In HOOKED, I referred to the "Lotronex Story" and elsewhere talked of "regulatory capture," a term I first got from reading the work of British sociologist John Abraham (to describe how an industry that is supposed to be the subject of regulation ends up learning how to manage the regulatory process to its own advantage). Now Abraham and a colleague have gone into much more depth on the Lotronex case and reached some interesting conclusions (subscription required to access article).
Brief recap: alosetron (Lotronex), manufactured by Glaxo Wellcome (later GlaxoSmithKline) was put on the market in 2000, withdrawn later that year, and put back on the market with restrictions in 2002. It was marketed for irritable bowel syndrome, a common condition that is chronic and relatively mild in most cases but is quite disabling for a small percentage of sufferers. It was the first drug specifically aimed at IBS and so attracted a lot of attention because of its novelty.
The initial data presented to the FDA in support of approval were, in hindsight, remarkably skimpy. It seemed that alosetron worked only in women, and only in IBS patients who had mainly diarrhea as the predominant symptom. (When a disease occurs in both sexes but you find that a drug works in only one, that increases the chance that the drug does not really work at all and you're seeing a spurious finding.) At best the FDA data indicated a very mild if any benefit to be expected from the new drug. After it was approved on these skimpy data, reports emerged of ischemic colitis (segments of large bowel dying as a result of blood supply being shut off, due to severe constipation with impacted feces) occasionally requiring surgery and causing some deaths. Eventually the FDA allowed the drug to return to the market with serious restrictions on how it could be prescribed--a financial hit for the manufacturer, who saw a potential $5B blockbuster drug reduced to sales of only about $100M annually.
Let's now see what Davis and Abraham add to this brief recap. They obtained a trove of internal FDA documents via FIOA and also interviewed some of the FDA insiders who worked on the drug application.
They first note that when the reports of deaths from ischemic colitis started to roll in (and of course Glaxo denied at first that their drug had anything to do with these deaths, though virtually no one dies of IBS alone), FDA folks sat down with Glaxo folks and proposed a plan that was quite close to the re-marketing strategy that was finalized in 2002. But Glaxo elected on their own to pull the drug, arguing that ther FDA's restrictions were so onerous that the poor firm could hardly make a buck off the drug that way. The authors comment, "Evidently, providing the drug to the comparatively small number of patients most likely to benefit to reduce the risk to other patients less likely to benefit, together with research into how those risks and benefits could be better understood, was, according to GW, not commercially viable within the constraints of the U.S. capitalist market system." I have not seen a starker comment on the incompatiblility between good scientific medicine and drug marketing.
Once the drug was off the market, the FDA next heard from IBS patients, in a barrage of e-mails. As I reported previously in HOOKED, the barrage was launched by two patient groups, Lotronex Action Group and International Foundation for Functional Gastrointestinal Disorders. I quoted sources available then to report that the LAG appeared to be an independent grassroots organization while the IFFGD was openly and principally funded by Glaxo. However, Davis and Abraham quoted one of their FDA insiders that LAG raised all the red flags in his own mind of an industry-sponsored outfit, even though a connection was never proven.
Davis and Abraham noted that individual patient tesimonials from IBS sufferers who claimed to have had their lives dramatically improved by Lotronex dominated the FDA hearings to discuss re-marketing in April 2002. (No one testified who had nearly died of ischemic colitis.) They argue that despite the scientific nature of the FDA panel, the ensuing discussion within the FDA amounted to a sort of "regulatory capture" as a result of what they label the "emerging patient-industry complex." That is, the available scientific evidence provided no good way to identify either who stood a better chance than average of benefiting from alosetron (if you believed the data, the best guess would be nobody) or who stood at the highest risk of suffering harm. Indeed there was no good evidence that even carefully watching patients with an eye toward the signs and symptoms of ischemic colitis would allow identification of cases early enough to do any good by stopping the drug. Davis and Abraham allege that at this point, anecdotal patient testimonials trumped science in determining the FDA's agenda. And the further research that might have clarified therse matters was being resolutely avoided by Glaxo despite earlier FDA requests that the company proceed with those studies.
What I reported in HOOKED, that Davis and Abraham did not discuss, is how several FDA officers were outraged by bring overruled by agency higher-ups when the drug was re-marketed, and that other officers known to be critical of alosetron were summarily taken off the case.
In conclusion, Davis and Abraham conclude that alosetron generated a perfect storm of confluent forces--the FDA under fire from Republican-led congresses to show that they were not holding up the approval of innovative drugs; industry pressure; and patient advocacy lobbying that in all likelihood was funded and coordinated by industry. Scientific medicine didn't stand any chance in that environment. (The excellent policy question which the authors identify is what to do with patient testimony--it is clearly important in a democracy to validate and accept testimony of personal experience, yet we also know that no one can personally distinguish a drug from a placebo effect, which is worrisome when the "placebo" can kill you.)
Hat tip to my former graduate student and now esteemed colleague Daniel Goldberg of East Carolina University for alerting me to this article.
Davis C, Abraham J. Rethinking innovation accounting in pharmaceutical regulation: a case study in the deconstruction of therapeutic advance and therapeutic breakthrough. Science, Technology & Human Values 36:791-815, November 2011.