Global Insight Perspective | |
Significance | The association of best-selling diabetes drug Avandia with a heightened risk of cardiovascular side effects does not bode well for GSK, which has vehemently criticised the study for being based on a meta-analysis, rather than large-scale long term clinical trials on patients with the disease. |
Implications | Because the findings of the study contradict evidence from long-term studies into the cardiovascular safety of the drug, Avandia is not likely to be pulled out of the market. However, the study will affect GSK’s bottom-line since it is its second-best selling drug and extremely profitable. |
Outlook | Likely beneficiaries of the fallout are diabetes treatment Actos, from Japan’s Takeda Pharmaceutical, and U.S. drug-maker Merck’s Januvia. The issue also highlights the FDA’s handling of the case, in the aftermath of the outcry over Wyeth’s withdrawn painkiller Vioxx. |
GSK’s Defence
British drug-maker GlaxoSmithKline (GSK) said it strongly disagrees with the findings of a study published yesterday in the New England Journal of Medicine (NEJM), which links its best-selling diabetes drug Avandia to a 64% increased risk of cardiac-related deaths and a 43% increased risk of heart attacks.
The study, headed by prominent cardiologist Steven Nissen of the Cleveland Clinic, was based on a meta-analysis, which is an analysis of summary information combining a number of studies. In this case, 42 studies were combined. However, GSK argues that a meta-analysis is not the “most rigorous way” to reach meaningful conclusions about adverse side-effects, because each study is designed to answer different questions.
The U.K. drug-maker also points to the editorial in the NEJM, which states that “the possibility that the findings were due to chance cannot be excluded’, before adding that even the authors themselves admit to the “fragility” of their findings. The most scientifically appropriate way to analyse the safety and benefit profile of medicines is to undertake large-scale, long-term clinical trials in patients with the ailment, according to GSK. The company then went on to name several types of these trials for Avandia which have results published and where patient safety concerns had not been raised by Safety Monitoring Boards. These included ADOPT (A Diabetes Outcome Progression Trial), DREAM and RECORD.
GSK stressed that data from the ADOPT trial demonstrated that the overall risks of serious cardiovascular events for patients taking Avandia were comparable to two of the most commonly-used oral medications to treat Type II Diabetes, metformin and sulfonylurea (glyburide). The study made safety and effectiveness comparisons between Avandia and oral diabetes drugs in over 4,300 patients for up to six years. Overall, the data shows that Avandia has a comparable cardiovascular profile to other oral anti-diabetic medicines. In this light, GSK continues to back Avandia, as the firm believes that its benefits significantly outweigh the risks.
Meanwhile, GSK has also defended itself against a press release on Avandia issued by the U.S. Senate Committee. The company refutes claims that it placed patients at risk and sought to quieten independent investigation, and also highlighted the transparency of its efforts to analyse the safety and effectiveness of the drug. The FDA and other drug regulatory authorities were made aware of any new data on Avandia “as quickly as scientifically possible”, GSK added.
Outlook and Implications
The drug is not expected to be withdrawn from the market, since the meta-study’s findings contradict the evidence from long-term trials into the cardiovascular safety of the drug. Even Robert Meyer, Head of the U.S. FDA office that reviews diabetes drugs, said that other data contradicts these findings. The U.S. regulator has not yet confirmed the “clinical significance of the reported risk in the context of the other studies”, Meyer said. However, the issue has raised questions about both how the FDA itself assesses investigational diabetes drugs and about GSK’s actions, particularly after the outcry over Wyeth’s (U.S.) withdrawn painkiller Vioxx.
The impact on GSK’s bottom-line is likely to be great since Avandia, with sales of more than US$3 billion in 2006, is quite profitable for the U.K. drug-maker. Last year, various forms of the diabetes drug accounted for about 37% of the U.S. market for oral diabetes treatments, according to GSK data. One of the likely beneficiaries from the fallout is Actos from Japan’s Takeda Pharmaceutical. This belongs to the same class of drugs as Avandia but did not demonstrate a link to heart attacks or strokes in a trial published in another reputable journal, The Lancet, in 2005. Both Avandia and Actos belong to a class of drugs called peroxisome proliferator-activated receptors (PPARs). Diabetes drugs with a different mechanism of action, such as Januvia from U.S. pharmaceutical giant Merck and older drugs such as metformin, could also gain revenue.