From The Editor | December 6, 2018

How Can The FDA Take Ownership Of Biosimilars In 2019?

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By Anna Rose Welch, Editor, Biosimilar Development

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*Editor’s note: This article was originally published in the December 2018 edition of Life Science Leader magazine. It has been split into two parts for publication on Biosimilar Development.

If there is one thing we’ve learned in the biosimilar industry over the past 12 years, it’s that a successful biosimilar market is contingent upon a highly involved and supportive government. In fact, if you were to look at the greatest biosimilar successes in countries abroad, you would likely track these triumphs to laws and guidelines put in place by a proactive government.

In the U.S., where uptake remains behind Europe, 2018 will clearly go down in the books as the “Year of Biosimilar Policy.” We saw a number of critical, biosimilar-friendly changes (or proposed changes) to Medicare Part B and Part D, as well as the passage of the Biosimilars Competition Act of 2018 and resurgence of the Creating and Restoring Equal Access to Equivalent Samples Act of 2018 (CREATES Act). There are also whispers about the U.S. Department of Health and Human Services (HHS) making changes to rebate models across federal programs.

But the most exciting occurrence in the biosimilar space in 2018 was the release of the FDA’s Biosimilar Action Plan (BAP). In lieu of the slow development of the U.S. biosimilar market, the FDA has stepped up to determine how it can improve biosimilar education, regulation, and market access.

After the industry comment period concluded in late September, I read many public comments from manufacturers, payers, and trade groups to learn their biggest market concerns, as well as what the FDA can do to solve these issues. One of the biggest takeaways I had was that the U.S. needs to implement a unified multi-stakeholder approach to solve the U.S.’ market access issues. This will, of course, require the FDA to continue broadening its purview and refining the regulatory pathway by implementing the actions outlined in the BAP. But it also will require the U.S. government healthcare agencies to take even greater charge of biosimilar policy in 2019.

A Brief Introduction To The BAP

Released in July 2018, the BAP is the FDA’s framework for revolutionizing biosimilar policies and making the development pathway and regulatory review more efficient. As the FDA spelled out:

The BAP is focused on four key areas: (1) improving the efficiency of the biosimilar and interchangeable product development and approval process; (2) maximizing the scientific and regulatory clarity for the biosimilar product development community; (3) developing effective communications to improve understanding of biosimilars among patients, clinicians, and payors; and (4) supporting market competition by reducing gaming of FDA requirements or other attempts to unfairly delay competition.  

Overall, the BAP contains a list of 11 key actions the FDA will undertake, including establishing new review tools and templates, exploring data sharing agreements with foreign regulators, expanding its biosimilar education resources, and clarifying or releasing new guidance documents. It provides a great look at some of the most pressing scientific, regulatory, and market-related challenges for biosimilars to date. Though many pressing concerns were highlighted in the industry responses, there are two broad areas that require the greatest efforts as we approach 2019: streamlining biosimilar development and encouraging more government involvement.

Waiving Bridging Studies: How Could This Impact Biosimilar Development?

In May 2017, I came across the BioDrugs publication, “A ‘Global Reference’ Comparator for Biosimilar Development,”  by Christopher Webster, principal of BioApprovals, and Avalere Health’s Gillian Woollett. At the time, this publication, which proposes a basis for selecting a comparator product that would eliminate the need for comparator bridging studies, was not widely known. On the occasions when this concept was brought up for discussion at U.S. conferences, it gained little traction or outright verbal support from regulators. That’s why it’s truly thrilling to see that eliminating bridging studies has become one of the most passionate calls-to-action from the biosimilar industry today.

Current FDA guidance requires a biosimilar sponsor to carry out bridging studies between a foreign-sourced reference and the U.S. licensed reference product, should the biosimilar sponsor wish to use the foreign-sourced reference as a comparator for biosimilar development. These studies provide a data bridge permitting a biosimilar shown to be similar to a foreign-sourced reference product to be approved as biosimilar to the U.S.-licensed product.

However, these studies, which include extensive analytical studies and often human pharmacokinetic (PK) studies, require significant amounts of time and money. Further, bridging studies have an inherent redundancy because they will be repeated by every sponsor developing a biosimilar to a particular reference product using the same foreign-sourced version of that reference as a comparator. As Webster and Woollett argue, because licensure of the reference biologic in multiple jurisdictions is based upon some of the same publicly available clinical trial data, these data provide the necessary bridge between reference products licensed in different jurisdictions.

In its BAP, the FDA asked what steps it could take to encourage global development programs that include non-U.S.-licensed comparator products. This left the door open for an impressive number of comments from companies and organizations, including the Association for Accessible Medicines (AAM), Novartis, Mylan, and the International Generic and Biosimilar Medicines Association (IGBA), pushing for the use of a global comparator reference product and, in turn, the elimination of bridging studies. Webster and Woollett define the global comparator reference product as a “single reference version of the originator biologic [that] may be selected for global biosimilar development,” as long as several key criteria are met. (For more information, I urge you to turn to their full text article online.)

Though the FDA did not explicitly express its intent to eliminate all bridging studies, the FDA Commissioner Scott Gottlieb has spoken in the past about the ethical quandary of continuing to place patients in trials “just because we can’t acknowledge something we know.” As such, the odds are good that, with Gottlieb at the helm, 2019 will be the year the FDA becomes more flexible about the use of non-U.S. licensed reference products — and, hopefully, pursues implementation of the global comparator reference product.  

More Global Regulatory Collaboration Could Modernize Biosimilar Requirements

Over the past few years, the FDA has been particularly active in establishing relationships with other regulators around the world, including forming what is known as the “biosimilars cluster” with Health Canada, Japan’s Pharmaceuticals and Medical Devices Agency (PMDA), and the European Medicines Agency (EMA). As noted in the BAP, the FDA is also exploring data-sharing initiatives to garner greater insight into biosimilars’ real-world performance. Arrangements such as these also can encourage greater scientific alignment and more efficient development protocols.

In fact, one of the areas I anticipate will see increasingly more discussion amongst regulators following increased data-sharing is the ongoing relevance of Phase 3 clinical trials in biosimilar development. Though this conversation has been broached in the industry over the past few years, it has increased in intensity throughout 2018, thanks to the publication of an article in BioDrugs by Francois-Xavier Frapaise entitled, “The End of Phase 3 Clinical Trials in Biosimilars Development?”

Frapaise voiced one argument against carrying out Phase 3 trials in biosimilar development: that these large and costly trials are not sensitive enough to determine the clinical equivalence of biosimilars versus their reference products. Rather, advancements in analytical methods and technology are providing the most in-depth information we’ve ever had on the molecular structure of both biosimilar and reference product molecules.

Webster further developed this argument in his BAP comments highlighting how, for over 20 years, these analytical characterization efforts have been the basis of post-manufacturing change comparability exercises for brand products. The experience of thousands of comparability studies — without clinical trials — has shown that where molecular structures and compositions are highly similar analytically, clinical pharmacodynamic inequivalence cannot occur. In fact, in the history of biosimilar development in developed nations, we have yet to see a biosimilar that was highly similar in analytical and PK testing but not equivalent in efficacy studies.  

Heading into 2019, the U.S. is in a strong position to rise as a leader in the biosimilar space. Given the FDA’s history as the first regulator to establish and publish guidance on comparability in 1996, which was the foundation of the ICH Q5E guidance on comparability relied upon globally today, the agency could lead the charge on minimizing clinical study requirements. And, as more agencies team up to share best practices and scientific advancements, all the necessary information about the role of analytics and clinical studies in biosimilar development will be right at regulators’ fingertips.

Stay tuned for the second part of this article which will discuss the role of the FDA in managing commercial market concerns, as well as how other government agencies can play their part in bolstering the biosimilar market.