We all know it is important in rare disease clinical research to seek out the knowledge of clinical and academic experts who can inform study design. In the EU, the bridging data including analytical studies that compare a biosimilar product, a European Economic Area (EEA)authorized reference product and a nonEEAauthorized reference product are required in cases in which nonEEAauthorized reference products are used in clinical trials 27. That means that the currently approved biosimilar Renflexis (infliximab-abda, Merck) does not have to wait until October to launch, explains Steven Lucio, Associate Vice President of Pharmacy Services for Vizient: The FDA has already approved Pfizers Inflectra [infliximab-dyyb], whose competitor biological is Remicade [infliximab] from Janssen. Providing definitions of these terms would be useful in providing greater clarity for developers and other stakeholders, she adds. FDA approval to market a biologic is granted by issuance of a biologics license. About AIS Health AIS Health is a publishing and information company that has served the health care industry for more than 30 years. The https:// ensures that you are connecting to the It is not clear how many of the companies with the five approved biosimilars have applied for an interchangeability designation, if any. Those potential changes give rise to a biologic from different batches being on the market at the same time and a patient being switched from one to another. Doubleblind, single dose (200gm, Study EP06107: replacing the phrase means any with the phrase means a, to conform with the text of 351(i)(1) of the Public Health Service Act; including protein (except any chemically synthesized polypeptide); and, adding paragraphs (h)(6) and (7) to 600.3(h) to include the above definitions of the terms protein and chemically synthesized polypeptide.. Many health system companies, too, say the draft is either unclear or sets its hurdles too high, or both. FUFRA Enacted; HP&M Issues Detailed Summary and Analysis, CMS Finalizes Rule on Medicare Part B Discarded Drug Rebates, Could the Road to an AKS Violation Be Paved with Good Intentions? www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM537135.pdf, www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM559967.pdf, https://biosimilarscouncil.org/wp-content/uploads/2017/03/Biosimilars-Handbook.pdf, www.gphaonline.org/media/cms/Council_Comments_on_Adalimumab_AdCom.pdf. These variations could impact patients differently, resulting in clinical studies that do not reflect the patient experience appropriately. The first FDA designation will help clarify requirements. The Cost Savings Potential of Biosimilar Drugs in the United States. The same studies will probably not be required for each interchangeable application. HOPA recommends that the FDA define the risk of immunogenicity and the strategy used to measure the risk compared to the reference molecule at the time of approval of each drug to facilitate practitioners monitoring the drug in practice. PK/PD studies of Epoetin alfa BS approved, Phase III studies for Epoetin alfa BS approved. The challenges in the development of biosimilar products in Japan are also addressed. The Japanese guideline basically requires that sponsors of biosimilar products demonstrate a pharmacokinetics (PK) profile that is similar to that of the reference product by all routes of administration used for the reference product. Epoetin alfa BS JCR has been approved for two indications: renal anaemia in dialysis and anaemia of prematurity, although the subjects for the Phase III studies were only renal anaemia patients on haemodialysis, as the extrapolation of clinical data to other indications based on the pharmacological actions was considered acceptable (Table10) 4. multiple dose (400gm, Study PDSC300 repeateddose: Clinical data package of infliximab BS approved. Pfizer Asks SCOTUS, Avoid CMC Challenges by Thinking Slow, Not Fast-Discussions at USPs Workshop, REMS Tracker (Historical Not Recently Updated), Generic Drug Labeling Carve-Out Scorecard, Biosimilars State Legislation Scorecard (Historical Not Recently Updated), Advertising and Promotion (Federal Trade Commission), Product Jurisdiction and Combination Products, Biosimilarity and Interchangeability: Additional Draft Q&As on Biosimilar Development and the BPCI Act, Questions and Answers on Biosimilar Development and the BPCI Act. In the EU, infliximab BS was also approved for all of the indications that the reference product has even though only studies of RA patients and AS patients are included in the clinical data package 23. In May 2017, an FDA advisory committee voted 141 in favor of the agency approving Pfizer subsidiary Hospiras version of epoetin alfa, an anemia biosimilar that would compete with Epogen (epoetin alfa, Amgen) and Procrit (epoetin alfa, Janssen).3 Another three or four biosimilar approvals are expected in 2017. doi: 10.1111/bcp.12931. The data packages of biosimilar products approved in Japan are summarized in Table1. Promotional Labeling and Advertising Considerations for Prescription Biological Reference and Biosimilar Products--Questions and Answers "DRAFT" (Issued 2/3/2020. Openlabel, single dose (400gm, Study PKSC300: There may be differences in raw materials and manufacturing processes, among other inputs, between branded and biosimilar products in the same category. A Sandoz spokeswoman did not answer emails requesting comment. These challenges include not only development strategies but also the realworld use of biosimilar products 14. Send ideas for topics and your comments to. The clinical data packages of individual biosimilar products approved in Japan are described in detail below. The bullets above outline the types of data and information to be included in a biosimilar product application. Korea Guidances, ADDITIONAL BLOG RESOURCES Considerations in demonstrating interchangeability with a reference productguidance for industry: draft guidance. Careers. The site is secure. In addition, comparative Phase III studies of renal anaemia patients on haemodialysis and studies of patients with anaemia due to cancer chemotherapy were conducted (Table3). In particular, CVS disputes the need to use U.S. reference products, which would increase costs and slow down any movement to interchangeability applications by companies that, for example, have started switching studies using European Union (E.U. Before Food and Drug Administration This LawFlash provides a brief overview of the draft guidances released today. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely. No major difference in the concepts used by the regulatory authorities for the clinical data of biosimilar products was revealed except that the Japanese regulatory authority, PMDA, requires data from Japanese subjects. For example, the agencys use of the expression fingerprint-like similarity to describe the endpoint of an interchangeable biosimilar has created some confusion. Singleblind, single dose (300g), Study FSK0808P04: Doubleblind The noninferiority study design is not mentioned in the Japanese guidelines 2 or the new Q&A 10, whereas in the revised EU guideline 30 and the US guidance 13, it is stated that a noninferiority trial alone may be accepted in some cases. For the purposes of this 25 guidance, formal meeting includes any meeting that is requested by a sponsor or applicant However, the revised EU guideline for nonclinical and clinical issues 30 and the new Japanese Q&A 10 state that if the reference product can be administered by both IV and SC routes, the evaluation of SC administration will usually be sufficient as it covers both absorption and elimination. and transmitted securely. The FDA has committed to providing at least one more needed guidance document: one to show what standards need to be met for a biosimilar drug to be considered interchangeable with the original drug. We are preparing a more detailed analysis, which will include potential implications for stakeholders interested in submitting applications under the developing biosimilars pathway. M~8B4#{>^s H00` %[g v/! w According to the Biosimilars Quality Guidance, "if the reference product and the proposed protein product cannot be adequately characterized with state of the art technology as recommended by this guidance, FDA recommends that the sponsor consult FDA for guidance on whether an application for the proposed protein product is appropriate for submission under section 351(k)" of the Public Health Services Act. In December 2015, the MHLW issued new Questions and Answers (Q&A) for a better understanding of the guideline 10. "Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009" (Biosimilars Q&A), "Scientific Considerations in Demonstrating Biosimilarity to a Reference Product"(Biosimilars Scientific Guidance), "Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product" (Biosimilars Quality Guidance), FDA-LF_DraftGuidancesForBiosimilars_9feb12, FDA Issues Three Draft Guidances for Biosimilars, Summarizes statutory requirements for biosimilarity and interchangeability, Provides general guidance on content to be included in the 351(k) application, Recommends that sponsors of biosimilar products that are to be submitted under 351(k) meet early with FDA to discuss the proposed plan for biosimilar development programs and anticipated study requirements, Responds to some preliminary questions concerning exclusivity. Learn more John Murphy, III, Deputy General Counsel of BIO, says the FDA needs to require an additional showing of safety and effectiveness of a biosimilar offered up for an interchangeability designation. A number of applications beyond the five already green-lighted have been submitted, and big and small pharma companies alike have substantial biosimilar dollars both committed and on the sidelines waiting to see whether the interchangeability guidelines are reasonable or instead present serious obstacles. The data package of Zarxio includes four PK/PD studies in healthy volunteers by SC administration only, three of which were conducted using EUapproved Neupogen as a comparator, and a comparative Phase III study between the biosimilar and the USlicensed Neupogen in breast cancer patients 12. The court sided with Sandoz, the first company to win biosimilar approval for its Zarxio (filgrastim-sndz), that biosimilar marketers do not have to wait six months to market a new biosimilar after it is approved by the FDA.2 That decision creates a bigger profit motive for biosimilar sellers, one that would potentially be expanded even more if the biosimilar received a simultaneous interchangeability definition. When global clinical trials are conducted for biosimilar development, it is more important to equally allocate patients to two arms based on the factors affecting the evaluation (e.g., a Japanese population if there is an ethnic difference) which were identified in the development of the reference product, rather than ensuring the number of Japanese cases. 1,4,5 95% of commercially insured patients have access to RETACRIT nationwide, as of April Other relevant guidelines have also been issued and revised based on the experiences obtained by the EMA regarding their Scientific Advice and the EMA's Marketing Authorization Applications (MAAs). about navigating our updated article layout. The new Q&A states that either a comparative PK study or a Phase III study should include a Japanese population. But there is no clarifying language suggesting that fingerprint-like is a different standard for approval either for a biosimilar or the same biosimilar submitted for an interchangeable designation. The apparent fuzziness of some of the terms in the draft complicates matters further. BIOs Murphy wants the FDA to clarify the meaning of the term fingerprint-like and to provide examples of specific tools, analytical processes, and other ways to demonstrate fingerprint-like similarity between the proposed interchangeable product and the reference product. PD markers of infliximab are not established as surrogates for efficacy. The AMCP says it has taken a proactive approach to pharmacovigilance by recently launching the Biologics and Biosimilars Collective Intelligence Consortium (BBCIC), an initiative to proactively monitor both biologics and biosimilars using data from distributed research networks for millions of de-identified patients. AARP continues to believe that requiring all biologic products to have unique nonproprietary names will jeopardize patient safety and inhibit the development of the biosimilar market intended by the BPCIA, thereby reducing much-needed price competition and patient access.. The US guidance states that comparative PK studies should use a route of administration that is adequately sensitive 13; thus, all PK/PD studies of Zarxio for the US's MAA were conducted by only SC administration 12. Initial guidance provides insights on regulatory pathway for biosimilars, but does not address many critical issues. Three filgrastim BS products have been approved in Japan: filgrastim BS F and Mochida 5, originally developed in Japan; filgrastim BS NK and Teva 6, which is a different formulation of the same substance as that in Tevagrastim; and filgrastim BS Sandoz 7, a different formulation of the same substance as that in Zarzio. 17 Switching between reference products and biosimilars is relatively common; in Italy, 46% of patients taking anti-TNF biosimilars between 2015 and 2019 The membranebound tumour necrosis factoralpha (TNF)mediated biological activities (i.e., antibodydependent cellmediated cytotoxicity [ADCC], complementdependent cytotoxicity [CDC] and apoptosis) that are considered important in granulomatous diseases such as CD were similar, in addition to neutralizing activity against TNF. It is possible the FDA will change its naming convention for interchangeable biosimilars based on whatever comments it receives on the draft guidance, and patient groups certainly hope that will be the case. As a result, a separate report was created to capture information on biosimilar biologic INDs.