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An FDA advisory committee has voted to restrict indications for testosterone replacement therapy and require additional clinical trials to test the safety of the drugs, decisions that have drawn mixed reactions from urologists.
An FDA advisory committee has voted to restrict indications for testosterone replacement therapy (TRT) and require additional clinical trials to test the safety of the drugs, decisions that have drawn mixed reactions from urologists.
The panel’s conclusions reinforce the need to conduct a thorough diagnosis based on serum testosterone levels and clinical symptoms and to follow patients in whom treatment is indicated, according to John J. Mulcahy, MD, PhD, a member of the Urology Times Editorial Council. Abraham Morgentaler, MD, a urologist who made an oral presentation during the meeting’s public hearing portion, called the vote “a step backwards for our patients and for science.”
“There are many physicians and other providers treating low T without any background, and many are prescribing without proper patient evaluation or follow-up,” Dr. Mulcahy said, pointing out that 60% of prescriptions are written by primary care physicians versus only 20%-25% by urologists and endocrinologists, ”the ones usually with the most testosterone prescribing expertise.”
“For physicians treating men for symptoms of low T, it is important that an accurate description of symptoms be obtained as well as serum levels of T and other appropriate related hormones,” said Dr. Mulcahy, a urologist in Madison, AL. “If low T is documented, a trial of TRT may be instituted with follow-up to ascertain if the therapy has been effective in improving symptoms and that the T level has been brought to a satisfactory range or that dose adjustment is needed.”
The FDA’s Bone, Reproductive and Urologic Drugs Advisory Committee voted last week 20-1 to limit the prescribing of testosterone therapies to men with specific medical conditions and not those with an age-related decline in serum testosterone, the New York Times reported.
“Because the intended use of testosterone is ‘replacement therapy,’ 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 FDA said in a background statement prior to the meeting. “This approach is reasonable for patients with ‘classic’ hypogonadism (ie, those who have an absence or deficiency of testosterone due to documented testicular or hypothalamic/pituitary disease). In these patients, replacing testosterone is necessary for the development or maintenance of secondary sexual characteristics.
“A more controversial treatment population is aging men who have low serum testosterone concentrations for no apparent reason other than age, and who experience non-specific symptoms of aging that overlap with those of classic hypogonadism,” the statement said.
“The vote by the FDA advisory committee in favor of revising the label on testosterone products so as to restrict their use was a step backwards for our patients and for science,” Dr. Morgentaler, of Men’s Health Boston and Harvard Medical School, told Urology Times.
He pointed out that the committee’s conclusion that testosterone is often used inappropriately was based on the FDA’s assertion that the indications for which testosterone was originally approved was comprised of a specific set of medical conditions such as pituitary tumors, mumps orchitis, and Klinefelter’s syndrome.
“It was not recognized that this class label was put forth in 1981, when our knowledge of hypogonadism was rudimentary,” Dr. Morgentaler said. “Many additional causes of T deficiency have since been identified, including the largest group, which is idiopathic. It was not recognized at this meeting that men develop symptoms of hypogonadism when there is a deficiency of testosterone, regardless of whether there is a known underlying condition or not.
“The analogy is that we should only treat hypertension when there is a known underlying condition, such as renal artery stenosis. This makes no sense.”
Dr. Mulcahy advised: “Patients with normal T levels or those seeking treatment for marginal or inappropriate reasons should be given a thorough explanation of their problem, be provided a more appropriate treatment, and be denied TRT.”
On the issue of safety, the FDA panel similarly voted 20-1 to require sponsors of testosterone products to conduct a post-marketing study to further assess the potential cardiovascular risk associated with TRT use. The drugs’ cardiovascular safety was called into question by recent studies that have suggested a link between TRT and increased rates of myocardial infarction, stroke, and death. Those studies have come under criticism for using poor methodology, and other studies have shown a positive impact of TRT on cardiovascular health.
“It appears that restoring T levels to the eugonadal range in aging men has a positive effect and in general no serious long-term adverse sequelae,” Dr. Mulcahy said.
“If the FDA ultimately decides to restrict the label to the original rare conditions, insurance companies are sure to follow,” Dr. Morgentaler added. “This will mean that most affected men will have to pay out of pocket for treatment, which is fine for men of means, but tough luck for those who cannot afford it.”
Separately, the FDA committee voted 18-3 that the overall benefit/risk profile of an investigational formulation of testosterone undecanoate (Rextoro) was not acceptable to support approval. The panel also voted 12-8 with one abstention that there was not sufficient evidence that the agent is effective.
"We strongly believe the clinical data we presented demonstrate the safety and efficacy of Rextoro and are consistent with other testosterone replacement products that have been approved by the FDA," said Robert E. Dudley, PhD, of Clarus Therapeutics. "We will work closely with the FDA to respond to the panel's concerns, and remain committed to bringing Rextoro to the market as soon as possible."
In a news release, Clarus Therapeutics said the drug met its primary endpoint of restoring testosterone to normal levels in at least 75% of subjects and demonstrated efficacy similar to currently approved treatments in two phase III trials.
“Multiple studies have shown Rextoro has a safety profile similar to other testosterone replacement therapies,” the release stated.
The FDA assigned Rextoro a Prescription Drug User Fee Act goal date of Nov. 3, 2014.
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