From The Editor | November 22, 2019

Transition Biologics: FDA, Industry Examine Regulatory Nuances

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By Anna Rose Welch, Editorial & Community Director, Advancing RNA

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*Editors Note: This article was published just days prior to the release of the FDA's "Clinical Immunogenicity Considerations For Biosimilar and Interchangeable Insulin Products" guidance. In this guidance, the agency writes that, should comparative analytical assessments demonstrate high similarity, comparative clinical immunogenicity studies will no longer be necessary for biosimilar insulins and interchangeable insulins.

In March 2020, the U.S. biosimilar industry is poised to celebrate two big events. Not only will it be the 10th anniversary of the passage of the Biologics Price Competition and Innovation Act (BPCIA), but it will also mark the addition of several newly deemed biologic/biosimilar products. In line with a Congressional directive, the FDA must transition products previously approved as drugs under the Federal Food, Drug, and Cosmetic Act (FD&C Act) to biologics under the Public Health Service Act (PHS Act) by March 23, 2020. Though this directive applies to 90 soon-to-be biologic products, including growth hormones, the insulin products have been garnering the most attention given the size of the patient population and the current crisis of affordable access in the U.S. Seeing as insulins are given out via the pharmacy, stakeholders have also expressed excitement that this transition could encourage the development of interchangeable insulin biosimilars, leading to even greater competition in the space.

Following this transition, biosimilar makers investing in follow-on biologics to current branded products will have their products approved via the 351(k) biosimilars pathway. Novel products will be transferred to the 351(a) biologics pathway. It’s important to note that this directive is unique to the U.S. regulatory pathway, seeing as these transitional products have long been regulated as biologics in Europe.

At the recent DIA biosimilars conference, there was a panel discussion on this very topic, featuring the insights of the FDA’s Eva Temkin, Biocon’s Sundar Ramanan, the Juvenile Diabetes Research Foundation’s (JDRF’s) Marjana Marinac, and Avalere’s Gillian Woollett as the panel moderator. During this panel, each stakeholder — whether it be a regulator, patient, or biosimilar manufacturer — expressed great excitement at the prospect of this regulatory change. Though these experts all believe this transition should go off without a hitch and will not hinder insulin access, there are several overarching regulatory and educational considerations the industry should be aware of as March continues to creep closer. In this first article of two, I’ll share the regulatory considerations that will primarily be impacting manufacturers moving forward.

Only Minimal Adjustments In Agency Requirements Expected Post-Transition

In the biosimilar industry, we hardly need anything else slowing access to lower-cost biologic competition — and, at least on paper, a regulatory transition may sound akin to a market-stopping force of nature. In fact, the biosimilar industry has expressed concerns about delays of biosimilar and interchangeable biosimilar approvals that could be caused by the roll-over. As Avalere Health's Gillian Woollett and Kelly George discuss in their BioDrugs article, it's unlikely we will see an insulin biosimilar approval until 2021 due to the "regulatory gap year" created by the transition. Due to the nature of this transition, biologics and biosimilar makers will not be able to begin the regulatory process until the date of the roll-over. Similarly, since any biosimilar insulins approved will not be considered interchangeable (i.e., substitutable at the pharmacy counter), this will cause additional delays in greater insulin access.

Thankfully, the FDA’s Temkin doesn’t anticipate this regulatory change will cause any unforeseen regulatory hiccups or market access barriers to future products at least none due to the information manufacturers must provide to the FDA moving forward. This is especially important to understand and shout out to all who will listen, along with the fact that the currently approved products being rolled-over will not be changing in any way.

As she said about the transition: “We don’t foresee any effects on patients. The products are going to be the same. We don’t anticipate disruption in supply, so you can all take a collective deep breath.”

But, of course, there will be a few slight changes manufacturers will need to be aware of — all of which the FDA elaborated upon fully in its Q&A guidance for industry about the “Deemed to be a License” provision. Overall there are two areas that will be impacted by this transition — the label of the products and some of the chemistry, manufacturing, and controls (CMC) requirements.

On the labeling side of things, the FDA has provided an additional window of time for manufacturers to comply with their labeling requirements. Though the transition is indeed happening in 2020, manufacturers will have until March 23, 2025 to revise their labels. For example, biologic container and carton labels will need to be updated with the proper (a.k.a. the nonproprietary) name of the biologic product and the BLA license number. Prescribing information will also need to be tweaked to comply with the PHS Act; manufacturers have to include the company’s name and address, and the product’s license number. It’s important to note that, though the newly established biologics naming standards require the addition of a suffix to the non-proprietary name of new, novel biologic and biosimilar products, the FDA is not requiring the transition biologics to adopt a suffix following the transition. The suffix will only be applied to biologics or biosimilars approved following March 23, 2020 and will not affect currently approved insulins.

On the CMC side, Temkin does not foresee major differences between the information required under the FD&C Act and the PHS Act. Most of the products previously approved as drugs will have demonstrated potency, sterility, purity, and identity, all of which are included in a biologics license application (BLA). But manufacturers may now need to provide the agency with information about lot release, distribution reports, and any manufacturing problems for products distributed on the market. 

“These differences are fairly minor, and we expect the practical effects will be minimal,” Temkin concluded. But she also repeated the agency’s desire to continue hearing from the industry about any overlooked aspects on which the agency can provide guidance or consider to make biosimilar/interchangeable development and approval more efficient.

Interchangeability: Opinions Still Abound On Feasibility, Importance For Insulins

Back in May, the FDA held a Part 15 hearing highlighting the patient community’s needs, immunogenicity and interchangeability considerations, and device strategies. As a portion of my write-up on this hearing shared, interchangeability — and the standards required to meet this regulatory designation — remains a controversial topic for a number of stakeholders. When we talk about interchangeability in the context of today’s industry, there are, admittedly, many eye-rolls, mostly because today’s biosimilars are being given out in the hospital setting at the behest of a doctor. Patients in the hospital are not going to the pharmacy counter for their biologics and having the pharmacist switch them automatically to the biosimilar nor do we even have pharmacy-distributed biosimilars on the market yet.

But insulins are doled out from the pharmacy counter — and to a large population of patients. Once insulin biosimilars are approved, interchangeability at the pharmacy counter becomes a key consideration.  At the Part 15 hearing, one advocate passionately advocated for biosimilar makers to pursue interchangeability to ensure the greatest access to cost-effective insulins. Given the many access failures patients are facing today, some stakeholders are worried that simply approving a non-interchangeable biosimilar insulin would not result in a meaningful increase in patient access.

Temkin emphasized just how much she hoped to see attitudes change when it comes to perceptions of interchangeability in the biosimilar industry — especially once the regulatory transition occurs. For one, she emphasized the FDA’s efforts to make the final interchangeability guidelines flexible to encourage greater interest from manufacturers.

“While the statute does spell out additional legal requirements for approval of an interchangeable, we are hoping to get interchangeable applications, especially seeing as the transition products are differently situated from a business standpoint,” Temkin said. “I do think the agency is cognizant of the different incentives and business structures that might inform whether or not a sponsor chooses to seek interchangeability. But I also wanted to put it out there, since it doesn’t often come up in conversation, that Congress does provide an additional incentive — first interchangeable exclusivity — for companies that choose to undertake what might be perceived as additional regulatory risks.”

However, this remains a tricky argument to sell, given the ongoing regulatory debates about how much data is necessary to demonstrate biosimilarity, let alone interchangeability. Indeed, this discussion is now being held for biosimilar insulins. As Biocon’s Ramanan argued in his DIA presentation, insulins, which are much simpler molecules compared to monoclonal antibodies, do not, and should not demand the same burden of clinical proof that more complex molecules currently do. “We can characterize insulin down to the last Dalton,” he said. “There is no unknown or known residual uncertainty from the structural characterization of insulins.” In addition, you can glean safety and efficacy parameters using orthogonal in vitro assays, which also helps eliminate uncertainty about safety. This information goes a long way to eliminating the need for large clinical equivalence and switching trials.

In fact, in this day and age when talk of regulatory harmonization (or, at least greater regulatory alignment) is reaching new heights, it’s important to note that the European Medicines Agency (EMA) has actually stipulated in guidance that a large equivalence trial is no longer necessary to approve a biosimilar insulin. There are a number of factors informing this decision, including the presence of a PD marker for insulin, which serves as a surrogate for efficacy. Similarly, though anti-drug antibodies (ADAs) typically impact the clinical efficacy and safety of complex mAb treatments, multiple long-term studies in both Type 1 and Type 2 diabetes have deemed both human and analog insulins safe and effective, regardless of the presence of ADAs. (This was reiterated multiple times in the Part 15 hearing by physicians, as well.)

Given this lack of concern over immunogenicity, along with the molecule’s ability to be fully characterized, Ramanan emphasized the importance of making sure regulatory requirements for insulin biosimilarity and interchangeability are “proportionate to the complexity of the molecule.” He also urged the agency to utilize clinical trials from outside the U.S.

“If there was a value-add to doing an addition U.S.-specific 300-patient trial, then there would be no question,” he added. “But we should really ask the question: what is the value add for the patient when the biosimilar can enter the marketplace two or three years ahead of time by not carrying out additional trials? Could, perhaps, the agency consider all the available evidence, including real world evidence, and, if needed, require a post-approval registry for safety data instead, to enable earlier and greater competition?”

In fact, he even makes the argument that, in an ideal world, future biosimilars for insulin would be approved as interchangeable following characterization and a comparative PK trial, without the need for multiple switch studies. Though it may sound like a “pie-in-the-sky” goal, it might not be too far outside of the agency’s comfort zone. Afterall, he pointed out, in emergency situations, the agency has deemed different manufacturers’ versions of over-the-counter human insulins interchangeable. For example, taking a look at the x-ray crystallography of Humulin and Novolin reveals variations that seemingly would result in clinical differences given that the variations could impact PD. However, large differences in the crystal morphology doesn’t appear to have any clinical impact given the effective therapeutic range is the same (i.e., identical unit-per-unit dosage).

We also cannot ignore the current existence of authorized generics — soon-to-be authorized biosimilars — in our discussions on interchangeability in the insulin space. After all, a big, unanswered question keeping the industry on its toes is what will become of the insulins approved as “authorized generics?” In the generics industry, authorized generics are the exact same product that has just been rebranded and repackaged by the originator company and sold for a cheaper price on the market. In the small molecule realm, they are also able to be substituted for the brand at the pharmacy counter.

So far in the soon-to-be biologics space, Eli Lilly has launched an authorized generic (soon-expected-to-be biosimilar [or biologic?]) of its insulin lispro injection (Humalog) for 50 percent less than the brand. Novo Nordisk followed suit with authorized “biosimilars” of its NovoLog (insulin aspart) and NovoLog Mix (insulin aspart protamine and insulin aspart). (For a few great articles on this topic, check out here and here.)

The question remains: how will these products be categorized post-transition (i.e., as originators or biosimilars), and will they be considered interchangeable without the need to carry out switching studies? (They did hold interchangeable status as authorized generics prior to the transition.)

Interestingly, the presence of authorized generics is hardly just a U.S. concern; a RAPS article recently covered the ongoing effort to have the EMA crack down on the presence of “autobiologicals” in the EU, which function similarly to authorized generics. Generic and biosimilar manufacturers and trade groups have expressed concerns this practice can harm biosimilar competition, extend a brand company’s market dominance, and lead to shortages.

There are any number of theories I’ve heard of how these products could be transitioned in the U.S., but to-date, there’s been no regulatory clarity provided. While this topic was broached during the Q&A at DIA, the agency didn’t share how they plan to approach authorized generics moving forward.

Stay tuned for part two which will share several insights from the JDRF’s Marinac on how she anticipates this transition will impact the diabetes patient community.