In a previous blog (1) I explained how concerns about the increased incidence of heart attacks associated with treatment for diabetes by the drug Rosiglitazone (marketed by GSK under the brand name Avandia) had resulted in an investigation by the US Senate Finance Committee. The committee staff had access to about 250,000 documents and produced a comprehensive report which revealed details of the way in which one major drug company conducted its’ business (2). A paper by Nissen and Wolski in 2007 was the first public warning that there might be serious side-effects with Avandia (3). However the Senate report was able to investigate what was known within the company before this. In response to the Nissen/Wolski alert GSK published an interim report of its’ own trial referred to as “RECORD” (4). According to one of their senior executives in a sworn statement in 2007 this was: “very reassuring”. In a letter to The Lancet, GSK maintained that RECORD trial was “compelling evidence” for the safety of Avandia Despite these claims it was apparent that some executives in GSK were aware of the limitations of the RECORD trial. A briefing document in June 2005 noted that the results of RECORD will not be available until 2009 and that the current observed endpoint is very much lower (about 3.5% per annum) than anticipated in the original protocol (11% per annum). A slide presentation devised in 2004 acknowledged that RECORD did not have sufficient “power”, which means that the study would not provide enough data to test for cardiovascular safety. One reason could be that the number of participants was too small to detect a genuine difference between the treatments used. The slide presentation also revealed that RECORD was primarily a marketing exercise and was designed to counter the results of PROactive, a trial with a similar type of drug, namely Actos. This product was produced by the Japanese company Takeda and was regarded as the main competitor to Avandia. This was demonstrated by an email in June 2005, which discussed the need to respond to PROactive which included the following: “Clearly no patients will be recruited until [we] have made a decision based on the go-no go criteria from the PROactive data. However, there is a great deal of EU commercial push to initiate this study in 2005.’’ A briefing document for a meeting in July 2005 stated that: “Publication of the PROactive data may result in important commercial disadvantage in Europe. We therefore have the opportunity to start a CV (CardioVascular) outcomes study with the aim of getting superiority data in 2007” In fact the possibility that Avandia might be responsible for an increase in problems linked to heart disease had emerged as early as 2004. Notes of a meeting held in June state that: “There was disappointment verbalized about the morbidity and mortality table that showed that there were ten ischemia-related adverse events in the rosiglitazone group versus five events in the placebo group.” Later in 2004, GSK initiated a clinical trial to compare Avandia with a placebo which involved 11,586 participants. Analysis of the data in 2005 found that the Hazard Ratio (HR) for myocardial ischaemia was 1.29. This means that those patients treated with Avandia were 29% more likely to have a heart attack than those on the placebo. This is not too far away from the value of 43% in the Nissen /Wolski report. In a further clinical trial with 14,237 patients, analysis of the results in 2006 produced a HR of 1.31, which essentially confirmed the finding of the previous trial. The experience of Dr John Buse of the University of North Carolina is especially relevant because it not only demonstrates another nasty aspect of the GSK culture but also shows that questions had been raised about the cardiovascular safety of Avandia as early as 1999. This issue was considered by the Senate Finance Committee in 2007. Here is an extract from its report: “In particular, GSK’s attempt at intimidation appears to have been triggered by speeches that Dr. Buse gave at scientific meetings in 1999. During those meetings, Dr. Buse suggested that, aside from its benefit of controlling glucose levels in diabetics, Avandia may carry cardiovascular risks. The effect of silencing this criticism is, in our opinion, extremely serious. At a July 30, 2007, safety panel on Avandia, FDA scientists presented an analysis estimating that Avandia caused approximately 83,000 excess heart attacks since coming on the market. Had GSK considered Avandia’s increased cardiovascular risk more seriously when the issue was first raised in 1999 by Dr. Buse, instead of to smother an independent medical opinion, some of these heart attacks may have been avoided. According to documents provided to the Committee by, among others, GSK, and the University of North Carolina, it is apparent that the original allegations, regarding Dr.Buse and GSK’s attempts at silencing him are true; according to relevant emails, GSK executives labelled Dr. Buse a “renegade” and silenced his concerns about Avandia by complaining to his superiors and threatening a lawsuit. Even more troubling, documents reveal that plans to silence Dr. Buse involved discussions by executives at the highest levels of GSK, including then and current CEO Jean-Pierre Garnier. Also, GSK prepared and required Dr. Buse to sign a letter claiming that he was no longer worried about cardiovascular risks associated with Avandia. After Dr. Buse signed the letter, GSK officials began referring to it as Dr. Buse’s “retraction letter.” Documents show that GSK intended to use this “retraction letter” to gain favour with a financial consulting company that was, among other things, evaluating GSK’s products for investors. After cutting short Dr. Buse’s criticism, GSK executives then sought to bring Dr. Buse back into GSK’s favour. While publicly silent subsequent to signing the “retraction letter,” Dr. Buse still remained troubled about Avandia and its possible risks. Years later, he wrote a private email to a colleague detailing the incident with GSK: “[T]he company’s leadership contact[ed] my chairman and a short and ugly set of interchanges occurred over a period of about a week ending in my having to sign some legal document in which I agreed not to discuss this issue further in public.” Dr. Buse ended the email, “I was certainly intimidated by them…. It makes me embarrassed to have caved in several years ago.” “GSK’s behaviour since the Committee first brought these allegations to light has been less than stellar. Instead of acknowledging the misdeed to investors, apologizing to patients, and pledging to change corporate behavior, GSK launched a public relations campaign of denial. Specifically, GSK sent out a press release entitled “GSK Response to US Senate Committee on Finance” which stated that the allegations raised by the Committee were “absolutely false.” Further, CEO Jean-Pierre Garnier denied having any knowledge of the alleged intimidation of Dr. Buse in an interview that ran in July in The Philadelphia Enquirer” (4). CONCLUSION There is little doubt that on the basis of this evidence GSK has been totally irresponsible and that the recent bribing in China cannot be dismissed as an isolated event. The reality is that this is a company which is totally unscrupulous and has been responsible for an estimated 83,000 excess cases of heart disease, many of whom died as a consequence. GSK is one of the leading global players and its’ approach to business may well be typical of the industry as a whole. Despite the reports of the Senate Finance Committee, there is no convincing evidence that there has been any significant change in company culture. How many more people will die prematurely before governments decide to address this issue?

REFERENCES

1. http://vernerwheelock.com/?p=463

2. http://www.finance.senate.gov/newsroom/chairman/release/?id=bc56b552-efc5-4706-968d-f7032d5cd2e4

3. S E Nissen and K Wolski (2007) New England Journal of Medicine 356 (24) pp 2457-2471

4. P D Home et al (2007) New England Journal of Medicine 357 (1) pp 28-38

5. http://www.finance.senate.gov/newsroom/ranking/release/?id=3a1d9e3e-6ea8-4200-a86f-8aadc9338f5e