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Biosimilar path to FDA approval:

A substantial difference from generics.

Traditional, small-molecule generic drugs require bioequivalence tests to gain approval. Large-molecule medicines, biologics and biosimilars, are harder to characterize, as they are both made from living cells with a large, complex, inherently heterogeneous structure.2,3

FDA approval:

The difference is time, cost, and complexity

Generic Medicines
  • Same active ingredient3
  • Bioequivalent3
  • Abbreviated FDA approval process3,4
  • Average of 3 to 5 years in development5
  • $1 million to $4 million cost6
Biosimilar Medicines
  • Highly similar to reference product6
  • Same safety and efficacy profile6
  • Longer abbreviated FDA approval process5,7
  • 7 to 8 years in development6
  • $100 million to $250 million cost6

FDA's biosimilar pathway:
A totality of evidence

While small-molecule generic drugs are required to prove bioequivalence and typically take an average of 3 to 5 years to develop,5 reference biologic medicines can take 10 years or more to develop, requiring rigorous and costly de novo testing of efficacy and safety.8,9

Biosimilar medicines are on a longer abbreviated pathway than generics—about 7 to 8 years in development.5 And although this is less time than for a reference biologic, in fact, the data package required for approval of a biosimilar medicine is extensive.5,9

The FDA looks at the totality of evidence presented, from structural analysis to nonclinical studies, clinical pharmacology, and clinical studies.9

Additional Clinical Studies Additional Clinical Studies

Other comparative clinical studies, as needed.9

Clinical Pharmacology Clinical Pharmacology

A clinical study or studies sufficient to demonstrate safety, purity, and potency of the proposed biosimilar product in one or more of the indications for which the reference product is licensed. This typically includes assessing immunogenicity, pharmacokinetics (PK), and, in some cases, pharmacodynamics (PD) and may also include a comparative clinical study.9

Nonclinical Studies Nonclinical Studies

Animal studies if necessary, including an assessment of toxicity.9

Analytical (the foundation) Analytical (the foundation)

Detailed analytical (structural and functional) characterization demonstrating that the biological product is highly similar to the reference product, notwithstanding minor differences in clinically inactive components.9

FDA biosimilar approval pathway

Click or tap each “level” to learn more

Why are such extensive
data required?

Unlike chemical drugs, individual batches of biologic medicines are naturally heterogenous due to the living substances from which they are made, as well as the inherent variations that can result from their complex manufacturing processes.2,3 Differences are natural and expected; even in a reference biologic, no 2 batches are perfectly alike.3,6

As no biologic medicine can be shown to be identical to another, sophisticated tests using bioassays and other determinants of quality, stability, safety, purity, and potency are used to establish biosimilarity between batches of both biologic and biosimilar medicines.2,3,10

Extrapolation: Improving patient access to biologic medicines.

Part of the FDA’s abbreviated pathway for biosimilar drug approval is based on the concept of extrapolation.

Extrapolation means that a biosimilar may be clinically tested in one indication, and from that approval, safety and efficacy are extrapolated for additional indications—the same indications for which the reference biologic has already been tested in clinical studies.9

Rather than a new concept, extrapolation is a well-established scientific principle used routinely before the arrival of biosimilar medicines.11 When biologic medicines approved for multiple indications undergo changes to their manufacturing process (such as creating new formulations), clinical trials do not need to be repeated for all indications as long as quality and other parameters of comparability are demonstrated.10,11

Scientific guidelines for biosimilar medicines provided by both the European Medicines Agency (EMA) and FDA recommend testing in the most sensitive indication for which the reference biologic is prescribed, using a homogeneous patient population. This helps to identify any response variations rapidly and definitively.12-14

Indication extrapolation from clinical trials. Indication extrapolation from clinical trials.

Extrapolation: What is the experience in the EU?

Since 2006, when biosimilars were first introduced in the European Union,10 there have been more than 700 million patient-days of treatment with biosimilars, with no new safety or efficacy concerns.15

In addition to extrapolated approvals, a biosimilar’s sponsor may seek an “interchangeable” designation with the reference biologic.

An interchangeable biosimilar:

What is required to achieve this designation?

An interchangeability designation from the FDA requires additional clinical data, which may allow the biosimilar to be substituted at the pharmacy without direct authorization from the prescribing physician.3

To gain an interchangeability designation after demonstrating that a product is biosimilar to the reference product, the sponsor must conduct additional clinical trials. These additional trials must demonstrate that the biosimilar is expected to produce the same clinical results in any given patient and does not increase safety risks or decrease effectiveness compared to using the reference product without switching.3,9,16

If a product is administered more than once, the sponsor will need to conduct switching studies to prove that patients can be moved from the reference biologic to the biosimilar drug and back with no adverse consequences, including immunogenicity issues.3,16

States are legislating
“interchangeable biologic”

In America, pharmacy laws are decided by each state.17 Currently, nearly all states have passed or introduced legislation allowing for the substitution of interchangeable biosimilars, in anticipation of their eventual approval and availability.17,18

Most legislation adheres to the principles endorsed by the Biotechnology Innovation Organization (BIO), an industry trade group.18 BIO specifies that substitution should occur only when the FDA has designated a biologic product as interchangeable, that the prescribing physician should be able to prevent substitution, that physicians and patients should be notified of the substitution, and that pharmacists and physicians should keep records of the substitution.19

As of this writing, there are currently no FDA-approved interchangeable biosimilars; however, the FDA has issued draft guidance on meeting requirements.16,20

Going above and beyond

For a biosimilar drug to receive approval, the FDA requires a clinical study for at least 1 indication of the reference biologic.9,11 However, some companies are conducting clinical studies in 2 or more proposed indications for their biosimilar candidates.

To learn more about the biosimilar approval process, go to: Biosimilar Development, Review, and Approval
  1. 1. US Food and Drug Administration website. Prescribing biosimilar and interchangeable products. Accessed May 14, 2018.
  2. 2. Zezza D, Seamon K, Garnic R, et al.  Biologics: can there be abbreviated applications, generics, or follow-on products? Accessed December 21, 2017.
  3. 3. US Food and Drug Administration website. Biosimiliar and interchangeable products. Accessed May 14, 2018.
  4. 4. Hamburg MA. Celebrating 30 years of easier access to cost-saving generic drugs. US Food and Drug Administration website; FDA Voice. Accessed June 6, 2018.
  5. 5. Boehringer Ingelheim website. Biosimilars explained with Ivan Blanarik, Senior Vice President and Head of Therapeutic Area Biosimilars. Accessed May 18, 2019.
  6. 6. Blackstone EA, Fuhr JP Jr. The economics of biosimilars. Am Health Drug Benefits. 2013;6(8):469-478.
  7. 7. Healio website; HemOnc Today. Path to approval: how biosimilars are developed, approved in the US. Accessed June 4, 2018.
  8. 8. PhRMA website. Biopharmaceutical research & development: the process behind new medicines. Accessed June 1, 2018.
  9. 9. US Food and Drug Administration website. Biosimilar product regulatory review and approval. Accessed April 20, 2018.
  10. 10. European Medicines Agency website. Biosimilars in the EU: information guide for healthcare professionals. Prepared jointly by the European Medicines Agency and the Europoean Commission. Accessed January 31, 2018.
  11. 11. Krendyukov A, Schiestl M. Extrapolation concept at work with biosimilar: a decade of experience in oncology. ESMO Open. 2018;3:e000319. doi:10.1136/ esmoopen-2017-000319.
  12. 12. European Medicines Agency website. Guideline on similar biological medicinal products containing monoclonal antibodies—non-clinical and clinical issues. Accessed June 4, 2018.
  13. 13. Lai Z, La Noce A. Key design considerations on comparative clinical efficacy studies for biosimilars: adalimumab as an example. RMD Open. 2016;2:e000154. doi:10.1136/rmdopen-2015-000154.
  14. 14. US Food and Drug Administration website. Scientific considerations in demonstrating biosimilarity to a reference product. Accessed June 4, 2018.
  15. 15. Phan S. Biosimilar drugs offer promise for US health care system. The Hill website. Published October 2, 2017. Accessed January 25, 2018.
  16. 16. Oskouei ST. Biosimilar interchangeability: 9 things to consider. Center for Biosimilars website. Accessed June 1, 2018.
  17. 17. Cauchi R. State laws and legislation related to biologic medications and substitution of biosimilars. National Conference of State Legislatures website. Accessed June 20, 2018.
  18. 18. DiGrande S. South Dakota passes biosimilar substitution bill. Center for Biosimilars website. Accessed February 13, 2018.
  19. 19. Biotechnology Innovation Organization website. BIO principles on patient safety in the substitution of biologic products. Accessed June 21, 2018.
  20. 20. Federal Register website. Formal meetings between the Food and Drug Administration and sponsors or applicants of Biosimilar User Fee Act products; draft guidance for industry; Availability. Accessed June 20, 2018.