Insulin Transitions: A Dead Zone in the Gap Year, and Other Considerations

An Assessment With Gillian Woollett, MA, DPhil, Senior Vice President, Avalere Health

In this two-part conversation with one of the real go-to experts in the biosimilar field and US regulatory process, we talk with Dr. Woollett about the upcoming transition for insulins and other pharmaceuticals in March 2020, when they become regulated as 351(k) biosimilars.

BR&R: Partners Mylan and Biocon recently received a second rejection for its insulin glargine follow-on product, because of the FDA’s inspection results of Biocon’s production facility in India. If they do not get approval by the FDA by March 2020, will they have to submit a new 351(k) biologic licensing agreement (BLA)?

Gillian Woollett, DPhil, MA: In all likelihood yes, but they can’t submit a BLA yet, because there is no reference product for comparison. I’ve been calling this period before March 23, 2020 the “dead zone” and after the “gap year.”

Gillian Woollett

BR&R: Is it possible, since we’re not talking about clinical deficiencies in the product’s data, that some sort of appeal process can be implemented to spare Mylan and Biocon from having to start the BLA process from scratch?

Woollett: We should not presuppose the nature of the deficiencies as any complete response letter is confidential to the sponsor. If the FDA’s concerns are answered by this coming March, there may be no delay. However, after is more of a challenge.

Even if a sponsor is able to submit a BLA on March 24, 2020, it will likely take FDA at least another year to review the application (the “gap year”). Most of the physiochemical and clinical data can be expected to be the same, at least, but this is still a lot of extra work. We likely won’t have an interchangeable insulin until the end of 2021 at the earliest. Hence, as outlined in our paper, this transitional process for insulin will delay competition, not enhance it. And that is a pity for a product as fully characterized as insulin, where we need competition to enhance access.

BR&R: Based on an analysis we did back in June, very few manufacturers have publicly disclosed an interest in producing a biosimilar insulin at the moment. Do you think prospective manufacturers have been discouraged by the transitional timeline?

Woollett: Even in Europe, I think they’ve struggled a bit. Maybe that’s related to the nature of the reimbursement in Europe.

If they are part of the “prequalification” for biologics being undertaken at the World Health Organization (WHO), many other things should be considered in getting global access to your insulin. The WHO’s prequalification effort, albeit limited to date to a pilot for rituximab and trastuzumab, may be particularly helpful to countries with limited drug regulatory capacity. My understanding is that insulins have not been added to the list, as a regulatory matter, but are being considered.

Under this prequalification, if a biosimilar (or other drug) was approved by an agency in a highly regulated market, then that product can go on the list. However, for inclusion on the WHO’s list, the drug also has to be launched—not simply approved. This was addressed specifically in March at the Medicines for Europe meeting in Amsterdam as a problem for biosimilars. The WHO is applying a hurdle over and above FDA approval, which strikes me as a little unnecessary and somewhat counterproductive.

Some companies have extensive experience with their insulin products, but it is not documented in the manner of the highly regulated markets. We hear a lot about real-world evidence in the US, but it is not really being accepted yet.

This is another area I believe the WHO should be going—setting the ceiling as well as the floor, because what we tend to do in the highly regulated markets is overdesign things. We tend to measure parameters, simply because we can (regardless of whether they matter clinically). I call it the “EPA problem”: You only have a contaminant in the environment when you can measure it.


BR&R: Let’s talk about another instance of overdesign in our market, with insulin nomenclature and the transitional process.

Woollett: The FDA has indicated that they will not give these transitional products suffixes to their nonproprietary names. This is super important: The Agency apparently realized just how problematic and expensive changing the nonproprietary names to currently marketed products was going to be, and that they were being tracked adequately today. It would be a challenge to switch every database at midnight, throughout the supply chain, on the date of the transition to include the four-letter suffixes. This is a good decision and huge relief to many stakeholders.

The original draft guidance on nonproprietary names had the suffixes apply to approved biologics and biosimilars. The Federal Trade Commission (FTC) had made the case that having a suffix only for biosimilars flagged them as different, and anything that differentiates is necessarily a problem for competitiveness. This is what I call “friction” in the marketplace and will deter switches between reference and biosimilar products. By being fair, the suffix had to apply to all biologics, which raised the problem with the transitional products.

The databanks flagged the problem as a practical matter and massively expensive to reconcile. So, the FDA decided that drugs rolling over to the biosimilars would not receive suffixes. This will apply to all the transitional drugs—hyaluronidases, hormones, insulins, and somatropins, etc. All new products in these categories will get suffixes, irrespective of biosimilar or originator status. So “new” insulins, whether originator or biosimilar, will get suffixes, and this is going to be inordinately confusing, too, but not as expensive to implement.

Insulin biosimilars

BR&R: If they don’t apply a suffix to Basaglar®, for instance, and they do so for any transitional product approved after March 2020, it still undercuts the purpose of having the suffix—for identification of individual drugs.

Woollett: Agreed. It is evidence that you don’t need the suffixes in the first place. My overall objection to all of this is inconsistency. If you have a reason to do it, you’ve got to do whatever it is you’re doing for all products… and that is not what is happening.


BR&R: Well, consistency has not been the FDA’s strong suit. And that goes for the interchangeability of insulins as well.

Woollett: Further, none of the products rolling over can ever be designated interchangeable, because they are not biosimilar in the first place, not even Basaglar.

BR&R: Exactly! Here’s the inevitable problem where the rubber meets the road: You’re a patient at a health plan. You have been receiving Lilly’s Humalog® to control your elevated blood glucose levels. Unfortunately, you need to switch health plans next year, and the new plan doesn’t cover Humalog. It covers Novolog® and excludes Humalog or offers it at a nonpreferred copayment tier. The health plan is not interested in whether these two insulin products are interchangeable from a regulatory standpoint. The same is true with the infliximabs and filgrastims.

Woollett: It has always been true that formularies change, but it is still the physician who is doing the prescribing, and so that is OK. For interchangeability, we are only talking about someone other than the original prescriber making the switch.

And by the way, for a biosimilars, it’s not that you are not interchangeable, it’s that you are not yet designated as interchangeable. People are saying that biosimilars are “not interchangeable,” but there’s no such thing. There’s only “designated as interchangeable.” The labels of all the currently approved biosimilars are silent on interchangeability.

BR&R: From a coverage or health plan standpoint, it doesn’t really matter to them.

Woollett: At the plan level, no. Presumably, the plan would just say, “Basaglar® is covered” and simply that there’s no coverage for Lantus®, the reference product for Basaglar®. Today, Basaglar® could be designated as therapeutically equivalent with no extra clinical studies. But after the rollover, Basaglar can never, ever be designated an interchangeable product that the pharmacist can automatically substitute, which seems crazy.

BR&R: Right. Something else that you’ve pointed out in many of your pieces is the problem that these products—outside of being delivered via syringe and needle—they almost always have unique pen-delivery systems. They are a combination of device and product. If you approve these combination products through the 351(k) pathway, will the FDA then have to consider the delivery device in the determination of biosimilarity?

Woollett: That was addressed, if you remember, with the first guidance on interchangeability. The Federal Register notice had two questions outside the draft guidance itself, and one was about human factors and included the devices and self-administration questions. The FDA apparently decided to keep those outside the interchangeability guidance itself, and that was wise. Nonetheless, many of the insulins are essentially combination products.

In part 2 of this interview with Dr. Woollett, we discuss her call for the FDA to move away from totality of evidence, and to “confirmation of sufficient likeness” in its evaluation of biosimilar BLAs.

Biocon and Mylan: The Race to Approve Insulin Glargine Follow-on

Biocon received a second complete response letter relating to manufacturing plant problems in Malaysia. This may seem like a straight forward issue that could hamper its efforts to produce an insulin glargine follow-on agent, but it can become a major problem barring a very quick resolution.

In the filing Biocon made to the India Stock Exchange, the company said, “The CRL did not identify any outstanding scientific issues with the application. We remain confident of the quality of our application and do not anticipate any impact of this CRL on the commercial launch timing of our insulin glargine in the US.” However, that may be a fairly optimistic opinion.

Insulin copies are part of the class of biologics designated “transitional products” that will be approved only through the 351(k) biosimilar approval pathway after March 2020. The latest rules issued by the Food and Drug Administration (FDA) specify that if a product in this drug class (and others like growth hormones) does not receive approval by this date, the manufacturer must submit an entirely new biologic licensing application (for approval as a full-fledged biosimilar). That would require completing all of the necessary developmental steps—proving the physiochemical and pharmacodynamic equivalence to what would now be termed the reference product—Lantus®.

The FDA rules for transition products do not exempt agents that have already received complete response letters and may still be in the FDA’s queue. This is relevant because neither of Biocon’s rejection letters (the first issued in June 2018) pointed to problems with the scientific evaluation of its insulin glargine. Rather, both involved failed inspections at the plants at which Biocon was going to manufacture the agent. The drug was approved by the European Medicines Agency and is currently available by prescription in the EU.

As indicated in a previous post, pharmaceutical company interest in insulin biosimilars is fairly low. That may be because of the approaching transition date.

The question remains, can Biocon correct its Malaysian manufacturing plant deficiencies, can FDA reinspect, and can FDA issue final approval for this 505(b)2 agent before February 29, 2020? If not, even if Biocon’s plant passes inspection in December 2019, that will likely result in years’ long delay before the new BLA can be submitted.

New Biosimilar Guidances From the FDA Announced by Commissioner Gottlieb

On December 11, the Commissioner of the Food and Drug Administration (FDA), Scott Gottlieb, MD, issued a far-ranging statement on actions to be taken by the federal government to improve access to biosimilars and to begin the transition of insulins, growth hormones, and other selected drugs to biologic status, under section 351 of the Public Health Service Act.

“Today, we’re taking additional actions to advance this framework,” stated Dr. Gottlieb. “Among them, we’re issuing four new draft guidance documents today. The first two guidance documents provide greater clarity on scientific and regulatory considerations for the development of biosimilar and interchangeable products. We intend to update these new guidance documents regularly, to address development issues as they evolve.”

FDA Commissioner Scott Gottlieb

These actions were first signaled by the announcement of the Biosimilars Action Plan earlier this year.

Hiding Behind REMS to Deter Access to Samples

These guidance documents, created in question-and-answer format, address specific issues, some of which get to the heart of biosimilar development and access. For example, one section speaks to abuse of limited distribution systems requirements, in connection with Risk Evaluation and Mitigation Strategy (REMS) programs. These programs have been used as a way to “delay or derail access to reference product samples that biosimilar sponsors need for testing to support their applications for a biosimilar product.” Dr. Gottlieb said, “While the limited distribution programs can have a role in promoting patient safety, too many branded products are still misusing these programs as rhetorical smokescreens to hide anti-competitive behavior.”

Dr. Gottlieb said that FDA will, upon request only, “review study protocols submitted by biosimilar applicants to assess whether their protocols contain comparable safety protections to those in the REMS for the reference product they’re trying to reference.” The FDA will be willing to state in a letter to the reference manufacturer “that comparable protections exist, and that the FDA won’t consider it to be a violation of the branded drug company’s REMS to provide the biosimilar sponsor with a sufficient quantity of the reference product to perform testing necessary to support its biosimilar application.”

He also reiterated that it may be possible for biosimilar developers to obtain EU-licensed samples for use in comparative studies. Dr. Gottlieb indicated that the FDA was still evaluating this option.

New Routes of Administration for Biosimilars not Allowed

Another Q&A would put to rest the notion that a biosimilar maker can produce a new formulation or route of administration for an approved biosimilar product under the 351(k) pathway. The guidance states, “An applicant may not seek approval, in a 351(k) application or a supplement to an approved 351(k) application, for a route of administration, a dosage form, or a strength that is not the same as that of the reference product.” This would mean development of a subcutaneous form of infliximab, for example, would not be possible under the biosimilar regulatory pathway, because Remicade® is only available as an intravenous infusion.

On the Road Toward Interchangeable Insulins

One of the key provisions of the BPCIA is that insulins, growth hormones, and other agents for which reference products were not available under the FD&C Act, will be transitioned to the biologic regulatory pathway (under the Public Health Services Act) by 2020. The FDA has begun to consider just how this will occur.

Transition drugs

Starting in March 2020, this transition will take place. “Today, we’re laying out our policy on how these products will transition from the drug pathway to the biologics pathway, and in so doing, how we intend to use this new framework to promote competition,” said Dr. Gottlieb.

Under the “Deemed to be a License” Provision of the Biologics Price Competition and Innovation Act of 2009,” the final guidance from the FDA specifies that these newly deemed biologics will be subject to the same regulations as today’s biosimilars. “Anti-evergreening provisions under the biosimilars legislation—meant to prevent sponsors from being able to game the exclusivity provisions to forestall biosimilar entry—will apply to these newly deemed products, including insulin.”

Furthermore, these agents will not gain any additional exclusivities because of the transition (they will not get any additional exclusivity). It is assumed that once they are transitioned, and if their patents have expired, biosimilar competition can begin at once. This could mean far greater pricing pressure on insulin products (not simply glargine), and potentially even interchangeable designations that can be automatically substituted at the pharmacy.

As part of this transition, Dr. Gottlieb explained, biological products that have been approved under section 505 of the FD&C Act will be removed from the FDA’s Orange Book on March 23, 2020, based on the agency’s position that these products are no longer ‘listed drugs.’ That means that a follow-on applicant won’t be able to rely upon these NDAs for approval. They have to go down the biosimilars path after the transition.”

What Will Be Considered a Biosimilar in 2020?

Payers, providers, and patients in the US are narrowly focused on a limited set of biosimilar products; we all know them well—the anti-TNFs, the colony-stimulating growth factors, and most recently some antitumor drugs (e.g., trastuzumab, rituximab, and bevacizumab). In 2020, before the first biosimilar to Humira® hits the market, some medications may be reclassified as biosimilar status.

Tucked away in the Biologics Price Competition and Innovation Act of 2009 (BPCIA) is a set of obscure provisions that has the potential to create a good deal of confusion at that time.

“Transition drugs.” If you’re familiar with the term, you’re one of the few. Some medications are “transitioning” in the next couple of years. Specifically, drugs that will be transitioned include the insulins, but also other naturally occurring proteins, such as hyaluronidase, human growth hormones, and menotropins.

The mechanism is actually quite simple. Today, these products are all approvable under the original Food, Drug, and Cosmetics (FD&C) Act of 1962. By 2020, these agents will be approvable as biologics under the BPCIA. That means that they will not only be categorized as a biologic, but they will be subject to biosimilar—not generic—competition. No more new drug applications or abbreviated new drug applications, only biologic license applications of the 351(a) and 351(k) varieties.

In March 2016, the Food and Drug Administration (FDA) issued draft guidance on these transitional producinsulin-pensts. As the Regulatory Affairs Professional Society described it earlier this year, “Put simply: FDA will not approve any pending or tentatively approved application for a biological product under the Federal [FD&C] Act after 23 March 2020.”

This may have the effect of slowing approval of today’s so-called follow-on biologics, which will have to go through the 351(k) application process. For example, Lilly received approval for its insulin glargine product under a 505(b)2 application. This application process allowed Lilly to use clinical data from Sanofi’s originator product Lantus®. Under the letter of the new law, because no insulin glargine product has been approved via the biologic license application route, there are no “reference” or originator insulin products.

This can result in labeling and exclusivity period issues as well, possibly discouraging manufacturers of these products from applying for FDA approval. “Nothing in the [BPCIA] suggests that Congress intended to grant biological products approved under section 505 of the FD&C Act—some of which were approved decades ago—a period of exclusivity upon being deemed to have a license under the PHS Act that would impede biosimilar or interchangeable product competition in several product classes until the year 2032,” FDA said.

A legislative proposal was introduced in 2015 by Representative Michael Burgess (R-TX), which would have asked the Government Accountability Office to review the provisions and their potential impact before the 2020 transition took place. The proposal did not advance in the House.

A search revealed no updates on the legislative or regulatory sides of the fence, so we assume the transition will occur as intended. Currently stated policy by the FDA is that all biologics will receive a new four-character suffix to their nonproprietary names. Will this apply to the older insulins and growth hormones as well? Will coding, descriptors, or nomenclature for Lantus® have to change to reflect a new status as a reference biologic product? Or will this only apply to medications approved after March 2020 (in which case, there could be a confusing dichotomy here).

It could get a bit messy, folks.