From The Editor | August 29, 2018

How The Regulatory Pathway Shapes Biosimilar Business Decisions

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By Anna Rose Welch, Editor, Biosimilar Development

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*Shortly after the publication of this article, Chen stepped down as CMO and CSO of Pfenex. He remains a medical and scientific advisor to the company.

The biosimilar regulatory space has been alive with conversations the last few months. As I discussed in a recent article, the Medicines for Europe Biosimilar Medicines Group conference in April touched upon the biggest changes the industry would like to see made to the biosimilar regulatory pathway. These included implementing the global comparator reference products and eliminating large confirmatory Phase 3 trials, to name a few. Indeed, in just the last few months, the biosimilar space has welcomed a new publication in BioDrugs highlighting the analytical efforts better equipped to determine comparability than Phase 3 biosimilar trials. Similarly, a new response to this BioDrugs publication argues there is an ethical concern to continuing Phase 3 biosimilar trials when they have yet to contribute any new information about the molecule itself.

But there is one U.S. regulatory topic I have yet to discuss at length, and it currently raises more questions than answers: the FDA’s 505(b)(2) pathway. This pathway was created primarily to support the approval of new indications, routes of delivery, or sustained-release versions of existing drugs. However, it has also been leveraged to support the approval of follow-on, or “generic” versions, of biologics — for instance, growth hormone, insulin, and teriparatide — that were originally approved via a New Drug Application (NDA) as opposed to a Biologics License Application (BLA). While these follow-on biologics are not considered biosimilars, these same molecules are approved as biosimilars in the EU, Japan, Canada, and pretty much everywhere else in the world. Not only is this a confusing pathway to understand because of these designation differences, but it’s also facing a particularly big change. Come March 2020, the FDA plans to phase out this particular pathway for most follow-on biologics to ensure harmonization with the 351(k) biosimilar pathway. Recombinant peptides that are less than 40 amino acids in length are exempt from the switch.

As fate would have it, I had the opportunity to talk to Hubert Chen, CMO and CSO for Pfenex, at the World Biosimilars Congress earlier this year. At the time of the interview, the biotech had just received some fabulous news: its lead candidate PF708, a follow-on biologic of Forteo (teriparatide) for osteoporosis, demonstrated comparable results to the reference product in a Phase 3 study. The company plans to file PF708 via the 505(b)(2) pathway in the upcoming months.

As such, I took the opportunity to pick Chen’s brain, not only about the challenging decisions the company has had to make in the past year about its biosimilar pipeline, but also about Pfenex’s efforts getting its teriparatide follow-on ready for the 505(b)(2) pathway. One of the biggest questions we sat down to answer — and, honestly, what still remains to be seen — was when is a biosimilar not a biosimilar in the FDA’s eyes?

The 505(b)(2) Pathway At A Glance

Over the past few years, there have been a number of conversations about scientific alignment between the different regulatory agencies. In many cases, companies pursuing global development have been met with seemingly small but significant scientific differences between what the regulators require. The FDA, Health Canada, European Medicines Agency (EMA), and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) have increased their collaboration in order to streamline development requirements as much as possible. However, the 505(b)(2) pathway remains one of the larger differentiations between how the agencies address certain molecules.

As Chen explained, the 505(b)(2) pathway is currently used for follow-on biologics for which the originator was approved through the 505(b)(1) or NDA pathway. We can see how this difference has impacted the regulatory approve of follow-on insulins in the U.S. vs. the EU. While the FDA approved Admelog (insulin lispro injection) and Basaglar (insulin glargine injection) as follow-on biologics, these and other insulin products have all been approved in the EU via the biosimilar pathway. As an article from RAPS described, products like insulins currently are not permitted to use the biosimilar pathway because the reference products do not have full BLA on which the follow-on maker can rely. As such, the 505(b)(2) pathway allows for the drug maker to use some of the originator’s data from its NDA.

We’re all familiar with the fact that the 351(k) biosimilar pathway is abbreviated to ensure lower development costs and, in turn, more cost-effective products. But there are opportunities for abbreviated development using the 505(b)(2) pathway, as well. Traditionally, this pathway has been used to develop different formulations or add indications to a label. But Pfenex has been in conversations with the FDA about reducing the clinical demands for its candidate.

“Instead of requiring efficacy outcomes in a large Phase 3 for approval, we have proposed that we only need to demonstrate pharmacokinetics (PK) in healthy subjects and immunogenicity in patients,” Chen explained. “There’s no need for fracture outcomes studies, which require thousands of patients and years of follow-up. We also proposed that there would be no "hard" requirement to demonstrate improvements in bone mineral density, which is another common Pharmacodynamics (PD) endpoint to determine comparability of osteoporosis drugs. If all goes well, we will be the first to potentially receive approval for an osteoporosis drug based on only a 24-week trial in patients. This is really encouraging from a regulatory perspective.”

What was also encouraging, Chen noted, was the involvement of the FDA’s biosimilar team during Pfenex’s initial meetings with members of the Division of Bone, Reproductive, and Urologic Products. This involvement will be critical given the agency’s goals to eliminate the 505(b)(2) pathway for most follow-on biologics in 2020. Chen believes the biosimilar team’s presence in these meetings is a good indicator of the agency’s desire to harmonize the 505(b)(2) and 351(k) pathways. 

As it stands right now, there are several main differences between the follow-on and biosimilar regulatory requirements. For one, follow-on products are typically granted tentative rather than full approvals. The FDA’s approval for these drugs is linked to patent infringement lawsuits. So far, in the U.S., Basaglar and Admelog were granted full approvals. But Lusdana, a follow-on of Lantus made by Samsung Bioepis, has only received tentative approval due to outstanding patent litigation. Now, come March 2020, any products still in review will be required to resubmit their products as a new biologic product using a BLA — either a full BLA or a biosimilar BLA. (Though smaller peptides that are 40 amino acids or less in length, like teriparatide, will still be treated as "small molecules" by the FDA and qualify for the 505(b)(2) pathway, said Chen.)

In addition to these legal differences, one key difference Chen noted between the biosimilar and follow-on development requirements was in the analytical foundation. The two pathways differ in the terminology on this important concept. The term “similarity" is used in the 351(k) pathway, while “comparability” is used in the 505(b)(2) pathway. When the conference occurred, the FDA had yet to revoke its controversial statistical analysis guidance, which urged biosimilar makers to provide a statistical comparison for tier-one Critical Quality Attributes (CQAs). This would have been an expensive burden, requiring comparison of ten-plus lots of the originator and biosimilar candidate to demonstrate analytical similarity. In contrast, the 505(b)(2) pathway does not mandate a formal statistical approach in demonstrating analytical “comparability,” which is more qualitative in nature. As a result, the number of lots required is invariably smaller.

Another key difference Chen noted is that process performance qualification (PPQ) can be performed following a 505(b)(2) NDA submission, whereas the completion of PPQ is required in any BLA submission. This difference clearly impacts the timing and resource requirements to a value-inflection point: acceptance of the regulatory dossier by the FDA.

The Impact Of The Regulatory Pathway On Corporate Decisions

A company considers a number of key factors when deciding how to progress wisely with its pipeline. For instance, it’s important for any company to consider how much market competition would be facing the candidate (i.e. would the candidate be first to market or fourth?). It’s also critical to consider the market size. A $250 million market would provide a very different opportunity than a $3 billion market — especially for a small biotech. But Chen also emphasized how impactful the regulatory pathway can also be when making difficult pipeline decisions.

A few months ago, Pfenex announced it would temporarily halt development of its lead biosimilar products to focus exclusively on PF708. Pfenex didn’t give up its biosimilars for good; the company is still seeking partners to codevelop its versions of Neulasta and Lucentis. But because it’s a small company in this space, Chen emphasized the importance of considering the regulatory pathway and evaluating a company’s abilities to meet the demands of that pathway.

“For Lucentis, we knew we were going to have to conduct a large, comparative patient study that would require a one-year treatment duration,” Chen shared. “We knew what the timeline and resource requirements were going to be versus something like the Neulasta biosimilar, which could require only PK/PD and immunogenicity in healthy subjects.”

These different regulatory requirements pose drastically different value propositions. Chen used the analogy of deciding how many of your, say, six children should get to college. As he said, would you want to send all of them to college, regardless of the university’s quality, or would you prefer to prioritize one or two to make sure they get the best education possible? Ultimately, the company chose to advance its teriparatide candidate because it promised an abbreviated clinical development package and because the company had the necessary expertise in-house to get the appropriate dossier together.

As Chen specified, there’s no right or wrong answer — it all depends on the individual company’s size and goals. (In fact, he speaks more at length about this thought process in a Q&A about the decisions facing small platform biotechs managing both innovative and biosimilar development.) But as the biosimilar space with its wide variety of small and large players across the globe approach difficult pipeline decisions, it’s critical they continue to pay close attention to the ongoing discussions in the regulatory sphere. There are still some large questions that need to be answered by individual regulators, for instance, about the necessity of certain statistical tools in the EU and interchangeability in the U.S. On a broader scale however, there are ongoing discussions in the regulatory sphere that, one day, could positively influence the amount of candidates a company chooses to move forward through development and, in turn, the pricing of the product. As such, it behooves companies of all sizes to keep abreast of the movement within the regulatory sphere in order to plan the pipeline that best fits its capabilities — both for now, and in the future.