The Next Estrogen Or An Off-Label Star: Can FDA Turn Back The Clock On Testosterone?

Testosterone replacement products took a hit after an FDA advisory committee, but even if the agency follows their advice, panelists worried a label change will not curb use in the now infamous “Low-T” population; meanwhile, a vigorous pipeline of new testosterone formulations may be left in limbo.

It’s not yet clear whether the pharmaceutical industry’s male fountain of youth – widely used billion dollar testosterone treatments – is in jeopardy of collapsing following an advisory panel’s near unanimous recommendations that the drugs’ indication be significantly narrowed and cardiovascular outcomes studies be conducted.

In fact a handful of advisors told the agency they didn’t think a label change would have much affect at all on prescribing practices for age-related hypogonadism, commonly known as “Low-T” – the primary use of testosterone treatments today, but a use that FDA says was not intended based on the products’ development programs and approved labels.

FDA says the products were developed with study designs that are more acceptable to examine the risk-benefit profile of testosterone replacement in men with true primary or secondary hypogonadism, who require replacing testosterone for the development or maintenance of secondary sexual characteristics.

Indeed, some members of FDA’s Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee, which convened Sept. 17 to review the safety of the products, suggested there was hardly any on-label use at all and questioned whether changing the label would make any difference.

“As I look at this, it looks as though there is absolutely no demonstration of safety or efficacy of these drugs, with respect to clinical endpoints, for the indication for which they’re most frequently given,” Michael Domanski, Mount Sinai School of Medicine, said.

“I’m not so sure that labeling is going to change behavior very much. I mean there’s no data now; the fact that you put a label on it that you don’t see any indication for it, is not really news.”

FDA’s Office of Prescription Drug Promotion Review Officer Brian Tran told Domanski that if the indication changed, sponsors’ promotions would have to change to match the label.

“And that is what you see as the primary outcome of today’s deliberation?” Domanski replied.

“Yes, I think that is one of those things,” Hylton Joffe, director of the Division of Bone, Reproductive and Urologic Products, said. “How can we most accurately reflect what the science says in terms of who should be using these products. You know physicians can always use things off label, FDA doesn’t really get into that, but what we want to do in our labels is accurately reflect the patient population that the science supports.”

Domanksi countered, “in fact that’s precisely what’s happening now – it’s being used off-label.”

“I think that depends on how you define off-label,” Jofee replied. “If you fit these patients into that category ... of idiopathic hypogonadism then someone might say they are actually included somewhat in the indication.”

Joffee was referring to FDA’s Urology Medical Team Leader Mark Hirsch’s statements that “Low-T” use was not necessarily a clear off-label phenomenon, noting the age-related treatment may have unintentionally found its way into accepted use through current labeling terms such as “idiopathic gonadotropin or LHRH deficiency, a physiological condition that occurs in older men” (Also see "‘Low-T’ Drugs Need Randomized CV Safety Trials, FDA Panel Says" - Pink Sheet, 18 Sep, 2014.).

FDA’s Deputy Director for Safety Christine Nguyen also told the committee that labeling can affect use behavior because it helps guide recommendations to practitioners through educational materials or guidelines issued by professional societies and said a label could affect insurance coverage as well.

Others pointed out that much of the “Low-T” use may have been started by disease awareness ads that discuss the condition, something that FDA said at the meeting it is not in a position to regulate even when ads are making therapeutic claims.

Safety Studies Could Be True Turning Point

Given off-label use, the biggest impact on testosterone use could come if cardiovascular safety studies are conducted and do reveal a true safety concern. FDA advisors generally agreed there is an inconclusive, weak signal but that more data is needed.

A true CV risk would likely impact Low-T prescribing, particularly if there aren’t any studies that counterbalance this risk with clear clinical evidence testosterone replacement helps aging men.

Right now it’s still not known whether decreased testosterone in aging men is a physiologic phenomenon or a pathologic phenomenon, Peter Snyder, University of Pennsylvania, told the advisory panel.

FDA maintains the need to replace testosterone in aging men is “debatable” as it’s unknown whether the symptoms these men experience that are similar to those of classic hypogonadism are related to the age-related decline in testosterone.

Panelists expressed the need to determine both if declining testosterone is pathologic and whether replacing it has any benefits, lest there be a repeat of what happened when post-menopausal women were treated with estrogen replacement treatments.

Following widespread estrogen use, the Women’s Health Initiative study found an increased risk of breast cancer and cardiovascular events with the treatment, pulling the market out from under products such as Wyeth’s Prempro (estrogens/medroxyprogesterontone) (Also see "Prempro Cancer Risk Addressed In 550,000 Physician Letters, Label Review" - Pink Sheet, 15 Jul, 2002.).

If safety studies are required regardless of approved indication, particularly in the Low-T population, this could become a great burden on both approved sponsors and sponsors with drugs in the pipeline.

More Impact On Pipeline Products, Generics?

Those sponsors who have been on the market longest and already recouped an investment on their product may be less likely to want to conduct an efficacy study showing benefit in age-related hypogonadism, particularly if products still see enough off-label use. FDA cannot force sponsors who aren’t seeking such a labeled indication to conduct these efficacy trials.

There are more than a dozen marketed testosterone treatments approved in the U.S. from more than half a dozen sponsors, including generics, and more are in development.

Many of the marketed drugs have been approved for more than 10 years, like products from AbbVie Inc. (Androgel 1%), Watson Laboratories Inc. (Androderm), Endo Pharmaceuticals Inc. (Delatestryl) and Auxilium Pharmaceuticals Inc. (Testopel, Testim, Striant).

More recent products include Endo’s Fortesta and Aveed, Eli Lilly & Co.’s Axiron, AbbVie’s AndroGel 1.62%, Acerus Pharmaceuticals Corp.’s Natesto and Upsher-Smith Laboratories Inc.’s Vogelxo.

New sponsors could see more of a hurdle if FDA requires new types of clinical studies for initial testosterone treatment approval, even if they aren’t seeking an age-related hypogonadism indication.

In the past FDA has only required testosterone therapies to demonstrate they increased serum testosterone concentrations to normal levels. Companies have not had to demonstrate any clinical outcomes.

Clarus Therapeutics Inc. – which had its product reviewed by the committees the day after they discussed the class-wide issues – is in a particularly awkward position with a user fee date coming up on Nov. 3. However, FDA and its advisors have concerns with the company’s oral testosterone Rextoro that stretch beyond the class-wide concerns, indicating the product could be headed for a “complete response” letter regardless (Also see "Clarus’ Oral Testosterone’s Perceived Advantage Becomes Downfall At FDA Panel" - Pink Sheet, 18 Sep, 2014.).

There are seven products in the testosterone pipeline, according to BioMedTracker. Repros Therapeutics Inc. plans to submit its oral treatment Androxal to FDA late this year. TesoRx Pharma LLC is also working on an oral treatment. It anticipates FDA approval in 2016.

Generic makers may also be impacted by FDA’s decisions on labeling for testosterone. Generics of AbbVie’s blockbuster Androgel are expected in 2015 (Also see "FTC vs. AbbVie Pay-For-Delay Suit Crafted For Supreme Court’s ‘Red Flag’ Test" - Pink Sheet, 8 Sep, 2014.).