DRW Monthly
October 2009
Issue No. 34

Singapore Issues Guidance on Biosimilar Product Registration

The Health Sciences Authority (HSA), Singapore's drug regulatory agency, released its Guidance on Registration of Similar Biological Products in Singapore in August 2009. The recent expiration of many biological product patents has spurred the development of a number of these products as similar biological products in Singapore. Consequently, the HSA developed this guidance which is largely adapted from the European Medicines Agency's (EMEA) biosimilar product guidelines. The guidance reviews basic principles, procedures, documentation, and registration requirements for similar biological products, also referred to as biosimilar products. The EU, as the first to introduce biosimilar drug approval guidelines as well as the region that has served as a testing ground for biosimilar products, has provided the HSA with the most definitive guidelines to address the clinical, non-clinical and quality issues surrounding biosimilar product market approval.

The HSA guidance formally defines a biosimilar product "as a biological medicinal product referring to an existing registered product, submitted for medicinal product registration by an independent applicant, and is subject to all applicable data protection periods and/or intellectual property rights for the original product."(1) Like EMEA, the HSA chose to exclude initially all products of a "more complex nature" such as vaccines, blood or plasma-derived products and their recombinant alternatives, gene or cell products used for advanced therapy, and human tissues or cells intended for human application. The "highly purified products" that are permitted to undergo an HSA comparability assessment must be able to meet characterization requirements using reliable analytical procedures, manufacturing processes and expert clinical/regulatory analyses.

Application & Documentation Requirements

The preliminary requirement for companies seeking to register a biosimilar product is that a medicinal product registered in Singapore must be used as the reference product for comparability studies. "Data generated from comparability studies with medicinal products registered in other countries may only provide supportive information."(2) A pre-submission consultation is recommended prior to a company's submission of a biosimilar product application and must be requested in writing. The application is to be submitted as a new drug application (NDA) via the abridged dossier evaluation route. The administrative requirements, applicable timelines and fees are discussed in detail in the Guideline for Medicinal Product Registration in Singapore. In addition, the biosimilar product "is to be evaluated and approved by at least one of HSA's reference agencies namely, Australia's Therapeutic Goods Administration, Health Canada, EMEA and US FDA. If not, the submission is to be submitted with the complete dataset as required for a new biological product."(3)

The HSA comparability assessment encompasses quality, non-clinical, and clinical documentation requirements and the same reference product is be used to demonstrate all three parts of the dossier (quality, safety and efficacy). The quality data for a biosimilar product must fulfill the technical content requirements for Module 3 of the International Conference on Harmonization (ICH) Common Technical Document (CTD) or Part 2 of the Abbreviated CTD, and satisfy pharmacopoeial monograph technical requirements as well as any additional requirement defined by HSA and ICH guidelines. The HSA uses EMEA's Committee for Medicinal Products for Human Use (CHMP) Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality Issues (CHMP/49348/05), and Guideline on Comparability of Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality Issues (CHMP/BWP/3207/00 Rev 1 as a framework to outline its own comparability study requirements for the quality dossier.

The HSA's non-clinical and clinical documentation requirements are both adopted from EMEA's CHMP The HSA's non-clinical and clinical documentation requirements are both adopted from EMEA's CHMP Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Non-clinical and Clinical Issues (CHMP/42832. Non-clinical studies including in vivo and animal studies are to be performed prior to initiating clinical studies. Also comparative in nature, these studies should be designed to detect differences in response between the similar biological product and the reference medicinal product. The clinical comparability data review is based on pharmacokinetic and pharmacodynamic studies followed by clinical efficacy and safety studies in which the data is generated using the test product produced with the final manufacturing process, thereby representing the quality profile of batches to be commercialized.

Pharmacovigilance and Post-approval Batch Release Requirements

Due to the inherent risk of biosimilar products to produce immunologic reactions, the HSA guidance emphasizes the need to closely monitor and report on both serious and non-serious adverse reactions. The following additional activities are required by biosimilar product license holders to supplement the current pharmacovigilance activities laid down for medicinal product license holders:

• the basic adverse drug reaction (ADR) reporting requirement for suspected serious ADRs in which a report must be filed within 15 days from the first report receipt has been extended to include non-serious adverse reaction reporting;
• the requirement to submit global periodic safety update reports (PSURs) to the HSA every six months for the first two years has also been extended to yearly for three additional years for a newly registered biosimilar product;
• a risk management plan must be submitted for a biosimilar product when an NDA is submitted;
• additional educational materials must be provided to physicians to inform them of specific risks associated with biosimilar products and measures included on how to reduce them; and,
• quarterly product sales data must be supplied to the HSA's pharmacovigilance branch.