Author: Suzanne Broussard, PhD
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.
The Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology-derived Products “describes those steps that manufacturers may perform and which FDA may evaluate to allow manufacturers to make manufacturing changes without performing additional clinical studies to demonstrate safety and efficacy.”
The Q5 Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process is “intended to assist manufacturers in the collection of relevant technical information that serves as evidence that the manufacturing process changes will not have an adverse impact on the quality, safety, and efficacy of the drug product.”
If changes are needed to an approved license, the Changes to an Approved Application: Biological Products Guidance for Industry is available on the FDA website.
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.
In January 2019, FDA announced that the final industry guidance on immunogenicity testing is available: Immunogenicity Testing of Therapeutic Protein Products–Developing and Validating Assays for Anti-Drug Antibody Detection.
This guidance provides:
- 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.
Watch the recording of this webinar
Companies face constant pressure to conduct comprehensive data-gathering activities in response to increasing regulatory expectations and demands for information. Data identification through Systematic Literature Review (SLR) supports critical functions throughout the company, from MDR requirements through IND submissions.
This session will review currently accepted SLR best practices and provide practical guidance for designing and conducting a rigorous literature review, from search strategies through screening and data extraction. Case studies will provide real-world examples of how data identified through the SLR process helped inform the decision-making process.
Our President Laurie Mitchell joins Jennifer Tetzlaff, Research Product Specialist with Evidence Partners, to talk to you about the following points:
- Examples of how the use of published data can support regulatory expectations
- When to conduct a systematic literature review
- Best practices for conducting a methodologically-sound SLR
- Use of available tools and technology
This webinar is co-hosted by Criterion Edge and Evidence Partners.
Author: Suzanne Broussard, PhD
One of the first steps toward obtaining approval to market drug products or biological compounds in the United States is the submission of an Investigational New Drug (IND) application. Your research team is hard at work developing a very promising new drug, and they are naturally anxious to get a product to market. An important part of this process is to have a spot-on IND submission that sails through the FDA’s evaluation program.
The Process
New drug products and biological therapies go through a rigorous review process to prove they are safe and effective. So, what role does the IND submission play in this process? Prior to marketing, a New Drug Application (NDA) or Biological License Application (BLA) must be submitted and approved by the FDA’s respective consumer watchdog organizations, the Center for Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER). In order to submit an NDA or BLA application, products must first be tested for safety and efficacy in human clinical trials, which is where INDs come into play. Federal Law prohibits transportation of drugs across state lines without an approved marketing application. Approval of an IND allows the drug or biologic to be legally transported and distributed across state lines for use in the clinical trials that support the NDA and BLA applications.
An IND application is a request for authorization to administer a drug or biologic to humans for testing the product’s safety and efficacy. The IND application must contain information in three broad areas:
- Animal Pharmacology and Toxicology Studies
- Manufacturing Information
- Clinical Protocol and Investigator
Once the IND is submitted, the clock starts ticking and the FDA has 30 days to comment. Following a review process, the FDA will either approve the IND indicating the product is “safe to proceed”, thus allowing the product to be used as an investigational drug or biologic, or a “clinical hold” will be placed on the IND application to delay or suspend the proposed clinical investigation. The sponsor is given an opportunity to address the issues cited in the clinical hold and the process then starts over again. Even a technical problem in submitting the IND can trigger a clinical hold and cause a significant delay in getting a product to market.
Let’s look at a number of common problems with IND submissions to help your organization avoid these mistakes and get your product to market on time.
1. Sponsors that do not take full advantage of the two programs offered by FDA to accelerate the approval of innovative medical products put themselves at a disadvantage in the review process.
The FDA now has two programs to promote the accelerated approval of innovative medical products, INitial Targeted Engagement for Regulatory Advice on CBER producTs (INTERACT) and Pre-Investigational New Drug Application (IND) Consultation Program.
These programs provide an opportunity to set the stage and build a relationship with the FDA. For small companies, the IND submission process is likely their first interaction with FDA and vice versa. First impressions matter! Be prepared and build a solid reputation that can benefit your company for years to come. Listed below is a little more information about how these programs work.
INTERACT
The INTERACT is the newest FDA initiative (announced June 22, 2018) and is designed to enhance early communication amongst sponsors and the FDA; INTERACT replaces the pre-pre-IND meeting and allows sponsors to obtain feedback from CBER before they are ready for a pre-IND meeting. Thus, sponsors can get some initial advice from the FDA regarding “the chemistry, manufacturing and controls, pharmacology/toxicology, and/or clinical aspects of the development program” that is not binding. FDA suggests that each meeting consists of only one issue that needs to be addressed by the sponsor allowing for a focused consultation.
Pre-IND Meeting
The Pre-IND Consultation Program is highly encouraged by FDA as part of their commitment to help accelerate the approval of innovative medical products.
Here are some of the benefits that can be obtained from a Pre-IND meeting:
- Verification that the appropriate animal model is being used to determine product safety
- Determine if the toxicology data is sufficient to justify a First-in-Man study
- Discuss any data concerns or potential roadblocks
- Develop a relationship with the agency team that will be reviewing the submission
Going into the INTERACT and pre-IND meetings prepared and with total transparency will help you get the most out of these meetings, and ultimately will circle back to strengthen point #3 of making sure your plan is ready to drive your product forward. Plus, these are a great opportunity to build a strong relationship with the FDA.
2. Having a poorly written document that frustrates and confuses the reviewers will not help your cause.
One of the biggest reasons’ sponsors receive a clinical hold independent of poor study design is that the IND document lacks organization and clarity.
It is the sponsor’s job to make sure that the IND is well-written and easy to understand. Like me, I’m sure you have read a plethora of manuscripts and documents that leave you wondering what the take-home message is or spent way too much time interpreting findings. All aspects of the IND should be presented in a cohesive manner in an format that is easy to read; also remember, it is much easier to look at the data when you have a big picture concept and know the project’s key message upfront.
In the 2018 fiscal year, the FDA received 675 original INDs and took a total of 1,224 actions against IND submissions. That’s a lot of information to process! Make sure your submission is clear and to the point.
The easier it is for the reviewer to find the pertinent information, the more likely they are to provide a review that is in line with your expectations. Keep these points in mind when generating the IND application.
- Create a document that is easy to review.
- Include the supporting data and protocols.
- Provide rationales for each conclusion.
- Do not ignore the comments from the INTERACT and Pre-IND meetings!
Involving regulatory experts, either in-house or contracted from a respected CRO like Criterion Edge, early in the IND application phase may save both time and money.
It’s not too late to spring ahead. Read about what our top medical writers have to say: insider secrets for project management.
3. Using nonclinical data or manufacturing information that does not adequately support the clinical protocol ultimately hurts the IND application.
It is critical to ensure that the nonclinical data supports the clinical design and that both provide adequate justification of the desired labeling claims, including basic exposure data. This requires detailed planning among your various teams and a strong knowledge base of the IND regulations.
Most importantly, specify how patient safety will be assured during the study. Include sufficient information to both assure the proper quality, purity, and strength of the drug or biologic, and to assess the adequacy and consistency of production.
4. Leaving out data pertinent for evaluating the procedures makes it difficult to determine the quality of the proposed studies.
Take extra care to make sure there is evidence that supports the robustness of the assay to be used for evaluating the clinical trials. Also, include representative output data such as chromatograms and procedural details in the form of standard operating procedures (SOPs). This can be a big undertaking, especially with complex biological products.
5. Including massive amounts of data and assuming it is self-explanatory slows down the review process.
While this seems to be the opposite of mistake number 4, not having the information presented concisely is a major flaw with many submissions. Being brief and guiding the document with clearly presented points helps the reviewer know what is relevant for the product under consideration.
6. Not clearly stating the potential risk of the drug or biologic in the submission raises red flags.
Potential issues of concern need to be presented in a forthcoming and transparent manner during and after the regulatory review. Failure to do so will impact the sponsor’s credibility. It is the sponsor’s responsibility to provide the FDA with the information in a manner the helps them understand what the safety issues are and how they will be mitigated.
7. Sponsors should note that Study Data Standards are required for commercial INDs as of December 17, 2017, for both nonclinical and clinical studies.
This is a specific requirement to comply with the Clinical Data Interchange Standards Consortium (CDISC). FDA states this very clearly; “FDA will not accept an electronic submission that does not have study data in compliance with the required standards specified in the FDA Data Standards Catalog.”
Details are accessed in the Providing Regulatory Submissions in Electronic Format—Standardized Study Data guidance document.
8. Making inadvertent submission mistakes in the IND submission is the most common reason for technical rejection of an eCTD filing.
A surprising number of IND applications are rejected for technical issues. Double check the application to make sure that the correct eCTD format is being followed and that all the pre-clinical data and documents are included. It is also worth a second look to ensure the IND submission is sent to the correct center.
9. Underestimating the time required to develop an IND application and complete the submission is easy to do.
It can take 12 to 14 months to complete the IND application package, and this does not include the time commitment for the INTERACT and pre-IND meetings. Do not wait until the last minute to begin the process!
As of May 5th, 2018, Commercial INDs and the Master Files must be submitted using the Electronic Common Technical Document (eCTD) standard format. Ensuring that all files contain the proper information and are in the proper format will require some technical expertise.
In summary, the IND application is a complex document. A poorly developed IND will result in delays moving forward with clinical trials and will ultimately slow getting products into the marketplace. If you are inexperienced in this area of regulatory compliance, outside experts that are fully up to speed with the newest regulations and procedures can help you breeze through the IND submission process.
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.
| 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.
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.
Author: Suzanne Broussard
Clinical evaluation is an integral part of technical documentation mandated for regulatory compliance of medical devices sold in the European Union (EU); therefore, having a well-designed and clearly written clinical evaluation report (CER) is paramount for manufacturers of both existing and new medical devices.
This is especially true with the passing of Medical Device Regulation 2017/745 (MDR). The MDR directive places stricter regulations on medical device safety and performance.
Not only are new devices seeking regulatory compliance impacted, devices on the market prior to the initiation of the MDR directive are also affected as every device must be re-submitted for CE marking before the end of the May 2020 transition period. This effect will require manufacturers to update the CER for each device to current MDR standards in order to be in regulatory compliance.
A survey of medical device manufacturers revealed that 78% of respondents do not sufficiently understand MDR, while 58% do not have a strategy in place to correct gaps in their clinical data or a process for collecting the data needed (KPMG & RAPS).
With so little time left to meet the MDR May 2020 transition deadline, consider hiring a professional to help your organization prepare the CER document.
Why is the CER Important for Marketing in the European Union?
The CER documents a device’s entire clinical evaluation process and is required to achieve regulatory compliance for marketing in the EU. Essentially, the CER outlines the assessment and the clinical data that determine if evidence sufficiently verifies the clinical safety and performance of the medical device. Furthermore, the CER is considered a living document and must be updated on an ongoing basis throughout the devices’ life cycle.
Key Updates in MDR as Outlined in MEDDEV 2.7/1 Revision 4
Device Equivalence and Risk/Benefit Profile
The MEDDEV guidance document 2.7/1 revision 4 outlines the stricter regulatory requirements placed on medical device manufacturers. Several key differences exist between the previous EU Medical Device Directives (MDD) and MDR, including the data requirements to determine device equivalency and clarification on the risk/benefit profile.
For a detailed gap analysis of the differences in the requirements for device equivalency and risk/benefit profiles between the previous and the current standards see our white paper Gap Analysis Report: MEDDEV 2.7/1 Guidance and Risk/Benefit Profile.
State of the Art is a Central Theme in the Clinical Evaluation
Establishing and describing the state of the art for each medical device is central to the clinical evaluation because it establishes a reference standard that is used to determine if the device’s safety and performance are compatible with current treatment options. This information is used throughout the clinical evaluation process and is documented in the CER.
Criterion Edge’s Founder and President Laurie Mitchell outlines steps for developing state of the art to comply with MEDDEV 2.7/1 revision 4 in the white paper “State of the Art: Best Practices and Literature Review Using DistillerSR.”
Experience Writing CER Documents Matters
Manufacturers have a lot at stake. Having experienced CER writers that can integrate the complex regulatory requirements with the device’s specific characteristics and can present the information with clarity can save both headaches and money. Pulling together the CER document requires a thorough understanding of the regulations’ meaning and, as importantly, the ability to apply the MDR regulations to each device’s specific situation.
The role of the clinical evaluator is so pivotal that expected qualifications for the clinical evaluation authors and evaluators are outlined in the MEDDEV 2.7/1 rev 4 guidance document right along with the stricter standards for device equivalency, risk/benefit justification, and scientific validity of data.
“The clinical evaluation should be conducted by a suitably qualified individual or a team.”
The list of qualifications to consider when choosing a clinical evaluator to author the CER is clearly stated in section 6.4 of the MEDDEV 2.7/1 rev 4. Foremost on this list are the author’s and evaluator’s qualifications and experience, including an advanced degree, documentation experience, and knowledge of the device being evaluated, research methodology, information management, regulatory requirements, and medical writing.
All of these requirements can be difficult to find in-house. Poorly organized or incorrect CER documents can hold up the compliance process delaying obtaining a CE mark or result in removal from the market during subsequent inspections.
Professional CER writers at contract regulatory agencies such as Criterion Edge can help manufacturers on multiple levels:
- Provide a gap analysis
- Provide a thorough knowledge of the current regulations
- Author a complete QC’ed CER document
- Review existing submission documents
- And so much more…
At Criterion Edge, our clients enjoy our transparency in the services we provide as our candid scoping includes a time frame for delivering the CER and detailed information on gaps in compliance. All of our writers have experience writing CERs and are up to date on current regulations. Providing a comprehensive analysis and subsequent solutions sets us apart from other vendors. Contact us if you would like to have a conversation about what we can do to help with your writing and regulatory needs.