Clinical trials, outcome switching and its dangers

Pharmaceuticals:

Jagath C. Savanadasa

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."

Biggest fine

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.

Deception

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 go wrong.

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

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 reasons.

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.

'Modus Operandi'

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]