Key Takeaways
- Since 2022, four GLP-1 drugs, including those indicated for weight loss, have been on FDA’s drug shortage list due to extraordinarily high patient demand. The shortage has, in turn, resulted in widespread compounding of GLP-1 products that would otherwise be prohibited under the relevant statutory provisions.
- Patient demand has remained high for these compounded versions; however, if and when the GLP-1 shortage comes to an end, all compounded versions will become unapproved drugs. This is likely to leave FDA in an unprecedented position as it grapples with patient access issues and potential legal challenges from compounders.
- Regardless of how FDA responds, GLP-1 compounding is unlikely to portend a change in FDA’s approach to compounding given the unique factors in play in the GLP-1 market and the safety concerns surrounding drug compounding.
What Are GLP-1s?
Glucagon-like peptide-1 receptor agonists, also known as GLP-1 drugs, are a class of medications that mimic the action of the glucagon-like peptide-1 hormone, which is involved in the regulation of blood sugar levels. These drugs can also slow gastric emptying, which contributes to weight loss. GLP-1s were first approved by FDA to treat type 2 diabetes, with more recent entrants approved to treat weight loss and an increasing number of GLP-1s receiving a label extension for the reduction of major cardiac adverse effects. GLP-1s also are being studied for many other potential indications, including chronic kidney disease, psychiatric disorders, neurodegenerative disorders and gastrointestinal disorders, among others.
The effectiveness of GLP-1s, both as a weight loss drug and a diabetes treatment, led to a meteoric rise in demand and, ultimately, to FDA declaring a shortage in late 2022, after which the market for compounded versions of these products took off. In this article, we explore what compounding is, why compounders are allowed to make GLP-1s and what may happen when approved GLP-1s are no longer in shortage.
FDA Regulation of Compounding
Compounding is the process of combining, mixing or altering ingredients in approved drugs to make medications for individual patients. Regulation of compounding in the U.S. changed significantly after the New England Compounding Center (NECC), a compounding pharmacy in Massachusetts, was linked to a nationwide outbreak of fungal meningitis. This outbreak was caused by contaminated steroid injections produced by NECC, which led to over 60 deaths and hundreds of illnesses across multiple states.
In response to this crisis, Congress passed the Drug Quality and Security Act (DQSA) in 2013. The DQSA aimed to strengthen the regulation of compounding pharmacies and clarified the roles of state and federal authorities in regulating compounding, aiming to prevent similar public health emergencies in the future. Per FDA regulations enacted under the DQSA, compounding can be done in two settings: pharmacies (503A compounding) and outsourcing facilities (503B compounding).
Section 503A permits compounding of drug products “as customized therapies for identified individual patients whose medical needs cannot be met by commercially available drug products.”1 For example, drugs may be compounded under 503A for pediatric or elderly patients who require liquid dosing or patients who may be allergic to an inactive ingredient and need a different formulation. 503A compounding is typically performed at a pharmacy by a licensed pharmacist, pursuant to a specific prescription for a particular patient, and is exempt from current good manufacturing practices (cGMP), FDA approval and the requirement of labeling with adequate directions for use. 503A does permit compounding of an FDA-approved drug if a change to the compounded product (such as dosage form) makes a “significant difference” for an individual patient, but 503A cannot be relied upon to produce “essentially a copy” of an approved drug or to compound a drug “regularly or in inordinate amounts.” Importantly, FDA has stated explicitly that a lower price does not constitute a significant difference for patients that would allow copies of approved drugs to be compounded.2
503B compounding, on the other hand, is performed at “outsourcing facilities,” which are subject to stricter FDA oversight, including cGMP requirements, a requirement to register with FDA, periodic FDA inspections and an obligation to submit adverse event reports and other product-specific information to FDA. Unlike 503A, 503B permits the production of compounded medicines in bulk without individual prescriptions. Nevertheless, 503B, like 503A, does not permit compounding of “essentially copies” of commercially available, FDA-approved products.
This prohibition is driven by policy considerations, including a preference for patients to take an FDA-approved drug, if available. In addition, without this prohibition, compounders could immediately begin making copies of any drug that FDA approves, undermining both the FDA approval process and the generic drug market. This prohibition does include certain exceptions, including that a drug product is not considered by FDA to be commercially available if it “appears on the FDA drug shortage list in effect under section 506E of the FD&C Act.” If an FDA-approved drug appears on the shortage list, then compounded versions are not considered essentially a copy of a commercially available drug, and the rules about making it regularly or in large amounts do not apply.
Compounding and GLP-1s
Since 2022, four GLP-1 drugs, including those indicated for weight loss, have been on FDA’s drug shortage list. As a result, these drugs have not been subject to the “essentially a copy” prohibition on compounding or the quantity restrictions under 503A. As a result, both 503A compounding pharmacies and 503B outsourcing facilities have been permitted to produce compounded GLP-1 products in large quantities to meet market demand. Compounders have taken advantage of the business opportunity created by the shortage to produce high volumes of compounded GLP-1s. Patients have relied on this increased availability to access compounded GLP-1s via telehealth or other services at a more accessible price than their branded counterparts.
Importantly, while compounded GLP-1s have the same active pharmaceutical ingredient (API) as the branded versions, the products may not be identical. There are hundreds of bulk pharmaceutical manufacturers registered with FDA to manufacture the APIs in GLP-1s, but FDA does not confirm that API produced by the bulk manufacturers is identical to the API used in branded versions because it is never reviewed by the Agency. In addition, as noted above, GLP-1s compounded by 503A compounding pharmacies are not required to have directions for use. This is particularly significant because compounded GLP-1s generally come in vials, which require patients to measure out the correct dose to inject with a syringe, rather than the easier-to-use, pre-measured auto-injectors generally used for approved GLP-1s.
Future of the Compounded GLP-1 Market and Potential Legal Risks
As discussed above, the proliferation of compounded GLP-1s was triggered by a widespread shortage of approved GLP-1s. If and when FDA determines that GLP-1s are no longer in shortage, compounded versions will be tantamount to unapproved drugs. 503A facilities will be required to cease compounding immediately, while 503B outsourcing facilities will have a 60-day wind down period.3
Usually, the end of a drug shortage is a good thing — signaling patient access and adequate supply of a much-needed medicine — and met without resistance. However, the demand for the compounded versions of GLP-1s puts FDA in a different, and unprecedented, place in evaluating what the end of a shortage may mean for patient access. FDA has already seen this reality first hand: In October 2024, FDA changed the status of one GLP-1 weight loss drug to no longer in shortage, and was immediately sued by the compounding industry on the basis that FDA’s determination that the shortage was over was arbitrary and capricious. FDA responded by issuing a statement allowing for continued compounding of that drug, even though it is no longer in shortage, and advising that FDA will continue to allow compounding of all GLP-1s, regardless of whether a particular drug is in shortage, until the shortage is resolved for all GLP-1s.
Despite FDA’s backtracking in this instance, we are at the beginning of the end of the GLP-1 shortage, and there is already significant agitation by patients about what it will mean for their access to weight loss drugs. For their part, compounders have had different reactions to what comes next. A few declared that they will immediately stop compounding GLP-1s that are no longer in shortage,while others have vowed to tweak presentations or formulations to attempt to avail themselves of the “significant difference” exception under 503A or the “clinical difference” exception under 503B.4 Still others may choose to challenge FDA through litigation or take their chances that FDA’s resources are stretched too thin to pursue enforcement action without evidence of a significant harm to public health from compounded products. On the flip side, manufacturers of branded GLP-1 drugs are petitioning FDA to place the active ingredients on the “demonstrably difficult” to compound list and initiating patent infringement litigation to block post-shortage compounding.
Are Compounded Drugs Our Future?
While it is tempting to see the explosion of compounded GLP-1s as a potential harbinger of things to come, particularly amid continued policy focus on reducing the costs of prescription drugs, it is unlikely that we will see a repeat with other drug classes. The uniqueness of the circumstances leading to the GLP-1 shortage and the resulting influx of compounded versions of these drugs should not be understated and was driven by a few major factors:
- Enormous consumer anticipation for these products.
- The promise of effective weight loss treatment.
- High list prices and hurdles to reimbursement by private payors.
- Inadequate supply at launch and an almost immediate shortage.
- Extremely high patient demand and resulting willingness to take compounded drugs rather than approved versions.
- An indication that is easily diagnosed via telehealth.
- Consumer-facing businesses and retailers that benefit from offering the drugs via telehealth.
FDA has repeatedly made clear that compounding is not supposed to be a quicker alternative to the ANDA pathway for generic drugs. To bring generics to market early, manufacturers must challenge or design around brand patents, which compounders are not required to do. Compounded drugs also do not undergo any review by FDA, which makes then inherently less safe than FDA-approved drugs. As such, while FDA has tolerated the burst of GLP-1 compounding activity because of the shortage, it is not incentivized to encourage, or permit, further compounding of GLP-1s or other drugs in the future.
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1 Id. at 3.
2 FDA Guidance for Industry: Compounded Drug Products That Are Essentially Copies of a Commercially Available Drug Product Under Section 503A of the Federal Food, Drug, and Cosmetic Act at 8.
3 FDA Guidance for Industry: Compounded Drug Products That Are Essentially Copies of Approved Drug Products Under Section 503B of the Federal Food, Drug, and Cosmetic Act, at 8.
4 In either of these cases, the prescribing practitioner must determine that the patient requires the different compounded version.
This memorandum is provided by Skadden, Arps, Slate, Meagher & Flom LLP and its affiliates for educational and informational purposes only and is not intended and should not be construed as legal advice. This memorandum is considered advertising under applicable state laws.