Companies face constant pressure to meet the increasing regulatory expectations and demands for information. Data identification through Systematic Literature Review (SLR) supports critical regulatory functions throughout the company, from MDR requirements through IND submissions.
In this session, we review:
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This webinar is co-hosted by Criterion Edge and RAPS.
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Author: Suzanne Broussard, PhD
The Premarket Notification 510(k) Program is the pathway used by manufacturers of low- to moderate-risk devices that are substantially equivalent (SE) to a device already on the market in order to begin the process of legally marketing in the United States. The Food and Drug Administration’s (FDA) release of 4 updated 510(k) guidance documents on September 13, 2019 was intended to both help streamline the FDA reviewer process and help sponsors save time and resources.
The 510(k) Program is required for any device that does not need a Premarket Approval Application (PMA) and does not meet the specified exceptions. The sponsor must demonstrate that a device is at least as safe and effective, e.g. SE, to a legally marketed device that is not subject to PMA. The 510(k) submitters must receive a SE order from the FDA in order to market the device in the U.S. The SE determination typically takes 90 days, although that time is decreasing. Indeed, faster response times are one of FDA’s anticipated outcomes of these 4 guidance documents. The FDA hopes another outcome will be more guidance for the sponsors to streamline their submission process which will save time and resources. These outcomes are prevalent throughout the document and summarized in the FDA statement that 510(k) submissions “address the recommendations of an FDA guidance document should be easier to prepare by manufacturers and for FDA to review.”
Legally marketing a device based on a claim of substantially equivalent to devices legally marketed prior to May 28, 1976 (preamendments devices) requires the manufacturer to submit a Premarket Notification 510(k). The majority of premarket devices use the 510(k) program; hence, it is important to clarify FDA’s definition of a legally marketed device.
A Legally Marketed Device must fit one of these 4 criteria:
Note that the legally marketed device(s) used for equivalence is commonly referred to as the “predicate.”
The Refuse to Accept Policy for 510(k) Final Guidance Document contains nonbinding recommendations and supersedes the “Refuse to Accept Policy for 510(k)s” issued early in the same year (February 21, 2019). The newest Refuse to Accept (RTA) policy includes an early review that will inform the submitter within the first 15 calendar days after receipt of the 510(k) submission of issues against specific acceptance criteria with information as to the administrative completeness and if not, includes identification of missing element(s). This guidance includes checklists of which items a sponsor should include in their 510(k) submission if they want to ensure their application is reviewed in a timely fashion.
The Abbreviated 510(k) Program is used by the FDA as an optional approach to the traditional 510(k) Program to demonstrate SE in premarket notifications by using guidance documents, special controls, and/or voluntary consensus standards to facilitate review of 510(k) submissions. This review relies on summary reports that “briefly describe and summarize the testing performed to support the submission as recommended in relevant guidance document(s).”
Device manufacturers can choose the Abbreviated 510(k) pathway if the submission relies on one or more of the following:
The FDA provides specific guidance for the general framework of Traditional 510(k)s and Abbreviated 510(k)s in the Final Guidance Document. These formatting guidelines do not apply to Special or other premarket 510(k) submissions. FDA believes that using this Formatting Guidance will conserve both FDA and industry resources as well as facilitate timely 510(k) review.
The Special 510(k) Program is designed to provide an optional and potentially expedited pathway to legally market “well-defined device modifications where a manufacturer modified its own legally marketed device and design control procedures produce reliable results that can form, in addition to other 510(k) content requirements, the basis for substantial equivalence (SE).”
The Special 510(k) Program: Guidance for Industry and Food and Drug Administration Staff provides the FDA’s current thinking and intent on premarket notifications that are appropriate for review as a Special 510(k). This Final Guidance Document describes an optimal pathway for certain well-defined device modification for manufacturers that modify their own legally marketed device and clarifies the types of technological changes that are appropriate for review including changes to design, labeling, and indications for use.
To further help clarify the Special 510(k) Program, the FDA recently held a webinar to discuss the Special 510(k) Program Final Guidance, and to answer questions. It is packed with useful information for those considering filing for the Special 510(k) Program including eligibility factors and examples of devices appropriate and those not appropriate for a Special 510(k). The recording of the webinar can be accessed here.
Author: Suzanne Broussard, PhD
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.
In order to help sponsors prepare a QOS that facilitates the regulators’ understanding of the product’s risks as outlined in the NDA, ANDA, or BLA applications, the FDA’s Office of Pharmaceutical Quality (OPQ) published a white paper that provides practical tips for putting the quality pieces together and explaining what regulators would like to see in the QOS: A Regulators Perspective on the Quality Overall Summary: Putting the Pieces Together.
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).
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:
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.
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.
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.
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.
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:
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.
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:
This webinar is co-hosted by Criterion Edge and Evidence Partners.