Tuesday, April 27, 2004

Latest Information on Safety of Antidepressant Use in Children

Here is an editorial from Lancet, possibly the world's most prestigious medical journal.  The editorial accompanies an article (free registration required for abstract; subscription for full access) about the safety of SSRIs in children with depression.  While it is not the entire story, it is a topic of interest and it comes from an authoritative source.  It points out some of the problems that can arise from industry-funded research.  

The authors of the editorial suggest that "Changes are required at every level of the global health-care infrastructure."  I would suggest that there ought to be a fundamental change in the way the pharmaceutical companies are run.  Specifically, at the board-of-director level, there should be mandatory input from scientists.  A board composed entirely of businesspersons will make decisions like businesspersons do.  There should be a requirement that all boards have at least 51% of their members holding advanced degrees in the biomedical sciences. 

Of course, incentive programs such as stock options and profit-sharing need to be re-evaluated.  Given the effect that a news release can have on stock prices, there is a strong incentive for squelching negative news.  This is true even if the news only sounds  negative.  Even the if scientific significance of the news is minor, people will dump their stock at the slightest hint of a problem.   For example, negative drug trials are common in all areas of medicine.  This is true especially when the drug is in the early stages of development, when clinicians do not yet know the best way to use the drug, have not determined the optimal dose, or have not yet defined the disease states for which the drug is most effective. 

If Ford Motor Company came out with a new Mustang, and the first prototype got flat tires more often that other cars, you probably would not go out and dump all your Ford stock.  You expect glitches like that.  But a negative drug trial tends to get people all worried. 

The Lancet recommends that "Governmental institutions such as NICE require legal powers to ensure that biomedical research is used to improve health even if this does not equate with improved profits."  It is difficult to imagine that this could happen in the USA, where profit is king.  Perhaps we will have to rely upon our EU brethren to look out for our safety on the biomedical front.  This could work: we will keep the terrorists from killing them; they will keep large corporations from killing us. 

One aspect of this story that I have not seen anyone else comment about, is the different approach taken to drug approval in the USA compared to Europe.  European countries seem to be quicker to release drugs for sale, but they also are quicker to pull them from the market.  I'm sure there is a sociological lesson in there somewhere, but I don’t know what the lesson is.

Note that I am not advocating that the USA ban use of antidepressants in children.  However, I agree with most people that we need to be exceptionally cautious about such uses.  There has not been nearly enough testing of any kind of pharmaceutical product in the pediatric population.  The reasons for this are complex.  There is an interesting history of the FDA's policies on testing of drugs in children and adolescents.  It is a long, strange, politically-charged story that I am still piecing together.  I will post that sometime soon.

Editorial from The Lancet

Volume 363, Number 9418; 24 April 2004

Depressing research (registration required)

It is hard to imagine the anguish experienced by the parents, relatives, and friends of a child who has taken his or her own life. That such an event could be precipitated by a supposedly beneficial drug is a catastrophe. The idea of that drug's use being based on the selective reporting of favourable research should be unimaginable. In this week's issue of The Lancet (p 1341), however, a meta-analysis by Craig Whittington and colleagues suggests that this is what has been happening for research into the use of antidepressants in childhood. Their results illustrate an abuse of the trust patients place in their physicians. They also represent an abuse of the trust placed by trial volunteers in the medical and pharmaceutical establishments.

The story of research into selective serotonin reuptake inhibitor (SSRI) use in childhood depression is one of confusion, manipulation, and institutional failure. Although published evidence was inconsistent at best, use of SSRIs to treat childhood depression has been encouraged by pharmaceutical companies and clinicians worldwide. Last month, the Canadian Medical Association Journal  (link here; see also 1 2 3 -- links added by CC) revealed excerpts from an internal GlaxoSmithKline memorandum demonstrating how the company sought to manipulate the results of published research. Concerning a study of paroxetine use in children, the memorandum states "It would be unacceptable to include a statement that efficacy had not been demonstrated, as this would undermine the profile of paroxetine". Last year the UK Committee on Safety of Medicines prohibited the treatment of childhood depression with any SSRI except fluoxetine. Despite this, the Food and Drug Administration in the USA appears last week to have failed to act appropriately on information provided to them that these drugs were both ineffective and harmful in children.

In a global medical culture where evidence-based practice is seen as the gold standard for care, these failings are a disaster. Meta-analysis of published data supports an increasing number of clinical decisions and guidelines, which in turn dictate the use of vast levels of health-care resources. This process is made entirely redundant if its results are so easily manipulated by those with potentially massive financial gains. The global sales of the GlaxoSmithKline SSRI paroxetine, for example, amounted to US$4·97 billion last year alone. Moreover, the utility of organisations such as the National Institute for Clinical Excellence (NICE) is significantly undermined in circumstances where they are only able to access data on health-care products that are seen as advantageous to the products' manufacturers.

How confident is society that similar failings will not occur on a larger scale in the future? UK Biobank intends to recruit and follow a cohort of around 500 000 volunteers. The data collected will be used in part to develop new pharmaceutical products and diagnostic tests. Much time and effort has already been invested into ensuring appropriate regulatory and ethical principles are in place for all stages of the project. However, the links of UK Biobank with the pharmaceutical industry are already clear. John Bell, chair of the UK Biobank science committee is also a director at Roche. In addition, at least part of the estimated £70-500 million required to complete the project is envisaged as coming from industry sources. With this level of involvement, will a pharmaceutical company really feel obliged to publish information derived from these volunteers that one of its products does not work?

Changes are required at every level of the global health-care infrastructure. Governments need to collaborate effectively over issues of patients' safety rather than duplicating efforts. Governmental institutions such as NICE require legal powers to ensure that biomedical research is used to improve health even if this does not equate with improved profits. On an individual level, doctors and pharmaceutical company employees must remember that without the trust of trial volunteers and patients medical research and practice will become impossible. People around the world understand the desire to achieve success and to work in a profitable environment. They will not, however, tolerate the notion that in biomedical research this could be at the expense of their children's lives.

The Lancet