The New Frontier for Improved Access to Medicines

Biosimilar Development Process

The approach to biosimilar development is fundamentally different to that of new molecule biologics.

New biologics are approved on the basis of demonstration of a significant clinical benefit. This is done by determining efficacy and safety, either against placebo, or currently available standard of care, and this is done through extensive clinical trials.

Typically, clinical trials are conducted in a series of steps, called phases. Each phase is designed to answer a separate research question. Before a drug is approved, there are generally three phases of clinical development:

A new biologic is evaluated in a small group of patients for the first time to look at safety, to begin to determine what is the most appropriate dose for use, and to identify side effects. This is called Phase I. Phase I studies can also include pharmacokinetic (PK) evaluations, designed to determine how the body affects the drug after administration, from absorption to elimination, and pharmacodynamic (PD) evaluations that look at how the drug impacts the body.

The biologic is given to a larger group of patients, further evaluating the best dose, determining if it is effective, and to further evaluate its safety. This is called Phase 2.

The biologic is given to large groups of patients (hundreds or thousands) to confirm its efficacy and further evaluate its safety in studies that are called Phase III. Generally, one phase III study is performed for each product indication sought. As such, the clinical program portion of new biologic development is very extensive, time-consuming and expensive. On the other hand, determination of the new biologic’s molecular structure and function, performed through analytical and in vitro evaluation (analytical characterization), is less intense and comprehensive.

Full Text of BPCIA Law laying out biosimilar pathway- (Section 351(k) of the Public Health Service Act):
‘‘(k) LICENSURE OF BIOLOGICAL PRODUCTS AS BIOSIMILAR OR INTER- CHANGEABLE.—
(1) IN GENERAL.—Any person may submit an application for licensure of a biological product under this subsection.

(2) CONTENT.—

(A) IN GENERAL.—
(i) REQUIRED INFORMATION.—An application submitted under this subsection shall include information demonstrating that—
(I) the biological product is biosimilar to a reference product based upon data derived from—
(aa) analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components;
(bb) animal studies (including the assessment of toxicity); and
(cc) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in 1 or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biological product;
(II) the biological product and reference product utilize the same mechanism or mechanisms of action for the condition or conditions of use prescribed, recommended, or suggested in the proposed labeling, but only to the extent the mechanism or mechanisms of action are known for the reference product;
(III) the condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biological product have been previously approved for the reference product;
(IV) the route of administration, the dosage form, and the strength of the

biological product are the same as those of the reference product; and
(V) the facility in which the biological product is manufactured, processed, packed, or held meets standards designed to assure that the biological product continues to be safe, pure, and potent.
(ii) DETERMINATION BY SECRETARY.—The Secretary may determine, in the Secretary’s discretion, that an element described in clause (i)(I) is unnecessary in an application submitted under this subsection.
(iii) ADDITIONAL INFORMATION.—An application submitted under this subsection—
(I) shall include publicly-available information regarding the Secretary’s previous determination that the reference product is safe, pure, and potent; and
(II) may include any additional information in support of the application, including publicly- available information with respect to the reference product or another biological product.

(B) INTERCHANGEABILITY.—An application (or a supplement to an application) submitted under this sub section may include information demonstrating that the biological product meets the standards described in paragraph (4).
(3) EVALUATION BY SECRETARY.—Upon review of an application (or a supplement to an application) submitted under this subsection, the Secretary shall license the biological product under this subsection if—
(A) the Secretary determines that the information submitted in the application (or the supplement) is sufficient to show that the biological product—
(i) is biosimilar to the reference product; or
(ii) meets the standards described in paragraph (4), and therefore is interchangeable with the reference product; and
(B) the applicant (or other appropriate person) consents to the inspection of the facility that is the subject of the application, in accordance with subsection (c).
(4) SAFETY STANDARDS FOR DETERMINING INTERCHANGEABILITY.—

Upon review of an application submitted under this subsection or any supplement to such application, the Secretary shall determine the biological product to be interchangeable with the reference product if the Secretary determines that the information submitted in the application (or a supplement to such application) is sufficient to show that—
(A) the biological product—
(i) is biosimilar to the reference product; and
(ii) can be expected to produce the same clinical result as the reference product in any given patient; and
(B) for a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.

(5) GENERAL RULES.—
(A) ONE REFERENCE PRODUCT PER APPLICATION.—A biological product, in an application submitted under this subsection, may not be evaluated against more than 1 reference product.
(B) REVIEW.—An application submitted under this subsection shall be reviewed by the division within the Food and Drug Administration that is responsible for the review and approval of the application under which the reference product is licensed.
(C) RISK EVALUATION AND MITIGATION STRATEGIES.—
The authority of the Secretary with respect to risk evaluation and mitigation strategies under the Federal Food, Drug, and Cosmetic Act shall apply to biological products licensed under this subsection in the same manner as such authority applies to biological products licensed under subsection (a).

(6) EXCLUSIVITY FOR FIRST INTERCHANGEABLE BIOLOGICALPRODUCT.—Upon review of an application submitted under

this subsection relying on the same reference product for which a prior biological product has received a determination of inter changeability for any condition of use, the Secretary shall not make a determination under paragraph (4) that the second or subsequent biological product is interchangeable for any condition of use until the earlier of—
(A) 1 year after the first commercial marketing of the first interchangeable biosimilar biological product to be approved as interchangeable for that reference product;
(B) 18 months after—
(i) a final court decision on all patents in suit in an action instituted under subsection (l)(6) against the applicant that submitted the application for the first approved interchangeable biosimilar biological product; or
(ii) the dismissal with or without prejudice of an action instituted under subsection (l)(6) against the applicant that submitted the application for the first approved interchangeable biosimilar biological product; or
(C)(i) 42 months after approval of the first inter changeable biosimilar biological product if the applicant that submitted such application has been sued under sub section (l)(6) and such litigation is still ongoing within such 42-month period; or
(ii) 18 months after approval of the first interchange able biosimilar biological product if the applicant that submitted such application has not been sued under subsection (l)(6). For purposes of this paragraph, the term ‘final court decision’ means a final decision of a court from which no appeal (other than a petition to the United States Supreme Court for a writ of certiorari) has been or can be taken.
(7) EXCLUSIVITY FOR REFERENCE PRODUCT.—
(A) EFFECTIVE DATE OF BIOSIMILAR APPLICATION APPROVAL.—Approval of an application under this sub section may not be made effective by the Secretary until the date that is 12 years after the date on which the reference product was first licensed under subsection (a).
(B) FILING PERIOD.—An application under this sub section may not be submitted to the Secretary until the date that is 4 years after the date on which the reference product was first licensed under subsection (a).

(C) FIRST LICENSURE.—Subparagraphs (A) and (B) shall not apply to a license for or approval of—
(i) a supplement for the biological product that is the reference product; or
(ii) a subsequent application filed by the same sponsor or manufacturer of the biological product that is the reference product (or a licensor, predecessor in interest, or other related entity) for—
(I) a change (not including a modification to the structure of the biological product) that results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device, or strength; or
(8) a modification to the structure of the biological product that does not result in a change in safety, purity, or potency.
GUIDANCE DOCUMENTS.—
(A) IN GENERAL.—The Secretary may, after opportunity for public comment, issue guidance in accordance, except as provided in subparagraph (B)(i), with section 701(h) of the Federal Food, Drug, and Cosmetic Act with respect to the licensure of a biological product under this subsection. Any such guidance may be general or specific.
(B) PUBLIC COMMENT.—
(i) IN GENERAL.—The Secretary shall provide the public an opportunity to comment on any proposed guidance issued under subparagraph (A) before issuing final guidance.
(ii) INPUT REGARDING MOST VALUABLE GUIDANCE.—
The Secretary shall establish a process through which the public may provide the Secretary with input regarding priorities for issuing guidance.
(C) NO REQUIREMENT FOR APPLICATION CONSIDERATION.—
The issuance (or non-issuance) of guidance under subparagraph (A) shall not preclude the review of, or action on, an application submitted under this subsection.
(D) REQUIREMENT FOR PRODUCT CLASS-SPECIFIC GUIDANCE.—If the Secretary issues product class-specific guidance under subparagraph (A), such guidance shall include a description of—

(i) the criteria that the Secretary will use to deter mine whether a biological product is highly similar to a reference product in such product class; and
(ii) the criteria, if available, that the Secretary will use to determine whether a biological product meets the standards described in paragraph (4).

(E)CERTAIN PRODUCT CLASSES.—
(i) GUIDANCE.—The Secretary may indicate in a guidance document that the science and experience, as of the date of such guidance, with respect to a product or product class (not including any recombinant protein) does not allow approval of an application for a license as provided under this subsection for such product or product class.
(ii)MODIFICATION OR REVERSAL.—The Secretary may issue a subsequent guidance document under subparagraph (A) to modify or reverse a guidance document under clause (i).
(iii)NO EFFECT ON ABILITY TO DENY LICENSE.—Clause (i) shall not be construed to require the Secretary to approve a product with respect to which the Secretary has not indicated in a guidance document that the science and experience, as described in clause (i), does not allow approval of such an application.

References

  1. BioWorld, “Biologics’ Share of Medicine Chest Grows, and so do the Pricing Concerns.” Accessed August 24, 2017.
  2. Statement of John D. Ludwig, Pfizer. Available at https://www.future-science.com/doi/10.4155/tde.11.58.
  3. PhRMA, “Medicines in Development for Biologics 2013 Report.” April 8, 2013.
  4. Express Scripts, “The $250 Billion Potential of Biosimilars.” Accessed May 31, 2017.
  5. CVS Caremark 2012 BOB trend cohort. Enterprise Analytics. 2013.
  6. European Medicines Agency, “Biosimilars in the EU: Information Guide for Healthcare Professionals.” 2017.
  7. U.S. Food and Drug Administration, “Biosimilars: Additional Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009.” May 2015.
  8. IMS Health, “U.S. Drug Spending Growth Reaches 8.5 Percent in 2015.” April 14, 2016.
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  10. IMS National Prescription Audit. IMS Health. April 2014.
  11. The PharmaLetter, “Biosimilars set to take center-stage as exclusive biologic bubble bursts,” August 9, 2016.
  12. U.S. Pharmacist, “Biosimilars: Current Approvals and Pipeline Agents,” October 14, 2016
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  14. QuintilesIMS Institute and Association for Accessible Medicines, “Generic Drug Access and Savings in the U.S. Report.” 2017.
  15. Scientific American blog, “Will ‘Biosimilar’ Medications Reduce the Cost of Biologic Drugs?” March 9, 2017.
  16. Chemistry World, “Biosimilars Battleground.” May 15, 2017.
  17. Supreme Court of the United States, “SANDOZ INC. v. AMGEN INC. ET AL.” June 12, 2017.
  18. GaBi: Generics and Biosimilars Initiative, “Biosimilars Approved in Europe.” March 31, 2017.
  19. Haustein R, de Millas Christoph et al. “Saving money in the European healthcare system with biosimilars”. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(3-4). 120-6.
  20. IMS Health, “The Impact of Biosimilar Competition on Price, Volume, and Market Share.” June 2016. Accessed on August 4, 2017.
  21. National Institute of Health. “The Economics of Biosimilars.” September 2013. Accessed on August 4, 2017.
  22. FDA Center for Biologics Evaluation and Research. “What Are ‘Biologics’ Questions and Answers.” Accessed May 31, 2017. Available at: https://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cber/ucm133077.htm.
  23. Pharmacy & Therapeutics. “Biosimilars Part 1: Proposed Regulatory Criteria for FDA Approval.” Accessed August 4, 2017. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3737980/