FDA Regulatory News and Trends - October 31, 2022

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

• FDA proposes select updates to Breakthrough Devices Program guidance, including clarification of how the program applies to products that address health disparities. On October 20, the FDA released a draft guidance document setting forth updates to the existing 2018 final Breakthrough Devices Program guidance to clarify (i) what type of devices qualify for the program and (ii) confidential treatment of breakthrough designations and decisions. This voluntary program, for device products that provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating diseases or conditions, aims to expedite the development, assessment and review of device products that receive the designation. The lengthiest of the select updates in the draft guidance document concerns how the breakthrough designation may be leveraged by devices that promote health equity, which appears to be the latest step taken by FDA to help reduce existing disparities in US healthcare. The draft guidance also proposes additions to clarify that certain non-addictive medical products to treat pain or addiction may be eligible for the program and to describe how the FDA discloses the breakthrough status of designated devices once they receive marketing authorization. The FDA intends to incorporate updates into a final guidance document after considering public comment on these proposed select updates. The deadline to submit comments on the draft guidance is December 20, 2022.
• FDA temporarily extends enforcement discretion policy on UDI data submission for certain devices, clarifies which others will remain subject to ongoing enforcement discretion. With the release of its updated final guidance “Unique Device Identification: Policy Regarding Compliance Dates for Class I and Unclassified Devices, Direct Marking, and Global Unique Device Identification Database Requirements for Certain Devices,” FDA has extended for 75 days its enforcement discretion policy regarding GUDID reporting requirements under Section 830.300 for Class I and unclassified medical devices other than implantable, life-supporting or life-sustaining (I/LS/LS). The agency now does not intend to enforce the requirements before December 8. The guidance also finalizes a separate October 2021 draft guidance, “Select Updates for Unique Device Identification: Policy Regarding Global Unique Device Identification Database Requirements for Certain Devices,” in which FDA announced its intent to exercise ongoing enforcement discretion on GUDID submissions for Class I consumer health products, finding them to be a particularly high burden to stakeholders given the changeability of UPC codes and of lesser usefulness “in evaluating and improving device safety throughout a product life cycle” for devices of a consumer product nature. The updated guidance maintains this policy (and thus enforcement discretion for consumer health products will continue after December 8) and also clarifies which devices are considered to be consumer health products, outlining how labelers can determine whether its device falls within the scope of the policy.
• First-ever draft guidance on tissue-agnostic cancer therapeutics development. Following several landmark approvals in recent years, the FDA has issued draft guidance for the first time on tissue-agnostic cancer drug development, outlining when and how sponsors may consider development programs for drugs that could treat multiple cancer types based on molecular alterations (a kind of biomarker). A significant distinguishing factor of tissue-agnostic drug development compared to traditional approaches is the inherent need to generalize treatment effects across cancer types when few or no subjects with the extrapolated cancer types were included in the clinical trials. Additionally, key considerations in determining whether tissue-agnostic drug development may be appropriate include (i) the biology across cancer types; (ii) whether a drug could be developed more efficiently in a specific, common cancer type; (iii) whether there might be meaningful dosage and pharmacokinetics or pharmacodynamics differences across cancer types; (iv) justification for the number and types of cancers to be studied; and (v) any unique safety considerations for the drug that might limit its use in a particular population. The guidance also suggests that sponsors have early and frequent discussions with FDA to discuss development approaches that are critical to tissue agnostic oncology drug development, including the nonclinical data, justification for the sample sizes for the overall population and for subgroups of specific cancer types, and approval pathway (traditional or accelerated approval).
• New form for submitting inquiries to FDA’s Import Compliance Branch. For the first time, FDA has made Form 5054 available, which serves to initiate new inquiries with Import Compliance. The intuitive two-page form, with only nine fields to complete, should help streamline communications with the Agency in a standardized manner. Sources of inquiries are not limited, and may include consumers (public stakeholders, not including business/industry or government entities); industry (business entities and corporations, and/or their representatives); government (any official, employee, agent or representative acting on behalf of any domestic or international government department or agency); FDA internal (coming from a FDA office); and others. According to FDA’s Forms page, New Inquiry Forms should be sent to Pooja Sawhney, with any additional documentation attached to the e-mail.
• FDA implements updates to two compliance programs on preapproval inspections and routine GMP inspections. On October 17, 2022, FDA officially implemented two updated compliance programs that were initially issued on September 16, 2022.  CP 7346.832, which covers preapproval inspections, was updated to add elements covering: 1) the control of nitrosamine impurities; 2) FDA’s use of alternative tools for evaluating facilities (eg, remote regulatory assessments) 3) FDA’s goal to provide 60 days’ notice to the facility if FDA determines it is necessary to conduct the PAI during manufacturing operation; and 4) the incorporation of International Council for Harmonization (ICH) guidances for industry Q10 Pharmaceutical Quality System and Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management. CP 7356.002, which covers drug quality assurance routine GMP surveillance inspections, was updated to reflect similar changes made to CP 7346.832, including the control of nitrosamine impurities, FDA’s use of alternative evaluation tools, and the incorporation of ICH guidances, also including the ICH Q9 guideline on Quality Risk Management.
• FDA provides lists of laboratories offering notified laboratory-developed monkeypox tests. These laboratories submitted notifications pursuant to the Policy for Monkeypox Tests to Address the Public Health Emergency (Policy) published by FDA September 7, 2022, the same day the HHS secretary declared that circumstances exist justifying the authorization of emergency use of in vitro diagnostics for detection of monkeypox virus. The policy announced that FDA intends to exercise enforcement discretion for (1) monkeypox diagnostic tests developed and performed by high complexity CLIA-certified laboratories, (2) modifications by high complexity CLIA-certified laboratories to FDA-cleared or EUA-authorized diagnostic tests, and (3) serology tests that are developed and performed by certain laboratories, as described in Sections IV.A.2, IV.A.3, and IV.C of the Policy, respectively. To qualify for such enforcement discretion, laboratories must notify FDA within five business days of offering the test that it has appropriately validated the test. The deadline to submit the notification was October 13, 2022. So far, FDA has listed 70 PCR-based LDTs that use lesion swabs under section IV.A.2 of the Policy and one CDC-developed serology test under section IV.C. Notable, no laboratory is listed pursuant to section IV.A.3. FDA emphasizes that the agency has not reviewed the laboratory's validation of these tests and has not issued EUAs for these tests.
• FDA has announced the latest step in its effort to incorporate the use of real-world data (RWD) and real-world evidence (RWE) in regulatory decision making for drugs, including in approvals and the monitoring of post-market safety and adverse events: the Advancing Real-World Evidence Program.  As FDA’s Oct. 20, 2022 public notice explains, the Program “provides sponsors who are selected into the Program the opportunity to meet with Agency staff– before protocol development or study initiation – to discuss the use of RWE in medial product development,” and is an optional pathway for sponsors submitting RWE proposals. Rollout includes publication of a web page on the Agency’s website, as well as receiving meeting requests from drug sponsors through March 31, 2027. FDA’s focus on the use of RWE is a progeny of the 21^st Century Cures Act, passed in 2016, which aimed to accelerate medical product development and bring innovative medical products more efficiently to patients. RWD has proliferated exponentially in the past decade as the collection of health-related data has increased from such sources as mobile devices, wearables, medical claims, and billing. The widening availability of RWD has prompted the development of RWE, which includes clinical evidence regarding a medical product from the analysis of RWD. In 2018, FDA released its framework for its real-world evidence program, in which the Agency said its framework will include consideration of the fitness of particular RWD for use; whether a trial or study design used to generate RWE can provide adequate scientific evidence to contribute to FDA’s regulatory analyses; and whether the study meets FDA regulatory requirements. In this latest step, FDA aims to implement the benefit of dialogue with sponsors about specific iterations of RWD and RWE by presenting studies designed through the program in a public forum (either through a guidance or public workshop).
• Advisory committee says Covis Pharma’s Makena should be withdrawn. On October 19, the Obstetrics, Reproductive, and Urologic Drugs Advisory Committee voted 14-1 that Covis Pharma’s Makena was ineffective at preventing pre-term birth and that the product should be withdrawn from the market. Makena received an accelerated approval in 2011, but confirmatory trials have failed to demonstrate effectiveness needed to convert the accelerated approval to a full approval. Previously, the FDA has only instituted one formal hearing to withdraw an accelerated approval for a confirmatory trial’s failure to demonstrate efficacy, but even in that situation the drug, Avastin, remained on the market for other indications. In October 2019, the FDA’s Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC) met to consider the results of Makena’s confirmatory trial, concluding unanimously that the findings failed to verify the clinical benefit of Makena on neonatal outcomes. Nine members of the advisory committee voted that FDA should pursue withdrawal of Makena from the market. A year later, CDER determined that the evidence met the statutory and regulatory criteria for withdrawal, and it published a Proposal to Withdraw Marketing Approval and a Notice of Opportunity for a Hearing (NOOH). AMAG, Makena’s owner at the time, requested a hearing following the publication of the NOOH. FDA received comments regarding the proposed withdrawal and FDA and Covis exchanged correspondence regarding the hearing until August 12, 2022, when CDER published a proposal to withdraw Makena and set hearing dates of October 17-19. The hearings concluded with the advisory committee’s vote to withdraw the drug. The commissioner has ultimate authority to withdraw the drug. A final decision is expected in the coming days.
• Warning letter to wheelchair maker arises from April 2022 inspection. In September, FDA issued a warning letter to Forcemech International LLC related to observations from an April 2022 inspection. The Office of Medical Device and Radiological Health found that Forcemech failed to conform to good manufacturing practice requirements of the Quality System regulations for failing to maintain a sufficient device master record (DMR). The device labels were coded using a system that does not comply with FDA’s unique device identifier (UDI) Final Rule. Other packaging and labeling processes and verification procedures were also deemed insufficient. For example, the firm’s Final Acceptance Inspection procedure did not include the acceptance/release criteria and failed to describe the process for assigning internal lot numbers for new products. The investigator also found that the firm failed to adequately establish procedures for acceptance activities including quality control inspections and that the document control procedures were not adequately established or maintained. The letter also took issue with the firm’s servicing activities and procedures. The FDA found that the firm had no procedures for servicing and ensuring devices would work as intended following repair. The firm posted instructional videos online for customers to follow to repair power wheelchairs on their own. The warning letter mentions that the investigator observed customer service personnel talking customers through repairs. The FDA found that these procedures were inadequate and were further compounded by failures to properly track distribution of replacement parts. FDA found additional labeling and packaging violations related to UDI and Global Unique Device Identification Database (GUDID) requirements.
• FY 2023 guidance priority lists published. On October 17, FDA published its FY 2023 guidance priority lists, categorized into “A” and “B.” Items on the A list contains guidances that FDA will prioritize to complete before the end of FY 2023, whereas the B list contains guidances that FDA will try to complete depending on available resources. On this list is the Evaluation of Sex-Specific Data in Medical Device Clinical Studies which was issued as final guidance on August 22, 2014. That guidance was intended to bolster the collection of sex-specific data (on women, specifically) in recognition of the general lack of study data including women and relevant to women. Given FDA’s ongoing focus on matters of clinical trial diversity and inclusion with the issuance of a draft guidance in April 2022, this new guidance on sex-specific data will likely undergo major updates.
• LAAF Small Entity Compliance Guide.In October 2022, FDA issued a Small Entity Compliance Guide on the “Laboratory Accreditation for Analyses of Foods” (LAAF) program. This program, established under the authority of the Food Safety Modernization Act, directs FDA to establish a laboratory accreditation program where FDA recognizes accreditation bodies that will accredit laboratories. The LAAF program applies only in certain circumstances related to food safety (for example, commodity-specific testing for sprouts, shell eggs, and bottled drinking water) and requires testing to be conducted by a laboratory participating in the LAAF program. Further, the laboratory test results must generally be sent by the participating laboratory directly to FDA. This guidance covers a wide range of topics such as the scope of the LAAF Rule, oversight of accreditation bodies, and applicable requirements and processes for laboratories that wish to become LAAF accredited.