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In the News: May 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.

Approval of the Month: Non-Opioid for Post-Surgical Pain Gets FDA Nod

Heron Therapeutic received FDA approval for its bupivacaine/meloxicam extended-release solution product to treat post-operative pain after total knee replacement, bunionectomy, and groin hernia repair. Since two-thirds of the more than 50 million U.S. patients undergoing such surgeries today receive an opioid, and given the increasing number of opioid-related deaths, this approval is indeed good news. The new product, Zynrelef, is the first modified-release formulation for pain that will be labeled as extended-release; in the three Phase 3 clinical trials, it demonstrated pain reduction through 72 hours.

Because of the significant public health need, FDA granted this 505(b)(2) pathway product a fast track designation in late 2017. In mid-2018, it granted the product a breakthrough therapy designation. However, as is often the case for products using this pathway, the FDA issued a Complete Response Letter (CRL) in May 2019 for chemistry, manufacturing, and controls (CMC) issues. Another CRL came in June 2020 for nonclinical issues, and the FDA finally approved the product in May 2021.

The labeling for Zenrelef is typical for a 505(b)(2) approval, relying to a large extent on approved product labeling for products containing bupivacaine and meloxicam. Since this new product is applied via instillation, Heron bridged from the topically applied product to the systemic data in the public literature.

The product was approved for use in adults, and the Pediatric Research Equity Act (PREA)-required pediatric studies were deferred. The FDA required that Heron Therapeutic conduct several post-marketing studies, including two nonclinical studies and multicenter studies of the pharmacokinetics, safety, and pharmacodynamic response of Zynrelef administered for postoperative analgesia in pediatric patients undergoing unilateral open inguinal herniorrhaphy (groin hernia). The Camargo/Paidion team has extensive experience navigating PREA requirements and conducting both juvenile toxicology studies and pediatric clinical trials for sponsors with post-marketing requirements. Contact us to find out how we can streamline your program.

FDA-Issued Guidances Offer Clarification on PREA, QIDP Designation, Post-Marketing Requirements, and More

May was a very active month for FDA guidance documents – here are some of the highlights:

FDA Reauthorization Act Implementation Guidance for Pediatric Studies of Molecularly Targeted Oncology Drugs

Another procedural (i.e., somewhat technical) guidance released in May involved the implementation of pediatric study requirements set forth in PREA and the FDA Reauthorization Act (FDARA). When PREA was first instituted, the statutory requirements did not apply to products that received Orphan Drug Designation (ODD). This was altered somewhat by amendments made by FDARA to Section 505B of the FD&C Act, which specified the requirement for pediatric studies in some oncology product applications:

Section 504 of FDARA amended section 505B of the FD&C Act to require—for original applications submitted on or after August 18, 2020—pediatric investigations of certain targeted cancer drugs with new active ingredients, based on molecular mechanism of action rather than clinical indication. Specifically, if an original NDA or BLA is for a new active ingredient, and the drug that is the subject of the application is intended for treatment of an adult cancer and directed at a molecular target FDA determines to be substantially relevant to the growth or progression of a pediatric cancer, reports on the molecularly targeted pediatric cancer investigation required under section 505B(a)(3) of the FD&C Act must be submitted with the marketing application, unless FDA waives or defers the requirement. . . .

This requirement applies even if the adult cancer indication does not occur in the pediatric population, and, per section 505B(k)(2) of the FD&C Act, even if the drug is for an adult indication for which orphan designation has been granted. (emphasis added)

The guidance covers the content of Initial Pediatric Study Plans, a description of recommended studies, the basis for waivers and deferrals, and, importantly, both the “Relevant Molecular Target List” and the “Non-Relevant Molecular Target Leading to Waiver List.” The guidance is an important one for sponsors pursuing an oncology product, and Camargo is ready to assist with its implementation in sponsors’ programs.

Qualified Infectious Disease Product Designation—Questions and Answers

In this procedural guidance, the FDA provides information about its implementation of Title VIII of the FDA Safety and Innovation Act (FDASIA), titled Generating Antibiotic Incentives Now (GAIN). The GAIN provisions create incentives for product applications receiving Qualified Infectious Disease Product (QIDP) designation for development of antibacterial and antifungal drug products that treat serious or life-threatening infections. The guidance provides clarification as to what products meet that definition and therefore qualify for the designation and whether a QIDP designation applies to any product containing a given drug substance or only to a specific sponsor’s drug product. It also provides insight into the mechanics of obtaining the designation and the attendant benefits, including a 5-year extension of any exclusivity for which the product qualifies.

Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management

CDER and CBER issued a final guidance on product lifecycle management that is part of the International Council on Harmonisation (ICH) series aimed at standardizing requirements across regulatory systems worldwide, streamlining those requirements, and making them more predictable. The framework is based in science and risk-based approaches for the post-approval lifecycle management of pharmaceutical products. The guidance covers several topics:

  • Established Conditions
  • Pharmaceutical Quality System
  • Categorization of post-approval CMC changes
  • Post-approval Change Management Protocol
  • Product Lifecycle Management document
  • Relationship between regulatory assessment and inspection
  • Approaches for frequent CMC post-approval changes
  • Stability data approaches to support the evaluation of CMC changes

The FDA also issued companion documents in May, Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management Annexes and ICH Q12: Implementation Considerations for FDA-Regulated Products (draft).

Considered as a whole, the information provides opportunities for reducing a sponsor’s regulatory burden post-approval. While it is a substantial amount of information to digest and integrate, Camargo can help with navigation.

Information Sheet Guidance for Sponsors, Clinical Investigators, and IRBs (Revision 1)

A sponsor has arranged for the start of its clinical studies, and some of the sites are outside of the US. Now, some of the investigators at these non-domestic sites are saying that their laws or regulations prohibit them from signing Form 1572, which is needed for filing an IND. Stymied? No, there is a way around it: the FDA will typically grant a waiver. Confusion around this topic is dealt with in a short guidance in a Q&A format.

The Unapproved Drug Initiative is Back!

In November 2020, the HHS (not the FDA) published a notice in the Federal Register terminating the FDA’s Unapproved Drugs Initiative (UDI). The UDI was FDA’s risk-based approach to regulate the hundreds (possibly thousands) of illegal drugs that remain on the U.S. market after the 1938 and 1962 FD&C amendments (which required both a demonstration of safety and efficacy, respectively, and subsequent scientific reviews of unapproved products remaining on the market under DESI). The HHS notice, which states that it came from the FDA but was signed only by then-HHS Secretary Alex M. Azar II, withdraws the FDA’s guidance concerning the marketing of unapproved drugs and indicates that the UDI was responsible for reduced competition and higher drug prices as an explanation.

In May, current HHS Secretary Xavier Becerra and acting FDA Commissioner Janet Woodcock withdrew November’s notice due to “multiple legal and factual inaccuracies.” The FDA’s notice describes these inaccuracies and lays the blame squarely on HHS for exceeding its authority in issuing its notice. We can briefly examine some of these issues:

  1. The FD&C Act provides that the Secretary of HHS will be responsible for executing the FD&C Act “through the [FDA] Commissioner.” However, the FDA’s notice in May claims that there was no evidence that that HHS consulted with or even notified the FDA before issuing its notice in November.
  2. The HHS misconstrued the definitions of “drug” and “new drug.” The term “drug” encompasses the whole drug product, including the active ingredient(s), formulation, packaging, and labeling. However, the HHS’s notice confines its definition to include only the active ingredient and suggests that “drugs” that were marketed prior to 1962 or that are generally recognized by qualified experts as safe and effective (GRASE) could be legal. In truth, unless the drug product is identical to that on the market prior to 1962 (a highly improbably scenario) or approved via DESI (including labeling), it is illegal and subject to FDA action.

While the UDI guidance cannot be un-withdrawn, the FDA outlines in the May notice a plan to provide a new draft and comment period. It also makes clear that the UDI is alive and well, so industry should be prepared to remove illegal drugs with safety or efficacy concerns from the market. Camargo has helped many companies over the past two decades obtain approval for such older drugs via the 505(b)(2) pathway.


Ken Phelps
President and Founder

Bill Stoltman, JD
Vice President, Regulatory Operations