Monday, September 1, 2008

CROs: How Independent, Really?

My friend the excellent investigative health journalist, Jeanne Lenzer, recently did a news commentary for the BMJ (; subscription required to access) on Contract Research Organizations (CROs) and their cousins, academic research organizations (which academic medical centers set up when they discovered that the CROs were eating their lunch and taking away all the research trial grants that used to come to academic centers as a matter of course). I have to say that compared to previous writings by Jeanne, this piece is rather high on the inneundo side of the ledger--showing just how hard it is to really get the goods on research bias, one might retort. However, reading through patiently will reward you with a couple of pearls, which I will now proceed to summarize.

The core question is whether a CRO is truly independent because (as its defenders claim) it won't get research grants in the future unless it keeps a good reputation for high quality work, and it works for no single drug company; or is ultimately the creature of the industry because (as its critics claim and as I review in HOOKED) in the end, if you don't give drug firms the results they want to market their product, they'll take their business elsewhere. Lenzer gives many examples, mostly drawn from the world of academic CROs, that at least hint strongly at the existence of a decided pro-industry tilt that could seriously bias the research results. She also gives somewhat clearer evidence of a money-laundering operation--that the med school can form an academic CRO, the CRO can take money from a drug company, med school faculty can conduct the research, and when the study is published, all the publicity states that faculty at the med school discovered such-and-such, with nary a mention of the CRO or the company sponsorship.

What I took to be the major pearls from the paper--in the form of smoking guns, to mix metaphors--were:

  • One of the relatively few major trials demonstrating that serotonin-type (SSRI) antidepressants work in children and teenagers was the TAPS (Treatment of Adolescent Depression) study. This study was carried out by Duke University's academic CRO. The drug under study was Prozxac, made by Eli Lilly. The CRO does a fair amount of work for Lilly. Officially, the TAPS study was sponsored by the NIH. Lilly presumably simply donated the drug. However, TAPS has a number of design features that suggest a considerable bias in favor of Prozac. The worst was the fact that a couple of the arms of the trial were non-blind, when they just as easily could have been blinded, and the non-blind data accounted for a great deal of the total effect size atributed to Prozac. Lenzer noted another bias-suggestive feature--that the scoring system reported those who did better on the drug but omitted any mention of the number who did worse. She then tried to obtain the raw data, on how many did worse, from both the NIH and the principal investigator at Duke. The NIH refused, saying these data were in the possession of the PI. The PI and Duke refused to disclose those data. For a "publicly funded" study this seems strange behavior indeed.
  • Quintiles Transnational, based in North Carolina, is the world's largest CRO. Its founder and CEO, Dennis Gillings, recently donated $50 million to UNC's School of Public Health--now named the Gillings School of Global Public Health. UNC's chancellor, in writing to Gillings to thank him for the gift, stated that in return, the School would commit to "alignment of faculty behind focused programs," with the priority to be "new methodologies to speed clinical trials innovation." Now, this is odd. A school of public health as a rule is not in the pharmaceutical clinical trials business. If there is any school at the university that you'd expect would be looking at the importance of non-drug approaches to health problems, the School of Public Health would be it. Lenzer also noted that 8 current or former Quintiles executives now either head school programs or sit on advisory boards. Hmm--sounds like a CRO just bought a school of public health--and that UNC meekly handed it over.

1 comment:

Anonymous said...

published on

The Human Injury of Lost Objectivity

If I were to categorize the corruptive tactics implemented by big pharmaceutical companies in particular, the intentional corruption of implementing fabricated and unreliable results of clinical trials would be at the top of the list. Pharmaceutical companies manipulate the trials they sponsor because of their power to control others involved in the process largely absent of regulation. This is a matter of requiring authenticity and, more importantly, assuring the safety of the public health.

Decades ago, clinical trials were conducted in academic settings that focused on the acquisition of knowledge and the completely objective discovery of novel medicine. Then, in 1980, the Bayh-Dole Act was created, which allowed for such places to profit off of their discoveries that were performed for pharmaceutical companies in the past. This resulted in the creation of for-profit sites, called Contract Research Organizations (CROs), which are composed of community research sites with questionable investigators void of necessary experience or quality regarding their research purpose and ability. Since they are for-profit, the trials conducted at CROs are sponsored by pharmaceutical companies that control and manipulate all aspects of the trial. This coercion is done by various methods of deception in subtle and tacit methods. As a result, research in this manner has been transformed into a method of marketing, which includes altered results of the trial to favor the sponsor’s medication. Their activities are absent of true or applied regulation, and therefore have the autonomy to create whatever they want to benefit the collusive relationship between the site and the sponsor. The CROs have multiplied in recent years, and now represent what may be a 20 billion dollar a year market.

Further disturbing is that once the trials are completed, the medical articles are then written by ghostwriters, who are not identified and acknowledged by the sponsor, and are not trained in clinical research overall, as they are simply freelance writers. How often ghostwriters are utilized by pharmaceutical companies remains a mystery. This activity removes accountability and authenticity of the fabricated clinical trial even further. The corruptive act is finally completed by the sponsor hiring an author to be placed on the trial that likely had no involvement with the trial, and, along with others, was paid by the sponsor. To have the trial published, the sponsor pays a journal, along with the promise of purchasing thousands of reprints of the study from the journal. Again, how often this process is performed is unknown, yet frequent enough to create hundreds of such false writers and research sites to support the industry. So benefits of medicine studied in such a malicious way can potentially harm patients and their treatment options. The purchased reprints are distributed to the sponsor’s sales force to share the content with prescribers — your doctor.

Such misconduct impedes research and the scientific method with frightening ethical and harmful concerns. Our health care treatment with medications is now undetermined in large part in such situations, as well as the objectivity that has been intentionally eliminated regarding the trust in the scientific method in this type of activity illustrated in this article. More now than ever, meds that are removed from the market are given black box warnings. Now I understand why this is occurring.

The pharmaceutical industry needs transparency and disclosure in order to correct what we have historically relied upon for conclusive proof — the scientific method. More importantly, research should not be conducted in a manner that the sponsor can interfere in the ways I described in this article. We should call for independent sites with absolutely no involvement with the drug maker. And clearly, regulation has to be enforced not selectively, but in a complete fashion. Public awareness would be a catalyst for this to occur, after initially experiencing a state of total disbelief that such operations actually are conducted by such people, of course. We can no longer be dependent on others for our optimal health. Knowledge is power, and is also possibly a lifesaver.

Ethics and Science need to shake hands.
– Richard Cabot

Dan Abshear
Author's note: what has been written is based upon information and belief.