FDA to Testosterone Makers: 'Work Together on a Single Trial'

Marlene Busko

August 20, 2015

To clarify how testosterone therapy may affect cardiovascular outcomes — which is especially important since many men are using it inappropriately for "age-related hypogonadism" as opposed to "classic hypogonadism" — the US Food and Drug Administration (FDA) is now requiring testosterone manufacturers to conduct a controlled clinical trial.

Moreover, to speed up the needed research, "we are encouraging companies to work together on a single trial," Dr Christine P Nguyen, from the FDA, Silver Spring, Maryland, and colleagues write in a perspective published in the August 20 issue of the New England Journal of Medicine.

In March 2015, the FDA issued a communications requiring that testosterone labels mention stroke and MI risk. The current article stresses that better testosterone trial data are also needed. "We believe the health of American men will be well served by the presence of accurate drug labels and reliable data to inform clinical decision making," the perspective concludes.

As previously reported by Medscape Medical News, on September 17, 2014, the FDA held an advisory meeting to discuss a signal for cardiovascular risk with testosterone therapy, partly prompted by the increasing use of testosterone by older men (who are targeted in direct-to-consumer advertising suggesting they will benefit from treating "low T").

The FDA approved the use of testosterone for men with low levels of testosterone due to "well-recognized medical conditions such as Klinefelter's syndrome, pituitary injury, or toxic damage to the testicles," but it is being increasingly marketed to older men "for a controversial condition the FDA calls 'age-related hypogonadism,' " Nguyen and colleagues write.

A briefing report at the advisory meeting noted that 28% of men received an initial prescription for testosterone without having serum testosterone levels measured first, which is "troubling" given recent observational studies suggesting a potential signal of cardiovascular risk, they add.

The FDA reviewed five retrospective cohort studies and two meta-analyses looking at this risk. Of the five retrospective studies, two found a significant increase in cardiovascular events, two found a significant reduction in all-cause mortality, and one found no significant change in the risk of hospitalization for MI among testosterone users. The studies had different patient populations, testosterone formulations, and duration, making it difficult to integrate the findings.

The two meta-analyses also had conflicting findings: one reported an increased risk of cardiovascular-related adverse events, and the other did not find any added risk of major adverse cardiovascular events in testosterone users.

The advisory panel recommended that labels state that the safety and efficacy of testosterone on age-related hypogonadism has not been established and that low serum testosterone should be confirmed before treatment is started.

It is important that companies conduct a "definitive" trial to establish the cardiovascular safety of testosterone, since, "given the widespread use of testosterone for age-related hypogonadism, the lack of substantial evidence to support such use, and the unknown effect of the label changes on prescribing patterns, the cardiovascular safety of testosterone products in older men remains an important public-health concern," Nguyen and colleagues conclude.

N Engl J Med. 2015;373:689-691. Article.

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