Perspective from Paresh Dandona , MD, PhD
Perspective from Ronald Swerdloff , MD
September 18, 2014
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FDA committees near-unanimous on need to investigate testosterone therapies

Perspective from Paresh Dandona , MD, PhD
Perspective from Ronald Swerdloff , MD
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COLLEGE PARK, MD — Two FDA advisory committees voted 20-1 in favor of revising the current indication for testosterone replacement therapies following several hours of charged presentations by clinicians, industry representatives and the public at a joint meeting Wednesday.

Members of the Bone, Reproductive and Urologic Drugs and Drug Safety and Risk Management panels were divided 16-4 on whether the FDA should require further investigation into potential cardiovascular risks for only certain indications or regardless of the indication, respectively, with a single vote for no investigation.

“It’s a weak cardiovascular safety signal. We need to inject some reality into what has really been an uncontrolled use of the drug,” committee member A. Michael Lincoff, MD, of Cleveland Clinic, said.

Definition and Populations Treated

Early on, guest presenter Peter J. Snyder, MD, of the University of Pennsylvania highlighted the Endocrine Society Guidelines from 2010 that clinically define hypogonadism as having unequivocally low morning serum testosterone.

Snyder said, “300 ng/dL is the lower limb of normal for testosterone assays; unequivocal depends not just on an absolute number, but the time of day and the number of times.”

But Snyder urged consideration for symptoms in deciding treatment, a sentiment echoed by presenters throughout the day.

“We always have to pick a number for practical purposes, but it’s likely that there is no one number; the lower, the more certain,” Snyder said. “What if it’s associated with a disease known to cause low testosterone, or if someone has 100 ng/dL and a large pituitary adenoma? This has to be part of our education.”

An explanation of primary and secondary hypergonadism, with a breakdown of “classic” vs. age-related, or andropause, by presenter Mark Sigman, MD, of the Warren Alpert Medical School of Brown University, gave the room a clear picture of the range of potential treatment populations.

Sigman underscored low-testosterone related comorbidities including obesity, type 2 diabetes and reduced bone mineral density as particularly controversial areas for treatment since causation and association remain uncertain.

“We cannot really separate those who benefit from those who do not,” Sigman said. “That’s likely because signs and symptoms are multi-factorial.”

Current State and Clinical Benefits

Industry representatives mounted their evidence for the efficacy and safety of prescribing therapies to distinct demographics, including the extent of testosterone use by age and the reasons for use.

In an introduction, Kraig Kinchen, MD, senior medical director, global urology, at Eli Lilly, said the FDA has not yet required randomized placebo-controlled trials or demonstrated improvement in symptoms and has preferred class labeling except for safety labels to reflect formulations and modes of delivery.

“Registration study populations have been enrolled without regard to etiology and have included men with age-related hypergonadism,” Kinchen said. “The primary efficacy endpoint of most phase 3 registration studies is to demonstrate that at least 75% of patients achieve and average serum testosterone concentration level within the normal range, between 300 and 1,000 ng/dL.”

The FDA’s consideration to revise the indicated patient population, based on lack of clear etiology differentiation and varied interpretation, was encouraged.

“The current indications for the population is not who is being treated right now,” committee member Toby Chai, MD, of Yale School of Medicine, said. “The age range is not the range of most people getting prescriptions.”

Data presented from the SHA Integrated Database showed usage in 2013 was highest among men aged 55 to 64 years, followed by 45 to 54 years. The total number of testosterone therapy prescriptions jumped ninefold from 2000 to 2013, with primary care physicians writing the most.

Adrian S. Dobs, MD, of Johns Hopkins University and a member of the advisory boards for three sponsors present at the hearing, offered a look at the benefits of testosterone replacement therapy, from body composition to sexual function to mood and fatigue, and limitations to data, from heterogeneous populations to variable baseline levels, endpoints and study design.

The sponsors vocalized their willingness to find clarity.

“I thank the sponsors for coming today with an open mind,” committee member John R. Teerlink, MD, of the University of California, San Francisco School of Medicine, said.

Risks and Recommendations

A key presentation by Shalender Bhasin, MD, of Harvard Medical School, with advisory board seats for two of the sponsors, broached the biggest topic of concern in the room during a presentation on cardiovascular events and testosterone therapies.

“Testosterone’s effects in preclinical and clinical models are diverse,” Bhasin said. “Some effects are beneficial, and some may be potentially deleterious.”

Bhasin conceded biologic plausibility for the association of testosterone with cardiovascular events. He presented data from a meta-analysis demonstrating lower testosterone levels were associated with higher all-cause mortality, epidemiologic studies showing mixed results and a small randomized placebo-controlled trial showing increased cardiovascular events with therapy.

“It’s important to distinguish between classical hypogonadism and age-related decline,” Bhasin said. “In young men with classical hypogonadism, testosterone replacement therapy improves symptoms with low adverse event frequency. In older men, with age related decline or frailty, neither benefits nor risks have been clearly demonstrated.”

Two speakers in the public portion raised safety concerns about testosterone transdermal gel —one sharing a personal story about a thromboembolism in the spine that led to paralysis and the other telling about a heart attack still taking its financial toll.

Rita Jain, MD, vice president of global pharmaceutical research and development at AbbVie, noted several on-going randomized placebo-controlled trials by sponsors — T-Trial, NCT01816295, TEAAM —and NIH-funded epidemiological studies — University of North Carolina, Kaiser Foundation, Seattle Institute of Biomedical and Clinical Research.

“New data from the T-trial is expected to report in the first half of 2015,” Jain said. “These results may alter the approach on the benefits and cardiovascular risks of testosterone replacement therapy.”

Fair labeling, education

Educating consumers about the benefits and risks of testosterone therapies was a topic visited throughout the day, with a presentation by Trung-Hieu Brian Tran, PharmD, a FDA regulatory review officer in the Office of Prescription Drug Promotion (OPDP), shedding light on the specifics of various methods.

“Prescription drugs are misbranded if the labeling or advertising is false or misleading, or if it fails to reveal material facts, including about consequences which may result from the use of the drug as suggested in the labeling or advertising,” Tran said.

Tran advised the room that a category called “disease awareness communications” are not subject to the requirements of the Federal Food, Drug, and Cosmetic Act or FDA regulations; OPDP has already received complaints regarding disease awareness communications for hypogonadism.

Product claim promotional materials must comply with the regulations, Tran noted; the submission of such materials to OPDP for testosterone therapies has increased in the past several years.

The sponsors are proposing label changes, based on the limitations of data in less-defined populations, including age-related, and to include elements of professional society guidelines for testing and monitoring testosterone.

“Right now there’s no proof that in this older age group there’s any efficacy at all and I think the label should reflect that,” committee member Michael Domanski, MD, of Mount Sinai Hospital, said.

Hylton V. Joffe, MD, of the FDA, assured the room the committees would carefully review what was discussed and come back with a decision Thursday. — by Allegra Tiver

For More Information: See the Endocrine Today Twitter feed for a live update of the committee meeting. www.Twitter/com/EndocrineToday