Edna Astbury-Ward, PhD

When we think of the movies, we don’t instantly think of clinical trials, but a new psychological thriller may well change that by focusing the spotlight on big pharma and anti-depressants.

The Steven Soderbergh film, Side-Effects, poses more questions than it answers. It depicts one of the main characters, Dr. Jonathan Banks (played by Jude Law), as a caring but overambitious psychiatrist who has moved ‘across the pond’ from the U.K. “because Americans have a healthier attitude towards mental illness.” Although the impression the viewer gets is that the only thing healthier about it all will be Dr Banks’ wallet at the end. 

The film raises many important issues regarding the complex relationships that the pharmaceutical industry has with prescribing psychiatrists, as well as ethical clinical trials and academic credibility. Significantly, it also poses the question whether psychiatrists can indeed be duped by their patients, who (for reasons best known to themselves) may display characteristic traits (classic side-effects) of anti-depressant medication, despite their non-compliance. It’s an interesting angle to consider, especially if the said behavior is implicated in any antisocial, criminal or harmful circumstances warranting intervention by courts of law.

The hapless Banks soon realizes that not only has he been duped by his patient but also by his colleague Dr. Victoria Siebert (Welsh-born Catherine Zeta-Jones), who, as author of a less than meticulous piece of research into the (fictional) new wonder drug ‘Ablixa’ has financially benefited from insider trading. So everyone is happy… or so it seems. Banks gets rich, the patient (Emily) gets fixed and Siebert makes a name for herself. That is until in a moment of absolute sanity - yes, you read it correctly sanity - Emily (the patient) acts crazily and gets away with it on the grounds of Not Guilty by Reason of Insanity (due to ‘taking’ Ablixa).

A memorable quote in the film relates to the question of culpable guilt….Did the person do it? Are they guilty? Banks replies, “In this case, those are two very different things”.

We all know that being prescribed a drug does not confer automatic compliance and it could be said that the patients for whom anti-depressants are prescribed are the ones who are most likely not to take them. The ‘poisonous fog’ of depression descends upon patients, clouding judgment and stealing their motivation to commit to the most simple of daily tasks such as medication compliance. It is the responsibility of those involved in clinical research to ensure that such cases like ‘Ablixa’ never become reality.

The film leaves us feeling uncomfortable and wondering whether we should be more afraid of depressed patients who are not taking their medication or those who are.

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Does a "Poisonous Fog" Hang Over Clinical Trials for Anti-Depressants?

Many promising compounds for inflammatory bowel disease (IBD) are lost during the complex development process, and it is vital to find out why and discover some solutions to prevent further leakage from the clinical trials pipeline. Translating basic science into clinical practice is proving difficult in IBD, partly because of the immunological problems suffered by trial subjects and partly because no good experimental model exists, particularly for Crohn's disease. 

These are the views of Jean Frédéric Colombel, MD, Professor of Hepatogastroenterology at Centre Hospitalier Régional Universitaire, Lille, France. He gave the closing plenary lecture at the 6th Congress of the European Crohn's and Colitis Organization, held in Dublin in late February.  

"Keeping drugs in the clinical trials pipeline is often a difficult challenge," he said. "The placebo effect is a killer of drugs." 

To optimize the chances of success, he recommends a reduction of concomitant medication, selecting a robust identifiable endpoint, only entering patients with active disease into clinical trials, a short duration for induction studies, and the minimization of clinic visits. Focusing on patients with active disease is the most important of these factors, but another important issue is the length of the evaluation, noted Colombel, who is a visiting professor at the Inflammatory Bowel Disease Center, Mount Sinai School of Medicine, New York. He argued that a longer evaluation time also raises the possibility of increasing the placebo effect. It is best to opt for an open point of six weeks clinical remission in IBD trials, but this may be too short a time, particularly for those subjects who enter a trial with severe active disease, and it might be prudent to wait longer to observe a clinical effect. 

Better endpoints are also needed, he noted. In many IBD trials, the chosen endpoint is mucosal healing (the absence of ulcers is used as a marker to indicate healing). This simple endpoint is easy to identify, especially in Crohn's disease, and is a strong indication of a drug's effectiveness. However, it does have limitations, not least because there is no full validation of what exactly an ulcer is. Colombel thinks qualitative studies of this aspect are necessary, and queries whether one small ulcer is evidence of non-mucosal healing. 

The Crohn's Disease Endoscopic Index of Severity (CDEIS) may be a much more sensitive score when assessing mucosal healing, even though many physicians appear reluctant to use the index because they regard it as a complex tool. Using the CDEIS helps to define the endpoints, and therefore is a useful instrument in IBD trials, he pointed out. When considering that the gold standard of healing in patients with IBD is "minor lesions," the endpoint of definition of mucosal healing on the CDEIS should be six. If clinicians are looking for a more stringent endpoint of "no lesions," then the CDEIS should be three. 

Currently physicians are assessing the limitations of endpoints on very short-term periods, he stated. Short-term studies are "the black box of clinical trials," and therapeutic strategies are of value for assessing a greater proportion of the patient's life. Induction studies are currently being undertaken up to a maximum of two years. Colombel made a plea that during this time, physicians ought not to define patients' lives in terms of flare-ups and remissions. New endpoints are needed in IBD trials to accurately assess digestive damage. He anticipates that future work will involve the use of a new index of digestive damage, and this may help to provide clinicians with a clearer definition of early Crohn's disease. 

This new index is known as the Lémann Score. The score was developed to understand cumulative bowel damage and the impact of early intervention, and it is based on a comprehensive assessment of structural bowel damage. This score is based on damage, not disease activity, and it will take into account damage location, extent, and severity. The Lémann Score will allow physicians to assess the cumulative and progressive damage and to study the effects of early intervention on damage progression. 

When only looking at clinical disease activity in patients, physicians may miss the progressive accumulation of digestive damage. The current endpoints of the clinical picture, histology, and endoscopy can no longer be used to assess digestive damage and the impact of drugs on the long-term natural history of IBD, he said. Following the path of rheumatologists when assessing endpoints, he supports using the "Sharp Index," which is an index of bone destruction and is used in many clinical trials as a primary endpoint. 

The challenge for future clinical trials in IBD is to look at large studies with robust endpoints and to begin thinking about non inferiority trials. Access to patients in the early stages of the disease is vital when designing IBD trials, and also of interest are long-term studies looking at disease modification with new endpoints, innovative strategies (tight control, dose reduction, and discontinuation), and personalized medicine. 

Edna Astbury-Ward, PhD

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