Thank you for the opportunity to speak today. My name is Dr. Megan Polanin, and I am a Senior Fellow at the National Center for Health Research. Our research center scrutinizes scientific and medical data and provides objective health information to patients, providers, and policy makers. These are the perspectives I bring with me today. We do not accept funding from the pharmaceutical or medical device industries, so I have no conflicts of interest.
Testosterone replacement medications are widely prescribed in the United States. Five years ago, experts estimated that over 2 million men in the United States were on a testosterone drug, commonly receiving their prescriptions during a primary care visit.
Currently, we do not have compelling evidence that testosterone supplementation for age-related hypogonadism works, though we know it carries many risks. Prescribing this drug off-label for uses that are not FDA-approved could unnecessarily harm many patients. This real-world use must be taken into account as we address the impact of this drug.
The indication that you are here to discuss today is for replacement therapy in adult men for conditions associated with a deficiency or absence of endogenous testosterone. As you are well aware, testosterone replacement therapy can substantially benefit these patients, and the relative ease of taking this drug orally will likely attract both patients and doctors.
Though the 225 mg twice daily regimen of this drug met its primary efficacy endpoint, the exposure period for the 24-day trial was too short to extrapolate long term benefits for a drug designed to be taken for decades. Also, the original 52-week study was open label and had a high drop-out rate in the group receiving the drug, which preclude an accurate assessment of the drug’s long term effects.
In addition to questionable benefits, we are also concerned about the risks and whether they outweigh the benefits:
#1. We are concerned about the cardiovascular safety of this drug and agree with the FDA that non-duplicative cuff pressure readings call into question this drug’s safety. Blood pressure is dynamic, and we agree with FDA cardiologists that the sponsor should conduct ambulatory blood pressure monitoring to fully evaluate the effects on blood pressure and heart rate. We urge this panel to recommend that ambulatory blood pressure monitoring is needed before this drug is approved.
#2. We are also concerned about the adrenal effects of this drug. Adrenal insufficiency can be life-threatening, so we need data to establish this drug’s safe use. Potential signals of adrenal insufficiency in rats and dogs are very concerning. In humans, the exposure time of approximately 24 days was too short to draw conclusions about a drug that patients could take for months, years, or even decades. Is 24 days long enough to decide whether this drug causes adrenal insufficiency? Obviously not. We urge this panel to strongly recommend that the sponsor be required to assess the effects on adrenal function in a well-powered study with standardized methodology prior to approval.
#3. Unless patients and their physicians have very clear warnings about scientifically established risks, many patients are likely to stay on the drug when they should be taken off. The sponsor’s analysis indicated that all patients who had excessive levels were identified and the drug was appropriately stopped. In the real world, that is less likely to happen. Our concern is that the stopping criteria on the drug’s label will not be effective in persuading physicians and patients when the drug should be discontinued.
For example, the sponsor’s proposed label indicates that serum total testosterone concentrations be checked “periodically” and to discontinue the drug if concentrations are “consistently” below a certain threshold. This language is much too vague and will be interpreted differently by unique physicians. Physicians need clearly defined specifications about timing, testing, and discontinuation of the drug on the drug’s label and as part of a required training program in order to ensure patient safety.
As the FDA pointed out, if approved, this drug will likely dramatically change the landscape of testosterone replacement therapies. It will likely be favored for prescriptions for hypogonadism and prescribed off-label. Thus, it is important for this panel and the FDA to make approval decisions based on good science and strong data. Are panel members convinced that the current data represent rigorous evaluation of this drug’s impact? Are you confident that you know what this drug’s real-world impact will be?
In conclusion, testosterone replacement therapy can substantially benefit patients with hypogonadism. While we recognize that oral administration is preferable to more inconvenient routes of administration, we cannot disregard concerns about this drug’s potential harms. This drug was not studied for a long enough time to know if the benefits outweigh the risks, and off-label use makes it even more likely that the risks will often outweigh the benefits.
We urge you to consider what the FDA should require of the sponsor to prove that this drug is safe and effective for its intended long-term use and what is needed to prevent misuse. We strongly urge you to not recommend approval at this time.
Thank you for the opportunity to share our perspective.
All NCHR articles are reviewed and approved by Dr. Diana Zuckerman and other senior staff.
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The Bone, Reproductive, and Urological Drugs Advisory Committee (BRUDAC) voted against approval of Tlando 13-6. Read more coverage of the 2-day testosterone meetings here.