The Affordable Care Act amended the Public Health Service Act (PHSA) to include an abbreviated approval pathway for biological products that are demonstrated to be “highly similar” (biosimilar) to an FDA-approved biological product. This pathway is provided in the part of the law known as the Biologics Price Competition and Innovation Act (BPCI Act), under Section 351(k) of the PHSA. Back in 2012, we looked at three FDA guidance documents meant to assist industry in developing biosimilars in the US. Now, two years later, FDA has come out with a more detailed 17-page draft guidance, which offers specific steps that companies looking to a file a 351(k) biosimilar application should consider. FDA’s added clarity is welcomed from many companies looking to enter the biosimilars market, but leaves open many areas for which FDA is seeking responses.
The objectives of the BPCI Act are similar to those of the Drug Price Competition and Patent Term Restoration Act of 1984 (known as the “Hatch-Waxman Act”), which established abbreviated pathways for the approval of drug products under the Federal Food, Drug, and Cosmetic Act (FD&C Act). However, the inherently complex nature of biologic drugs makes them expensive to develop and impossible to copy in the manner traditionally associated with the approval of generic drugs. Most biological products are produced in a living system such as a microorganism, or plant or animal cells, whereas small molecule drugs are typically manufactured through chemical synthesis. Biologicals include vaccines, blood and blood components, gene therapies, tissues, and proteins.
2014 Guidance – Pharmacology Studies
U.S. companies have been hesitant to embrace the FDA biosimilar pipeline without formal clarification of what data the FDA will expect to see in 351(k) applications. Companies have to show that their biosimilar “is highly similar to the reference product notwithstanding minor differences in clinically inactive components” and that “there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.”
In the new guidance, FDA emphasized companies follow a “stepwise approach” for testing biosimilars. The guidance is meant to help companies in the “design and use of clinical pharmacology studies to support a decision that a proposed therapeutic biological product is biosimilar to its reference product.” Specifically, the guidance pertains to biological products for which pharmacokinetic (PK) and pharmacodynamic (PD) data are required to support a demonstration of biosimilarity. Pharmacokinetics study what the drug does to the body; pharmacodynamics refers to studying what the body does to the drug.
The FDA identifies three “critical considerations” that it will take into account in evaluating the use of clinical pharmacology studies to support a biosimilar application: 1) exposure and response assessment; 2) evaluation or residual uncertainty; and 3) analytical quality and uncertainty. They describe these studies thoroughly beginning page 3 of the guidance.
Drug Comparison Analysis:
FDA recommends that companies compare the quality attributes of the proposed biosimilar product with those of the reference product using a meaningful fingerprint-like analysis algorithm. Depending on what differences those analyses find, FDA will file each submitted treatment into one of four tiered categories:
- Highly similar with fingerprint-like similarity – the proposed biosimilar is deemed nearly identical to the reference product, based on multi-parameter approaches that are extremely sensitive. Such drugs would need only “targeted and selective” further study to demonstrate their biosimilarity.
- Highly similar – the proposed biosimilar product meets the statutory standard for analytical similarity, but is not as similar as the above category;
- Similar – additional analytical data or other studies are needed to determine if the products are indeed highly similar;
- Not similar – the proposed biosimilar is not actually similar, according to FDA; further progression through the 351(k) pathway is not recommended.
Maria Zacharakis, a partner at Boston law firm McCarter & English, gave her opinion about the FDA guidance to BizJournals recently. According to Zacharakis, drug innovators still have many ways to protect their drugs from biosimilar competition. The generic drugmaker has to prove a drug is similar along two lines, as described above: pharmacokinetics (what the drug does to the body) and pharmacodynamics (what the body does to the drug). Zacharakis notes: “The exact methods of measuring both those properties (for instance biomarkers used to gauge pharmacodynamics) can be patented, thereby making it impossible to prove similarity until those patents expire. Such patents would likely be applied for years after the original patent for a drug, effectively extending it significantly.”
The biosimilar market is projected to grow at an unbelievable rate in the coming years. Genetic Engineering & Biotechnology News just published their take on the market in an article entitled: “Biosimilars: 11 Drugs to Watch.”
Comments
While comments are accepted at any time, comments must be received within 90 days of Federal Register publication to be considered before FDA begins work on the final version of the guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.