Makers of controversial testosterone-replacement therapies are braced for some intense scrutiny in a few weeks’ time, when a panel of experts convened by the FDA will meet to review the evidence for and against their safety.
Several companies have a stake in this market, which has already been dented by safety concerns caused by studies linking these products to an increased risk of heart problems (see table below). The FDA’s stance to date suggests that it is not considering punitive steps to restrict use dramatically, so any sign that the panel believes that prescriptions should be radically curtailed will be a blow to those still hoping to make money from this market.
Briefing documents released yesterday by the FDA ahead of the panel described the two main issues the regulator wants addressed: the appropriate indicated population for testosterone-replacement therapy and the potential they carry to cause cardiovascular problems. The latter has already caused prescriptions for these products, particularly the gels, to slump.
Two studies in men on these therapies are largely responsible. The first, published in JAMA in November 2013, detected a 30% increase in the risk of cardiovascular events in a group of older men, many with pre-existing heart conditions. A second observational study, published in Plos One, reported a twofold increase in the risk of heart attack among men aged 65 and above, while younger men with a pre-existing history of heart disease experienced a two- to threefold increased risk.
This safety concern was not a bolt from the blue. In 2010 a placebo-controlled study of Auxilium’s Testim, conducted in men 65 years old or above with limited mobility, was stopped early after a higher rate of CV events was seen. At the time, the FDA said there was insufficient evidence to conclude that that testosterone replacement in older men was associated with an increased risk, and it appears still to be fairly comfortable with this position.
Yesterday’s briefing documents clearly pointed out the weaknesses of these studies and highlighted others that have come to opposite conclusions. In March the agency approved Endo’s Aveed, an injected testosterone formulation, suggesting that it is still open-minded about the benefits of these products. And in July it denied a citizen's petition requesting a black box warning for CV issues for these drugs.
Even so, the FDA summoned this panel to review the evidence and consider the strength of any safety signal. Should it believe that this exists, the panel has been asked to consider whether warnings are needed on prescribing labels.
This represents one of the biggest threats to the commercial future of these products. A recommendation for prominent or even black box warnings would prompt a bigger drop in their use, as would any recommendation for a risk evaluation and mitigation strategy programme. Any recommendation for post-marketing studies to assess the potential risks would also be considered an unwelcome burden by manufacturers.
The panel is also being asked to consider whether “age-related” hypogonadism could be supported as an indication. Idiopathic hypogonadism is already indicated, but this can simply happen as a result of aging. A backing for this age-related use would effectively sanction big uptake, and any movement in this direction would be a win by manufacturers.
What is more likely to emerge from this panel is a recommendation that doctors only prescribe these products to people who are considered medically in need. This was always the FDA's intention – current indications specify men with an associated medical condition.
Financial analysts believe that the market for prescription testosterone products peaked last year, EvaluatePharma data show. Sales of $1.8bn in 2013 are forecast to dwindle to $1.2bn by 2020. Consensus seems to assume that the fallout from this panel is not going to alter that picture of a shrinking market radically.
However, given the lack of real evidence of the long-term benefit of these therapies, it seems far more likely that the FDA will come down on the side of risk aversion.
|A decade of Low-T: from market peak to decline|
|Annual Sales ($m)|
|Product||Company||Patent Expiry||Routes of Admin.||2010||2013||2017||2020|
|Androderm (Low Dose)||Actavis||20/10/2014||Transdermal||-||74||63||57|
|Tostran||Kyowa Hakko Kirin||-||Transdermal||-||19||33||34|
|Total market incl other products||1,063||1,779||1,313||1,180|