FDA Regulatory News and Trends - July 21, 2023

Welcome to FDA Regulatory News and Trends, designed to help you identify significant legal developments and navigate the evolving business, legal, and regulatory world.

Reflection paper on real-world data and real-world evidence standards.

• A new reflection paper from the International Council on Harmonisation (ICH) focuses on the need for standardization of principles and terminology for real-world data (RWD) and real-world evidence (RWE). 
  
  
• The paper acknowledges various existing regulatory efforts relating to RWD/RWE, including an annex listing out examples of regulatory initiatives and guidances related to RWD/RWE from different jurisdictions, drawing attention to similarities and differences between them.
  
  
• ICH’s objectives include (1) global convergence on terminology for real-world data and real-world evidence, (2) common principles for the formatting of protocols and reports of study results submitted to regulatory agencies, and (3) promotion of transparency through registration of protocols and reports.
  
  
• The paper is under public consultation until September 30, 2023.
  
  

GAO decides REMS is an adjudication, not a rule. 

• Risk evaluation and mitigation strategies (REMS), which FDA may require for certain drugs or classes of drugs, are plans developed to ensure that products with known and serious safety risks are used properly.
  
  
• In January 2023, the Government Accountability Office (GAO) received a request for a legal decision as to whether REMS is a rule for the purposes of the Congressional Review Act (CRA), which gives Congress and the US Comptroller General the opportunity to review and block certain agency rules.
  
  
• On July 6, 2023, GAO determined that a REMS is adjudication, rather than the product of rulemaking, as adjudication has an immediate effect on specific individuals in specific cases, much like how FDA’s process for drug approval and REMS impacts the specific sponsor and companies implementing the REMS. Further, agency actions granting authority or approval related to products are specifically exempted from CRA review.
  
  
• Had GAO determined REMS to be a rule, the additional step of undergoing congressional review could have created a challenging and time-consuming process for both FDA and industry.
  
  

CDER updates MAPP for peptide and protein drug product quality assessment process. 

• Manual of Policies and Procedures (MAPP) No. 5016.3 describes how the responsibility for peptide or protein drug quality assessments will be divided among the suboffices of the Office of Pharmaceutical Quality (OPQ) for most drug-related applications and supplements/amendments.
  
  
• In its first revision since the Manual went into effect in December 2018, OPQ updated the document’s policy and procedures to, among other things, conform to the revised definition of “biological product” under the Public Health Service Act and 21 CFR 600.3(h). While the Manual continues to exclude ANDAs and products containing amino acid polymers used solely as excipients from the scope of the MAPP, OPQ added emergency-use authorizations to be covered by the document.
  
  
• Currently, OPQ divides product quality assessments among its four suboffices – the Office of Biotechnology Products (OBP), Office of Lifecycle Drug Products (OLDP), Office of New Drug Products (ONDP), and Office of Pharmaceutical Manufacturing Assessment (OPMA) – based on size, ranging from small peptides to large glycoproteins, regardless of manufacturing method (ie, synthetic, naturally occurring, or biotechnologically derived).
  
  

Revised FDA Manual on CDER’s risk-based site selection model for inspections.

• In late June, FDA released a revised “MAPP No. 5014.1 - Understanding CDER’s Risk-Based Site Selection Model,” which aims to explain how FDA prioritizes inspections based on risk. Section 510(h)(4) of the Federal Food, Drug, and Cosmetic (FD&C) Act provides a list of risk factors that FDA can use to prioritize surveillance inspections – however, neither the statute nor FDA’s regulations provide for a specific method of using or weighing the risk factors. 
  
  
• The revised MAPP does not explain how FDA weighs each risk factor, but it does provide a list of the actual variables used by FDA to measure the risks outlined in the FD&C Act.  There are essentially two categories of variables: site-related and product-related.   
  
  
• Site-related variables include site type, FDA compliance history, field alert reports (FARs), MedWatch reports, and recalls. Product-related variables include API load, dosage form, route of administration, therapeutic class, therapeutic index or range, and whether the product is intended for emergency use.
  
  

Updated draft guidance on inborn errors of metabolism. 

• On July 11, 2023, FDA issued an updated draft guidance, titled, “Inborn Errors of Metabolism That Use Dietary Management: Considerations for Optimizing and Standardizing Diet in Clinical Trials for Drug Product Development.” Inborn errors of metabolism (IEM) are a group of rare inherited diseases in which the metabolic system fails to process carbohydrates, fatty acids, and proteins. FDA published the initial draft five years ago, aiming to optimize dietary management for patients diagnosed with IEM before and during clinical trials. 
  
  
• The updated draft guidance clarified the following points: (1) drug products should be studied in conjunction with dietary management for conditions where dietary management is the current standard of clinical care; (2) the most informative design is a randomized, double-blind clinical trial that includes a concurrent control group (approved drug or placebo); (3) metabolic control may be evaluated by biochemical analytes and clinical assessment as substantiated by current clinical standards of care; (4) dietary optimization should be based on dietary standards for the relevant population and account for the severity of the patient’s metabolic defect and the patient’s age, growth, and general health status; and (5) baseline dietary management standards among patients from different countries should be explained in the protocol.
  
  
• Notably, FDA does not recommend using a historical group as the control group. 
  
  
• Interested parties should submit comments by September 11, 2023. 
  
  

Transitional Coverage for Emerging Technologies (TCET) pathway for medical devices.

• On June 23, 2023, CMC issued a proposed procedural notice outlining a new Medicare coverage pathway that aims to provide timely access to FDA-designated breakthrough devices.
   
• TCET pathway is a voluntary program where manufacturers of eligible FDA-designated breakthrough devices can participate on their own initiative. When an eligible device is accepted into the TCET pathway and receives FDA marketing authorization, CMS will initiate the national coverage determination (NCD) process. In general, such a device can obtain national coverage for up to five years until a predictable, long-term Medicare coverage determination can be reached. 
  
  
• Interested parties should submit comments on or before August 28, 2023. 
  
  

FDA to transition to electronic export documents.

• On July 10, 2023, FDA released a Letter to Industry notifying medical device manufacturers that, starting on January 2, 2024, FDA will be transitioning from paper export documents to electronic export documents.  
  
  
• Relevant documents that will be issued electronically include Certificates to Foreign Government, Certificates of Exportability Section 801(e)(1) or 802, Non-Clinical Research Use Only Certificates, Certificates to Foreign Government for Device Not Exported from the United States, and Export Permit Letters.  
  
  
• Export documents will be issued electronically as downloadable PDFs through the CDRH Export Certification Application and Tracking System (CECATS) and may be validated by foreign governments and others by using FDA’s FURLS Export Certificate Validator (FECV) database for the time period they are in effect.  
  
  
• Requests received by December 15, 2023 will continue to be issued as paper certificates, and requests received after December 16, 2023 will continue to be issued as paper certificates if the review is completed prior to January 2, 2024.  
  

Final guidance on chronic rhinosinusitis with nasal polyps.

• On June 30, 2023, FDA released a final guidance, “Chronic Rhinosinusitis with Nasal Polyps: Developing Drugs for Treatment.”  This guidance finalizes FDA’s draft guidance on the same topic, issued December 10, 2021.  
  
  
• The purpose of the guidance is to assist sponsors in the development of drugs or biological products for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP).  
  
  
• The guidance addresses FDA’s current thinking regarding clinical trial population and design, effectiveness, statistical analysis, safety considerations, corticosteroid-specific issues, and drug-device considerations for drugs being developed to treat CRSwNP.