Author: Suzanne Broussard, PhD

The unique characteristics and manufacturing processes of therapeutic biological products and drug compounds lays the framework for the differences in regulatory requirements for getting into the marketplace. While, biologics and drugs are both used for the same purposes — to treat, prevent, and cure diseases — biological products are much more complex in nature. By comparison, common drug compounds are relatively simple.

What exactly is a biological product?

Biological products are comprised of large and complex protein structures that are primarily derived from living material, including human, animal, and microorganisms. Proteins are often post-transcriptional modified, including glycosylation, oxidation, deamidation, and this has a profound effect on protein properties.  As seen in the figure below, this contrast with conventional drug compounds, such as aspirin, that have a smaller molecular weight and are chemically synthesized. Peptides can fall into either regulatory category and are comprised of amino acids just like a protein, but peptides are smaller.

The vast differences in complexity and size are depicted in this figure.

Defining biological products and drug compounds is the first step to understanding the common and unique regulatory requirements for each. FDA’s definition is the only one that matters for the purpose of obtaining marketing approval in the United States, and the definition for biologics is in a transition period.

Hang in there while we get to the precise definitions as we transverse the regulatory pathways described in the next section.

The FDA Has Separate Agencies with Oversight for Biologics and Drugs.

CBER and CDER

To deal with products of dramatically different composition and manufacturing protocols, the FDA created two independent specialized centers with premarket review and oversight responsibilities: The Center for Biologics Evaluation and Research (CBER) and The Center for Drug Evaluation and Research (CDER).

FDA defines which center a product is funneled into based on its definitions. While there has been some overlap in regulatory oversight for biologics and drugs under the current regulations, new guidelines will take precedence next year.

FD&C Act and PHS Act

Therapeutic biological products are a subset of drugs and thus regulated by the Food Drug and Cosmetic Act (FD&C Act) just like common drugs. In addition, biological products are regulated by the Public Health Service Act (PHS Act) due to their complex manufacturing processes.

Current center responsibilities are listed below flowed by the newest changes.

Drug Compounds

CDER traditionally is the only center with regulatory oversight of drug products.

Biological Products

Up until March 22^nd of 2020, both CBER and CDER have regulatory responsibility for therapeutic biological products under the FD&C Act and PHS Act. CDER currently regulates the following categories of therapeutic biological products.

• Monoclonal antibodies for in vivo use
• Most proteins intended for therapeutic use, including cytokines (e.g., interferons), enzymes (e.g., thrombolytics), and other novel proteins, except for those that are specifically assigned to CBER (e.g., vaccines and blood products). This category includes therapeutic proteins derived from plants, animals, humans, or microorganisms, and recombinant versions of these products. Exceptions to this rule are coagulation factors (both recombinant and human-plasma derived).
• Immunomodulators (non-vaccine and non-allergenic products intended to treat disease by inhibiting or down-regulating a pre-existing, pathological immune response).
• Immunomodulators (non-vaccine and non-allergenic products intended to treat disease by inhibiting or down-regulating a pre-existing, pathological immune response).
• Growth factors, cytokines, and monoclonal antibodies intended to mobilize, stimulate, decrease, or otherwise alter the production of hematopoietic cells in vivo.

New Definition of Biological Product

The definition of biologics changed with the newest amendments to the Biologics Price Competition and Innovation Act of 2009 (BPCI Act). The BPCI Act was enacted on March 23^rd, 2010, and 2020 marks the end of the 10-year transition period to allow sponsors time to make a seamless transition between the CDER and CBER regulatory agencies.

The BPCI Act amends section 351(i) of the PHS Act modifying the definition of a biological product to include a “protein (except any chemically synthesized polypeptide).

Here is the FDA’s definition of these keywords in section 351(1) of the PHS Act:

Biological Product – “…a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.”

Protein – “any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size…:”

Chemically Synthesized Polypeptide – “…the term chemically synthesized polypeptide would mean any alpha amino acid polymer that: (1) is made entirely by chemical synthesis and (2) is greater than 40 amino acids but less than 100 amino acids in size.”

Peptide – “…a polymer composed of 40 or fewer amino acids…”

BLA and NDA Applications for Marketing Approval

As we will discuss in an upcoming post, both biologics and drugs must first go through a rigorous process to determine their safety and efficacy in humans before they can be sold in interstate commerce. This involves basic research and subsequent supporting clinical trials in humans. Approval of the relevant Biological Licensing Application (BLA) or New Drug Application (NDA) is the last major hurdle to getting a biologic or drug approved for marketing in the United States.

The BLA / NDA is the formal process by which a sponsor applies to FDA asking for permission to approve a new biologic or pharmaceutical for sale and marketing in the United States (21 CFR 601.2).  The application tells the products full story of development and supports its use for a specific disease condition. The IND application precedes the BLA / NDA application, and the IND is actually part of the BLA / NDA as it is the living document that is kept up to date throughout the clinical evaluation process.

A key consideration is that an NDA needs to show that the drug is “safe and effective,” while the BLA is required to ensure the licensed biological product’s “safety, purity, and potency.”

The FDA ultimately makes the decision to either “approve” or “not to approve” the product based on the product’s safety and efficacy in the population for its intended use as outlined in the application. Thus, having a highly organized and well written BLA / NDA is critical for getting a product to market. Many sponsors utilize a CRO to facilitate faster market approval.

Be aware that starting March 23^rd, 2020, the BPCI Act requires that approval of all “biological products” needs to be submitted and approved through a BLA. After this date, even pending or tentatively approved 505(b)2 applications will not be approved by the FDA, at least according to the current guidance document.

Therefore, the FDA recommends sponsors that are unable to complete the NDA by the transition deadline, to start down the BLA pathway now. Failure to receive final approval by the 2020 deadline for applications in progress will likely have a significant impact on proposed protein products.  

Here is FDA’s preliminary list of approved biological products that will be deemed BLAs on March 23, 2020.

For questions pertaining to Project Jurisdiction, contact the CBER Product Jurisdiction Officer directly.

For questions on how Criterion Edge can help you better understand the regulatory landscape for BLAs and NDA, contact us at info@criterionedge.com.