Tuesday, August 28, 2007

Nissen and Califf on the Avandia Case, and the Evils of Suppressing Data from Clinical Research

We have posted quite a bit about the controversy sparked by a meta-analysis of the cardiovascular adverse effects of rosiglitazone (Avandia, by GlaxoSmithKline) by Nissen and Wolski. (For example, see this post.)

Medscape just published a conversation between Dr Robert Califf and Dr Steven Nissen. (Nissen, who wrote the controversial meta-analysis, is at the Cleveland Clinic, while Califf is at Duke.) Much of the discussion addressed technical and methodologic aspects of the Avandia controversy. But I was struck by what the two had to say about suppression of clinical research.

Starting with Dr Nissen, edited for clarity:

I believe that if you ask human subjects to participate in an experiment that the results of that experiment belong to the public. That it is not acceptable to do such an experiment and then to deep-six the results. And I want that to be a matter of law. I think if it's not a matter of law, we will continue to see negative publication bias where the studies that get published are the ones that show favorable effects of drugs. Things have gotten out of balance, Rob. We hear about the efficacy of drugs through media, on television, through advertising, detail people, CME, but we need to see all of the data in order for us to make good clinical judgments.

Response by Dr Califf:

I've asked the question: 'Will everyone in the room who's in favor of secret human experimentation please raise your hands?' And so far I haven't really had anyone -- well, maybe one exception, but I don't want to reveal who that was -- say they're in favor of that.

The definition of research ... is something that's done to create generalizable knowledge. And generalizable knowledge to me can't be present if the result is kept from the public if it's negative.

Back to Dr Nissen:

Well, ... [companies] argue that the data is proprietary. And they have gotten a lot of traction in the Congress. The companies have said through their lobbyists and so on that when they spend the money to run a clinical trial that they own those results and they should be free, in a free enterprise system, to do whatever they want with those results. And if they don't like them and they want to put them somewhere other than in the public domain, that should be their right.

And from Dr Califf:

while there are lobbyists arguing that, there are many good people in companies who feel quite differently and would like to have permission, as you say, with regard to their corporate boards, who are always looking after optimal profitability, they'd like to have that happen.

The fiduciary responsibility of the corporate board is to not do things that damage the profitability of the company, and that leads, I think, to a very distorted perspective on the ethics that are involved.

Although in the past the argument has been made about trade secrets and so on and so forth, but when you get into the human experiment arena, if we level the playing field so all companies are working under the same rules, then the best products will win out because the public will have better information and people will make better decisions about what to do.

So let's summarize the main points:
  • People participating in clinical experimental research are told that their participation will benefit science and patient care.
  • This benefit could only occur if the results of the research are made public, even if they go against the commercial (or idological) interests of the people who paid to have the research done.
  • For the financial supporters of research to keep data they do not like secret violates the trust of the research subjects.
  • However, if hiding data has no negative consequences, commercial sponsors will continue to hide data unfavorable to their interests.
  • Government regulation would be one way to impose negative consequences for hiding data.
  • Preventing the suppression of data from clinical research ultimately will favor the products that are actually best for patients, which would be good for patients, and, incidentally, good for companies that make the better products.

Sounds good to me. But will any politician have the courage to advocate the punishment of companies that hide data they don't like?

Another solution would be to ban research on humans done or supported by those who have financial interests in the products or services tested by such research. That would require some massive redirection of the flow of money that supports human research.

I am wondering when some clever attorney will figure out how to sue a company on behalf of a research subject in a trial whose results were suppressed by its commercial sponsor. That particular sledge hammer might prompt some re-thinking of the issue.


Anonymous said...


Thanks for the great post. I'm cutting and pasting it into a message to both my Senators (I've had to give up on my do-nothing Congressman). Wish your other readers would follow suit.


Anonymous said...

Another terrific post!

But the issue isn't hidden data as much as the bigger problem of studies being reported but carefully spun, data statistically (creatively) interpreted so as to support the sponsor. Studies are also carefully designed to virtually guarantee positive results. I watch reearchers do this daily to ensure staying in good graces with the drug sponsors, guaranteeing continued prestige, perks and future funding. One quickly becomes incredibly unpopular in academia and research for speaking the truth. University research centers thrive on the millions of dollars they bring in conducting drug company research.

Anonymous said...

"if we level the playing field so all companies are working under the same rules, then the best products will win out because the public will have better information and people will make better decisions about what to do."


Steve Lucas

Anonymous said...

A good example of industry spin is today's WSJ opinion piece by Scott Gottlieb The War on (Expensive) Drugs. In this piece Dr. Gottlieb calls for more open sharing of results. The reason being so industry can show (spin) their side of the story.

He questions the governments funding of head to head testing. It seems this is not fair to the new drugs. He also states that there has been no change in the prescribing habits of doctors in the psychiatric field, so old vs. new drug testing, is not warranted.

He also questions the off label use of Avastin to contain cost in eye care. At one point he declares this to be "illegal compounding."

What we see here is a former government employee answering the needs of his new employer. This piece is slick and smooth. The problem is all of the government faults can be found in pharma. Only when Dr. Gottlieb calls for pharma to follow the same rules will his criticism be valid.

We once again see the revolving door in Washington enriching those who choose to leave government service and turn to the private sector. 60 Minutes has repeated a piece on the legislators, and their assistants, who have done very well financially after the passing of the Medicare prescription act.

Dr. Gottlieb is correct: it is about the money.

Steve Lucas