The Food and Drug Administration (FDA) is promoting the Quality Overall Summary (QOS) as a powerful tool to promote effective communication between regulators and sponsors of drugs as well as a tool that can substantially impact the efficiency and quality of the regulator’s assessment. The QOS is required for all New Drug Applications (NDAs), Abbreviated New Drug Applications (ANDAs) and Biologics License Applications (BLAs), thus the QOS has significant potential to impact the regulatory review process for getting marketing approval.
The QOS summarizes all quality-related information in the application. As part of Module 2 of the electronic Common Technical Document (eCTD), the QOS links to the sponsor’s larger body of data in Module 3. The QOS is expected to provide the regulator with sufficient information to understand the contents of Module 3 in a high-level overview. However, FDA suggests that many sponsors are falling short of these expectations and are not fully utilizing this powerful tool as an effective guide for regulators to assess the application.
The QOS provides the sponsor with an opportunity to summarize the key aspects of the new drug or biologics application, explain specific items for the regulators to consider, and extend to post-approval comments. Yet, a poorly written QOS requires regulators to spend significant effort to “understand, summarize, collate, and interpret quality data from module 3 (Figure 1).
Figure 1. There can be a disconnect between applicants and regulators regarding the communication of quality data and its impact on the assessment. Currently, it takes time and/or communications (e.g., information requests) to fully understand the quality of data and its significance in an application.
The FDA’s white paper describes key considerations for creating a high–quality QOS to ensure regulators have a good idea of the potential risk to the patient and the control of this risk in the commercially manufactured product. The 3 key considerations are:
Identifying the main risks to the patient from a product quality perspective.
Understanding how the proposed overall control strategy controls and/or mitigates the identified failure modes of the manufacturing process or products.
Acknowledging potential considerations for the quality assessment of the submission.
These key considerations are designed to help regulators evaluate the potential risks related to quality, and their potential impact on the patients, in a summarized benefit and risk assessment. Indeed, the FDA is encouraging sponsors to explain important aspects of the new drug or biologic such as how the product was formulated, and how the risk might impact the patients. Further clarifications on the 3 key considerations are provided in the FDA’s white paper.
Writing these technical documents to concisely convey information is challenging and you might want to consider these project management and quality control tips when putting you QOS together. These tips might just help improve your QOS, which will reduce the number of information requests from the FDA and thus decrease your NDA / BLA review time.
Biological products warrant special regulatory consideration because of their complex nature and susceptibility to variation during manufacturing. Biologics are not only complex in their physical structure, they are produced from living organisms and thus pose a myriad of potential issues in the manufacturing and isolation processes that all have the potential to induce immunogenicity. Regulations for developing a biological product take these potential risks into consideration
In this second piece evaluating BLA and NDA, we focus on understanding some of the nuances between biologic and drug development. See the first BLA vs NDA blog for a more focused look at regulations.
Manufacturing of Biological Products is Inherently Riskier than Production of Drugs.
The manufacturing processes for biological products are different than processes for pharmaceuticals. Traditional drug products are typically manufactured using pure chemical substances that are sterile, and the end products can be relatively easily analyzed. On the other hand, biological products are made from living organisms and are much more complex in nature — making product analysis very difficult. Indeed, most biological products are defined by the manufacturing processes used for production. The manufacturing process and manufacturing facilities are so crucial to biologics that “purity” is part of the agency’s requirements for licensing.
The FDA strictly controls changes to the manufacturing processes that evolve during the development of the biologic, as well as after licensing. Biologics are much more sensitive to process changes than are drugs – even a small change in the manufacturing process can result in an adverse change in the biological product. This is why biological products are regulated under the PHS Act. Initial manufacturing procedures are detailed in the IND application and then modified as needed throughout the IND phase of clinical evaluation and through the final BLA submission.
Modification to manufacturing may be needed to scale up from pilot to full-scale production or to improve efficiency; this can include any changes in equipment, facilities, handling, or storage and testing of cell substrates that may be required.
Changes to the biologic’s manufacturing process, equipment, facilities, or handling have the potential to affect the products identity, safety, purity, and potency. Therefore, any changes to production must be brought to the attention of the regulatory authorities, and the FDA will use its “comparability” ruler to determine if additional studies are required to support the license application.
Comparability Testing
FDA issued two guidance documents to help manufacturers understand the concept of comparability and gracefully jump through the hoops to achieve a license to sell their therapeutic biologics.
For any situation, the FDA encourages sponsors to consult with them prior to implementing changes.
Clinical Development of Biologics Must Include Assessment of Immunogenicity
There are unique clinical considerations for biologics since they are derived from living organisms. Either the biologic itself or impurities from manufacturing could trigger an immune response with potentially disastrous consequences. Therefore, the clinical development of biologics must include the assessment of immunogenicity. This differs from manufacturing and isolation of drug molecules which do not typically pose an immunogenicity threat.
Recommendations to facilitate industry’s development and validation of assays for assessment of the immunogenicity of therapeutic protein products during clinical trials
Applies to assays for the detection of anti-drug antibodies (ADAs) and may also apply to some peptides, oligonucleotides, and combination products on a case-by-case basis
Includes recommendations regarding the development and validation of screening assays, confirmatory assays, titration assays, and neutralization assays
Finalizes the revised draft guidance for industry entitled “Assay Development and Validation for Immunogenicity Testing of Therapeutic Protein Products” issued in April 2016 and includes a revised title
Conclusion
The biggest differences between the approval of therapeutic biological products or drug compounds center around the complex nature of biologics and the many challenges that occur in their manufacturing. Because biologics come from living organisms, immunogenicity is always a concern. The FDA’s regulatory landscape is complicated and always changing. We are happy to help your organization stay abreast of the current regulations and ensure your BLA and NDA applications are on target and on time.
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.
Acronym
Full Name
BLA
Biologic License Application
BPCI
Biologics Price Competition and Innovation Act of 2009
CBER
Center for Biologics Evaluation and Research
CDER
Center for Drug Evaluation and Research
FD&C Act
Federal Food, Drug, and Cosmetic Act
NDA
New Drug Application
PHS Act
Public Health Service Act
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 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
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 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.”
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 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.
State of the Art: Building a Solid Foundation for your PER to Support IVDR Readiness
In this webinar, Dr. Sarah Chavez provides an overview of the State of the Art section, and explains how it fits into the overall process of writing a successful, IVDR-compliant Performance Evaluation Report (PER) in a reasonable time frame. A complete readiness assessment and gap analysis will help you identify critical resources, feeder documents, and expertise needed to establish that your IVD may be considered “state-of-the-art.” Ultimately, knowing what the Notified Body expects to see will help you avoid project delays and discover efficiencies in the SOA development process.
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