(aka “A Bad Day for GSK”)
Such is an original idiom from one of my college roommates, good friends, and one of a select few individuals for whom I would ever consider working for as a government official. Like many young government reformers, he is idealistic, hopeful, and believing in our generation as being the one that will restore credibility to federal authority. As much as I would like to share his optimism, I am more guarded in my faith in the ability to enact change through legislation and regulation: knowing what it means to spend years in the process of seeking citizenship and witnessing the combined effects of a presidential administration’s reluctance to provide meaningful, timely aid to a largely poor, Democratic city and the painful lack of coordination between federal, state, and local governments in the revitalization of the city of New Orleans have tempered my positive outlook on government as a medium for positive change. Nonetheless, I do believe that the government can be an incredibly positive force, perhaps the only sufficiently large, funded, and organized force, that can counteract large scale abuse and unseemly manifestations of human nature – when it functions properly and with the right tools.
Last Monday, I attended the morning session of the FDA advisory committee meeting on the safety of thiazolidinediones (Avandia/rosiglitazone and Actos/pioglitazone). Of all of my experiences while working at the National Institutes of Health this summer, this was the most eye-opening and revealing. I took from the meeting this one insight:
The protection of the freedom of speech, above all things, is the most powerful tool against tyranny and the worst parts of our nature.
Repression comes in many forms, but most notably in these cases in the form of job security. The “hero” of the hour was Dr. David Graham, a drug safety and public health expert at the FDA who thoroughly (and objectively) skewered Avandia, despite the weak arguments in favor of its safety by the GSK scientists/vice-presidents. Tying together the data provided by the other FDA presenters, Dr. Graham asked the important question: If Avandia/rosiglitazone offers no benefit over a safer alternative in the same class of drugs, why should anyone take Avandia/rosiglitazone? Although the data on Actos/pioglitazone still needs to be as rigorously reviewed as that on Avandia/rosiglitazone, all of the studies on the pioglitazone “compass” point towards it being neutral towards coronary heart disease risk (though both drugs increase risk of non-lethal heart failure, which is a different disease) while all of the studies on the rosiglitazone “compass” point towards an increased risk of acute myocardial infarctions (heart attacks). Graham furthermore concluded with this point: Not only is there a projected multimillion dollar public health cost in the form of cardiovascular disease treatment if we keep Avandia/rosiglitazone on the market, but there is also an additional (up to one-third or so) opportunity cost if Actos/pioglitazone truly has a “protective” effect against acute MIs. His presentation, which unfortunately would take me forever to report in full here, was extremely solid.
Interestingly, after Graham’s presentation (the last of the presentations before the concluding statements of the morning sessions), the FDA department director who approved Avandia/rosiglitazone didn’t disagree with most of Graham’s presentation, but he did disagree as to the utility of glycemic control as an important objective in the treatment and management of diabetes (Graham argued that Avandia has no proven clinical benefit for the complications of diabetes mellitus, and it is the complications of diabetes mellitus that are directly linked to morbidity and mortality in the disease, not hyperglycemia/high glucose by itself. However, it is thought that hyperglycemia is the origin of the complications. Nonetheless, if that is so, one would expect that Avandia would decrease heart attacks, not increase them, since it reduces blood glucose by increasing insulin sensitivity, suggesting that the drug has specific negative effects.). Graham’s department head agreed with the presentation, indicating some of the fundamental disagreements within the FDA as to how to handle the regulation of Avandia. Nonetheless, before his presentation, Graham gave a verbal disclaimer that his boss fully endorsed his presentation but that it wasn’t the official stance of the department as his boss has to show it to the rest of the department, and that he (Graham) wasn’t presenting as an “FDA whistleblower.” (Graham, as muckrakingly noted by some popular news sources, has been involved in several previous drug safety disputes as a behind-the-scences champion for public health safety.) I was later told that Graham’s job security is under the protection of Congress: apparently, it has not been unknown for drug safety experts working for the FDA to be silenced and retired shortly after they exposed drug safety issues. This seems to correspond with the reports that there was an FDA safety official reviewing Avandia at its introduction to the market whose responsibility was removed after she expressed concerns on the drug.
Unfortunately, the suppression of honesty is not just within the government. As objective and open-minded as I was when I entered the room, I couldn’t help but feeling both very sad for the GlaxoSmithKline representatives and disgusted by them. The two physician-scientists who presented for GSK spoke very differently from the FDA presenters: they were monotone, they spoke slowly, and they repeated themselves frequently. However, it was painfully clear that the FDA officials and the invited committee members (physicians, scientists, patient advocates, etc.) were not at all convinced by the “new” data or the GSK meta-analysis provided by the GSK representatives, and it almost seemed like watching a cat-and-mouse game when questions were asked after the GSK presentations: they simply couldn’t answer many of them (effectively, if at all), such as why they chose an integrated rather than stratified stastical approach to their meta-analysis (which was an objection that spawned an FDA analysis which confirmed the Nissen and Wolski findings and provided further, more nuanced conclusions) which would “clearly favor rosiglitazone’s safety” and whether or not they were aware of a recently published study suggesting that pioglitazone reduces the risk of heart attacks as compared to active comparators (metformin and sulfonylureas) (despite GSK’s claims that “rosiglitazone and pioglitazone are exactly the same with respect to cardiovascular health”). While the two GSK representatives gave the impression of being sleazy and dishonest, another interpretation was suggested to me: they don’t have the freedom of speech. When things go well, it is great to be an industry scientist, but as soon as there is question as to the safety of a drug, the scientists have to toe the party line or they suddenly find themselves unemployed. I found this notion to be incredibly sad: I would hate to be in that position. Although Dr. Graham’s job is undoubtedly difficult and stressful, at least he can feel justified and have a clear conscience about his work; not so with the GSK scientists, or so it seems.
I think my friend described his saying to me as meaning this: “If you’re a barnacle on a whale, you have a pretty good life. You don’t need to expend any energy moving around, and the food comes to you. However, if the whale is beached or is killed, that’s a bad day to be a barnacle.” That must be what the GSK physician-scientists feel (to some degree, if we give them credit): despite their very hard work to produce an excellent product to save lives and treat disease, they have been put in a terrible position of suppressing their knowledge and the truth in order to preserve their livelihoods. Self-preservation over the lives of others.
It reminds me of this quote I recently rediscovered upon my adventures in our nation’s capital:
“I have sworn upon the altar of God eternal hostility against every form of tyranny over the mind of man.” – Thomas Jefferson (inscription at the Jefferson Memorial in Washington, D.C.)