Have you ever gotten a prescription from your doctor for an off-label medication? Did you know that every one in five prescriptions written today are for “off-label” use? Are off-label prescriptions safe? Effective? What are the risks? In this blog, we discuss the history of off-label prescriptions, why doctors prescribe medications off-label, and what that means for you when it comes to hair loss and off-label hair loss treatments, like dutasteride.
What is off-label usage?
In short, when we receive a prescription from our doctor, the prescription can either be on- or off-label. On-label, which is the typical form of prescription, means that the compound being provided has been approved by the FDA to treat the condition that it’s being prescribed for. Off-label usage, on the other hand, means that the prescription is being given to treat a condition for which the FDA has not approved its usage, though it has still passed FDA clinical trials for other indications.
As we’ve detailed in other pieces, the Food and Drug Administration (FDA) is a federal regulatory authority that was put in place to oversee the development and sale of commercial foodstuffs and therapeutic products. This agency played an important part in cracking down on public crises that arose as a result of the sale of items, branded as cosmetic products or medicinal treatments, that suffered from a lack of rigorous safety testing, sanitary practices, or both. These implementations were landmark achievements that helped to address both the safety and quality of products running the gamut from common foodstuffs to novel therapeutics.
As part of putting in place the necessary safeguards to ensure product safety, the FDA developed a variety of different formal applications for drugs and biologics:
- Investigational New Drug (IND), an application for developing new drugs that allows developers to transport the novel compound across state lines to collaborators like clinical research facilities.
- New Drug Application (NDA), the full formal application submitted to the FDA by the developer of a novel therapeutic once the developer believes that the results from their preclinical and clinical studies will meet the standards and scrutiny of the FDA. Once approved, the product can legally be marketed and sold to consumers in the United States.
- Abbreviated New Drug Application (ANDA), a form of the aforementioned NDA that allows manufacturers of generic versions of previously patented and marketed drugs to bypass the process of preclinical and clinical trials if the applicant can demonstrate that their generic version is bioequivalent to a preexisting product that has previously been given approval by the FDA via a successful NDA. ANDAs can be seen as preventing other manufacturers from investing substantial capital resources only to reinvent the wheel during preclinical and clinical phases, instead focusing on the way in which the generic version performs and whether its manufacturing protocols are acceptable.
- Over-the-Counter Drugs (OTC), of which there are 80 subcategories of drugs based on application and class that regulate formulations more broadly. OTC drugs must still meet the same safety and efficacy standards of what would commonly be considered prescription drugs, while enabling consumers to self-diagnose, self-treat, and self-manage the ailment and the usage of the OTC drug in question. On occasion, a drug that was once available by prescription only can become approved for OTC use over time. The FDA maintains a list of recent common cases, with the antihistamines Claritin and Allegra, the acid reducers Prilosec and Nexium, the emergency contraceptive Plan B, and the hair loss foam Rogaine being notable examples (schematic adapted from: Chang et al).
- Biologic License Application (BLA), an application for therapeutics that may not consist of a single, easily identifiable and synthesizable compound like minoxidil, but instead may exert their effects through more complex compounds like proteins or nucleic acids. Biologics are often used to treat immune disorders, like psoriasis and rheumatoid arthritis.
Refresher: The FDA in action
Why the number of different applications and the seemingly bloated structure of the approval process? Let’s review the merits and drawbacks of the FDA as a regulatory body while discussing a few current and topical examples of its importance to society.
When the FDA approval process becomes a barrier to entry
While criticisms of the FDA do exist and there’s certainly room for improvement to reduce the cost-prohibitive barriers of entry to nascent and developing companies, the existence of the FDA contributes to improved consumer confidence knowing that even though it may not be the ideal watchdog, it remains a watchdog for the public interest nonetheless.
Though the consequences have been dire, a timely example of the importance of the FDA and its enforcement of regulations and standards in the production of food products and medications has been the American shortage of baby formula during the late spring of 2022. The catastrophic shortage of baby formula due to reported failures to comply with standard sanitary practices at a formula manufacturing plant run by Abbott Laboratories, which controls 40% of the American market share of baby formula, producing 40% of its formula in the now-shutdown facility in Sturgis, Michigan. The cause for the shutdown was contamination of Abbott baby formula with Cronobacter sakazakii, a type of bacteria that can cause severe cases of foodborne illness and, according to the CDC, has reportedly contributed to the death of 2 infants as of mid-May.
Combined with supply chain issues from upstream manufacturers and wholesalers due to the ongoing COVID-19 pandemic and rising inflation, the shutdown of the Abbott plant—with its substantial concentration of market share—has led to the nationwide shortage of infant formula. Though the coinciding timing of FDA enforcement and global economic pressures is an unfortunate coincidence, it represents a reminder of the service the FDA provides to the public when it comes to monitoring not only prescription-strength medications, dietary supplements, and medical devices, but everyday edibles and specialty foods, too.
Operating within the bounds of FDA approval
In prior posts, we’ve highlighted the lengthy process that companies in the pharmaceutical and biomedical industries must go through in order to obtain FDA approval, or clearance, for the distribution of their products and the content of the advertising claims used in marketing campaigns, the listing of ingredients on labels, and other limitations.
We’ve also established that, in the hierarchy of phases for generating clinical data on a potential new therapeutic compound, the first stages primarily involve generating a safety and dosage profile for the compound in question, then addressing the issue of efficacy for the primary treatment indication when compared against a placebo. As fewer and fewer compounds are able to successfully progress through each stage of the FDA approval process, many of the investigational drugs that are still deemed safe enough for human consumption may not be shown to be efficacious for the proposed indication. However, that doesn’t mean that they aren’t efficacious for every indication: Many treatments—from minoxidil to finasteride to low-level laser therapy (LLLT)—were originally developed to address different ailments. Through the process of clinical trials, it was found that minoxidil, finasteride, and LLLT all contributed to hypertrichosis, or hair regrowth, in certain instances.
Part of the reason treatments like minoxidil and finasteride are available for the indication of treating hair loss is because the corporations developing those compounds made a pivot to seeking approval for a different indication than the manufacturers had originally intended. As long as the manufacturing of the compound, the delivery method, and the dosage remained similar to what was conducted in preclinical or early clinical trials that determined that the safety profile of the compound remained equivalent, corporations could rely on their prior work and investment in order to validate the pursuit of an application for a new treatment indication.
All this is to show that many compounds may meet the safety profile for New Drug Approval required by the FDA, but not the efficacy for a given indication, meaning that further investment in the development of a particular therapeutic may grind to a halt.
Why might a company pursue FDA approval for a different, or even second, indication?
This also raises the obvious question: Can one investigational compound receive approval for a second treatment indication at a later date, even though it may already have received approval for a different one in the past? The answer is yes, with finasteride being an easy example: Originally developed and approved as a treatment for an enlarged prostate, commonly branded as Proscar, with 5mg of finasteride per dose, finasteride was later approved for a second indication in treating hair loss with the branded Propecia at 1mg per dose.
Though the investment in getting approval for a second indication isn’t insignificant, if preliminary data suggests that the efficacy might warrant the investment, that second approval could allow for access to a larger, untapped market without requiring any new investment in the exploratory and far less cost-effective phases of manufacturing and early R&D.
It’s that cost-benefit analysis of being able to legally tap into that potential market is a driving factor in whether or not an investigational treatment is developed and pursued, whether for one indication or many.
Off-label prescriptions give medical professionals flexibility
Part of that cost-benefit analysis; however, relies upon the answer to another key question that often flies under the radar: Once a prescription drug receives FDA approval for marketing and distribution, how do consumers acquire that drug in the first place? If it’s not approved by the FDA as an OTC drug, then it requires a prescription from a licensed medical doctor. Though it may seem surprising, FDA approval for a given indication only regulates the claims that a manufacturer is allowed to make about the efficacy of a drug in addressing a certain ailment—it doesn’t dictate what medical professionals are able to prescribe the therapeutic for.
As part of patient privacy and deference to medical expertise, Congress has typically affirmed the legality and protection for doctors to prescribe FDA-approved medications for treatment regimens other than those explicitly approved for public marketing by the FDA. In prescribing medications, licensed medical professionals are given leeway to lean on the scientific consensus, rather than being constrained by the explicit recommendations and limitations of the federal government. This is known as off-label prescribing.
Why does off-label prescribing exist in the first place?
FDA approval for a novel therapeutic isn’t just expensive, it’s time-consuming, often taking several years to advance through the necessary clinical stages to demonstrate safety and efficacy. As we’ve mentioned, corporations rely on a cost-benefit analysis between investing the requisite number of resources into receiving approval for a second indication and the possibility of lucrative returns. If that analysis doesn’t show a large potential return, or if the efficacy for the new indication isn’t overwhelmingly compelling when compared to the current standard of care for the additional indication, a manufacturer might not find it worth their time to go through the necessary steps to formally receive approval to market the drug for as a treatment for additional diseases or conditions.
That doesn’t mean that preliminary research into additional uses for existing compounds doesn’t continue within the scientific community, however. As a general example:
- An FDA-approved Compound X exists for the treatment of Condition A. The potential market for Compound X is large given that Condition A affects many people, and the condition is severe enough that consumers suffering from Condition A are willing to pay a premium for the treatment.
- A second, more severe disease, Condition B, afflicts substantially fewer people. As part of the development and approval process for Compound X, research indicated that the therapeutic showed the potential to address Condition B. The severity of Condition B means that patients suffering from it are possibly willing to pay a higher premium for the treatment.
Though patients suffering from Condition B may be willing to pay substantially more to relieve the symptoms of Condition B, because of the smaller number of people afflicted by the disease, the cost-benefit analysis for embarking on FDA approval for Compound A to additionally treat Condition B and its smaller number of afflicted patients—unfortunately, being viewed as potential customers—shows that the investment isn’t warranted.
If the scientific consensus in the published and peer-reviewed medical literature suggests that Compound X could better the lives of patients suffering from Condition B, however, medical professionals are legally empowered (allowed) to prescribe Compound X to those patients to alleviate their symptoms. As a check against reckless overprescription—though the complexities of the prescription opioid crisis of the 21st century suggest otherwise—the regulated licensure of medical professionals by government-approved boards helps to make sure that doctors operate within the bounds of accepted medical practice.
The advantages to off-label prescribing are manifold for all sides. Let’s walk through a couple reasons for each.
From the perspective of the FDA
By definition, therapeutics that can be prescribed off-label have already demonstrated safety in patients and non-patients as part of the clinical review process. Off-label prescribing, when done in a safe and legal manner in accordance with all necessary regulations, frees up the regulatory agency to investigate new and novel compounds and expand the pool of potential safe therapeutics, rather than spending time reviewing and repurposing old ones.
From the perspective of the medical community
The legality of off-label prescription allows physicians to treat their patients for diseases that might have significant detrimental impacts on quality of life, but whose treatments might not have been seen as worthwhile investments from the vantage point of pharmaceutical or biomedical corporations. Latitude in prescription also represents deference and respect for their medical authority and discretion, rendering unto doctors what is theirs, rather than relying on interpretations by bureaucratic institutions that may not have the bandwidth or expertise to move the treatments through the approval process in a timely manner.
From the perspective of pharmaceutical and biomedical companies
Off-label prescription represents an avenue for additional commercial revenue for an already established therapeutic without the sizable investments required for full approval. Though failure to receive FDA approval means that the company can’t formally advertise the therapeutic for treating an additional condition to patients or doctors, doctors are able to request additional information and assistance within certain legal bounds. Though off-label revenue may be a fraction of what revenue from formal approval could be, it’s certainly greater than zero and helps recoup additional costs from the research and development process.
From the perspective of the patient and consumer
Off-label prescribing expands the pool of possible therapeutics and can expedite the process of receiving meaningful treatments without waiting for formal FDA marketing approval. Given that time is a precious commodity and something that can’t be gotten back when lost, treating a condition sooner can restore the quality of life for a patient on an accelerated timetable. Note that for patients suffering from hair loss, the list of FDA-approved treatments for that indication contains only two compounds: The additional clinical data showing hypertrichosis and efficacy in treating hair loss allowed for the medications to transition from being prescribed off-label and towards formal approval, acceptance, and full confidence in their usage for the explicit treatment of hair loss.
What are the downsides to off-label usage?
Consider the following: If your doctor recommended a treatment plan that relied on off-label prescriptions, rather than FDA-approved treatments, would you feel any differently about accepting the recommendation?
Either answer can be valid for legitimate reasons. If you answered yes, you’re likely concerned that the government hasn’t formally vetted the drug as an efficacious treatment—in this case, you’re highlighting the importance and significance of the FDA when it comes to building consumer confidence!
If you answered no, you’re likely satisfied with the medical advice of your physician and are placing trust in their authority and prior experience to provide a proper, timely, and cost-effective level of care. Trusting scientists and medical professionals is another positive, too!
Both of these answers highlight the drawbacks to side-stepping the formal FDA approval process, however. In the first case, the concern about FDA approval correctly implies that off-label prescribing may lack the rigor and foundation of formally approved prescriptions. The additional efficacy testing could, at best, demonstrate that the therapeutic was equally effective to the existing treatment on the market. At worst, that testing in a larger population could reveal rare conditions that affect a small proportion of the population—blood clotting from the Johnson & Johnson COVID-19 vaccine is one such example of a rare condition that required the resolution of a large sample size to emerge.
In the latter example, placing trust in more proximate and familiar sources—like a long-term doctor—means that you may receive a more personalized and relevant level of care from a provider with a more intimate understanding of your needs and goals. On the other hand, relying on a singular, local source means that more trust in your own wellbeing is placed in a single individual and point of failure, rather than a system with checks, balances, and multiple points of failure. The expertise of a single medical provider is substantial, but it isn’t infinite—everyone makes mistakes. The bureaucratic layering of the approval process, however, means more opportunities for those mistakes to be caught before they adversely affect a patient directly.
In some cases, even FDA-approved treatments may demonstrate a failure of efficacy or exhibit greater safety concerns when made available to the general public. Though it isn’t a prescription therapeutic, the aforementioned example of the shortage of baby formula represents the recall process in action: The formulation process and standards of manufacturing were found to have deviated from what had been outlined, contamination occurred, and a recall and intervention aimed to limit further harm.
Off-label and hair loss
When it comes to addressing hair loss, a variety of options exist outside of the two FDA-approved treatments for androgenic alopecia, minoxidil and finasteride. In some cases, medications similar to finasteride like dutasteride, commonly branded as Avodart, have shown promising results in treating hair loss and are currently approved for such an indication in Japan and South Korea. For androgenetic alopecia in women, spironolactone represents an additional tool for treating hair loss with fewer off-target hormonal effects.
All in all, from vitamins to prescriptions and all the supplements and devices in between, a plethora of hair loss treatments exist and can make marginal improvements at getting hair growing again. Not all of the treatments have undergone the rigors of the FDA approval process, but many have shown a satisfactory safety profile for off-label treatment. When it comes to addressing hair loss and considering solutions for a particular diagnosis, it never hurts to keep these thoughts in mind.