Pharmaceutical Technology - May 2019

Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING 2019 45 the regulatory agency. In Europe, it takes an aver- age of 12–13 months to obtain a positive recom- mendation from the Committee for Medicinal Products for Human Use (CHMP), the body that advises the EU commission on market approval. The approval process is quite transparent, and after approval, EMA publishes a European Public Assessment Report (EPAR) that includes all the details of the scientific assessment. If there are re- sidual uncertainties, these are incorporated in the post-marketing surveillance program imposed by the regulator. Once regulatory approval has been received and market exclusivity of the reference product has expired, the products become avail- able for use by patients. In most EU countries, there is no hurdle for biosimilars to obtain full reimbursement (or with a small co-payment), and so patients have quick access to the licensed more cost-effective alternative. In most EU countries, there is no hurdle for biosimilars to obtain full reimbursement ..., and so patients have quick access to the licensed, more cost-effective alternative. The US Biologics Price Competition and In- novation Act (BPCI Act) of 2009 provided an abbreviated pathway for FDA approval of a bio- similar product. FDA recommends use of a step- wise approach for the development of biosimi- lar products: analytical studies, animal studies, clinical PK/PD studies, clinical immunogenicity assessment, and additional clinical studies. At each step, the sponsor should evaluate the level of residual uncertainty about the biosimilarity of the proposed biosimilar product to the refer- ence product and identify the next step to address remaining uncertainty. If there is a residual un- certainty about biosimilarity after conducting structural analyses, functional assays, animal testing, human PK and PD studies, and a clini- cal immunogenicity assessment, then additional clinical data may be needed to adequately address that uncertainty. A clinical study should be de- signed to investigate whether there are clinically meaningful differences between the biosimilar product and the reference product. FDA requires US-Reference Listed Drug (RLD) for comparability studies—analytical, clinical PK/ PD—to demonstrate biosimilarity. For a PK/PD clinical study, the most sensitive dose to detect and evaluate differences in the PK and PD profiles is suggested. FDA has also established an additional approval classification called an "interchangeable biosimilar". To achieve this designation, the bio- similar manufacturer must demonstrate that an interchangeable product is expected to produce the same clinical result as the reference product in any given patient. Also, for products administered to a patient more than once, the risk in terms of safety and reduced efficacy of switching back and forth between an interchangeable product and a refer- ence product must have been evaluated. The FDA guidance for the interchangeable biosimilar des- ignation was published in 2017. The consequence of the interchangeable biosimilar designation is that pharmacists in the US would be permitted to automatically substitute the interchangeable biosimilar for the reference product without the prior approval of the prescriber (similar to small molecule generic products). Thus far, none of the

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