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Path to approval: How biosimilars are developed, approved in the US
As part of the Biologics Price Competition and Innovation Act of 2009 within the Affordable Care Act, an abbreviated licensure pathway was developed for biologics that are “biosimilar” to or “interchangeable” with FDA-approved reference products, with the goal of increasing competition in the biologics market, reducing costs and expanding patient access to these therapies.
While there are key differences between biosimilars and generic drugs, this pathway, although more rigorous, shares similarities with the development pathway for generics, according to Stephen B. Hanauer, MD, AGAF, FACG, the Clifford Joseph Barborka Professor of Medicine in the division of gastroenterology and hepatology at Northwestern University Feinberg School of Medicine.
“In the past, the primary health care costs for conditions such as ulcerative colitis and Crohn’s disease were related to hospitalizations and surgery, and over the past decade since the introduction of biologics ... the health care costs have been shifted to costs of medications, and the government wanted to create a pathway somewhat similar to the pathway for generics after the exclusivity of the originator patents wears off,” Hanauer told Healio.
Unlike generics, however, which are identical to their original compounds, it is impossible to make an exact copy of biologic agents, he explained.
“While it is possible to replicate the protein structure, ... post-translational carboxylation ... adds sugars all around the protein that create the tertiary and quaternary structures of these proteins that lead to their functional activity, and you can’t 100% replicate it,” he said. “So, you can make one very similar to the other, but even minor differences can cause significant functional differences.”
Biosimilars are in effect “reverse engineered,” as David T. Rubin, MD, Joseph B. Kirsner Professor of Medicine at the University of Chicago Medicine, and colleagues described it, relying on analytical and functional data to establish biosimilarity to the originator, rather than establishing independent clinical efficacy and safety data.
This “inverted” process aims to limit the number of human clinical trials in each disease, which incur the highest costs in drug development, Hanauer said. “The pathway allows clinical evaluation in a limited number of indications for any particular compound, and allows extrapolation to the other indications.”
Stepwise approach establishes totality of evidence
To seek approval for a biosimilar agent, manufacturers must submit a marketing application under Public Health Service Act Section 351(k), including evidence that the product is biosimilar to its reference product and uses the same known mechanisms of action for proposed indications, as well as the same dosage form, strength and route of administration. It must also demonstrate that the agent’s manufacturing facilities meet appropriate standards.
For approval, the FDA considers the “totality of evidence” showing the agent is “highly similar” to its reference product with no clinically meaningful differences in safety, purity and potency. This is established by first considering public information and experience with the reference product, followed by comparative analyses using a “stepwise approach.”
Foundational knowledge
Published data on the reference product’s mechanisms of action, structure and function, as well as clinical trial and observational study results that have been peer reviewed, all serve as the foundation of knowledge about a biosimilar candidate. Additionally, the biosimilar sponsor performs hands-on testing of legally purchased reference product to study its active ingredients and formulation, which collectively informs development of the biosimilar candidate.
Step one: Analytical data and functional activities
The first step in the “stepwise approach” is comparative analytical testing to show the biosimilar is structurally and functionally highly similar to the reference product. This involves physiochemical studies of the biosimilar’s molecular structure, its functional activities like receptor binding, and its immunochemical properties. The agent will also be analyzed for impurities, and the biosimilar molecule and finished drug product are also tested for stability.
As Hanauer said, relying on analytical data and functional activities is a crucial component of the abbreviated development pathway, and the source of the potential cost-savings in development. Because current analytical testing methods and pharmacology assays are so sensitive, they can detect structural or functional differences better than human clinical studies, and therefore, relying on these analytical data can obviate some of the clinical data needed to address “residual doubt” of the candidate’s biosimilarity, according to the FDA. Accordingly, the agency may determine that certain clinical elements in the following steps are unnecessary based on data from a previous step.
Step two: Nonclinical studies
After analytical testing, the next step involves nonclinical, comparative pharmacological studies in animals, if necessary, to further evaluate similarities in function and activity and evaluate the impact of any analytical differences observed in the prior step.
Step three: PK/PD human studies
Next, comparative pharmacokinetic and pharmacodynamic (PK/PD) studies are performed in humans — either patients or healthy volunteers — to assess the drug’s absorption, concentration and clearance, physiological response to the drug, or to help establish the relevance of structural or functional differences observed in the analytical or animal studies.
Step four: Confirmatory clinical studies
Finally, confirmatory clinical studies may be performed, not to establish benefit–risk profiles de novo, but to reduce any residual uncertainty of biosimilarity. These studies should compare the biosimilar and the reference product in a patient population that is sensitive enough to detect any differences, meaning the patients should be uniform, show high treatment effect, and avoid other medications when possible. Moreover, confirmatory clinical studies evaluating immunogenicity preferably should be performed in healthy volunteers or patients who are not immunocompromised so any differences can be detected.
Extrapolation
Through extrapolation of the totality of evidence, the FDA may approve a biosimilar for use in an indication for which its reference product is licensed, despite the absence of a comparative clinical trial in that indication. This expedites development by reducing clinical studies and their associated high costs.
The FDA considers extrapolation for each indication on a case-by-case basis, and it must be scientifically justified by the manufacturer based on the known mechanisms of action and any factors that may affect safety or efficacy within the context of the totality of evidence.
The concept of extrapolation to clinical indications based on analytical data remains an area of concern for many physicians, including members of the FDA advisory panels on Inflectra (infliximab-dyyb, Celltrion) and Amjevita (adalimumab-atto, Amgen).
However, according to Hanauer, it must be understood that extrapolation is foundational to the biosimilar development pathway. “If a biosimilar product is required to undergo testing in every approved indication for the innovator product, there would be no cost savings to develop biosimilars and, hence, no cost-savings for these expensive therapies,” he said.
Interchangeability
In the U.S., an “interchangeable” designation — indicating that the same safety and effectiveness as the reference product can be expected in any given patient, as well as no impact on the safety or effectiveness when switching between the reference product and the biosimilar, even multiple times — is separate from a biosimilar approval, and would permit substitution for a reference product without a prescriber’s intervention. While the FDA has issued designations for interchangeable products, substitution is regulated at the state level, and state legislation regarding this matter is currently evolving to reduce state-to-state variability in these policies.
Interchangeability is perhaps the most significant area of concern for physicians, as there is the potential for development of immunogenicity when hypothetically switching between multiple biosimilars in the future, according to Hanauer.
While “switch studies” of Inflectra and Amjevita have demonstrated noninferiority in patients who switch from the reference product to the biosimilar, these biosimilars are unlikely to be tested against different biosimilars in humans, he said. “So, my concern is not necessarily switching or substituting the biosimilar for the parent compound, it would ... be if someone tries to switch ... from one biosimilar to another biosimilar, because we do not know the comparative similarity between two biosimilars.” In other words, because A = B and A = C, it does not mean that B = C, he said.
This highlights the importance of establishing effective naming conventions for post-marketing surveillance “to see if a specific biosimilar ends up having different attributes from others,” he added.
In January 2017, the FDA issued guidance on interchangeability. This includes information on the type and quantity of evidence needed to demonstrate interchangeability of a proposed therapeutic protein product; how switching studies or other studies to support interchangeability should be designed; how reference products should be used in switching studies; and how to develop presentations for proposed interchangeable products.
References:
Biosimilars Forum: Overview. Biosimilars Forum website. http://www.biosimilarsforum.org/sites/default/files/uploads/biosimilars_overview_032816opt_-_copy_0.pdf. Accessed November 3, 2016.
Leitenberger A. FDA advisory committee unanimously recommends approval of biosimilar to Humira. Healio website. http://www.healio.com/gastroenterology/inflammatory-bowel-disease/news/online/%7B04fbba10-f483-4ea3-af65-ada9e422aaa3%7D/fda-advisory-committee-unanimously-recommends-approval-of-biosimilar-to-humira. July 12, 2016. Accessed October 27, 2016.
Paramsothy S, et al. Gastroenterology & Hepatology. 2016;12:741-51.
For more information:
Stephen B. Hanauer , MD, AGAF, FACG, can be reached at Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave., Chicago, IL 60611; email: shanauer@northwestern.edu.
David T. Rubin, MD, can be reached at the University of Chicago Medicine, 5841 S. Maryland Ave., Chicago, IL 60637; email: drubin@medicine.bsd.uchicago.edu.
Disclosures : Hanauer reports receiving consulting fees from AbbVie, Amgen, Boehringer Ingelheim, Hospira, Janssen, Merck, Pfizer, Samsung, Takeda and UCB. Rubin reports consulting for and his institution has received grant support from AbbVie, Amgen, Janssen, Pfizer and Takeda Pharmaceuticals Inc.