestimate their efficacy. They chose
doxorubicin because it had been used alone or in combination since the
early 1970s and was still widely used as a comparison against which to
evaluate new breast cancer drugs.
"Under the effect of the biases we describe we would expect to observe a
declining response rate to doxorubicin that was still detectable after
taking into account changes in disease management over time," said Dr Fossati.
This was what the research team found, although Dr Fossati stressed that
results should be interpreted within the context of the limitations to the
study, which was that they looked at only one drug (doxorubicin) in one
clinical context (advanced breast cancer).
According to Dr Fossati, blinding is uncommon in these types of clinical
trials. In an earlier meta-analysis by the Milan team of 189 trials
involving chemotherapy and hormone therapy for metastatic breast cancer,
only six involved blind evaluation and only 23 trials had involved
independent or extramural assessment. There was no reason to suppose that
these were not typical of cancer drug trials.
"Since indirect evidence for the existence of a wish bias emerged from our
analysis, we believe that blinding should be strongly recommended for any
subjective endpoint assessment such as response, time to progression of
disease and so on, and the search for this kind of bias should be
unremitting in order to push the medical research community to guarantee
objectivity and maintain public confidence."
* Does a drug do better when it's new? R. Fossati et al. Annals of
Oncology. Vol. 13. No. 3. pp 470-473.
** A double-blind trial is one where neither doctors nor patients know
which treatment the patients are receiving.
Ann's NOTE: Advocate Kay Dickersin has suggested that these trials should be called 'masked' so that blind people are not trivialized by the language.
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