FDA Biologics License Application ("BLA")
In contrast to regulations for new drug applications, which provide detailed explanations of the type and quality of information required for a complete NDA, the regulation governing BLA submissions only briefly identifies broad categories of information required for the submission.
Generally, the regulations require that in order “[t]o obtain a biologics license . . . , the manufacturer shall submit:”
 an application to [CDER or CBER] . . . on forms prescribed for such purposes,
 data derived from nonclinical laboratory and clinical studies which demonstrate that the manufactured product meets prescribed requirements of safety, purity, and potency;
 with respect to each nonclinical laboratory study, either a statement that the study was conducted in compliance with the requirements [of good laboratory practices], or, if the study was not conducted in compliance with [good laboratory practices], a brief statement of the reason for the noncompliance;
 statements regarding each clinical investigation involving human subjects contained in the application, that it either was conducted in compliance with the requirements for institutional review . . . or was not subject to such requirements, . . . and was conducted in compliance with requirements for informed consent. . . .
 a full description of manufacturing methods;
 data establishing stability of the product through the dating period;
 sample(s) representative of the product for introduction or delivery for introduction into interstate commerce;
 summaries of results of tests performed on the lot(s) represented by the submitted sample(s);
 specimens of the labels, enclosures, and containers, and
 any Medication Guide.
21 C.F.R. § 601.2(a).
The BLA applicant is required to submit “data that are adequate to assess the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations.” 21 C.F.R. § 601.27(a); see also 42 U.S.C. § 262(a)(2)(B). However, the applicant may request a deferral of submitting pediatric data until after licensing of the biological product “if, among other reasons, the product is ready for approval in adults before studies in pediatric patients are complete [or if] pediatric studies should be delayed until additional safety or effectiveness data have been collected.” 21 C.F.R. § 601.27(b)(1).
Basis for Approval
The statute requires FDA to approve a BLA if the application demonstrates that “the biological product . . . is safe, pure, and potent; and designed to assure that the biological product continues to be safe, pure, and potent.” 42 U.S.C. § 262(a)(2)(C)(i)(I).
According to the regulations, “safety means the relative freedom from harmful effect to persons affected, directly or indirectly, by a product when prudently administered, taking into consideration the character of the product in relation to the condition of the recipient at the time.” 21 C.F.R. § 600.3(p).
The regulations define “purity” to mean “relative freedom from extraneous matter in the finished product, whether or not harmful to the recipient or deleterious to the product” and “relative freedom from residual moisture or other volatile substances and pyrogenic substances.” Id. at 600.3(r).
Finally, “[t]he word potency is interpreted to mean the specific ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner intended, to effect a given result.” Id. at 600.3(s).
Conditions for License Issuance
As noted above, the applicant must demonstrate that the biological product is “designed to assure that the biological product continues to be safe, pure, and potent.” 42 U.S.C. § 262(a)(2)(C)(i)(I).
This statement could be understood to refer to the shelf-life stability of the manufactured biological product. However, the regulations make clear that this requirement refers to stability of the manufacturing process to continually and reliably manufacture the biological product without significant variation in product quality.
As a condition of issuing a license, FDA must be satisfied that no “part of the process of or relating to the manufacture of [the product] . . . would impair the assurance of continued safety, purity, and potency. . . .” 21 C.F.R. § 601.20(c). In assessing the stability of the manufacturing process, FDA requires the applicant to provide samples and analyses of the biological product and access to the manufacturing facilities for inspection. Id. at 601.20(a) – (d).
Issuance or Denial of License
FDA will issue a biologics license if it finds that the BLA “meets the applicable requirements,” and the license will be valid until suspended or revoked by FDA. 21 C.F.R. § 601.4(a).
If FDA determines that the BLA cannot be approved in its current form, then FDA will send the applicant a “complete response letter” identifying the deficiencies in the BLA. 21 C.F.R. § 601.3(a). After receiving a complete response letter, the applicant must either (1) “resubmit the application . . . , addressing all deficiencies identified in the complete response letter” or withdraw the application. Id. at 601.3(b)(1) – (2). If the applicant withdraws the BLA, the applicant may resubmit the BLA at a later time. Id. at § 601.3(b)(2).
If FDA “determines that . . . the product does not meet the requirements . . . , [the BLA] shall be denied.” Id. at 601.4(b). In such situations, FDA is required to provide the reasons for denying the BLA, and the applicant may request a hearing before FDA to address those reasons. Id.
Changes to An Approved Application
After issuance of a license, the manufacturer has an ongoing duty to inform FDA about any “change in the product, production process, quality controls, equipment, facilities, responsible personnel, or labeling” that formed the basis of the approval. 21 C.F.R. § 601.12(a).
The manufacturer may be required to file an application for supplemental approval if any of those changes “has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product.” Id. at 601.12(b)(1). Specific examples of changes that may require supplemental approval include, but are not limited to:
(i) [C]hanges in the qualitative or quantitative formulation, including inactive ingredients, or in the specifications provided in the approved application;
(ii) Changes requiring completion of an appropriate human study to demonstrate the equivalence of the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product;
(iii) Changes in the virus or adventitious agent removal or inactivation method(s);
(iv) Changes in the source material or cell line;
(v) Establishment of a new master cell bank or seed; and
(vi) Changes which may affect product sterility assurance, such as changes in product or component sterilization method(s), or an addition, deletion, or substitution of steps in an aseptic processing operation.
21 C.F.R. § 601.12(b)(2)(i) – (vi).
The applicant must obtain supplementary approval from FDA before distributing product made as a result of any of these changes. Id. at 601.12(b)(3).
Other, less potentially severe, changes require a supplemental submission at least 30 days prior to distribution of product made using the change where the change “has a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product.” Id. at 601.12(c)(1).
Such changes include but are not limited to:
(i) An increase or decrease in production scale during finishing steps that involves different equipment; and
(ii) Replacement of equipment with that of similar, but not identical, design and operating principle that does not affect the process methodology or process operating parameters.
(iii) Relaxation of an acceptance criterion or deletion of a test . . . that is consistent with FDA statutory and regulatory requirements.
Id. at 601.12(c)(2)(i) – (iii).
In some situations, FDA may approve moderate-risk changes immediately where there is prior experience with the particular type of change and the information provided is complete. Id. at 601.12(c)(5).
12-Year Marketing Exclusivity for First Licensure
The statute provides a generous 12-year marketing exclusivity period for the first licensing of a new biological product. This means that for a period of 12 years following the licensing of the new biological product, FDA will not approve an aBLA, application for a biosimilar or interchangeable biological product, that relies upon or refers to the new biological product for the basis of approval. See 42 U.S.C. § 262(k)(7)(A).
Moreover, during the four-year period following the licensing of the new biological product, FDA will not accept any aBLA application for a biosimilar or interchangeable biological product, that relies upon the new biological product for the basis of approval. See 42 U.S.C. § 262(k)(7)(B).
This 12-year exclusivity period is also called “reference product exclusivity” because the new biological product may be “referred to” or relied upon as the basis for approving biosimilar or interchangeable biological products under Section 262(k). The statute explains:
“The term ‘reference product’ means the single biological product licensed under [Section 262(a)] against which a biological product is evaluated in an application submitted under [Section 262(k)].
42 U.S.C. § 262(i)(4).
This 12-year reference product exclusivity is analogous to the five-year New Chemical Entity marketing exclusivity awarded to newly approved drugs. As with the New Chemical Entity exclusivity, the reference product exclusivity, does not depend upon the existence of patents, trade secrets, or any other intellectual property rights. The exclusivity is awarded as an incentive to manufacturers to develop new biological products. The relatively long period of exclusivity recognizes the particular technological difficulties of developing biological products.
The start of the 12-year reference product exclusivity period is calculated from date of “first licensure” of the biological product. Id. at § 262(k)(7)(A). For each approved biological product, there is only one 12-year reference product exclusivity period. Exclusivity is not awarded for the approval of supplemental applications or for the approval of subsequent applications by the manufacturer for “new indications, routes of administration, dosing schedule, dosage form, delivery system, delivery device, or strength” and for “a modification to the structure of the biological product that does not result in a change in safety, purity, or potency.” Id. at § 262(k)(7)(C).
CBER and CDER each track the dates of first licensure and reference product exclusivities in charts they publish called the “Purple Book: Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations.”
Following is an excerpt from CDER’s Purple Book:
Here, it is important to understand the difference between “date of licensure” and “date of first licensure” as presented in the Purple Book. The date of licensure is the most recent licensure date for the product, e.g., approval of a supplemental application due to some change in the product or process as discussed above. FDA reports that it will calculate the “date of first licensure” only “for reasons of regulatory necessity and/or at the request of [an aBLA applicant].” Accordingly, there is no “date of first licensure” listed for many of the product entries in the Purple Book.
The entry for the Granix biological product reports a first licensure date of August 29, 2012, corresponding to a reference product exclusivity period that expires 12-years later on August 29, 2024. The earliest date on which an aBLA for a biosimilar or interchangeable product could be filed would be four years after the date of first licensure, or August 29, 2016. And, FDA could not approve the aBLA until after the reference product exclusivity period expires on August 29, 2024.
The “NA” or “not applicable” in the TNKase entry indicate that FDA has calculated the date of first licensure and determined that the reference product exclusivity period has expired and is no longer applicable. Presumably, the date of first licensure for TNKase was on or before June 2, 2000, meaning that the reference product exclusivity period for this drug, at the latest, would have expired on June 2, 2012.
Finally, the “B” reference in the entry for the Ogivri biological product indicates that at least one biosimilar product has been approved. The entry does not report a date of first licensure. However, the biosimilar approval indicates that any applicable reference product exclusivity for Ogivri has expired.