Season 4, Episode 7: Hearts and Minds

This episode focuses on NorBAC's investigation into the safety of an autoimmune inhibitor, Lefalin, amid concerns over the drug's possible link to an increased risk of congestive heart failure. A safety panel hears testimony from David and from virology researcher Enuka Okimba, who had been hired by the makers of Lefalin to study the drug's effects. Dr. Okimba's research led her to conclude that the drug was harmful to those taking it - but the drug manufacturer took steps to prevent her from disclosing the results of her studies, arguing that doing so would be in violation of her confidentiality agreement. Having provided testimony in support of Lefalin, David wants to determine whether or not there really is a link between Lefalin and heart failure.

Issues re: disclosure v. suppression of clinical trial data by pharmaceutical companies

Sadly, the suppression of clinical trial data by pharmaceutical companies is not just a product of fiction. In the past 10 years, there have been a number of high profile cases in which the pharmaceutical industry has withheld or suppressed the release of data from clinical research.

Take the Vioxx case, for example. Vioxx is an anti-inflammatory medication that was approved by the FDA in 1999 to treat various forms of arthritis. In 2004, this blockbuster drug, with annual sales of $2.5 billion, was voluntarily withdrawn by its manufacturer due to evidence that it increased the risk of heart attack and stroke in some patients. This move generated a great deal of controversy: There were charges of data manipulation and suppression of evidence, and allegations that the potentially fatal side effects were known and covered-up for almost four years. Litigation by patients who believe that they have been harmed by Vioxx is ongoing. The manufacturer of the drug has set aside over $4 billion to cover potential legal claims.

In Canada, perhaps the most famous case of research "interference" by a pharmaceutical company centered on University of Toronto hematologist, Dr. Nancy Olivieri. Dr. Olivieri had been conducting clinical trials of a drug called deferiprone, used to treat thalassemia, a hereditary blood disorder. Upon concluding from her study data that the drug posed a potential risk to her patients, she felt obligated to disclose this information. Although legally bound by a confidentiality agreement with the drug's manufacturer - which they threatened to enforce through legal action - she felt that she had a moral duty to protect the welfare of her patients even if it meant being sued.

Upon airing her concerns, she was indeed subjected to several lawsuits and lost her job, though some have suggested that confounding factors contributed to her being dismissed. Some commentators have also suggested that Dr. Olivieri was the focus of what amounted to a public smear campaign by her employer, though this too is somewhat controversial. After six years of struggle, she was finally vindicated and reached a settlement with the hospital and University.

What went wrong in both of these cases? What lessons can be learned?

Follow the money

Developing drugs is an expensive business. It can cost hundreds of millions, even billions of dollars to bring a new drug to market. The sheer magnitude of this investment provides an enormous financial incentive for drug developers to achieve favourable clinical trial results.

A 2003 systematic review from the British Medical Journal reported that industry-sponsored clinical trials were four times more likely to show favourable results than similar studies with independent funding. What makes this result even more alarming is that between two-thirds and three-quarters of the clinical trials published in the major medical journals are funded by drug companies.

How could pharmaceutical companies improve the likelihood of achieving positive results?

The success of industry-sponsored trials probably has much less, if anything, to do with evil scientists faking data, and more to do with trial design and publication practices.

Ideally, trials should compare new drugs to existing treatments to decide whether or not there is a clear benefit to the new drug over the standard therapy. For drug companies, these "head-to-head" trials are usually avoided. There is much less risk involved in testing new drugs against an inactive compound, or "placebo", or in using sample sizes that are too small to show significant differences relative to competing drugs.

Multicentre trials or studies with multiple endpoints can be combined in a manner that reflects favourably upon the drug in question. There is also the issue of publishing bias, whereby positive results are more likely to be published than negative ones. This produces a systematic bias that makes drugs look more effective than they really are.

It's complicated

But framing pharmaceutical companies as villains is a gross oversimplification of the problem. These same companies produce drugs that save millions of lives every year. They spend billions of dollars annually, searching for cures to some of the most devastating diseases afflicting humanity.

Indeed, pharmaceutical companies should not be thought of in terms of good and evil, but as corporations trying to provide value to their shareholders and effective treatments for the sick. They operate within the legal and regulatory confines determined by government institutions. These institutions are supposed to be acting on behalf of the public interest. If the actions of pharmaceutical companies conflict with the public good, it is the responsibility of democratic citizens to demand reform of the regulatory system.

Can we do better?

How should society balance the benefits versus the risks of new drugs? Drug assessment is tricky business, and the answers aren't always black and white. There is sometimes contradictory evidence and often a considerable degree of uncertainty involved. Science doesn't have all of the answers, but if we can remove the known sources of bias and financial influence, we can expect the quality of clinical evidence to improve.

There are signs that things are improving. Recent reforms such as an initiative for the mandatory registration of clinical trials (i.e. as a prerequisite for publication in many leading clinical research journals) are a step in the right direction. This should dramatically improve the transparency of clinical research. The internet also helps to empower citizens, providing them, now more than ever, with access to the information they need to make informed decisions about their own health.

-- Ryan Fobel, M.Sc.

About the Author

Ryan Fobel is a researcher in the Department of Medical Biophysics at the University of Toronto. He studies the physical and statistical processes underlying various neuroimaging procedures. He is also an editor of the student-run journal, Hypothesis (www.hypothesisjournal.ca.)

Want to read and learn more?

To read more about the Vioxx recall, click here:
http://en.wikipedia.org/wiki/Vioxx

These sites have more information about the Dr. Olivieri case:
http://hypothesisjournal.com/pdfs/vol3num2/5.pdf
http://www.ecclectica.ca/issues/2005/3/index.asp?Article=2

Read more about research bias here:
http://dx.doi.org/10.1371/journal.pmed.0020138

To learn more about clinical trials and the trial registration database, click here:
http://content.nejm.org/cgi/content/full/NEJMe048225
http://www.clinicaltrials.gov/