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In the News: October 2021 Regulatory and Development Updates

Each month, Camargo’s “In the News” series highlights important changes and advancements in the regulatory and development space and explores how those changes could impact your program.

FDA Guidance Addresses Real-World Evidence Data Standards

The 21st Century Cures Act generated a good deal of excitement and interest when it added a section called “Utilizing Real World Evidence” to the Food, Drug, and Cosmetic Act (Section 505F). It created the possibility of more easily obtaining information to support new product indications or to help with post-approval study requirements. But what real-world evidence (RWE) would be accepted, and in what format? In October, the FDA took a step towards clarifying these questions with a guidance called “Data Standards for Drug and Biological Product Submissions Containing Real-World Data.”

Real-world data (RWD) may include, but is not limited to, electronic health records, medical claims data, data from product and disease registries, patient-generated data, and data gathered from sources that can inform on health status (such as mobile devices).

The FDA freely acknowledges that there are challenges involved in standardizing the use of RWD, identifying four examples:

(1) the variety of RWD sources and their inconsistent formats (e.g., EHR, registry); (2) the differences in source data captured regionally and globally using different standards, terminologies, and exchange formats for the representation of the same or similar data elements; (3) a wide range of methods and algorithms used to create datasets intended to aggregate data; and (4) the many aspects of health care data that can affect the overall quality of the data, including business processes and database structure, inconsistent vocabularies and coding systems, and de-identification methodologies used to protect patient data when shared. (Emphasis in the original)

The FDA points out that, currently, submissions which include clinical and nonclinical study data, whether derived from RWD sources or not, must abide by the formats described in the Study Data Guidance and the supported standards listed in the Data Standards Catalog. This can be a major hurdle. Thus, FDA indicates:

FDA plans to issue further guidance and/or to update the Catalog with standards for study data that are derived from RWD sources. . . .

Sponsors should discuss early, with the appropriate FDA review division, any planned submission of study data derived from RWD sources in an applicable drug submission and their approaches for transforming the data to the current FDA-supported data standards. Sponsors should describe these approaches, including in the protocol, data management plan, and/or final study reports.

The guidance also contains some useful information, despite the limitations described above. For example, there are almost three pages of definitions useful for those interested in exploring the data standard requirements for employing RWE for a product application. Any number of challenges going forward with RWE clearly remain, however, and Camargo can assist sponsors with navigating those challenges.

FDA Publishes ICH Guidelines on Continuous Manufacturing

The FDA recently published the ICH’s Harmonised Guideline Q13, titled “Continuous Manufacturing of Drug Substances and Drug Products.” The guidance aims to address country-specific versus global continuous manufacturing (CM) requirements for any new product and to harmonize global regulations. The document is at Step 2b of the Formal ICH Procedure for new topics (Adoption of Draft Guideline by Regulatory Members) and is currently in the public consultation phase through December 2021.

Recent advances in manufacturing technology and process analytical technology (PAT), along with regulatory initiatives, have encouraged the industry to consider replacing batch manufacturing with CM. In CM, a drug substance or drug product intermediate moves through two or more directly connected unit operations in an automated fashion, with the aim of minimal intervention or stoppage of the process. CM throughput may be smaller than a standard batch process, but it can operate 24/7 and therefore achieve a similar output without the need for scale-up. One major advantage is the ability to reduce batch losses by diverting materials not meeting quality standards through the use of PAT.

The new guidance document describes the scientific approaches and regulatory considerations for the development, implementation, operation, and lifecycle management of CM for drug substances and drug products (small molecules and biologics). Three examples of CM of varying complexities are described:

  1. A small molecule drug substance manufacturing process consisting of two chemical reaction vessels, a liquid phase extraction, two filtration steps, and a crystallization step. Batch steps include filter drying, milling, and packaging.
  2. A process to manufacture tablets utilizing continuous feeding, blending, and tablet compression, followed by a batch-mode film coating
  3. A biologic manufacturing process utilizing perfusion with continuous capture chromatography and automated viral inactivation, followed by two polishing chromatography steps, viral filtration, and tangential flow filtration

In all three examples, material hold points are used to collect adequate material before moving to the next stages. PAT is required to control the quality of the batch, and diversion points are included to remove materials failing quality attributes.

CM is applicable both to new products and to existing products that can be converted from batch manufacturing. Potential benefits include higher quality and overall yield (due to reduced batch loss), which in turn could result in improved product availability and lower prices. The potential negatives are the costs associated with re-tooling current processes and with obtaining regulatory approval for the retooled process. In addition, quality units will need to undergo a paradigm shift away from a batch operation mindset and toward CM.

Camargo’s talented team of technical and CMC scientists can help sponsors navigate new regulatory guidance documents and advise them on whether CM is a good fit for their processes. Contact us today to learn more!

More Details Revealed Regarding CDER’s Voluntary Pilot Program for Novel Excipients

In the September 2021 edition of In the News, we noted the Center for Drug Evaluation and Research’s (CDER’s) rollout of the Novel Excipient Review Pilot Program. The program offers a pathway to evaluate novel excipients prior to use in a drug product formulation, reducing the risk of delaying applications due to safety concerns. Proposals for novel excipients that have not been previously used in an FDA-approved drug product, and do not have an established use in food, are being accepted through December 7, 2021, for the first stage of review.

This initial proposal stage (Stage One) allows manufacturers to provide a high-level overview of the novel excipient for consideration. CDER plans to accept four proposals (two for each year of the pilot program) for evaluation in Stage Two of the program, with the ultimate goal of recognizing one or more novel excipients. Excipients recognized through the program can then be used by product manufacturers in INDs within the defined use without additional justification.

CDER has now provided guidance on the contents of the summary proposal. Proposals must demonstrate the potential public health benefit and the excipient’s characteristics that may lead to new drug development, as well as the ability of the manufacturer to submit a complete safety package in the required time frame for Stage Two evaluation. Camargo’s expertise can help sponsors and manufacturers that want to take advantage of the benefits that using a novel excipient can bring, in both preparing and submitting a Stage One summary proposal and in compiling the complete safety information package required for Stage Two.

FDA Acts on Drug Reclassifications

Recently, we highlighted the Genus decision from the U.S. Court of Appeals and the subsequent FDA Federal Register notice regarding the potential reclassification of some drug products to devices or drug-device combination products. That potential has now been realized. On October 25, Eyenovia received a Complete Response Letter (CRL) for its MydCombi™ product NDA. While not fatal to the application, this development is certainly a setback for the sponsor, primarily in terms of a delay in approval. The move demonstrates that the FDA plans to pursue the reclassification initiative in a robust fashion; this has implications for any product using a delivery system, potentially even one as simple as a dropper bottle. Camargo can assist the sponsors of implicated products in navigating this significantly altered landscape.


Bill Stoltman, JD
Vice President, Regulatory Operations

Dean Chamberlain, PhD, CBiol, MRSB
Director, CMC Services

Jenny Fielder
Manager, Regulatory Compliance