Although I’m one of the few non-clinicians writing here at SBM, I think about clinical trials a great deal – especially this week.

First, our colleague, Dr. David Gorski, had a superb analysis and highly-commented post on The Atlantic story by David H. Freedman about the work of John Ioannadis – more accurately, on Freedman’s misinterpretation of Ioannadis’s work and Dr. Gorski’s comments. While too rich to distill to one line, Dr. Gorski’s post struck me in that we who study the scientific basis of medicine actually change our minds when new data become available. That is a GoodThing – I want my physician to guide my care based on the latest data that challenges or proves incorrect previously held assumptions. However, this concept is not well-appreciated in a society that speaks in absolutes (broadly, not just with regard to medicine), expecting benefits with no assumption of risk or sacrifice in reaping those benefits. Indeed, the fact that we change our minds, evolving and refining disease prevention and treatment approaches, is how science and medicine move forward.

Then, I had the opportunity to hear an excellent talk on pharmaceutical bioethics by Ross E. McKinney, Jr., MD, Director of the Trent Center for Humanities, Bioethics, and History of Medicine at Duke University School of Medicine. McKinney is a pediatrics infectious disease specialist who led and published landmark Phase I and Phase II trials zidovudine (AZT) for pediatric AIDS patients. While he continues working in this realm, McKinney also studies clinical research ethics, conflicts of interest, and informed consent. I was absolutely fascinated and refreshed by hearing from an expert who while describing and citing major ethical lapses in our system of drug development is also willing to propose solutions and do the hard thinking required for us to maximize the benefits we derive from pharmaceuticals while minimizing unethical behavior.

From his presentation abstract:

The system the United States uses to develop and approve new drugs and devices is fraught with ethical problems. On the one hand, tremendous strides have been made in the treatment of HIV, cancer, and heart disease. Drug development can work and save human lives. On the other hand, drug companies have repeatedly withheld vital information that directly affects human health. Sins of omission that cost human lives have become part of the cost of doing business. Why have we allowed this situation to evolve, and what can we do to improve ethical behavior on the part of the pharmaceutical and device industry.

(Related: See this Dr. Peter Lipson SBM post on our “tremendous strides” in heart disease.)

Evil drug companies

The primary case for discussion was the well-known Avandia episode where GlaxoSmithKline was shown in a 2007 NEJM paper by Steven Nissen to have knowledge of the increased cardiovascular risk of their PPARγ agonist diabetes drug, rosiglitazone, effects not reported for pioglitazone (Actos), a similar drug from Takeda. He then cited the 2008 Winklemeyer article in Archives of Internal Medicine that retrospectively assessed the risks of the two drugs in 28,000+ patients over 29,000+ patient-years and concluded that rosiglitazone was associated with 15% greater mortality and 13% more cases of congestive heart failure than in patients taking pioglitazone. It was in the public’s best interest that a prospective trial of the two drugs be done and while GSK ultimately tried to launch such a study, patient recruitment was hindered by news of rosiglitazone’s safety.

McKinney began by noting that we need to accept the fact that a pharmaceutical company’s primary mission is to produce a return for shareholders by bringing the most effective drugs to market for the largest population whose benefits far outweigh their adverse effects.  While sitting there, I also began to think about this concept more braodly: for readers who think that “drug companies” are evil profit-mongers, I encourage you to take a look at the precise stock holdings in the mutual funds of your 401(k) or 403(b) retirement accounts.

These are my words, not Dr. McKinney’s: It’s disingenuous and intellectually lazy to say that all “drug companies” care about is profits when many, many folks – including those objectors who populate the comment threads of this blog and others – benefit financially from the business practices of the industry. Let he who is without sin cast the first stone.

What would YOU do?

What I enjoyed next was that McKinney challenged the audience to declare what they would have done next if they were working for the company and their jobs and the jobs of others depended on the sales of what had become a $3 billion/year drug. He wouldn’t just let us sit passively and – for just a brief moment – you had to really think about being in the decision making shoes. I took a moment during the talk to pull up the Nissen paper and look at the actual numbers and look at the absolute risk of adverse effects instead of the relative numbers.  I encourage you right now to go to Table 3 and look at the actual numbers of myocardial infarctions and deaths from cardiovascular causes in control patients versus patients taking rosiglitazone in each of the trials. Yes, the analysis of the data as a whole showed that rosiglitazone exhibited significant risk but can you see how easy it might be to convince yourself that there wasn’t really a problem with your drug?

In another part of his talk, he challenged us (still as hypothetical company employees) to come up with designing a study to test our hypothetical new drug for mild-to-moderate pain and expressing whether we thought it best to compare against aspirin, ibuprofen, codeine, or celecoxib (Celebrex). What’s the right comparison drug to test yours against if you want to do the study correctly? Do you want to chance your $200/month drug against the pennies-per-dose aspirin or ibuprofen? Do you want to play hardball against equally-expensive Celebrex and risk that your drug might not perform better?

What’s the right study to do in the interest of patients?

What’s the right study to do in the interest of your continued employment?


McKinney also spent time talking about how the need for stronger disincentives for pharma management to behave unethically. The $2.4 billion that GSK had to set aside for Avandia litigation may not be large enough of a penalty. For a drug that had such a huge market, this might simply be viewed as the cost of doing business. Recent legislation to reward inside whistle-blowers personally might increase the revelations of wrongdoing similar to this week’s award, also related to GSK, to a drug manufacturing quality manager.

Finally, McKinney also spoke of the unavoidable conflicts of interest by academic investigators conducting industry-sponsored clinical trials – again reminding the uninitiated in the audience that the NIH funds vanishingly small numbers of clinical trials and that Pharma’s total clinical trial expenditures are roughly twice that of the entire NIH budget.

Caring too much can also be a COI

McKinney noted that conflicts of interest are not necessarily always nefarious or driven by money. As a physician who treats infants and kids with HIV/AIDS, McKinney stated that he has a conflict of interest in just simply wanting a new drug to work for his patients. Trying to keep kids from suffering is a strong motivator. In fact, the desire is so strong that if an investigator is not blinded, some bias may creep in on variables that are more subjective.

What can we do? We’re only addressing half the job by simply pointing out problems with the system. We have to propose and experiment with solutions. We have to work hard to minimize the introduction of any bias into studies. We have to provide strong disincentives to companies to behave unethically. But solutions will also have their own costs we must also be willing to accept. For example, if fines are levied that drive a major multinational company to bankruptcy, we must accept the loss of innovation to the collective worldwide drug discovery effort.

The solutions are not easy. The discussions are difficult. It’s just as easy to bleat that doctors don’t care if they kill patients because they take drug company money as it is to say that rainbows and unicorns flow forth from drug company research campuses. Having the discussions, pushing others to evaluate their own ethics, and thinking through tough financial and clinical decisions is grueling. I was delighted to have the opportunity this week to be pushed outside my comfort zone. It should happen more often.



Posted by David J Kroll