Almost a year after FDA formally issued its Biosimilars Action Plan (3), with the challenging goal of balancing patient safety with innovation, the spring and summer of 2019 brought several US congressional hearings on drug prices and greater focus on biosimilars, including an FDA meeting devoted exclusively to the future of biosimilars for insulin.
Since 2015, when FDA approved its first biosimilar, Sandoz’s filgrastim-sndz (Zarxio), 19 biosimilars have been approved in the US. Thomas Linneman, head of regulation CMC customer solutions at Solvias, divides them into monoclonal antibodies, hormones, and Fc fusion proteins and cytokines (4). Although approved, these drugs are not “interchangeable” with name-brand biopharmaceuticals, as that term has been defined in the US. Unlike small-molecule generics, biosimilars cannot automatically be dispensed at the pharmacy level, in place of name-brand products, without a physician’s specific prescription. Given the relative novelty of biosimilars in the US, studies of physician patterns have found doctors to be conservative about filling patient prescriptions with biosimilars (5–7).
Establishing interchangeability has required additional clinical studies. So far, Boehringer-Ingelheim has been the only company to have pursued a US strategy that combines basic biosimilar approval and approval for interchangeability for its adalimumab (Humira) biosimilar, Cytelzo (8). It began clinical interchangeability studies for the drug back in 2017.
Biosimilar advocates have been pressuring FDA for more guidance on biosimilars interchangeability, and an update to draft guidance that the agency had issued in 2017. In August 2018, in a letter (9) to former Commissioner Gottlieb, representatives from hospitals, insurance companies, and patient groups complained that the lack of final guidance would discourage biosimilar development and leave the public without lower-cost options to name-brand biopharmaceuticals.
A flurry of guidance documents in May and June
With the clear intent of removing perceived roadblocks to biosimilar development, FDA issued a number of guidances in May and June 2019, including long-awaited guidance on interchangeability (10). Acting FDA commissioner Ned Sharpless commented in an FDA press release, the guidance will enable biosimilar or interchangeable insulin products to enter the market (11).
The agency also published draft guidance on the analytical methods to be used to establish biosimilar comparability and quality (12). According to reports on May 13 and May 21 in the Regulatory Affairs Professional Society Journal, the draft updates 2015 guidance on quality that FDA had withdrawn after receiving critical comments from the industry and also replaces 2017 draft guidance (13,14). It recommends best practices for chemistry manufacturing and control (CMC) programs for biosimilars, provides detailed recommendations for assessing lot-to-lot variability in product that might be traced to manufacturing variables, and also spells out clear requirements for nine crucial analytical steps, which include manufacturing process, stability, target binding, impurities, and references.
In June, FDA also issued clarification and a proposed revision to regulations that have not allowed biosimilar developers to refer to drug master files (DMFs) in applications (15). The proposed rule, now in the Federal Register for industry and public comment, would affect 89 compounds, mainly enzymes and hormones, including insulin, that are currently licensed under the Food, Drug and Cosmetics (FD&C) Act, but that will transition to licensing under the Public Health Service Act in March 2020 (16).
Intended to prevent potential shortages, the rule would allow developers of biosimilars in these categories to reference data on intermediates, drug products, or drug substances contained in DMFs, even after their drugs have been licensed. The proposal’s language suggests that, for the products involved, which have been established and regulated under FD&C for decades, any potential risk would be minimal.
Is FDA moving too quickly on interchangeability?
But in a broader sense, given the complexity of biomolecules when compared with small molecules, there are questions of what interchangeability should mean for biosimilars, particularly more complex molecules, because the term cannot mean what it does for small molecules. “I understand regulators’ and Congress’ urge to make biopharmaceuticals less expensive,” says Sheila Magil, managing director of the BioProcess Technology Group, part of BDO USA, who stresses that these are her personal opinions and do not represent her employer’s. “Biopharmaceuticals may be costly, but they are also very expensive to develop, “she says.
In the current environment, however, there is a danger of oversimplifying issues in the interest of speeding products to market without sufficient caution. In turn, lay people (e.g., most members of congress and many executives on the payer side) may be put in the position of having to make decisions on complex issues that they may not fully understand, Magil says. In general, she says, “I appreciate FDA’s goal for interchangeability, but at this point I am not entirely convinced that current guidance and regulations will get us there.”
For instance, she explains, politicians, patient groups, and payers may view biopharmaceuticals the same way as they do small molecules, without realizing the potential risks entailed with large molecules, and issues such as immunogenicity and variability. For small molecules, where bioactivity is found in the first dimension, interchangeability is not a problem and it is easy for different manufacturers to produce virtually the same product and to achieve product purity levels of 99% or higher, she says. But she notes that is not always true for biopharmaceuticals, for which biological activity is in the third dimension. “With biopharmaceuticals, a great deal depends on how the individual molecule is folded and how it is affected by its environment,” Magil says.
Lost in translation
In its new guidance, FDA has acknowledged that these issues need to be recognized, says Magil. But that still doesn’t make it correct to use the term “purity” for biopharmaceuticals in the same manner as it would be used in the small-molecule world, at least not without specifying how that purity was determined, e.g., whether measured by ion exchange, spectroscopy, or some other analytical method. “It’s not the same for biopharmaceuticals as it is for small molecules, and there is great complexity in existing forms,” Magil says. “We might not know how to test for those differences,” she says, since a change or structural difference that might seem very minor in a biomolecule can have a major biological impact, and that impact may not be understood or known before problems occur.
Magil recalls a biopharmaceutical product that she had worked with when she worked as a scientist in drug development in the industry. As this particular product aged, its structure unfolded and it became more active. “If one were to develop a biosimilar for that molecule today, one would most likely choose to test and evaluate it at the point of product release, and thus would be very likely to miss this critical characteristic,” she says.
These issues could be less of a concern for a company that had developed a branded biopharmaceutical and then opted to develop a biosimilar to that product later on, Magil says. “In that case, they would have all the original cell lines. But another company developing a biosimilar would be using a different cell line, posing potential risk because of the inherent variability in complexity for biosimilars, specifically in the drug substance,” says Magil.
Immunogenicity, always a concern
“I’m not sure that this issue is fully covered in FDA’s guidance,” she says. “I also have big concerns about immunogenicity. We don’t yet have a good way to test for that in-silico, to look at a molecule and gauge its immunogenicity, so we have to test the molecule in people, not even in animals, and there is not enough data out there at this point,” she says.
Bioanalytical techniques and associated software have become much more powerful, and far beyond what was available in the early days of innovator molecules, Magil says, and techniques such as mass spectrometry make it possible to evaluate the higher order state of biomolecules. However, she suggests, “At this point, there are still too many things that we cannot measure or control, to be talking about interchangeability.”
Magil also questions the idea of biosimilar developers relying on DMFs for product, ingredient, and other data, unless they have already developed all of this data internally and are able to compare it. “Doing this could be dangerous, since a company might wind up pointing to data that refute its own product data, unless they had made head-to head-comparisons between the data they had with data in the DMF.”
Although the current aim is to encourage the development of biosimilars for treatments such as insulin, FDA and industry clearly face challenges in meeting the goals outlined in the Biosimilars Action Plan for novel and complex formulations.
1. J. McCarthy, “Big Pharma Sinks to the Bottom of US Industry Rankings,” gallup.com, Sept. 3, 2019.
2. FDA, “Statement from FDA Commissioner Scott Gottlieb on New Actions Advancing the Agency’s Biosimilars Policy,” Press Statement, fda.gov, Dec. 11, 2018.
3. FDA White Paper, The Biosimilars Action Plan, July 2018.
4. T. Linnemann, “Regulatory Strategies for the Analytical Development of New Biological Entities and Biosimilars,” a Solvias Webcast, xtalks.com, April 17, 2019.
5. E. Leonard et al., Journal of Managed Care and Specialty Medicine 25 (1) 102–112 (2019).
6. J. Waller et al., Patient Prefer Adherence 11, 519–530 (2017).
7. A. Gaffney, “How Comfortable are Physicians with Biosimilars? Not Very (Yet),” PwC.com, Oct. 24, 2018.
8. Boehringer-Ingelheim Press Release, boehringer-ingelheim.us, July 27, 2017
9. Letter to Scott Gottlieb, csrxp.org, Aug. 23, 2018.
10. FDA, Guidance for Industry: Considerations for Demonstrating Interchangeability with a Reference Product, (Rockville, MD, May 2019).
11. FDA, “Statement from Acting FDA Commissioner Ned Sharpless on Policy Advancements to Help Bring Interchangeable Insulin,” Press Statement, fda.gov, May 10, 2019.
12. FDA, Draft Guidance for Industry: Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality Related Assessments (Rockville, MD, May, 2019).
13. Z. Brennan, “FDA Replaces Withdrawn Biosimilars Guidance With New One On Quality Related Consideratons,” RAPS.org, May 21, 2019.
14. Z. Brennan, “Updated: Interchangeable Biosimilars: FDA Finalizes Guidance,” RAPS.org, May 13, 2019.
15. FDA, "FDA Takes New Step to Help Advance Transition of Certain Medical Products, fda.gov, June 27, 2019.
16. US Federal Register, “Proposed Rule, Biologics License Applications and Master Files,” federalregister.gov, June 28, 2019.