The pharmaceutical industry and the FDA are being battered by testimony and discussion in the wake of Vioxx. Presumably this will soon die down: news stories appear, flare up and soon fizzle out when their energy (and the public’s interest) is spent. For now, however, the drug surveillance story is still burning bright. David Graham, the gaunt FDA whistle-blower, is enjoying his Warholian fifteen minutes of fame. And this week’s online edition of JAMA pre-publishes six pieces that will appear in next week’s print edition. These articles are about Baycol (cerivastatin), a drug no longer in the news but relevant to the topic. Very briefly summarized:
- The FDA’s Graham et al examine the incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs, an inception cohort study of 252,460 patients treated with various statins and fibrates between 1998 and 2001. The number of patients needed to treat for one year to produce one case of severe rhabdomyolysis was roughly 23,000 for monotherapy with atorvastatin, pravastatin or simvastatin; 3500 for monotherapy with a fibrate, 2000 for monotherapy with cerivastatin, 1500 for fibrate plus a statin other than cerivastatin and only about 10 for fibrate plus cerivastatin.
- Psaty et al discuss the potential for conflict of interest in the evaluation of suspected adverse drug reactions. They discuss the FDA’s regulatory process, noting that: “…the proportion of new molecular entities that are first introduced in the United States has increased from 2-3 % in the early 1980s to 60% in 1998” and “in contrast to the highly structured premarketing evaluation, postmarketing surveillance has little structure” (and is underfunded).
They describe the information that was publicly available on Baycol, mainly from SADR’s, and contrast this with the information that was available to Bayer but not to the public (which they derive from litigation documents, in which they were expert witnesses for the plaintiffs). They suggest that there was information posessed by the company which should have been made public, but which represented a conflict of interest for Bayer.
The authors argue that, given the speed with which new agents enter the market, the public is at increased risk due to the lack of resources available for post-marketing surveillance and the conflict of interest inherent in the pharmaceutical companies’ positition. This should be dealt with by strengthening the post-marketing surveillance structures and possibly creating an independent agency to deal with this.
- Pierkowski responds to this article on behalf of Bayer, emphasizing that Psaty et al were expert witnesses against Bayer. He argues that both the FDA and Bayer took appropriate actions at the appropriate times.
- Psaty et al then respond to Pierkowski’s points, arguing that whether or not Bayer took appropriate action is less important than whether or not the post-marketing system needs to be dramatically improved.
“While Piorkowski, as an attorney representing Bayer, properly defends some of the company’s specific actions, the purpose of our article was to raise an important public health issue. For us, the cerivastatin-rhabdomyolysis case report served as an illustration. We were primarily concerned to demonstrate how the current postmarketing surveillance system and the current FDA regulations may not, under certain circumstances, be adequate to protect the health of the public.”
- Strom reviews the whole post-marketing surveillance system. His manuscript was submitted to JAMA by Bayer. He notes that much data is supplied by the SADR system, but the data itself is, necessarily, of limited quality and must be considered hypothesis generating. It needs to be followed up by appropriate hypothesis testing, which is where the system can and should be improved. He believes that, from a regulatory standpoint, the FDA is up to the task if given the appropriate resources. From a scientific standpoint, other organizations (such as the publicly funded Centers for Education and Research in Therapeutics) need to be developed and strengthened in order to analyze and respond to hypotheses generated from the SADR’s. This cannot be left up to the pharmaceutical industry, given its inherent conflict of interest.
- Finally, in an excellent editorial, JAMA editors Fontanarosa, Rennie and DeAngelis sum it all up nicely. If you only read one of the six articles, I would suggest reading this one. The authors provide the background to the articles published in this issue, and make several suggestions, including decoupling the drug-approval and post-marketing surveillance processes, since “it is unreasonable to expect that the same agency that was responsible for approval of drug licensing and labeling would also be committed to actively seek evidence to prove itself wrong”. They conclude:
“The postmarketing surveillance system requires a long overdue major restructuring. Until that occurs—as indicated by the articles in this issue of JAMA, as epitomized by recent evidence of serious harms from widely used and heavily promoted medications, as demonstrated by the influence of industry over postmarketing data, and as illustrated by the lengths to which some manufacturers will go to protect their interests—the United States will still be far short of having an effective, vigilant, and trustworthy system of postmarketing surveillance to protect the public.”
That being the case, what is the practitioner to do? Assuming that there will continue to be delays before adverse drug effects are discovered and publicized, prudence before prescribing the latest “hot” drugs seems warranted, more than ever. About a year ago, the pharmaceutical rep promoting one of the newer statins asked me when I would be comfortable prescribing this particular medication. I said I would wait at least a year. Now that same representative is reminding me that it’s been a year. I’m still not ready.