What does FDA approved mean? Have you wondered that? Well I’m going to discuss what FDA approved means in a circuitous way by discussing the FDA’s recent decision to require label changes for testosterone products.
The FDA now requires makers of prescription testosterone products to make changes on the product label that clarify the approved uses of testosterone as well as add label information that the use of the products may increase the risk of heart attacks and strokes.
The FDA’s opinion contradicts that of the Coordination Group for Mutual Recognition and Decentralised Procedures-Human (CMDh) which is a regulatory body representing member countries of the European Union that says there is no consistent evidence of an increased risk of heart disease with testosterone products.
Some of the FDA’s statements on testosterone seem contradictory and even illogical. According to the FDA testosterone replacement therapy is approved “only for men who have low testosterone levels due to disorders of the testicles, pituitary gland, or brain that cause hypogonadism.”
Yet, the FDA “has become aware that testosterone is being used extensively in attempts to relieve symptoms in men who have low testosterone for no apparent reason other than aging. The benefits and safety of this use have not been established.”
Well here is what happens as men age. With aging men lose Leydig cells. Leydig cells are the actual cells in the testes that produce testosterone. In fact, they lose them at a rate of about one cell every four seconds after age 30. Fortunately, men start life with millions of such cells.
Secondly, the Leydig cells that remain viable each produce less testosterone.
Thirdly, the testicles become less responsive to luteinizing hormone (produced in the pituitary of the brain) which stimulates Leydig cells to produce testosterone. The end result is less testosterone.
All of that it would seem to represent a disorder or malfunctioning of the testicles, pituitary, and the brain. Also, how to do you distinguish or separate out low testosterone that occurs solely from aging from that of a specific disorder (pituitary tumor) since aging occurs in everyone?
Does it really matter if testosterone becomes low from aging, or from trauma to the testicles, or related to a tumor of the pituitary gland? As a prominent politician might say, “what difference does it make?” Imagine if we didn’t treat poor vision, hearing, or osteoporosis related to aging.
What I find interesting in the FDA statements above is the emphasis on levels in the first FDA statement and symptoms in the second FDA statement. This distinction highlights how the practice of medicine is evolving.
We were taught in medical school and residency that you treat patients, not lab tests. But, more and more it seems that we are treating diagnostic studies without addressing patient concerns or individual circumstances.
The FDA suggests with these statements that with testosterone we do the opposite. The FDA wants to make low testosterone a laboratory diagnosis, yet Abraham Morgentaler, MD who is widely consider the leading authority on androgen deficiency in this country says androgen deficiency is a clinical diagnosis.
The FDA by the way, and this cannot be emphasized enough, does not dictate how medicine is to be practiced (though it tries to cross that line). The practice of medicine is left up to individual state medical boards with medical/professional societies establishing the so-called standards of care.
Drugs are approved by the FDA for specific conditions. But, once a drug is approved a physician can prescribe a drug in his/her professional opinion for any condition in which he/she feels might be beneficial . The FDA does not dictate how medicine is to be practiced. Pharmaceutical companies, however, can only market a drug for the specific conditions that the drug is FDA approved. That is what FDA approval limits – the marketing of a drug, not how the drug is used which falls under the scope of the practice of medicine. Along those lines the FDA does not determine or dictate how physicians diagnose a particular condition, either. That, too, falls under the practice of medicine.
For example, statin drugs were originally only FDA approved for lowering cholesterol in individuals who had already had heart attacks. Very quickly, though, physicians began prescribing statins for individuals at high risk for heart disease who had not had heart attacks. Today they are written commonly for anybody with elevated cholesterol even without risk factors.
The FDA’s primary role is to determine if a drug is safe and effective for the specific conditions that a pharmaceutical company is seeking drug approval. Using a drug for conditions not FDA approved is called off-label use. Off-label use is quite common and it is not illegal. It is estimated that 20% of prescriptions written are used for off-label purposes including about 80% of chemotherapy agents and 40% to 50% of the medications written in pediatrics.
Now back to testosterone.
We really don’t know what a “normal” level of testosterone is numerically in a given male (though observational studies suggest a testosterone level of at least 550 and higher is associated with less heart disease, less cancer, and decreased all-cause mortality). Thus, it seems to make sense that a “normal or healthy” level is that numerical level at which a given male has no symptoms of low testosterone. And, that will vary from male to male.
The reference ranges of testosterone is purely statistically derived. A lab measures testosterone levels establishes its reference range using the middle 95% of the levels. Roughly this is 300 ng/ml to 100 ng/dl. But, a male can most, if not all, of the symptoms of low testosterone with a level of 450 or higher.
So in cases where we don’t know what a healthy level is it seems reasonable to treat patients with symptoms like those of low testosterone regardless of the cause while taking into consideration that the reference range for testosterone (and most labs for that matter) is arbitraily set and is not based on medical evidence.
FDA Approved: What’s it Really Mean?
Once again, FDA approval limits how a pharmaceutical company can promote and market a drug. It does not limit how a physician prescribes a drug. A pharmaceutical company can only market a drug for the specific condition(s) for which it was approved.