Two years ago, a study called JUPITER looked at AstraZeneca’s Crestor cholesterol pill and measured levels of a protein called CRP that can indicate arteries are inflamed and point toward heart disease. But the results prompted debate over the extent to which CRP should be used as a guidepost for treating cholsterol and prescribing Crestor and other statins to people with low cholesterol (see here).
In June, a “critical reappraisal” appeared in The Archives of Internal Medicine calling the trial “flawed,” because there were various methodological problems and a “strong commercial interest” may have resulted in biased outcomes. Nine of 14 authors had ties to AstraZeneca and the principal investigator, Paul Ridker of Brigham and Women’s Hospital (pictured), is a co-holder of the patent for the CRP test and headed the Data Safety Monitoring Board (see here and here). Yet another analysis found no evidence that prescribing statins to patients at risk of heart disease reduces the chance of premature death in the short run (see this).
Now, Ridker and co-author Robert Glynn have published a response in the American Journal of Cardiology, since the other journal would only publish a "brief" letter, which they found insufficient to explain the complexities. And it is complex, but worth reading (here is the abstract). To summarize, they argue JUPITER "addressed the core clinical question posed using the most robust and widely accepted form of clinical scientific inquiry available, the randomized-placebo-controlled, double-blind trial."
They also insist the trial "used high levels of scientific rigor, achieved exemplary participant follow-up, used rigorous end point adjudication, prespecified a highly conservative monitoring plan in the charter of its Data and Safety Monitoring Board, and followed a prespecified analysis plan conducted exclusively on an intention-to-treat basis."
Then, they take aim at one criticism that suggested the decision by the DSMB to halt the trial early "substantially overestimated trial benefits," that the rules were not prespecified and that the end point used to define those rules was not defined. However, Ridker and Glynn maintain there was a specified charter that spelled out any stoppage "would require proof beyond reasonable doubt that prolonged use...was clearly indicated or clearly contra-indicated for all or some specific types of patients.”
They then criticize the critics for failing "to address the appropriateness of continuing a trial after the main study question has been answered definitively; trialists and study monitors have an ethical responsibility to stop experiments and inform their participants as well as society when uncertainty and equipoise no longer hold with respect to the question under evaluation."
Yet another point raised by their critics was the magnitude of the effect of stopping the trial early and whether that effect is large enough to alter clinical interpretation. To that, Ridker and Glynn write "there is no credible evidence that early stopping of the JUPITER trial had anything more than a marginal effect on the true estimates of efficacy. If anything, the magnitude of benefit in the trial was increasing over time, not decreasing."
As to conflicts and industry influence, they argue the critics did not provide any evidence to back up their claims, and goes on to assert that the trial was initiated by the study team, AstraZeneca did not play any role in analyzing the data and drafting the manuscript, or had access to the unblinded trial data until after the manuscript was submitted for publication. However, they do not address the individual ties between the study team and the drugmaker or how Ridker benefits from the CRP patent.
For those of you who read this far, one of the critics, Michel de Lorgeril, last June posted this question-and-answer on his website in response to questions from a journalist about the controversy.
5 Comments
I gather Ridker and co-author Robert Glynn got some coaching from the AstraZeneca PR department on living in complete denial of their wrong doing.
When caught committing fraud and other felonies, AZ stated after writing a check for 520 million
"While we deny the allegations, AstraZeneca takes its obligations very seriously under its agreements with the government,"
Then for those permanently injured by their illegally marketed and unsafe products
AZ PR “We remain committed to a strong defense effort, but will also continue to participate in good faith in court-ordered mediation.”
“AstraZeneca has negotiated settlements with a number of firms to resolve claims in the aggregate,”
This shows that the key to running a successful and profitable illegal cartel is to never admit wrong doing whether it be with bogus research or criminal fraud.
"Paul Ridker of Brigham and Women’s Hospital (pictured), is a co-holder of the patent for the CRP test and headed the Data Safety Monitoring Board"... That way he can assure that the trail is run correctly.Picked as they said at the optimal moment.
Could someone find the numbers of these patents: I looked some time ago and it appears to me that it is not the hsCRP test itself that is patented, but just the IDEA of inflammation in heart disease, and that it was the IDEA that was leased to 2 pharmas, including AZ.
Either way, it could be millions to Harvard and the first author. Some journals require reporting of the magnitude of the conflict also; that would be warranted in such cases.
Clearly the conflict by Ridker should be better spelled out. That having been said, my beef with JUPTITER was that the bulk of the benefit was from fewer medical interventions, not in fewer dead people from heart disease. I know and respect several of the JUPITER authors but their reporting is clearly substandard. WHERE are the clinical report / result forms with the questions asked in this trial?? We have no clue as to what the questions were and we should.
Were the criteria for CV mortality too strict as the authors have claimed? These criteria were not a problem in other studies so the criteria and questions SHOULD be public.
Paul M. Ridker, M.D., M.P.H., F.A.C.C., F.A.H.A., Eugene Braunwald Professor of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston. Received investigator-initiated research support from Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb, Dade-Behring, Novartis, Pharmacia, Roche, and Sanofi-Aventis; served as a consultant to AstraZeneca, Dade-Behring, Isis Pharmaceutical, Sanofi-Aventis, and Schering-Plough. (JAMA. 2007 Jul 18;298(3):309-16.) Receives research support form AstraZeneca Pharmaceuticals LP and Novartis Pharmaceuticals Corp. (http://www.medscape.com/viewprogram/3878_authors; accessed 7/28/05) Receives research support from Novartis AG. (http://www.medscape.com/viewprogram/2888_authors; accessed 4/1/04) Research on C-Reactive protein and the risks of developing hypertension partially supported by Pharmacia, Inc. (J Am Med Assoc. 2003;290:2945-51.) Receives grant support from Bristol-Myers Squibb, AstraZeneca, and Roche Diagnostics. (N Engl J Med. 2003:348;1425-34.) Holds a patent for the development of "systemic inflammatory markers as diagnostic tools in the prevention of atherosclerotic diseases," which is licensed to The Brigham and Women's Hospital, Inc. (United States Patent Office, Patent No. 6,040,147; accessed 10/07/03) Participated in a collaborative clinical trial on the effects of the statin drug, Pravachol (prevastin), on blood levels of C-Reactive protein with Variagenics, Inc., a biotechnology company that develops molecular diagnostic tests. (Ferentz, A.E. and J.S. Mohr. "Variagenics, Inc.: Company Profile," Pharmacogenomics. 2002:3(5);713-17.); http://www.pharmaco-genomics.co.uk/admin/articlefile/variagenics.pdf; accessed 4/1/04) According to Business Wire (“Variagenics to Conduct Pharmacogenomic Evaluation of Major Cardiovascular Trial in Collaboration With Brigham & Women's Hospital,” July 30, 2002), Variagenics received "an exclusive option to license intellectual property resulting from the research, which may lead to the future development of cardiovascular diagnostic tests." According to Family Practice News (Zoler, Mitchel L., “Pravastatin Reduces C-Reactive Protein Levels,” May 1, 2001), research on the efficacy of pravastatin in reducing C-Reactive protein levels in the blood stream was funded by the drug's manufacturer, Bristol-Myers Squibb. Research on the effect of statin therapy on protein levels supported in part by Bristol-Myers Squibb. ( J. Am. Med. Assoc. 2001;286:64-70.) --------------------------------------------------------------------------------
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Thanks LILLYK. That is what I thought, he seems to have patented THE IDEA of using inflammation as a risk factor on heart disease. I don't see that he owns part of the hsCRP test. Here's the patent you mention and there is a similar one. http://www.freepatentsonline.com/6040147.html
Ridker is not any more clear than that in his declarations of conflicts.
It seems like he patented the IDEA of using blood pressure to predict risk, not the cuff itself. Now, how much has Pharma paid him and Harvard for mentioning that IDEA? It's more than fuzzy.