Wednesday, May 30, 2007

Did the New England Journal of Medicine Really Commit "Journalistic Malpractice"? And Who Says So?

The publication of a meta-analysis which suggested that rosiglitazone (Avandia, made by GlaxoSmithKline [GSK]) may increase cardiac risk has created quite a kerfuffle. (See our posts here and here. The meta-analysis is Nissen SE, Wolski K. Effects of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356, online here)

There have been several attempts to discredit the Nissen and Wolski article, most prominently in a commentary by Dr Scott Gottlieb in the Wall Street Journal (original version, requiring a subscription here). Yesterday, MedInformaticsMD posted about how the commentary, which blasted the New England Journal of Medicine for political bias, seemed designed to distract attention from problems in how pharmaceutical (and biotechnology) manufacturers dominate clinical research on their own products, and market the results of that research to patients and physicians.

Given the influential placement of this commentary, I thought it worthwhile to examine its specific criticisms of the New England Journal.

Dr Gottlieb started by faulting the journal because, he claimed, it " it rushed onto its Web site a limited and flawed analysis of safety concerns around the diabetes drug Avandia." Then, he claimed "the NEJM study doesn't add much new insight ... because of its own limitations." Furthermore, he charged, "NEJM editors gave short shrift to the study's flaws." Then he noted that the study "contained a number of serious limitations." Later, he decried, "he way data was misused by NEJM....," and that "these shortcomings didn't stop NEJM from spinning the preliminary data...."

So what were the limits of the analysis, how was it flawed, what were its shortcomings, and how was the data misused? After repetitively asserting that the study was imperfect, Dr Gottlieb actually only cited two specific problems with it, in a single sentence.



The authors of the NEJM study based their conclusions that Avandia caused a higher heart risk on just a handful of cardiac events, none of which they could go back and verify, because, unlike the FDA, the authors didn't have access to confidential patient records.


That was it, his whole discussion of the terrible flaws and shortcomings of the Nissen and Wolski meta-analysis, the data which the NEJM so grievously misused.

Yet these are flaws and shortcomings of the existing publicly available data from clinical trials of Avandia, not of how Nissen and Wolski combined that data in their meta-analysis.

The number of events observed in individual clinical trials depended on the size and duration of these previous studies. Similarly, if there were problems in how the original trials categorized cardiac events, the meta-analysis could not solve them.

It actually is not hard to criticize the available clinical research data on the adverse effects of rosiglitazone. It suffers from problems common in the literature on adverse effects of drugs and devices. The publicly available clinical studies were mostly too small, and of too short duration to have much statistical power to find any but the most common adverse effects. Instead, the studies, in the case of rosiglitazone, all sponsored by the drug's manufacturer, were seemingly designed to focus on possible good effects of the drug, not to find problems with it.

Nissen and Wolski's meta-analysis could not solve these problems. It did accomplish two things. First, it brought out from the internet's shadows clinical trial data which is only publicly available on GSK's rather obscure web-site. Second, Nissen and Wolski wrote the first published attempt to combine this obscure data with that from the few published trials to provide a better estimate than those previously available, however imperfect, of the cardiac adverse effects of rosiglitazone.

So why didn't Gottlieb criticize GSK for funding only relatively small, short studies that individually revealed little about the downside of its drug, and then releasing their results late, and only onto an obscure web-site forced into being by lawsuits against the company? Why didn't he criticize the company for not doing a big, definitive study in a timely manner?

(There is an ongoing study, RECORD, which will not be done until 2009 that may be of sufficient size and duration to eventually tell us more about the cardiac effects, good or bad, of rosiglitazone. See: Home PD, Pocock SJ, Beck-Nielse H et al. Rosiglitazone evaluated for cardiac outcomes and regulation of glycaemia in diabetes [RECORD]: study design and protocol. Diabetologica 2005; 48: 1726-1735.)

I can't answer those questions. But note that Dr Gottlieb, like others who have written to defend business as usual in the pharmaceutical industry (see most recent post here), has more relationships with that industry than were revealed by his one-sentence biography at the end of the WSJ article (" Dr. Gottlieb, a physician, is resident fellow at the American Enterprise Institute and was Deputy Commissioner of the FDA from 2005 to 2007.")

Just before he took that job, the Seattle Times reported, "Only a month ago, Dr. Scott Gottlieb was a Wall Street insider, promoting hot biotech stocks to investors." In fact, "Until last month, Gottlieb was editor of a popular biotechnology investor newsletter, Forbes / Gottlieb Medical Technology Investor. Forbes touted Gottlieb's stock-picking success on its Web site in mid-May...." Also, "he also has consulted for, and written positively about, a major matchmaking firm that links doctors with Wall Street investors, the Gerson Lehrman Group in New York."

A few months later, the Boston Globe reported that as FDA Deputy Commissioner, Dr Gottlieb had to recuse himself from discussions about dealing with an avian flu epidemic

because his past consulting work for [large public relations firm] Manning Selvage & Lee involved companies whose products would be used to combat a flu pandemic. Gottlieb's former clients include Roche -- manufacturer of the highly sought antiviral Tamiflu -- and Sanofi-Aventis, parent company of the nation's sole flu vaccine manufacturer.

Manning Selvage & Lee paid Gottlieb a $12,500 monthly retainer for nine months for business development projects that included eight companies. Other firms regulated by the FDA he was involved with include Inamed Corp., one of two companies seeking to return silicone gel implants to the market. He also did private consulting work for VaxGen Inc., a California firm that won a $878 million federal contract to supply 75 million doses of anthrax vaccine for the nation's protective stockpile. The $9,000 he accepted from VaxGen for consulting work between May and July prevents him from doing FDA work related to that company until August 2006.

Furthermore, since Dr Gottlieb left the FDA, Bench International boasted, "Bench International Places Eminent Regulatory Advisor Scott Gottlieb, M.D., as Senior Counsel to Novartis." Its text stated that Dr Gottlieb was to assume "a senior-level regulatory advisory position for Novartis Pharmaceuticals Corporation [NYSE: NVS]. Under an exclusive consulting agreement, Scott Gottlieb, M.D., will provide advisory services to Novartis on matters of global regulatory policy and strategy."

So once again, a strident but weakly supported attack on those who would dare criticize an expensive product of a big pharmaceutical company turns out to have been written by someone with extensive, and current financial ties to the pharmaceutical industry.

The pharmaceutical industry is now often regarded by the public as "shifty." A first step to regain public trust would be for people who work for the industry to make that fact clear when they speak publicly in its favor.

ADDENDUM (30 May, 2007) - PharmaLot also noticed Dr Gottlieb's ties to Novartis.

5 comments:

MedInformaticsMD said...

Gottlieb's article can be read without subscription at the AEI site here.

Morris Berg said...

I am sorry, but having read his dribble for many years now, I have just decided that Gottleib has zero credibility and should be summarily ignored.

I am not going to summarily dismiss any assertion or argument he makes as per se wrong just because he makes it (hell the sun does shine on a dog's arse). But if he ever does happen to make relevant and intellectually honest point, I will just have to have someone else persuade me of its veracity.

The only intellectually valuable insight that I could even partially attribute to the Good Doctor Gottleib is the realization that the SEC may honestly have more stringent disclosure requirements than the FDA.

You can massage and spin data to physicians and patients . . . but not to investors.

Anonymous said...

The drug was approved for use in 2001 and the main clinical safety trials were ongoing before that point. To help you with why there is no discussion about cardiac events at that time is because cardiac information was not required. That is why companies like gsk are performing those studies now.

Anonymous said...

The web site for the GSK Clinical Trial Register not at all obscure. There is a direct link to the register on the GSK home page. In other words, go to www.gsk.com and click on the words "Clinical Trial Register". The link has been there for a long time.

Roy M. Poses MD said...

Keep in mind that the original post was written 30 May, 2007. The web-site was as far as I know obscure then. It may be less obscure now.