Evidence based medicine: Selective use of evidence and the role of drug companies

Recently I was talking to my daughter Hannah about the work she was doing for one of her modules. Although her degree is in Marine Biology, for some reason she was looking at National Institute for Clinical Excellence (NICE) guidelines, and how they work.

We had some interesting discussions about what evidence is accessed by NICE, about randomised controlled trials (RCT’s) and the consultation process. What emerged from her review confirmed my suspicions regarding the use of evidence, particularly by drug companies who have a vested interest in their products being recommended in guidelines.

In 2003, the Department of Health agency responsible for ensuring that medicines meet appropriate standards of safety and effectiveness (the Medicines and Healthcare products Regulatory Agency—MHRA), released data regarding the risks and benefits of newer antidepressants used to treat depression in children and young people.

The information published on the MHRA's website included both previously published and never before published data obtained directly from the manufacturers of the SSRIs ("selective serotonin reuptake inhibitors") and other newer atypical antidepressant drugs. These data were collected after earlier work had raised concerns about the safety of paroxetine (Seroxat) and venlafaxine (Efexor, Efexor XL) in children and young people with depression.

Based on their review of the data, the MHRA concluded that all of the newer antidepressant drugs, other than fluoxetine (Prozac), carried serious risks that outweighed any benefits. The MHRA, therefore gave warning of the potential that these drugs could increase the risk of suicide-related behaviour (rather than decreasing it—as would be expected of an antidepressant) when using these drugs in the treatment of depression in childhood and adolescence.

The National Collaborating Centre for Mental Health (NCCMH) had been commissioned by NICE to produce national guidelines for the whole of the NHS on the treatment of depression in children and young people. NCCMH is an evidence-based guideline development unit jointly run by the Royal College of Psychiatrists and the British Psychological Society and funded by NICE.

However, the NCCMH only had access to published data, so, when the MHRA verdict on the SSRIs became public, it became evident that the MHRA had access to information about a total of 11 trials, of which the NCCMH had only seen 5.

Because of the inconsistency between the MHRA's findings and the published literature, several members of the NCCMH committee (Whittington et. al. 2004), decided to compare and contrast the published data with the unpublished data. This work was designed as an experiment to test out what the difference might (or might not) be if, in producing a guideline, the committee had access to the unpublished as well as the published literature.

They concluded that the published evidence was more favourable than the unpublished evidence, and most importantly that it was only when all evidence was examined that it was clear that the risks (particularly the increased risk of suicidal behaviour and thinking) outweighed the benefits.

They also found evidence to suggest that at least one of the drug companies who had undertaken trials of an SSRI in the treatment of childhood and adolescent depression had withheld publication of trial data on the grounds that it contained evidence that the drug was unlikely to be effective in treating depression in this age group.

A UK psychiatrist, David Healy, has been raising similar concerns for a while. He has general concerns about influence of pharmaceutical companies and the way that they don't mention the problems in the way that academics are expected to do so. He has evidence of one paper being written by a pharmaceutical company, but where academics appear to be the main authors. He has a particular concern about this influence on bipolar disorders, particularly since NICE guidelines quote one of the articles in which very young children are given the diagnosis of bipolar disorder and prescribed medication as part of a 'trial'.
You can access one of Healy’s papers here: http://www.furiousseasons.com/documents/healybp.pdf

In June this year, the New York Times published an article identifying that a world-renowned Harvard child psychiatrist, Dr. Joseph Biederman, whose work has helped ‘fuel an explosion in the use of powerful antipsychotic medicines in children’ earned at least $1.6 million in consulting fees from drug makers from 2000 to 2007 but for years did not report much of this income to university officials, according to information given Congressional investigators.

In my earlier article about Champix I didn’t mention that the manufacturers did not trial the drug with patients who have a history of mental health problems at all, and the drug was released on evidence that was derived from an ungeneralisable sample of the population.

Drug companies can afford to fund trials into their newly developed products. They may, as seen above, be selective in the evidence that they see fit to publish. The vast resources to fund for research into other therapies, for example talking therapies, are simply not available. Funding this type of research is down to practitioners on a local level, or perhaps interested University faculties. This means there is a huge disparity in what evidence is available for NICE (or those advising NICE) to base their decisions upon.

And the evidence is skewed.

Reference
Whittington C, Kendall T, Fonagy P, Cottrell D, Cotgrove A, Boddington E. Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. The Lancet, 24 April 2004; Volume 363: Number 9418, 1341-45.

Stopping smoking and the danger of Champix (varenicline) and alcohol

I have helped a lot of people stop smoking over the past few years, although my own struggle with cigarettes continues to be tempestuous!

I used a medication called Champix (varenicline) successfully in 2007, and gave up for seven months, but unfortunately started again. I used Champix a second time in June 2008, and have discovered some serious side effects, so much so that I can no longer recommend its use.

I was aware of the depersonalising effects of Champix, and associated these with the sleep disturbance, but while we were on holiday, one evening when we’d all been enjoying a few drinks, I experienced what can only be described as a psychotic episode. I could not explain this episode at all; up until then I had been pretty happy, enjoying a much needed break.

As you might imagine, I was pretty upset about what happened, but discovered by chance when doing some research for a teaching session on suicide that the mix of varenicline and alcohol can be extremely dangerous.

Recently there has been some discussion over the death of the musician Carter Albrecht, who was shot by a neighbour following his use of alcohol with Champix (known as Chantix in the US). Albrecht, best known as a member of Edie Brickell and the New Bohemians, started taking Chantix in late August 2007. He was well liked in the community, and had no prior history of violence. Immediately, Albrecht began to complain of vivid, hallucinatory dreams (a Chantix side effect). One night about a week after he started taking Chantix, Albrecht had a violent encounter with his girlfriend.

The episode occurred after Albrecht had consumed a couple of alcoholic drinks. Albrecht’s girlfriend reported that he was confused, and did not recognize her. Before the night was over, Albrecht had been shot dead by a terrified neighbour on whose property he had trespassed. After Albrecht’s death, many other Chantix users complained of similar episodes of violent or suicidal behaviour, especially when they had consumed alcohol. The Chantix label does caution against alcohol use, but it does not warn that drinking alcohol while taking Chantix could lead to violent or suicidal behaviour. Furthermore, Chantix’s reaction with alcohol has not been studied in clinical trials.

This page shocked me. Read some of the stories, and you might begin to imagine what might have happened while we were on holiday.


UPDATE: There is now accumulating scientific evidence that varenicline is associated with thoughts and acts of aggression/violence see these articles - 

Thoughts and Acts of Aggression/Violence Toward Others Reported in Association with Varenicline

Prescription Drugs Associated with Reports of Violence Towards Others