FDA Regulatory News and Trends - February 23, 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.

FDA finalizes guidance on cannabis and cannabis-derived compounds. FDA has finalized guidance on cannabis and cannabis-derived compounds, focusing only on the development of drugs for human use. This on the heels of the passage of the Medical Marijuana and Cannabidiol Research Expansion Act (MMCREA) in December 2022, which eased restrictions on the research of medical marijuana and CBD products, is a critical step forward in advancing the body of regulatory science for these products. The guidance outlines the Agency’s thinking on sources of cannabis, resources for information on quality considerations (making numerous references to the United States Pharmacopeia (USP) and National Formulary), and considerations of control status under the Controlled Substances Act.

For purposes of the development of drugs for human use, FDA makes clear that cannabis and cannabis-derived compounds are held to the same regulatory standards as any other botanical raw material, botanical drug substance, or botanical drug product. FDA also makes specific reference to the careful selection of a container closure system or device constituent part, providing adequate characterization information and safety assessment data for extractable and leachable compounds to support a marketing application, and making sure to identify specific concerns (for example, with pediatric patient populations) as early as possible in development.

Importantly, FDA also clarifies that the standard calculation for delta-9 THC (ie, a dry weight calculation) should not be used for other purposes, such as chemistry, manufacturing, and controls (CMC). Instead, FDA outlines calculation methods for both solution-based materials and solid oral dosage forms.

Finally, FDA explains that cannabis-derived drug products may raise concerns about drug abuse liability, and FDA may need to evaluate potential scheduling (or re-scheduling) under the Controlled Substances Act. This is consistent with FDA’s approaches with other approved cannabis-derived drugs and directs applicants to its guidance Assessment of Abuse Potential of Drugs (January 2017).

Petitions re CBD marketing denied. FDA recently denied three petitions requesting that the agency issue a regulation that would allow cannabidiol (CBD) products to be marketed as dietary supplements and announced that a legislative fix is needed to allow broader access to CBD products. While some may have been hoping for a more direct path forward under current authorities, the agency’s statement does indicate a desire to work toward a solution for the growing demand for these products. In three separate petitions, the Consumer Healthcare Products Association (CHPA), the Council for Responsible Nutrition (CRN), and the Natural Products Association (NPA) requested FDA to use its authority under section 201(ff) to create an exception to the “drug exclusion provision” through notice and comment rulemaking. In separate letters dating January 26, FDA denied all three petitions, stating that the agency has “considerable safety concerns” with CBD’s potential use as a dietary supplement, and that it is unclear how CBD would ever meet existing safety standards for dietary supplements. In a related announcement, FDA affirmatively stated, for the first time, that it did not consider its existing dietary supplement and conventional food pathways appropriate for CBD and that the agency is interested in working with Congress to develop a new pathway that balances consumers’ desire to access CBD products with the regulatory oversight necessary to better manage the risks these products present. In contemplating legislation, FDA will also be thinking about how more widespread availability of CBD and other cannabis products will affect clinical research on the therapeutic aspects of cannabis. The agency has stated in the past that it has a policy interest in incentivizing rigorous scientific research to support beneficial therapies.

FDA seeks comments on the use of “externally controlled trials” for drugs and biological products. On February 1, 2023, FDA released a new draft guidance, Considerations for the Design and Conduct of Externally Controlled Trials for Drug and Biological Products, providing the agency’s current thinking on the use of externally controlled trials as evidence of the safety and effectiveness of a drug product. The guidance focuses on patient-level data from other clinical trials or from real-world data (RWD), as well as the natural history of a disease, if well-defined. When determining the suitability of an externally controlled trial design, the FDA will make “a case-by-case assessment,” by considering multiple factors, including “heterogeneity of the disease, preliminary evidence regarding the drug product under investigation, the approach to ascertaining the outcome of interest, and whether the goal of the trial is to show superiority or non-inferiority.” The guidance offers some detailed considerations for study design, data and analysis when using external controls. For study design, the guidance advises sponsors to have prespecifying plans to address important confounding factors and sources of bias. The guidance additionally sets out FDA’s concerns when using data from an external control arm, such as comparability of participant characteristics, timing and frequency of data collection, patterns of care, and missing data from RWD sources. Last but not least, sponsors should develop a statistical analysis plan that prespecifies analyses of interest. Despite the detailed consideration discussed in the guidance, FDA cautions that it is very difficult to find a credible external control to support the efficacy profile of a drug. As always, sponsors should always engage with the FDA during the early phase of the study design. Interested parties should submit comments here (Docket ID FDA-2022-D-2983) on or before May 2, 2023.

White House confirms that the public health emergency will end in May 2023. On January 30, 2023, the Biden Administration announced that it plans to allow the COVID-19 public health emergency (PHE) to expire on May 11, 2023. The PHE was first declared on January 31, 2020, and it has been renewed every 90 days since then, most recently on January 11, 2023. The PHE declaration is made under section 319 of the Public Health Service Act and is distinct from the EUA declaration, which is made under section 564 of the Federal Food, Drug, and Cosmetic Act. The expiration of the PHE declaration will not impact the EUA declaration; existing EUAs for COVID-19 products will remain in effect, and FDA can continue to issue new EUAs going forward. However, there are 76 COVID-19 related guidance documents currently implemented, many of them tied to the PHE declaration. FDA has updated its websites related to these guidance documents with a header stating, “The FDA intends to issue a Federal Register notice regarding how HHS’ determination to end the COVID-19 public health emergency declared under the Public Health Service Act will impact the Agency’s COVID-19-related guidances and which of those guidances it is temporarily extending or letting expire.” Other COVID-19 policies also may change. For example, unless FDA obtains congressional authorization, manufacturers of COVID-19-related devices no longer will be required to report device discontinuances or interruptions that could lead to a disruption in the device’s supply. Additionally, PREP Act liability protection for activities not related to a government agreement may be limited, unless another federal, state, or local emergency declaration is in place for the area where countermeasures are administered; however, HHS is currently considering continue providing this protection going forward.

FDA releases draft guidance on bioequivalence for immediate-release solid oral dosage forms. On January 31, 2023, FDA adopted the draft M13A Bioequivalence for Immediate-Release Solid Oral Dosage Forms guideline in a draft guidance. The M13A draft guideline was originally released by the International Council for Harmonisation (ICH) on December 20, 2022. The intent of the ICH guideline is to harmonize requirements for bioequivalence studies across various regulatory jurisdictions, lowering the burden currently placed on drug developers submitting marketing authorization applications in multiple jurisdictions by avoiding study duplication and reducing the number of human participants needed. The draft guideline, adopted in FDA’s draft guidance, provides recommendations for conducting bioequivalence studies of immediate-release solid oral dosage forms designed to deliver drugs to the systemic circulation, such as tablets, capsules, and granules/powders for oral suspension, during both development and post-approval phases. The draft guideline focuses mainly on scientific and technical aspects of study design and data analysis. Under study design, it includes recommendations for study population, sample size, comparator products, fasting and fed conditions, sampling, and how to select the dose/strength to be studied and the moieties to be measured. Under data analysis, the draft guideline provides recommendations for presentation of data, statistical analysis, considerations for the bioequivalence analysis population, and bioequivalence criteria.

FDA’s CDER and CBER restarting face-to-face meetings from February 13. FDA has released a statement outlining its plan to gradually restart face-to-face (FTF) industry meetings as Agency staff transition to a hybrid workplace in 2023. According to the FDA, this transition will enable FTF formal meetings for the two Centers, with some caveats. Specifically, the Agency is taking a hybrid approach where core participants with a primary speaking role will be in-person while other attendees will join virtually to avoid overcrowding in the conference rooms. Because FDA is upgrading the rooms with new technology to support these hybrid meetings, meeting space availability will be somewhat limited at the start, but the number of in-person meeting requests granted is expected to increase over the course of 2023. Due to the limited hybrid room availability, FDA will start with Type A, BPD Type 1, and Type X meeting requests, while FTF meeting requests for other meeting types, if granted, will be held fully virtually. In addition to the above, as more conference room upgrades reach completion, CDER and CBER expect to start also fielding requests for Type B (milestone), BPD Type 2, and Type Y FTF formal meetings in its second phase of this transition. The final phase will enable any FTF formal meeting to be considered for in-person format.

Draft guidance for evaluating blood donor eligibility. FDA has released draft guidance for evaluating blood donor eligibility using individual risk-based questions. The public comment period is set to close March 31, 2023, and, once finalized, this guidance will supersede the April 2020 guidance entitled “Revised Recommendations for Reducing the Risk of Human Immunodeficiency Virus Transmission by Blood and Blood Products.” Under FDA standards, blood donors are screened to evaluate potential risk factors for both donor and recipient, which historically could result in a prohibition from donating for a set time period based on identified risk factors. Early in the COVID-19 pandemic, the Agency issued a series of immediately-in-effect guidance documents to help bolster the US blood supply in response to shortages. Maintaining the flexibility of its pandemic donation policies. Based on the Agency’s review of the available science and other countries’ policies, FDA recommends eliminating certain time-based deferrals and to instead assess donor eligibility using “gender-inclusive, individual risk-based questions relevant to HIV risk.” In a similar vein, FDA advises deferring individuals taking medications to treat or prevent HIV infection, as they can reduce the HIV viral load to undetectable or potentially false negative levels, which pose a risk of infection transmission through transfusion. As next steps, FDA recommends that blood establishments that collect blood or blood components revise donor educational materials, donor history questionnaires and accompanying materials, along with revisions to donor requalification and product management procedures, particularly as they pertain to donor deferrals for individuals with increased risk for transmitting HIV infection.