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  • York Faulkner

Biopharmaceuticals - Overview of FDA Regulatory Structure

Updated: Sep 10



One of the fastest growing categories of new FDA filings includes applications for the approval of biological drug products, which are often called “biopharmaceutical” products. Unlike the small molecule drug products discussed in preceding chapters, biological products include such structurally complex things as “[a] virus, therapeutic serum, toxin, antitioxin, vaccine, blood, blood component or derivative, allergenic product, protein . . . or analogous product . . . applicable to the prevention, treatment, or cure of a disease or condition of human beings.” 42 U.S.C. § 262(i)(1).


Early generations of biopharmaceutical products were made by extracting proteins, antibodies, enzymes, or other materials from biological tissues. Today, recombinant technologies enable genetic engineering of bacteria, yeasts, and other organisms to express the targeted biological products. These expression systems are fundamentally different from the chemical reaction processes used to make small molecule drugs.


Unlike chemical reaction processes, the production of biological products typically involves the large-scale propagation of living organisms that retain their engineered traits in each successive generation. In contrast to chemical production processes that typically achieve a high degree of batch-to-batch consistency, biological production processes are susceptible to batch-to-batch variability. Moreover, small molecules can usually be characterized with high precision and can be accurately reproduced based on their chemical structures. Biological products, however, are often not so easily characterized and cannot be accurately reproduced unless the same organism is used.


As a consequence of these and other differences between small molecule and biological products, biological products have their own FDA review and approval process. From a high level perspective, the biological product approval process follows a similar path to small molecule drugs: (1) pre-clinical in-vitro and in-vivo experimentation, (2) submission of an IND for permission to conduct clinical studies, and (3) application for commercial license. However, the statutory and regulatory standards on which FDA’s review is based are specially tailored to biological products.


The FDA submission analogous to a New Drug Application is a “biologics license application” or “BLA.” See 42 U.S.C. § 262(a). The Biologics Price Competition and Innovation Act of 2009 (“Biologics Act”) created an abbreviated path to FDA approval of biologics that rely on previously approved biological products as the basis for their approval. The FDA submission analogous to an Abbreviated New Drug Application is often referred to as an “abbreviated biologics license application” or “aBLA.” See id. at § 262(k). An aBLA may be submitted for one of two different types of biological products.


The first type aBLA is directed to the approval of a “biosimilar” product. See id. at § 262(k)(2)(A). Although a biosimilar application is based, in part, on a previously licensed biological product, a biosimilar product is not considered to be a “generic” product. Unlike an Abbreviated New Drug Application that is based on demonstrating “bioequivalence” with the previously approved drug, approval of a biosimilar aBLA is based on proof of “biosimilarity” with the previously licensed biological product. Accordingly, although a licensed biosimilar product may have structural and therapeutic characteristics in common with the previously licensed biological product, it is not a copy of the prior product. A biosimilar therefore has a different active ingredient than the prior product and provides an alternative therapy. A pharmacy, therefore, cannot dispense a biosimilar product as a substitute for the prior biological product, unless the physician has expressly prescribed the biosimilar.


The second type of aBLA is directed to the approval of an “interchangeable biological product.” See id. at § 262(k)(2)(B). An interchangeable biological product is much more analogous to a generic drug product. It is considered to have an active ingredient providing the same effect and therapy as the prior biological product. A pharmacy may, therefore, substitute an interchangeable biological product for the prior product. Accordingly, the criteria for approving an interchangeable biological product are considerably more stringent than the standards for approving biosimilars.


The reader should be aware that although the statute governing the licensure of biological products is codified at 42 U.S.C. § 262, as with new drug approvals, FDA and many practitioners often still refer to the pre-codification numbering of this statute when discussing biological product applications. Consequently, BLA submissions are referred to as “Section 351(a) applications” and aBLA submissions are referred to as “Section 351(k) applications.” See 42 U.S.C. § 262(a) & (k).


The Hatch-Waxman Act procedures governing Orange Book patent listing and patent litigation do not apply to biological drug products. Although FDA publishes an online listing referred to as the “Purple Book” that provides certain information about the status of licensed biological products, there is no information about patents in the Purple Book. As discussed below, the biologics statute awards certain marketing exclusivities to the approval of new biological products and interchangeable biological products that operate independent of any patent rights applicable to the biological product. Similar to the Hatch-Waxman Act, the filing of an aBLA for approval of a biosimilar or interchangeable biological product is considered an act of patent infringement, and the statute provides a structure for resolving patent disputes in the courts while the aBLA review is pending before FDA.


Internal FDA Assignment of Review Responsibilities


There are two organizations within FDA responsible for reviewing biological product applications: (1) the Center for Biologics Evaluation and Research (CBER) and (2) the Center for Drug Evaluation and Research (CDER). Due to overlapping similarities in the indications and uses of some drugs and biological products, there had been some historical confusion about which organization, CDER or CBER, should review a particular biological product application.


On October 31, 1991, the two centers signed an “Intercenter Agreement” (ICA) that largely clarified the roles and responsibilities of the two organizations in reviewing applications. According to the ICA:


A. CDER is responsible for the following classes of drug and antibiotic products:


1. Naturally ¬occurring substances purified from mineral or plant source materials (excluding vaccines or allergenics);


2. products that are produced from non-human animal or solid human tissue sources (excluding animal-derived procoagulant products or antisera, venoms, red blood cell replacement products, vaccines, allergenic products, products composed of living cells, and certain other products listed under B. below)


3. antibiotics as defined by Section 507(a) of the FD&C Act, regardless of the method of manufacture:


4. certain agreed-upon classes of substances constitutively produced by fungi or bacteria including:

a. disaccharidase inhibitors

b. HMG-CoA reductase inhibitors;


5. chemically-synthesized molecules (excluding vaccines and allergenics) including:

a. products produced by chemical synthesis that are intended to be analogies of cytokines, thrombolytics, or other biologic, or that function by binding to the receptors for biological products,

b. chemically-synthesized mononucleotide or polynucleotide products, including products complementary to RNA or DNA sequences; and


6. hormone products, regardless of method of manufacturing, e.g., insulin, human growth hormone, pituitary hormones.


B. CBER is responsible for the following classes of products:


1. Biological products subject to licensure:

a. vaccines, regardless of method of manufacture including those vaccines which at the effective date of this agreement are being studied under active INDs administered by CDER (For the purpose of this agreement, a vaccine is defined as an agent administered for the purpose of eliciting an antigen¬ specific cellular or humoral immune response);

b. in vivo diagnostic allergenic products, in vivo diagnostic tests for DTH, and allergens regardless of the method of manufacture intended for therapeutic use as “hypo-sensitization” agents;

c. human blood or human blood-derived products including placental blood-derived products, animal-derived procoagulant products and animal or cell culture¬ derived hemoglobin-based products intended to act as red blood cell substitutes;

d. immunoglobulin products, whether monoclonal or polyclonal, produced in humans, animals or in cell culture;

e. products composed of or intended to contain intact cells or intact microorganisms including bacteria, fungi, viruses or virus pseudo-types, or viral vectors;

f. protein, peptide or carbohydrate products produced by cell culture excepting antibiotics, hormones, products listed in A.3. above, and products previously derived from human or animal tissue and regulated as approved drugs;

g. protein products produced in animal body fluids by genetic alteration of the animal, i.e., transgenic animals; and

h. animal venoms or constituents of venoms.


2. Other product classes:


a. Synthetically-produced allergenic products that are intended to specifically alter the immune response to a specific antigen or allergen; and

b. certain drugs used in conjunction with blood banking and/or transfusion.


ICA, § III(A) & (B).


In addition to dividing review responsibilities, the ICA also contemplates the sharing of resources between the two centers. Specifically, the ICA states that “[t]he assignment of review responsibility to one Center does not preclude review involvement of the other Center.” ICA at § IV. The ICA notes that each center has developed specialized expertise and that cooperation and consultation among the two centers “will facilitate efficient utilization of existing resources and rational program planning.” Id. The agreement also identifies certain situations requiring “collaborative review” in which one center will assign responsibility for a specific task, such as medical review, to the other center. Id. at VI.


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