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
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
Biologic License Application
Biologics Price Competition and Innovation Act of 2009
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
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.
CDER traditionally is the only center with regulatory
oversight of drug products.
Up until March 22nd 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
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).
(non-vaccine and non-allergenic products intended to treat disease by
inhibiting or down-regulating a pre-existing, pathological immune response).
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
The BPCI Act was enacted on March 23rd, 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.”
“any alpha amino acid polymer with a specific defined sequence that is greater
than 40 amino acids in size…:”
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 23rd,
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.
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