GSK's Avandia survives FDA panel vote but damage may have been done

The majority of a 33-member FDA advisory panel has voted against the complete market withdrawal of GlaxoSmithKline's Avandia. However, considering the safety concerns surrounding the drug, and with 12 of the panelists voting for withdrawal, Avandia's sales are likely to decline further even if it remains on the market.

The future of GlaxoSmithKline's type 2 diabetes drug Avandia (rosiglitazone) is still unclear after the two-day FDA advisory panel hearing on the safety of the drug.

In the crucial vote on the withdrawal of Avandia, the majority of the expert panel showed strong concern about Avandia's risks by voting for withdrawal (12 votes) or increased restrictions on availability (10 votes). Seven panel members voted for stronger warnings and only three members voted for the drug labeling to remain unchanged. The FDA must now decide on Avandia's future.

The issue facing the panel was the possibility, first raised publicly in 2007, that Avandia may increase the risk of heart attacks and other ischemic events relative to other antidiabetic drugs. In comparison, Takeda's Actos (pioglitazone), a competitor drug in the same class as Avandia, has demonstrated no such risks.

While several meta-analyses and patient outcome studies have shown increased risk of ischemic events in Avandia patients, GlaxoSmithKline argues that clinical trials do not show evidence of cardiovascular risk. Recently, however, the company-sponsored RECORD trial, designed to study Avandia safety, has come under attack for poor methodology and breaches of protocol.

The FDA advisory panel heard a range of evidence and opinion before voting on questions about Avandia's safety and continued use. Majorities on the advisory panel voted that there was sufficient evidence to raise concerns about ischemic cardiovascular risks with Avandia relative to Actos and to other antidiabetic drugs, but decided that evidence was insufficient to find increased risk of overall mortality in each of these comparisons.

The inconclusive nature of the testimony presented was reflected by the fact that, despite having expressed concerns about Avandia's safety, a panel majority voted for the continuation of the TIDE trial comparing Avandia and Actos. Panel members require more evidence for Avandia's safety despite a market presence of 11 years. However, enrolment has been lower than expected in the TIDE trial and it seems likely that the latest FDA panel vote will not improve matters. Indeed, in June, the Indian government halted Avandia trials there because of safety concerns.

The fate of Avandia rests in part on the FDA's action on the advisory panel's mixed recommendations. In the absence of stronger evidence for risk, there may be an incentive to keep Avandia on the market to allow for wider clinician choice, a view expressed in panel discussions. Nevertheless, even if the FDA does not follow the panel's advice to withdraw or restrict prescribing of Avandia, physician and patient concerns about safety and litigation (and the availability of alternative therapies for most patients) are likely to lead to continuing decline in Avandia sales.

Avandia's decline opens the door for further growth by the antidiabetics that have already filled the gap created after the initial Avandia safety scare in 2007, namely class leader Actos and Merck's blockbuster DPP-4 drug Januvia (sitagliptin). With Avandia hit by safety fears and Actos approaching patent expiry in 2011, there is also the possibility for newer drug classes to seize market share, maintaining the attractiveness of type 2 diabetes as a commercial and clinical target.

Related research

Commercial Insight: Cardiovascular and Metabolic Market Overview - Diabetes to the fore as generics hit primary care markets priced $15,200

The Diabetes Market Outlook To 2014: Market dynamics, competitive landscape, emerging therapies $3,835

Avandia's MammaScreen - Answering the question of how to treat small tumours in breast cancer patients

As reported in our recent feature "Breast Cancer - Targeted Therapies, New Cytotoxics and Vaccines" the incidence of breast cancer in the seven major markets is close to 0.5 million, while over 100,000 women will die from the disease. Despite advances in treatment over the past decade, significant unmet needs remain. This level of demand and the large patient potential makes breast cancer a relatively attractive indication for drug developers. Collectively, late-phase pipeline candidates are forecast to achieve $2,230m in sales in 2017 in the seven major pharmaceutical markets.

There are over 100 drugs in clinical development for breast cancer. These are primarily targeted therapies and cytotoxics. Unlike cervical cancer (see our earlier editorial Advaxis lights up the future for cervical cancer ) therapeutic vaccines account for just a small part of clinical development . Importantly, the majority of clinical trials of drugs in late-phase development for breast cancer are in the metastatic setting. This reflects the higher level of unmet need, lower bar to market entry and shorter trial completion time as compared with the adjuvant or neoadjuvant treatment setting.

In addition to developing improved treatments, better diagnostic and prognostic tools are equally required. For example, primary tumor size, in addition to axillary lymph node status, is considered to be one of the most important prognostic factors in breast cancer, with small tumor size being an indicator of good prognosis. However, even small tumors can metastasize. Predicting which patients with small tumors will metastasize represents an unmet need that will likely be addressed by advances in the field of molecular diagnostics.

Another of our featured reports "Molecular Diagnostics in Cancer Testing" describes this rapidly-advancing area. New technologies and applications are being continually added. The technologies that come under the umbrella of molecular diagnostics include first-generation amplification, DNA probes, fluorescent in-situ hybridization (FISH), second-generation biochips and microfluidics, next-generation signal detection, biosensors and molecular labels, and gene expression profiling using microarrays.

Together the global in vitro diagnostics market generated sales of over $40bn in 2008. The market will generate nearly $60bn in 2014. One diagnostic tool described in"Molecular Diagnostics in Cancer Testing" is Agendia's MammaPrint. This prognostic tool was cleared by the FDA in 2007 to predict breast cancer recurrence.

Specifically MammaPrint provides a unique 70-gene signature to identify which early-stage breast cancer patients are at risk of distant recurrence following surgery, independent of Estrogen Receptor status and any prior treatment. Unlike previous generation genomic tests, MammaPrint interrogates all of the critical molecular pathways involved in the breast cancer metastatic cascade. It analyzes 70 critical genes that comprise a definitive gene expression signature and stratifies patients into two distinct groups — low risk or high risk of distant recurrence.

Breast cancers are staged according to the absence (N0) or presence (N1-3) of nodal involvement and the size of tumor. MammaPrint has previously demonstrated prognostic power according to nodal involvement. Today's featured journal article from the Annals of Surgical Oncology report on the prognostic ability of the MammaPrint signature specifically in patients with small invasive tumours. This is particularly important given that the number of patients presenting with such tumors is expanding in parallel with breast cancer screening programs and increased awareness

The study reported by Mook et al took a retrospective look at 964 breast cancer patients, 14% of whom had a pT1ab tumor (primary; 0-1cm), 86% had a pT1c tumor (1-2cm). The majority of patients were node negative. During follow-up 154 patients developed distant metastases. The probability of metastasis-free survival at 10 years was 90% and 86% for pT1ab and pTc patients classified as low risk compared to 76% and 72% classified as high risk. Simply put, the chance of metastasis-free survival at 10 years was increase 2.5-3.5-fold in the low risk group.

Among the 964 patients 57% received no adjuvant systemic therapy while almost all of the others received endocrine- and/or chemotherapy. The prognostic ability of MammaPrint was similar irrespective of therapy.

So what do these data mean? Mammograms have come under significant criticism over the past few years for a number of reasons. Firstly, false-positive results from mammograms expose women to unnecessary biopsies. Secondly, there is the issue of how to medically manage women who have been diagnosed with breast cancer following screening. The issue is particularly troublesome in those individuals with small tumours as treatment guidelines are vague for T1 stage disease. The present study demonstrates the significant benefit of MammaPrint; specifically it can identify those women who are at high risk and may require more aggressive adjuvant chemotherapy and likewise those at lower risk who may gain protection from endocrine therapy without suffering the adverse events of chemotherapy. Mammograms are undeniably useful; we hope that MammaPrint will address some of the criticism screening has attracted and contribute to the overall advance of breast cancer management.

See also:

• In Vitro Diagnostics Market Analysis 2009-2024
• The Worldwide Market for Cancer Diagnostics
• Cancer Diagnostic Testing World Markets
• Molecular Diagnostics in Cancer Testing