FDA Advisory Panel Urges Restrictions on Testosterone Use

Miriam E. Tucker

September 18, 2014

A combined US Food and Drug Administration (FDA) advisory panel has voted nearly unanimously to change the labeling for testosterone-replacement products, with the aim of tamping down on their current widespread use for "age-related" hypogonadism. The panel also indicated that large studies are needed to demonstrate both clinical benefit and safety of the products.

The votes of the joint Bone, Reproductive, and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee were 20 to 1 in favor of label changes, and the panel voted as follows for these respective outcomes:

• Not requiring a safety study (1 vote).

• Requiring a safety study only for certain indications (16 votes).

• Requiring a safety study regardless of indication (4 votes).

Testosterone products have 2 current indications. The first — for replacement of testosterone in men with congenital or acquired primary hypogonadism, including conditions such as cryptorchidism, Klinefelter's syndrome, or testicular damage from chemotherapy or heavy metals — was not in dispute.

The panel primarily addressed the second indication, currently worded as "Hypogonadotropic hypogonadism (congenital or acquired): Idiopathic gonadotropin or luteinizing-hormone–releasing (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation."

The "idiopathic" wording has led to the widespread use of testosterone products for men with relatively low testosterone levels related to aging as well as for men with signs and symptoms of "low T" but who in reality have either normal testosterone levels or, in many cases, do not even have testosterone levels tested.

"Benefit is unclear in men diagnosed with hypogonadism due to no apparent cause other than older age. Yet testosterone is being predominantly prescribed to men 40 to 64 years of age. This has prompted the FDA to question whether labeling accurately reflects the appropriate indicated population," Hylton V. Joffe, MD, director of the Division of Bone, Reproductive, and Urologic Products at the FDA, told the panel in his introductory remarks.

Call for Much Tighter Wording of Second Indication

The 2010 publication of a study showing a signal of cardiovascular risk among 209 men aged 65 and older taking testosterone-replacement therapy prompted the FDA's initial investigation into this area, and more recently published studies suggesting both cardiovascular risk and possible protection prompted further inspection, Dr. Joffe said.

An FDA analysis of national sales data found that use of testosterone therapy rose 65% from 2009 to 2013 in the United States, and the number of prescriptions rose from 1.3 million in 2010 to 2.3 million by 2013. Men aged 40 to 64 accounted for 70% of those prescribed testosterone products and were the group in whom usage rose the most during the 5-year period, FDA epidemiologist Mohamed A. Mohamoud, PharmD, told the panel.

Data also show that only about half of men taking testosterone therapy had been diagnosed with hypogonadism. Furthermore, there was no evidence in 25% of users to show they had had their testosterone concentrations tested prior to initiating therapy, and 21% of those prescribed testosterone replacement had not had their levels tested at any time while they were on the therapy, Dr. Mohamoud said.

Brian Tran, PharmD, an FDA regulatory reviewer, also noted that direct-to-consumer advertisements claiming benefits such as improved quality of life and sexual performance with testosterone products have prompted warning letters from the agency.

A few panel members advised restricting the indication to primary hypogonadism alone, while others said that the second indication should be tightened, by removing the "idiopathic" and including recommendations in the label for confirming the diagnosis of low testosterone and for monitoring throughout treatment, along with more information about cardiovascular safety.

Several said the labeling should include the Endocrine Society's 2010 diagnostic guidelines, which call for symptoms and signs consistent with hypogonadism and "unequivocally low" serum testosterone of less than 300 ng/mL, measured in the morning, and confirmed by a second test.

Panel member Marc Garnick, MD, clinical professor of medicine at Beth Israel Deaconess Medical Center, division of oncology, Boston, Massachusetts, said, "The aging male andropause patient is an appropriate population for consideration, but the criteria must be much more precise."

He said the label should call for "appropriately valued" low testosterone levels, along with documentation of symptoms such as erectile dysfunction, loss of libido, and/or diminution of bone-mineral density, as well as a detailed cardiovascular history, baseline ECG, and routine measurements of quality of life in order to determine when the product should be stopped for lack of efficacy.

"I believe the Madison Avenue catch-all of 'Low T' has some validity, but it has been totally misused and misrepresented," Dr. Garnick commented.

Trials Needed for Cardiovascular Safety

Regarding the safety question, Tobias Gerhard, PhD, from the Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey, said: "The evidence regarding cardiovascular safety is obviously very insufficient. We need more data. At this point, I don't think there's evidence for a clear causal association, but I believe we do have a signal of reasonable strength."

Given the magnitude of off-label use "and lack of strong data on effectiveness in this population, I think it's important to include something about cardiovascular safety in the label. Maybe not to the level of black box, but certainly that there are serious concerns that have not yet been adequately addressed," he added.

Several panelists said that a large, randomized clinical trial would be needed to determine whether or not the cardiovascular signal was real, noting that men with low testosterone are already at increased cardiovascular risk. Others felt that an observational trial would allow for the collection of more end points.

Toby C. Chai, MD, professor and vice chair of the department of urology at Yale University School of Medicine, New Haven, Connecticut, said, "For a population it was not originally intended to be used [in]…if we want to look at reality we have to do safety studies....Whether it should be randomized or observational, I think we'll be prospectively looking at those cardiovascular risks."

In a statement provided to Medscape Medical News, Androgel manufacturer Abbvie said, "Testosterone-replacement therapy is an important men's health topic. AbbVie is committed to our patients, and we will work with the FDA during its review."

FDA advisory panel members are vetted for conflicts of interest and waivers granted for participation if necessary. For this hearing, Dr. Garnick was granted a waiver after disclosing that he holds stock valued between $25,001 and $50,000 in one of the affected companies.

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