Genetic Engineering & Biotechnology News

MAY15 2018

Genetic Engineering & Biotechnology News (GEN) is the world's most widely read biotech publication. It provides the R&D community with critical information on the tools, technologies, and trends that drive the biotech industry.

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22 | MAY 15, 2018 | | Genetic Engineering & Biotechnology News FDA's guidances on naming biosimilars. What's next? A bio- similars drive, one that promises to benefit many patients for whom the benefits of biologics might otherwise remain out of reach, even after the expiration of biologics' patent protec- tions. The drive is on track, even though the development, analysis, and market approval considerations for biosimilars are much more challenging than those for generic drugs. What's in a Name? The biosimilars space is evolving, suggests Jesse Peterson, Pharm.D., clinical development manager, Fairview Phar- macy Services. Dr. Peterson devotes much of his attention to tracking emerging therapeutics, following the progress of biosimilars in the development pipeline, and analyzing ap- proval trends. Dr. Peterson notes that as of April 2018, three of the nine biosimilars that have been approved by the FDA are commercially available. "Through the end of 2018, there are at least eight bio- similar products with FDA review dates," says Dr. Peterson. "In the coming months, we see additional opportunities to get exposure to these products." Although biosimilars continue to proliferate, they still need to penetrate the market. One barrier that could affect the penetration of biosimilars is the naming convention for these products. In addition to having a unique trade name, the FDA has added a unique four lowercase-letter hyphen- ated suffix to the core name of newly approved biosimilar products. These randomly generated suffixes differentiate FDA-approved biosimilars from the ones approved by the European Medicines Agency (EMA). While the FDA's naming convention intends to minimize inadvertent substitutions and facilitate postmarketing analy- ses, an intentionally meaningless suffix could obscure a bio- similar's association with a reference product. Also, suffix- carrying biosimilars could be perceived as being somehow inferior to suffix-free biologics, potentially decreasing patient and provider acceptance and slowing market penetration. To help keep biologics and biosimilars on a level naming field, the FDA has started giving suffixes to biologics, too. "In November 2017," Dr. Peterson observes, "the first origi- nator biologic was assigned a four-letter suffix, and all newly approved biologics have followed that convention." Another barrier faced by biosimilars is pricing. In the cur- rent landscape of biosimilars, with relatively limited competi- tion, originator products have been able to stay competitive with respect to pricing. "But as more biosimilar products become commercially available, we should see prices drop," comments Dr. Peterson. And as biosimilars become less ex- pensive, they may enjoy wider use, allowing providers gain more experience and confidence with these agents. Biosimi- lars may then become more recognized for their medical and pharmacy benefits. Biosimilar Equivalence Testing "Biological assays are very different from most physico- chemical assays," asserts David Lansky, Ph.D., president, Precision Bioassay. For example, biological assays are relatively poorly served by the traditional statistical methods that are used to establish similarity. In a traditional test of simi- larity, the null hypothesis, which researchers are attempting to disprove, states that there are no differences between the respons- es recorded for a test product and the responses recorded for a reference product. "Statistics works beautifully in this setting," remarks Dr. Lansky. However, for bioequivalence testing in the case of biosimilars, if the null hypothesis states that the test and reference responses are the same, and no evidence against the null hypothesis is obtained, one can incorrectly conclude that the test and reference responses are the same if an assay is noisy or if the amount of data that is analyzed is too small. "Before trying to use the tests to show that two things are equivalent, we need to protect ourselves against making that claim by mistake, and that is very hard to do with traditional hypothesis testing," cautions Dr. Lansky. Consequently, for biosimilar equivalence testing, the null hypothesis is usually turned around to state that a biosimilar is different, either superior or inferior, to the reference product. "If we can disprove that, and we can control the way in which we falsely disprove it, we can be confident that the two variables are the same," explains Dr. Lansky. "This is why we use the equivalence test." Although equivalence testing for similarity in bioassays has become broadly accepted, the shift from difference test- ing has been accompanied by the rise of a new challenge. One may find it necessary to set the margins or bounds of the equivalence tests. "There is guidance on how to do this in the United States Pharmacopeia (USP) regulatory documents," states Dr. Lansky. The USP describes four approaches to support the bounds for equivalence limits. However, three of these ap- proaches involve using historical data to compare a standard or a reference to itself. "All three 'historical data' approaches are quite danger- ous because they essentially measure the capability of the assay," insists Dr. Lansky. The fourth method recommends incorporating some type of sensitivity analysis to ask how much nonsimilarity actually matters. In a recent research ef- fort, Dr. Lansky and colleagues proposed a complete method to set equivalence bounds that depends only on assay perfor- mance requirements, and not on assay capability. In an assay that has been developed to support a prod- uct, the performance requirements must provide information about parameters, such as how much degradation or loss of potency may be tolerated or how much manufacturing varia- tion is acceptable. "All those get wrapped up into a package to express product specifications, measure the capability of the method, and manage the product," explains Dr. Lansky. From the package, which must work as a whole, it is possible to extract limits on bias, which provide limits on nonsimilarity. "Those limits are not driven by the capability of the as- say, but by the needs of the consumers and producers," as- serts Dr. Lansky. "This approach ensures that the product is effective, safe, and reproducible, and this is what universal equivalence bounds is about." Trends in Biosimilar Costs "As we gain more experience in the U.S. marketplace, and develop multiple biosimilars for the same agent, we will probably see their price come down," says Richard Brook, president, Better Health Worldwide. Mr. Brook per- forms retrospective claim analyses and strategic consulting for pharmaceuticals and biosimilars. Part of this work fo- cuses on managed care access intervention programs, which aim to identify value propositions that would be favorable to payers. Although it is anticipated that the introduction of bio- similars will lead to savings, the magnitude of these savings remains unclear. "We have yet to see some of these benefits Statistical methods for similarity testing, says Precision Bioassay, may focus on several curve parameters and how they differ between test and reference dose-response curves: A: nonsimilarity of range (difference between asymptotes); B: nonsimilary of curve shape; C: log potentcy or activity shift; and D: nonsimilarity of the no-dose asymptote. Assessing biosimilarity usually includes assessing all four curve parameters. Positively correlated shifts in A and D will cause appreciable bias in estimates of log potency (differences in C). Translational Medicine Feature Managing Biosimilars Is Like Herding Copycats Continued from page 1 " We are becoming much more comfortable with … extrapolation to indications not specifically studied in the biosimilar approval process." —James Stevenson, Pharm.D., University of Michigan College of Pharmacy

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