This article is a collaboration between MedPage Today and:
COLLEGE PARK, Md. -- Testosterone therapy and its potential cardiovascular risks will be front and center during a 2-day FDA joint advisory committee meeting that starts here on Wednesday.
On Wednesday, the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee will discuss the appropriate indicated population for testosterone replacement therapy and the potential for adverse cardiovascular outcomes associated with this use.
On Thursday, the committees will discuss Clarus Therapeutics' new drug application for oral testosterone undecanoate tablets for use as testosterone replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone, including both primary hypogonadism (congenital or acquired) and hypogonadotropic hypogonadism (congenital or acquired).
Testosterone has been approved in the U.S. since the 1950s as replacement therapy in men for conditions associated with a deficiency or absence of endogenous testosterone, the FDA noted in the briefing material for the Wednesday meeting.
Because it was formerly used mainly to replace testosterone in men who had a documented deficiency, "the FDA has only required that an investigational testosterone treatment demonstrate acceptable restoration of serum testosterone concentrations to the normal range to gain FDA approval," the agency continued. "This approach is reasonable for patients with 'classic' hypogonadism (i.e., those who have an absence or deficiency of testosterone due to documented testicular or hypothalamic/pituitary disease)."
But now testosterone is also being used in "aging men who have low serum testosterone concentrations for no apparent reason other than age, and who experience nonspecific symptoms of aging that overlap with those of classic hypogonadism," the FDA noted.
In such populations, whether their symptoms -- decreases in energy level, sexual function, bone mineral density, muscle mass and strength, and increases in fat mass -- "are a clinical consequence of the age-related decline in endogenous testosterone has not been established, and, therefore, the need to replace testosterone in these older men remains debatable."
Despite that uncertainty, use of testosterone replacement therapy (TRT) has increased among older men, especially with direct-to-consumer advertising featuring disease awareness campaigns for "low-T."
"In 2010, 1.3 million patients received a prescription for testosterone, and by 2013, this number has risen to 2.3 million patients," with men 40 to 64 accounting for 70% of the prescriptions, the agency said.
However, "FDA's analysis revealed that 21% of patients prescribed TRT did not have evidence of laboratory testing for serum testosterone concentrations at any time during TRT treatment, including testing prior to the first TRT prescription," the FDA noted. "This is particularly concerning because the diagnosis of hypogonadism requires documented evidence of low or absent serum testosterone concentrations, and the appropriate TRT dose cannot be determined without following serum testosterone concentrations on therapy."
The FDA decided to start looking at the cardiovascular risks of TRT in 2010 after a small, placebo-controlled TRT trial in elderly men was stopped early due to an overall increase in cardiovascular adverse events. At that time, the FDA reviewed the study results and other scientific literature and decided there was not sufficient evidence linking TRT to adverse cardiac outcomes.
But after several more observational studies were published, the FDA decided to reassess the therapy's potential cardiac risks. One of the observational studies was on men with low serum testosterone who were undergoing coronary angiography for the assessment of coronary artery disease. The men in that study who received TRT had a 30% higher risk of adverse cardiac events compared with those who did not receive such therapy, the FDA said.
Another study the FDA looked at found "an increased risk of myocardial infarction in older men, as well as in younger men with pre-existing heart disease, who filled a prescription for testosterone therapy," the agency noted.
"The study reported a twofold increase in the risk of myocardial infarction among men ages 65 years and older in the first 90 days following the first prescription. Among men less than 65 years of age with a pre-existing history of heart disease, the study reported a two- to threefold increased risk of myocardial infarction in the first 90 days following a first prescription."
But not all the news on TRT was bad. Two other observational studies the FDA looked at -- which both included men with a mean age of about 60 -- showed a significant reduction in all-cause mortality associated with TRT therapy.
Because of these conflicting results, the FDA is asking the advisory committee to vote Wednesday on the following questions:
- Should the agency revise the current indication for TRT, which is "for replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone," including primary hypogonadism (congenital or acquired) and hypogonadotropic hypogonadism (congenital or acquired). Should the FDA revise the current indication for testosterone therapies?
- Should FDA require sponsors of testosterone products to conduct a study (e.g., observational study, controlled clinical trial) to further assess a potential cardiovascular risk with the use of testosterone replacement therapy?
The FDA isn't required to follow the advice of its advisory committees, but often does.