New draft industry guidance from the U.S. Food and Drug Administration (FDA) underscores the importance of randomized, double-blind, placebo-controlled trials to establish the efficacy of drugs to treat male hypogonadotropic hypogonadism when it is caused by obesity or another acquired condition. The draft guidance also asserts the potential importance of patient-reported outcome (PRO) instruments to such efficacy determinations, since they offer “direct evidence of how patients feel or function.”
Male hypogonadism is marked by low concentrations of serum testosterone. There are two forms of hypogonadism, differentiated by serum concentrations of gonadotropins, the hormones that stimulate the gonads—in men, the testes. In hypergonadotropic hypogonadism, which is related to testicular function, concentrations of follicle stimulating hormone (FSH) and luteinizing hormone (LH) are elevated. In hypogonadotropic hypogonadism, which is related to hypothalamic and pituitary function, FSH and LH concentrations are low or normal. The 2018 draft guidance pertains only to hypogonadotropic hypogonadism.
Released in January 2018, the FDA’s Establishing Effectiveness for Drugs Intended to Treat Male Hypogonadotropic Hypogonadism Attributed to Nonstructural Disorders focuses particularly on efficacy endpoints and criteria for enrolling subjects in clinical trials. It distinguishes “classic” hypogonadotropic hypogonadism—which is caused by intrinsic damage to the hypothalamus or pituitary gland—from hypogonadotropic hypogonadism that occurs in the absence of such damage.
As explained in the draft guidance, classic hypogonadotropic hypogonadism can occur following pituitary resection or be caused by congenital conditions that affect sexual development (e.g., Kallmann syndrome). Males with classic hypogonadotropic hypogonadism “are clearly testosterone deficient,” the FDA states. Puberty may be delayed and development impaired. A boy’s voice might not deepen, for example, or his penis and testicles remain immature. For men, symptoms can include erectile dysfunction, infertility, and decreased muscle mass and body hair, according to the Mayo Clinic.
As the guidance notes, some men develop hypogonadotropic hypogonadism after “normal” puberty and sexual development, and absent intrinsic hypothalamic or pituitary damage. (The many comorbidities associated with male obesity, for example, include reduced serum total testosterone with low or normal gonadotropins.) Unlike patients with classic hypogonadotropic hypogonadism, these men often experience “nonspecific” symptoms—such as low energy and depression—that “cannot definitively be attributed to the low testosterone concentrations,” the FDA states.
For patients not interested in preserving fertility, testosterone replacement therapy (TRT) is a standard treatment for all forms of hypogonadotropic hypogonadism.
For patients not interested in preserving fertility, testosterone replacement therapy (TRT) is a standard treatment for all forms of hypogonadotropic hypogonadism. Under the FDA’s draft guidelines, however, it is simpler to establish a testosterone drug’s efficacy when it is proposed for classic hypogonadotropic hypogonadism than when the condition was caused by a nonstructural disorder. To demonstrate efficacy for the classic form, a sponsor must show only that a treatment “reliably” raises serum testosterone concentrations to the normal range for a healthy young man.
In the absence of intrinsic hypothalamic and pituitary damage, it is “unclear” whether such reduced concentrations are “inappropriately low” and if raising testosterone concentrations leads to clinical benefit, according to the FDA. Because of these uncertainties, the agency does not accept serum testosterone as a valid surrogate endpoint for these patients, but advises sponsors to design clinical trials that link increased serum testosterone to improvements in how patients feel, function or survive.
Recommendations for clinical trials
The draft guidance presents FDA recommendations for clinical trials of drugs for hypogonadotropic hypogonadism caused by nonstructural disorders. Points related to efficacy endpoints include:
- Randomized, double-blind, placebo-controlled trials should demonstrate that the drug increases serum testosterone and provides “clinically meaningful improvement” in at least one sign or symptom.
- PRO instruments can be central to efficacy determinations. The agency notes, however, that it is “not aware” of existing PRO instruments that are adequate for regulatory use to evaluate patient improvement in signs or symptoms of hypogonadism, but that it is willing to evaluate instruments for their suitability. When creating or choosing an instrument, the FDA advises sponsors to consider recommendations in the agency’s guidance document, Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims.
- If using biomarkers to establish evidence of clinical benefit, they must be established surrogate endpoints for how patients feel, function or survive.
- For drugs that improve spermatogenesis, efficacy could be established by demonstrating improved fertility outcomes; changes in semen parameters alone would be insufficient. For drugs that do not impact spermatogenesis or that have an adverse effect, efficacy could be established by demonstrating improvement in other signs or symptoms of hypogonadism.
Recommendations related to patient enrollment include:
- Enroll subjects who have clinical and laboratory evidence of hypogonadotropic hypogonadism, including:
- Low serum total testosterone concentrations in the morning on at least two days (separated by at least three days).
- Low free testosterone concentrations in the morning on at least two days (separated by at least three days).
- Serum FSH and LH not exceeding the upper limit of the reference range.
- Normal serum prolactin concentration and normal thyroid function tests.
- The trial population should not have intrinsic damage to the hypothalamus, pituitary glands or testes, but should be “well defined” in terms of the underlying associated condition, symptoms and signs.
Recent FDA review of products for hypogonadism
FDA-approved TRT products are available in a variety of formulations, including topical gels and solutions, buccal systems for the gums, transdermal pellets and injections. To date, the only approved testosterone therapy that is orally administered is methyltestosterone, a synthetic derivative of testosterone that is associated with serious hepatic adverse events and, for that reason, not widely used.
In the first 10 days of 2018, the FDA asked its Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC) to review new drug applications (NDAs) for two oral products proposed as TRT for male hypogonadism, including hypogonadotropic hypogonadism; neither received the committee’s overall support.
On January 9, the BRUDAC considered Clarus Therapeutics’s NDA 206089 for Jatenzo (oral testosterone undecanoate capsules). Of the 19 advisory committee members who voted, only nine agreed that the proposed drug’s overall benefit/risk profile supported its approval as a TRT. The other 10 cited clinically significant cardiovascular events (e.g., elevated blood pressure, increased heart rate) associated with Jatenzo use as their reason for voting “no.”
The BRUDAC did not contest Jatenzo’s efficacy, however. The sponsor’s submission included the results of study CLAR-15012, a three-month pivotal phase lll trial; to meet the primary efficacy endpoint, at least 75% of subjects had to achieve testosterone Cavg in the normal range (252-907 ng/dL) and the lower bound of the corresponding 95% confidence interval (CI) had to be at least 65%. Results showed 87.4% of subjects within the Cavg normal range, and the lower bound of the 95% CI was 81.3%.
This was the second time the BRUDAC met to consider the Clarus application. In September 2014, a joint meeting of the BRUDAC and the Drug Safety and Risk Management Advisory Committee (DSaRM) discussed the same NDA (but with a different proposed trade name, Rextoro). The committees voted 17-4 against the drug’s overall benefit/risk profile, citing concerns that the easy-to-use oral formulation could be widely misused. The BRUDAC and DSaRM also advised the FDA to seek more data from Clarus (e.g., dose titrations, dietary concerns) and recommended additional study to evaluate cardiovascular risk.
On January 10, the BRUDAC voted 13-6 against the overall benefit/risk profile of Lipocine’s Tlando (oral testosterone undecanoate capsules). Again, the committee did not question the efficacy of the proposed product, but expressed concerns about its cardiovascular safety. Members called for additional safety data, particularly regarding a potential increased risk for adverse cardiovascular events, as well as Tlando’s effects on blood pressure, lipid parameters and hematocrit.
The outcomes of these latest BRUDAC meetings reflect ongoing FDA concerns about testosterone products and cardiovascular risk. Previous agency actions include:
- The FDA announced in January 2014 that it was investigating a potential risk for stroke, heart attack and death in men taking FDA-approved testosterone products, citing the published results of two observational studies linking testosterone therapy with increased risk for cardiovascular events.
- In March 2015, the FDA announced its conclusion that testosterone use carries “a possible increased cardiovascular risk,” and instructed manufacturers of approved prescription products to update product labeling.
- In October 2016, class-wide labeling changes for all prescription testosterone products focused on the risks associated with testosterone (and other anabolic androgenic steroids) abuse and dependence, including heart attack and heart failure.
Editor’s Note: A version of this article was originally published in the Journal for Clinical Studies.
This analysis was developed with data from Cortellis Regulatory Intelligence and Cortellis Clinical Trials Intelligence.