FDA WATCH FDA’s Interpretation of the “Deemed to be a License” Provision of the Biologics Price Competition and Innovations Act A look at how the FDA will administer the transition of NDAs to BLAs n 2010, Congress passed, and President “deemed to be a license” provision and a Product Time to Approval (months) Aprotinin --- 4 Obama signed, the Patient Protection draft Q&A guidance document providing Beractant --- 1 Iand Affordable Care Act, within which additional details regarding the imple- Calfactant 35 is the Biologics Price Competition and In- mentation of the provision. Choriogonadotropin alfa 10 novations Act (BPCIA)2 that codified the This article provides a summary of how Chorionic gonadotropin* --- ability of the Food and Drug Administra- the FDA will administer the transition of Chymopapain --- Desirudin 33 tion (FDA) to review and approve biosimi- NDAs to BLAs, as described in these two Follitropin alfa 22 lar medicinal products. To harmonize the guidance documents. Follitropin alfa/beta 50 regulatory system for biological products Follicle stimulating hormone --- in the U.S., the BPCIA included Section FDA’s plans for Implementation of the Hyalurionidase 9 7002(e) which requires that all marketing “deemed to be a license” Section of Imiglucerase --- Insulin aspart 21 applications for biological products (as de- the BPCIA Insulin degludec 48 fined in the statute) be submitted as Bio- As written, Section 7002(e)(4) only ap- Insulin detemir 30 logics License Applications (BLA) under plies to approved NDAs and requires their Insulin glargine 12 the Public Health Services Act (PHSA). conversion to BLAs on the date that is 10 Insulin glulisine 10 Furthermore, Section 7002(e)(4) of the years after enactment of the BPCIA. The Insulin human --- Insulin lispro --- BPCIA requires that any New Drug Ap- FDA interprets that this date would be the I-125 albumin --- plications (NDAs) for biological products day after March 20, 2020. However, since I-131 albumin --- that were previously approved under Sec- March 21 is a Saturday (i.e., not a busi- Albumin chromated --- tion 505 of the Federal Food, Drug, and ness day), the conversion of the biological Tc-99m albumin --- Lepirudin 15 Cosmetic Act (FFDCA) must be “deemed product NDAs will occur at 12:00 am on Mecasermin --- to be a License” for the product under Sec- Monday, March 23, 2020. Also, at this date Mecasermin rinfabate 11 tion 351 of the PHSA. In order to provide and time, the NDAs for these products will Menotropins** --- time to prepare for this transition from no longer exist in the FDA’s data system Pancrealipase --- NDA to BLA, the statute set the date for and the associated products and their ap- Pegvisomant 28 Poractant alfa 40 implementation of this requirement to plications will commence being regulated Sacrosidase 11 be 10 years after the passage of the BP- under the PHSA as biological products Somatropin --- CIA. As such, the implementation date is and BLAs, respectively.5 Taliglucerase alfa 24 March 20, 2020. There are several potentially important Thyrotropin --- In December of last year, the FDA impacts of this change: Urofollitropin --- Urokinase --- 3 published a final guidance document ex- Velaglucerase alfa 5 plaining the FDA’s interpretation of the • Because these products will no longer have an approved NDA, they will no Box 1. Biologic Products Currently Regulated under longer be listed in the Orange Book. Section 505 of the FFDCA6 Keith Webber, Ph.D. • Because they will no longer be consid- Lachman Consultant Services ered “listed drugs,” any 3- or 5-year More on exclusivities exclusivity will no longer block ap- As noted above, any 3-year or 5-year ex- Keith Webber, Ph.D., is Vice President, proval or submission of subsequent clusivity applied to an NDA-approved Biotechnology at Lachman Consultants and BLA applications; exclusivities will be biological product will end at midnight provides scientific direction, strategic guidance, discussed in more detail below. on March 20, 2020, and will not confer to and leadership regarding biotechnology products, • Because they will no longer be “listed the product when its NDA becomes a BLA new drugs, and generic drugs based on his 30+ drugs,” they cannot serve as a Refer- at 12 AM on Monday morning March 23, years of combined industry, U.S. FDA, and NIH ence Listed Drug (RLD) for a 505(b)(2) 2020. Likewise, biological product NDAs experience. NDA or ANDA application. that are “deemed to be a license” will not 20 Contract Pharma contractpharma.com March 2019 FDA WATCH be granted the 12-year and 4-year exclu- plication as an NDA is a logical strategy. • Seek approval for a same condition of sivity periods provided under 351(k)(7) However, it is worth considering that, for use; and (A) of the PHSA to BLAs that are first ap- 18 NDAs for biological products submitted • Efficacy must be based on the same proved under 351(a) of that Act. between 1995 and 2011 (for which public mechanism of action. The good news is that any orphan data6 is available), the average time from drug exclusivity or pediatric exclusivity submission to approval was 24 months What are the regulatory differences that an NDA-approved biologic product (S.D. = 14 months). See Box 1 on page for BLAs vs NDAs? has will confer to the “deemed to be a li- 20 for a list of NDA-regulated biological For the most part, the regulatory require- cense” application. products and their times for approval. ments for NDA products and BLA prod- For 505(b)(2) NDAs and ANDAs, if ucts are harmonized. However, there What about pending or tentatively timely approval is not possible because are some significant differences that one approved NDAs? there are patents or exclusivities that should be aware of when switching a sub- Since the FDA interprets Section 7002(e) would impede final approval until after mission from NDA to BLA: (4) of the BPCIA strictly to apply only to the March 20, 2020 transition date, then approved NDAs, a pending or tentatively your submission strategy will need to be • Generally, for an NDA, validation of approved NDA will not be deemed to be a adjusted. For these types of applications, the manufacturing process is com- pending or tentatively approved BLA. the critical factor is that, when Monday pleted after approval of the applica- A pending NDA submitted under March 23, 2020 comes, the RLD which tion, whereas for BLAs, approval of 505(b)(1) or 505(b)(2) of the FFDCA that your application refers to will no longer be the application requires completion of doesn’t rely on the FDA’s finding of safe- “listed” in the Orange Book. As such, your process validation; ty and efficacy of an RLD will have until application will no longer be able to rely • In accordance with 21 CFR 600.13, BLA midnight on Monday March 23, 2020, to on the FDA’s finding of safety and efficacy holders must retain product samples gain approval as an NDA. If it does not of the previously listed drug. under appropriate storage conditions achieve approval by this date, FDA will In such cases when it is unlikely that for at least six months after expiration issue a Complete Response (CR) letter to your NDA will be approved before the ap- of the product lot; the application. plicable transition date, you will probably • In accordance with 21 CFR 600.14, BLA A 505(b)(2) NDA or ANDA that does want to take a different path. If you have holders must submit Biologic Product not have full approval by midnight on the data to support a BLA under 351(a), Deviation Reports within 45 calendar March 20, 2020, will receive a CR Letter. you can submit such an application at any days of becoming aware of an event Although, the guidance documents do time. You don’t have to wait until after that may affect the safety, purity, or not provide details on the content of the the transition date in March of 2020. Of potency of an approved product; CR letter, it can be expected that it will in- course, the BLA must meet the existing fil- • Every six months, BLA holders must clude a statement regarding the fact that ing requirements for a 351(a) BLA, includ- submit Distribution Reports in accor- the RLD, upon which the application de- ing data from clinical safety, efficacy, and dance with 21 CFR 600.81; and pends, is no longer available for reference immunogenicity studies. • Labeling for biological products must and that the response to the CR letter will Unfortunately, one cannot submit a meet the requirements under 21 CFR have to be in the form of a new 351(a) or 351(k) application for a biosimilar product 610 Subpart G. (k) BLA submission. until an appropriate reference product is approved under 351(a) of the PHSA or an Summary What happens to NDA supplements NDA for an appropriate reference product Facing the future transition of biological that are pending approval when the is “deemed to be a license” on March 23, products from regulation as new drugs transition date occurs? 2020. In addition, it is important to note under the FFDCA to regulation as biolog- Any pending NDA supplements will be that many of the differences between the ics under the PHSA in March of 2020, it converted to pending BLA supplements at RLD and the proposed product allowable is not too early to begin incorporating this midnight on Monday March 23, 2020. The under 505(b)(2) (e.g., change in strength, transition into your regulatory strategy.