Clinical trials, outcome switching and its dangers
A report in the 'Economist' of the week covering March 24 to April 1
'For my next trick' reveals in a startling way, how medical trails
conducted by giant pharmaceutical companies, among others swap their
findings midway with a different lot of findings which leads to
deception and misleads everyone concerned.
A stand out example according to the 'Economist' was the case of a
drug named Paxil, a supposedly block buster anti-depressant.
In this stunning revelation, in the early years of 2000, Paxil earned
for its manufacturers, nearly US$ 2 billion annually by way of sales.
Used primarily by millions of children, it was a prescriptive drug
for the young (teenagers) administered to overcome depression.
However, the British medical regulators, re-examined or had a second
trial of the so-called efficacy of the drug and discovered (perhaps to
their horror) that it had been misleadingly presented. The second trial
was aptly called 'Study 329'.
"Paxil in reality did nothing to cure those youngsters whom the drug
was supposed to cure. But to the contrary Paxil made them worse to the
extent that it drove them to near suicidal levels of depression and
indeed some did commit suicide."
In 2012, the US Medical authorities slapped the biggest fine in the
history of the Pharmaceutical industry on its inventors, Glaxo
Smith-Kline (GSK) amounting to US$ 3 billion (an amount that is roughly
equal to half of Sri Lanka's GNP or to put it another way, equivalent of
what we need to get over the serious financial crisis we face today).
The fine was imposed on GSK on the charge of misreporting data.
The Economist observes that the 'Study 329' had then discovered as to
what University dons would commonly call 'academic sleigh of hand'. Of
course, 'Study 329' was conducted on drugs of different type and Paxil
happened to be one.
The case of Paxil has over the years become a classic in terms of the
answers to questions involving a scientific study that were swapped or
exchanged mid-stream with the findings of another similar study.
'Study 329' planned to measure, the impact of Paxil had on different
variables, eight in number. All were so designed to evaluate as to how
those who participated in the trails reacted to the drug.
And sensationally, it proved no better than a sugar-coated pill. The
Researches who drafted the paper had mentioned 19 new measures of
benefit. Apart from 4, the rest did not show any benefits.
And in the published paper giving the final outcome of the study,
those four had been given as the final outcome as if they had been the
main measures all along. 'Outcome switching' the label attached to
swapping information on clinical trials according to the Economist
emerges as a good example of the different ways in which science could
It is reportedly a hot topic currently, especially due to what is
known as a 'replication crisis' in fields ranging from psychology to
cancer research in which the results published are evaporated in the
process of duplication.
The remedy to this dangerous development which was said to be
foolproof has been proposed by a team of researchers from Oxford
University's Centre For Evidence Based Medicine. It is through a project
named COMPARE which is an endeavour to counteract the tendency to engage
in 'Outcome Switching'. Whilst this may yield positive results it is
believed that 'Outcome Switching' may also be resorted to for justified
Data collection is not easy by any means, since those who participate
in it, meaning those who respond, are reluctant to fill-in long
questionnaires. However this would, as repeatedly stated lead to
deception, and make unscrupulous people in research go on 'fishing
expeditions' a synonym for deceiving which leads to presenting what they
would want to project and not the genuine outcome of a research.
The 'modus operandi' of this is to gather date, provide correlations
which look statistically important by chance. Then proceed to pick them
out subsequent to the trials and prove that they were not the result of
flukes. The only way to find out the truth is through a repeat
demonstration or a retest.
Way back in 1998, 'Study 329' was completed. But the findings were
not correct and indeed by itself were an academic 'sleigh of hand'.
Now we are in 2016 and it is widely believed that such tricks are not
possible since trials regulators in the U.S. and Europe require that
trials be registered before hand.
The registration according to the Economist should incorporate varied
information pertaining to the study - in other words, what the study is
about and how it is done so that everything could be checked before the
trials commence. But once again, a major problem encountered was
monitoring the trials and enforcing the rules which were said to be lax.
In this connection the Economist says:
a) Non-confinement to measurements. For example, a published study on
trials observe that 31% did not conduct the measurements planned. In
PLUS one a study that had examined 137 medical trials, 18% over a period
of six months had resorted to altering the key outcomes midway, whilst
64% had resorted to alterations with less significant measures or
secondary ones, on success.
b) The COMPARE team had elicited to similar outcome,
67 Clinical Trials reported in some of the world's leading medical
journals like the New England Journal of Medicine, The Journal of the
American Medical Association, Lancet (in search of evidence of 'outcome
switching') had stated that:
1.In Nine (9) of the above number of trials completed, the
researchers had done a perfect job which in other words reflected what
they had at the outset declared.
2.And if on the other hand these nine trials did change measurements,
why they did so.
3.The balance 58, contained flaws and furthermore between them the
trails contained 300 outcomes. These should have been reported but were
not. But 357 outcomes not specially referred to in the papers that
provided the descriptions of the course of the trials or what was
possible, were 'silently' added.
A British doctor named Ben Goldacre an Epidemiologist, leading the
project COMPARE says that whereas the research referred to only defined
the problem, Project Compare expects to do something about the results,
or try put the record straight.
And in this connection the team involved in project Compare had
addressed letters to the relevant journals and mentioned specially what
is inconsistent. The idea was to set the record straight.
The responses have been of a mixed nature.
To conclude this highly disturbing trend in Clinical Trials in
advanced nations, we refer to the comments made by Dr. Goldacre who is a
trial blazer with a good reputation. Dr. Goldacre says that the
responses from some journals which said some results were not important
had added that in the case of the more industrious of the readers of
these journals, they could themselves search for the truth of the
findings of clinical trials reported.
Finally the article says that Dr. Goldacre hopes to publish another
paper, collecting the responses of the medical journals mentioned which
is intended to 'provoke the system' in other words to get to the bottom
of this whole complex question.
The writer is Secretary-General of the Business Chamber of Commerce.
He could be contacted on email [email protected]