In general, under the Pediatric Research Equity Act (PREA), submission of an initial pediatric study plan (iPSP) is required for a drug or biological product that includes a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration. Submission of an iPSP is required 60 calendar days after the date of the end-of-phase 2 (EOP2) meeting. In the absence of an EOP2 meeting, the sponsor should submit the iPSP before the initiation of any phase 3 studies, or combined phase 2/3 studies. In the absence of any phase 3 or combined phase 2/3 studies, an iPSP should be submitted 210 calendar days before the submission of the marketing application (CDER, 2005).
Under section 351(k) of the Public Health Service Act (PHS Act), a biosimilar product is defined as “highly similar to the reference product notwithstanding minor differences in clinically inactive components” and there should be “no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product” (CDER, 2015).
Most biological products contain large molecules that are industrially manufactured using living organisms such as reprogrammed bacteria or cells. Due to differences in manufacturing, such as the use of different cell lines and modification in harvesting process, a biosimilar biologic is not a generic version of the reference product but is “highly similar”, and is thus considered as “a new active ingredient.” Subsequently, PREA is triggered for biosimilar biologics (Sherman, 2012). However, even though requirement under PREA is triggered, extrapolation of data may be appropriate for biosimilar products. In addition, alternative strategies can be proposed in order to help the sponsor obtain a waiver or defer pediatric studies for biosimilar products.
By law, a reference biological product can be substituted with an interchangeable biologic, by the pharmacist, without seeking permission from the prescriber. Compared to the biosimilar biological product, an interchangeable biologic is a biosimilar biologic that will “produce the same clinical result as the reference product in any given patient” and “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” (CDER, 2017). When these conditions are fulfilled, an interchangeable biologic product is not considered to contain a new active ingredient. Therefore, it is likely that no pediatric studies will be required for interchangeable biological products as long as scientific justifications for the indication, dosage form, dosing regimen, and route of administration are made.
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CDER, CBER, Considerations in Demonstrating Interchangeability with a Reference Product. Guidance for Industry. Draft Guidance. January 2017.
CDER, CBER, How to Comply with the Pediatric Research Equity Act. Guidance for Industry. Draft Guidance. September 2005.
CDER, CBER, Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. Guidance for Industry. April 2015.
Sherman RE. Biosimilar Biological Products. Biosimilar Guidance Webinar. 2012.