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After the Rollover from Drugs to Biologics: What Remains Uncertain?

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The Biologics Price Competition and Innovation Act (BPCIA) mandates that specific protein products that were approved as drugs under section 505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) be licensed as biologics under section 351 of the Public Health Services Act (PHS Act) as of March 23, 2020.

As a result, 96 products that were biologics in science but that had historically been regulated as drugs were deemed to be licensed as a biologic a little over a month ago. The FDA has issued guidance about this transition, but uncertainties remain about what this transition means for the products that transitioned as well as for the regulation of biologics more broadly.

Authorized Generics

All 96 products that transitioned on March 23 had originally been approved either under 505(b)(1) or 505(b)(2) pathways of FD&C Act. No product approved through the Abbreviated New Drug Application (ANDA) pathway 505(j) was included in the transition. Applications for each of these pathways contain “full reports of investigations of safety and efficacy” as 505(c)s, albeit some also had a single designated reference product approved under 505(b)(1). Subsequently, all products transitioned into the 351(a) PHS Act pathway as standalone biologics.

Additionally, some sponsors of transitioning products also marketed authorized generics (AGs). These are identical to the branded drugs but are sold without the brand name on the label. In its final question and answer guidance in March, the FDA said standalone biologic manufacturers may not use the 351(k) pathway to bring an “authorized biologic” to market–a category the FDA has also referred to as “nonbranded biologics.” The agency has not yet publicly announced its plans for products that had authorized generics prior to March 23, other than to say that the former AGs cannot be biosimilars by reference to their branded counterparts.

Interchangeability for Biologics

The FDA released insulin specific draft guidance in November 2019. This purely advisory, nonbinding document significantly reduces the nature and the extent of the clinical studies potentially necessary for demonstrating interchangeability for insulins. It shows the FDA’s commitment to creating an efficient development program and increasing patient access. The guidance also opens the possibility of other product specific guidances.

Prior to March 23, all insulins were regulated as drugs. Consequently, no biologic had been approved to serve as a reference product under 351(a) for a biosimilar and no such application could be submitted to the FDA. It is notable that a therapeutic equivalence (TE) designation was possible for a biologic approved as a drug under 505(b)(2) or 505(j), but no such TE designation was issued by the FDA for any of the “rollover” products.

The statutory provisions in BPCIA allow the FDA to designate a biosimilar as interchangeable and thereby enable switching by someone other than a provider in the manner of generic drugs. This gives pharmacists the authority (subject to state law) to substitute the prescribed brand of insulin with the biosimilar. Each state has established laws about interchangeability requirements, including whether the prescriber or patient needs to be informed about the switch. No biosimilar has yet been given an interchangeability designation by the FDA. Given that insulins are dispensed in a retail setting under Part D, the opportunity for pharmacy substitution applies. As such an insulin could be the first biologic designated as interchangeable by the FDA.

Therapeutic Equivalence for Drugs

On March 23, the FDA transitioned the biologic products noted above into the Purple Book and removed them from the Orange Book. Pharmacists use the TE designation in the Orange Book to guide their recommendations for drug substitution. The Purple Book contains information on interchangeability for biologics, but none are yet so labelled.

The FDA is phasing in updates to make the Purple Book searchable, but it is organized very differently than the Orange Book, and it is unclear whether pharmacists will use it similarly. Whether a searchable tool that lists biosimilar and interchangeable products for each biologic will help pharmacists and other stakeholders navigate substitution as effectively as TE is unknown, not least given that biologics are being given suffixes to their nonproprietary names that imply the active ingredients are different.

Naming and Labeling

Starting in 2015, most biologics, including all biosimilars, were assigned a 4-letter suffix attached to their nonproprietary name. In 2017, the FDA updated guidance that all biologic products would receive a suffix. Despite this, the FDA issued guidance in March 2019 that transitioning “rollover” products would not receive suffixes but future biologics in these product classes will, irrespective of whether they are approved as 351(a) standalones or 351(k) biosimilars.

The agency has suggested suffixes facilitate pharmacovigilance, ensure identification by patients and providers, and minimize inappropriate substitution, but many who attended the FDA/FTC workshop on a Competitive Marketplace for Biosimilars on March 9, 2020 expressed concerns that suffixes create barriers to competition. Since the new products that transitioned do not have suffixes, there is precedent that suffixes are not necessary for product pharmacovigilance.

Changes in Bulk Compounding

Before the switch, some of the products were included in the 503B bulks list to be compounded in outsourcing facilities, including human chorionic gonadotropin, hyaluronidase, follicle stimulating hormone (urofollitropin), and menotropins. With the switch to being licensed as biologics, these products have been removed from 503B bulk list, since biologics are not eligible for compounding according to sections 503A and 503B of the FD&C Act unless directions to do so are included in the biologics license application (BLA). While the FDA released guidance in January 2019 that allows for able mixing, diluting, or repackaging BLA products, compounding of these products has aided healthcare professionals in providing care for many years, and their removal from being compounded will likely affect many practices.


The transition of 96 products that were previously regulated as drugs to being deemed to be licensed as biologics has implications not only for the products that transitioned but also for biologics regulation overall–including naming, labeling, and compounding. The FDA continues to work with stakeholders to approve new products, but the options for the rollover products changed substantially on March 23, and likely in a manner that delays competition from biosimilars. Timing and context are important considerations when engaging with the FDA, and Avalere’s experts can help your company determine the most effective approach. Call us to better understand the regulatory science and agency prior decisions that will allow you to better anticipate FDA’s next steps.

Since insulins may be the first products designated as interchangeable by the FDA, plans and pharmacists should prepare by understanding individual state laws around substitution.

The information presented in this insight features intelligence pulled from a State Reform 360 report, “2020 State Biosimilar Substitution Law.”

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