By John Facciponte, PhD

Understanding the regulatory process for approval of drugs and biologics, how insulins have been regulated and the pending regulatory changes forthcoming for insulins are all important issues for our clients who have products or pipeline products under development or will acquire products under development within the next 2 years. We begin by describing the current regulatory view of insulins and follow with a historical perspective on insulins as recombinant proteins. Next, we describe the arrival of biosimilars in the US and the 2010 enacted legislation that provided guidance to industry. Lastly, we describe the 2016 provision to that legislation that facilitates the long-awaited regulatory classification for insulins.

The Food and Drug Administration (FDA) approves drugs under the Food, Drug and Cosmetic Act (FDCA), listed in the Orange Book, while biologics are licensed under the Public Health Service (PHS) Act and are listed in the Purple Book.1,2 The Center for Drug Evaluation and Research (CDER) approves drugs, and the Center for Biologics Evaluation and Research (CBER) licenses biologics. A timely topic discussed in regulatory forums is that of the first recombinant proteins, namely recombinant insulins used to treat diabetes and why they are still regarded as drugs today. Although considered biologics in the scientific literature for some time now, they were originally approved as drugs at the FDA under section 505 of the FDCA and not licensed as biologics under section 351 of the PHS Act.

For a historical perspective, recombinant insulins and growth hormones were first approved as a new class of therapeutic proteins, the first biologicals products created via a biotechnology-driven process and developed during the recombinant DNA revolution of the 1980s. Specifically, Humulin® (insulin human injection) was approved as the world’s first recombinant ‘drug’ product in 1982, approved under the FDCA. These insulins differed from small molecule drugs due to their complex biological structure and the biological processes used to manufacture them—at first bacteria, then other living systems including human and animal cells—as well as other attributes such as aseptic sterile techniques used to manufacture these biological products. Biological products, or ‘biologics’ as they are known today, include a wide range of products such as vaccines, blood (components), gene therapy, and tissues, as well as recombinant therapeutic proteins (excluding insulins and other applicable therapeutics).

The fact that insulins are still considered drugs by the FDA has created a slight regulatory conundrum with the arrival of the first biosimilar approval in the US in 2015 (filgrastim-sndz). Biosimilars, approved in Europe for over a decade, are biologics that are highly similar to the reference biological product with no clinically meaningful differences in terms of safety profile, purity, and potency.3 Biosimilars are listed in the Purple Book with their reference biologic. A common analogy sometimes used is biosimilars are to biologics as generics are to drugs. The conundrum lies in that there are no insulin biosimilars in the US since insulins are currently considered drugs and as such cannot be considered a reference biological product. In 2015, the FDA approved Basaglar® (insulin glargine injection), similar to the insulin Lantus® (insulin glargine injection). The FDA circumvented this naming dilemma and refers to Basaglar® as a “follow-on” insulin as it cannot classify it as a biosimilar (check the Purple Book and Basaglar® is not listed there, it is in the Orange Book). Consequently, Basaglar® is currently also considered a drug by the FDA; interestingly, it cannot be considered a generic drug either since it is not a small molecule drug. So although Basaglar® is the first insulin biosimilar in the US, it cannot be marketed as such, at least not just yet.

The pending solution to this classification dilemma for insulins comes in the form of a 2016 draft guidance document which serves as a provision to the Biologics Price Competition and Innovation Act (BPCIA) of 2009 which outlined the biosimilar regulatory approval process. The implementation of the “Deemed to be a License” Provision of the BPCIA focuses on ‘roll-over’ of certain therapeutics as biologics that were initially approved as drugs: namely insulins, growth hormones, and certain other applicable biologics.4 For context, on March 23, 2010, the BPCI Act was enacted as part of the Patient Protection and Affordable Care Act (Obamacare) and the clock began to tick for the transition of these remaining ‘drugs’ to be considered as ‘biologics’ within a decade—March 23, 2020. The last several years have given the FDA time to prepare to implement these changes in the regulatory pathway processes at the Centers of the FDA and is sufficient time for the FDA to draft final guidance for industry leading up to the roll-over date.

After the roll-over date, Orange Book designations of insulins should automatically roll-over as biologics and be placed in the Purple Book. However, it is not clear whether currently approved drugs will become stand-alone biologics or biosimilars. Since the 2016 “Deemed to be a License” Provision of the BPCIA Act is a draft document, companies are anxiously awaiting a Final Guidance document that clearly specifies which products will be rolled-over by March 2020. There are different types of insulins (short- and long-acting) and several companies produce them, so the impact will felt across many insulin-producing companies as well as companies for the other applicable biologics.

Lastly, interchangeable biosimilars are a subset of biosimilars and interchangeability is seen as a major benefit to biosimilar development, as section 351(i) of the PHS Act allows for interchangeable biosimilars to be substituted for their reference biologic at the pharmacy level. Although there are no interchangeable biosimilars approved in the US and draft guidance has only been published in January 2017, it is anticipated that interchangeable biosimilars will be licensed by 2019.5 Depending on whether the reference product for the interchangeable is a licensed bona-fide biologic or an insulin will determine whether the first licensed interchangeable biosimilar is actually just that or will be considered another ‘follow-on insulin’ or some other label, adding to the number of agents that will undergo classification changes after the roll-over date. How this delay in labeling insulins as biologics impacts payer/physician/patient perception of insulin as biologics and/or biosimilars remains to be seen. As insulins are heavily prescribed drugs today, the impact of the roll-over date may have far-reaching impact on stakeholder perception of biosimilars in general.

How can our clients anticipate these changes? Clients need to first identify if any of their products or their pipeline products will be considered one of these roll-over products or if they are considering acquiring one of these products in the next year or two. Companies that are starting the application process within the next two years that are then potentially rolled-over as a biologic or biosimilar would need to refile as well as align on product naming and labeling changes. Developing a strategic timeline for the BLA application and FDA review process will need to be taken into account with the upcoming March 2020 roll-over date to minimize costly delays with the FDA. Interacting with the FDA for continual guidance moving forward will be pivotal for these companies.

What will we do as AXON? Once final guidance is published, we can discuss these regulatory changes with clients to inform, educate and ultimately partner with client both before and after the roll-over date. We can collaborate with client at every step along this process to align with the changing FDA regulatory landscape. As more biosimilars gain approval, the discussion of biosimilars will inevitably continue to gain momentum leading up to the roll-over date. Other than the renaming of insulins as biologics and ‘follow-on insulin’ to potentially ‘insulin biosimilar’, how the biologic roll-over date impacts the biosimilar marketplace remains to be seen. Lastly, an open question for consideration: with the pending roll-over date looming, what changes can be anticipated in the marketplace for our clients and how will this ultimately change their approach to communications?


  1. Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book). FDA Website. Accessed April 8, 2018.
  2. Purple Book: Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations Accessed April 8, 2018.
  3. US Food and Drug Administration. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. Rockville, MD: FDA; 2015. Accessed April 8, 2018.
  4. US Food and Drug Administration. Guidance for Industry: Implementation of the “Deemed to be a License” Provision of the Biologics Price Competition and Innovation Act of 2009. Rockville, MD: FDA; March 2016. Accessed April 8, 2018.
  5. Regulatory Affairs Professionals Society (RAPS). FDA: Interchangeable Biosimilar Approvals Expected Within 2 Years. Zachary Brennan. June 26, 2017. Accessed April 8, 2018.