From the beginning of the coronavirus (COVID-19) pandemic, FDA actively provided guidance to members of the drug and biologic industries, including sponsors, investigators, pharmacies, and compounders. Now, as states begin to reopen, FDA appears to be looking toward the future, specifically providing guidance on prospectively addressing the impact of COVID-19 on clinical trials and compliance with current Good Manufacturing Practices (cGMPs). Below we provide brief summaries of key points from FDA’s drug and biologic COVID-19 guidance to date.
- Companies and entities within the drug and biologic industries should continue to track FDA’s COVID-19 related actions, as additional guidance and modifications to existing guidances are likely to be issued as reopening plans are implemented and stay-at-home orders are lifted.
- As noted by FDA Commissioner Stephen Hahn, there will be lasting structural change to processes to accelerate review and approval of drugs and biologics, and companies should begin to evaluate and incorporate these structural changes into their strategic planning for R&D and regulatory functions.
- The National Institutes of Health (NIH) will likely continue to be critical to consideration of permanent structural changes in the drug testing and approval process, in view of its significant role in designing and sponsoring clinical trials for COVID-19..
- The pandemic is not yet over. A number of products and activities are still subject to regulatory exclusions and exemptions, and FDA’s exercise of enforcement discretion. Companies, however, should be mindful that once the emergency is lifted, many of these policies will be discontinued.
Guidance Regarding the Conduct of Clinical Trials
- Statistical Considerations for Clinical Trials During the COVID-19 Public Health Emergency – FDA provides statistical recommendations to address the pandemic’s impact on clinical data collection. Before database lock and/or unblinded interim analyses, sponsors should address the impact of the pandemic through protocol, endpoint, and statistical plan modifications, including amendments with respect to missing data strategies. When making trial changes, however, sponsors should be careful not to inadvertently introduce study bias. Sponsors should also document all COVID-19-related actions. If a sponsor decides to terminate a study early or add an interim analysis, consideration should be given to powering and statistical inferences. Finally, when a sponsor decides to continue a clinical trial, potential strategies to address COVID-19 data gaps may include increasing enrollment or extending follow-up periods.
- Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency (June 2020) – In a March 2020 Law Flash, we provided an overview of the FDA’s first iteration of its COVID-19 clinical trial guidance. Since that time, FDA updated the guidance to include Questions and Answers on topics such as study and investigational product suspensions, discontinuations, and initiation; deviation and protocol amendment management; virtual visits, and alternative site and dispensing arrangements; monitoring; informed consent procedures; post-market study requirements; safety reporting; electronic signatures; and FDA consultation and submissions. As the pandemic continues to evolve, FDA continues to update this guidance.
Guidance Regarding Development of COVID-19 Investigational Therapeutics
- Institutional Review Board (IRB) Review of Individual Patient Expanded Access Requests for Investigational Drugs and Biological Products During the COVID-19 Public Health Emergency (June 2020) – FDA outlines key IRB review considerations to address the substantial increase in requests for individual patient COVID-19 expanded access. IRBs may waive the full IRB review requirement with the concurrence of the IRB chair or another designated member. When reviewing individual patient requests, IRBs should focus on the risks and benefits of treatment for the particular patient. This assessment may not require the review of a formal protocol. IRBs should also ensure that informed consent documents clearly state that the product is not safe and effective for COVID-19 and that product use involves research.
- COVID-19 Public Health Emergency: General Considerations for Pre-IND Meeting Requests for COVID-19 Related Drugs and Biological Products (May 2020) – FDA recommends that sponsors initiate COVID-19 drug development interactions with the agency through pre-IND meetings, rather than the pre-Emergency Use Authorization (EUA) process. For COVID-19 products, FDA combined the meeting request and background package steps to permit a rapid response by a multispecialty, multidisciplinary team. Requests should include information to allow FDA to evaluate potential risks, as well as proposed protocols and safety monitoring plans. FDA also recommends that sponsors use a data monitoring committee. FDA will generally respond via a written response, prioritized based on the completeness of the submission and scientific merit.
- COVID-19: Developing Drugs and Biological Products for Treatment or Prevention (May 2020) – FDA issued this guidance to assist sponsors with phase 2 and 3 clinical development of COVID-19 drugs (other than vaccines and convalescent plasma), specifically outlining sponsor considerations related to subject populations, trial design, efficacy endpoints, safety, and statistical analyses. While the exact design of a trial will depend upon the product’s intended use, the guidance includes some points that would not necessarily be applicable to trials of products for other diseases. By example, FDA states that standard of care should be maintained in all study treatment arms, which may require that sponsors address off-label product uses and adapt to changes as the pandemic and medical knowledge evolves. Moreover, sponsors are encouraged to limit in-person data collection to those measurements needed to ensure subject safety, establish product effectiveness, or influence benefit-risk assessments. Sponsors are also encouraged to use a data monitoring committee and stopping criteria based on futility or harm.
Guidance Regarding Regulatory Compliance
- Good Manufacturing Practice Considerations for Responding to COVID-19 Infection in Employees in Drug and Biological Products Manufacturing (June 2020) – With reopening plans underway, FDA provides guidance regarding the intersection between cGMPs and COVID-19 risk mitigation. FDA recommends that manufacturers “vigilantly monitor” drug manufacturing employees that have been exposed to confirmed or suspected COVID-19. Employees that test positive or have COVID-19 symptoms must be excluded from drug manufacturing areas. Such employees should not return to manufacturing areas until they meet the Centers for Disease Control’s criteria for discontinuation of home isolation. As always, employees must practice good sanitation and health habits. Manufacturers should also assess their internal controls and conduct risk assessments to ensure existing procedures are sufficient to prevent COVID-19 cross contamination. Such steps require that manufacturers understand whether and how COVID-19 may adversely impact the safety and quality of materials, components, and products. All evaluations, follow-up and process control changes must be documented and approved by the manufacturer’s quality unit. Manufacturers of medically necessary drugs are also advised to develop contingency plans in case of high absenteeism, including remote work when possible.
- Temporary Policy on Prescription Drug Marketing Act Requirements for Distribution of Drug Samples During the COVID-19 Public Health Emergency (June 2020) – To address drug sampling challenges, FDA is exercising enforcement discretion for certain Prescription Drug Marketing Act (PDMA) requirements. FDA does not intend to take action against drug manufacturers or distributors that use signature alternatives to verify delivery and receipt of drug samples delivered via mail or common carrier. On a temporary basis, FDA will also permit manufacturers and distributors to delivery samples directly to an identified patient’s or the requesting practitioner’s home. Drug samples may not be distributed to retail pharmacies. Manufacturers and distributors should, however, be mindful of state pharmacy and drug distribution laws.
- Effects of the COVID-19 Public Health Emergency on Formal Meetings and User Fee Applications—Questions and Answers (May 2020) – FDA provides clarity on its meeting and user fee goal date plans. The agency shifted to a virtual/written response meeting format and continues to accept and grant new meeting requests. The agency also intends to hold virtual advisory committee meetings. With respect to user fee goals, except for 30-day Investigational New Drug application safety reviews, the agency’s efforts focus on products for COVID-19 and certain other life-threatening conditions. If the agency anticipates that it will miss a Prescription Drug User Fee or Biosimilar User Fee goal, it will communicate with the sponsor. If a Generic Drug User Fee goal date is missed, the sponsor should reach out to the appropriate project manager. Generic drug applications are being prioritized based on public heath priorities.
- Postmarketing Adverse Event Reporting for Medical Products and Dietary Supplements During a Pandemic (May 2020) – In an April 1 LawFlash, we provided a summary of FDA’s initial guidance on postmarket safety reporting. FDA has since updated this guidance to address outsourcing facility reporting. Specifically, FDA does not intend to exercise enforcement discretion for outsourcing facility adverse event reporting “because of the potential for increased production of compounded drugs during a pandemic . . .” FDA also now requires that death outcome reports be submitted within standard timeframes for New Drug Application and Abbreviated New Drug Application products.
- Exemption and Exclusion from Certain Requirements of the Drug Supply Chain Security Act During the COVID-19 Public Health Emergency (April 2020) – For the pendency of the current public health emergency, products subject to an EUA or that are approved for COVID-19, and products directly impacted by the COVID-19 emergency and that meet emergency medical needs (e.g., treatment of COVID-19 symptoms) are exempt from the Drug Supply Chain Security Act’s (DSCSA’s) tracing (i.e., transaction history, transaction information, and transaction statement) and product identification requirements. Wholesalers are also exempt from all DSCSA requirements with respect to such products. These exemptions are limited and do not apply to other products. Additionally, even if subject to the above exemptions, FDA expects that all companies maintain supply-chain security and continue to comply with the DSCSA to the extent possible. Finally, FDA makes the point that some people may try to profit from the pandemic by selling unproven and illegally marketed products with false COVID-19 claims. Accordingly, FDA encourages companies to engage in transactions with trusted and appropriately licensed/registered sources.
- Alternative Procedures for Blood and Blood Components During the COVID-19 Public Health Emergency (April 2020) – To address the need for blood and blood components, FDA issued exceptions and alternatives for certain blood and blood component requirements. First, if an error occurs during the donor eligibility determination process with respect to whether the donation would adversely affect the health of the donor, FDA is permitting the use of the blood and blood components. Donor facilities are still required to determine eligibility and not collect blood from donors found to be ineligible prior to collection. This alternative procedure also does not apply to donations that are unsuitable due to factors that would impact the safety of the blood or blood component. Second, FDA decreased the hold time for source plasma from paid donors to 45, rather than the standard 60, calendar days. Finally, establishments are now permitted to clarify donors’ responses to incomplete donor questions within 72 hours, rather than 24 hours, of collection. Licensed establishments that intend to implement the above changes must submit a Changes Being Effected supplement to FDA. Unlicensed establishments are not required to report these changes.
- Revised Recommendations for Reducing the Risk of Human Immunodeficiency Virus Transmission by Blood and Blood Products (April 2020) – Through this guidance, FDA reduced the blood donation deferral period from 12 months to three months for people with certain HIV infection risk factors. In addition to the revised deferral period, FDA provides additional recommendations with respect to donor education materials, donor history questionnaires (DHQs), donor requalification, product retrieval and quarantine, consignee notification, product disposition and labeling, and blood testing. FDA licensed establishments may implement DHQ and accompanying material revisions as a Changes Being Effected Supplement. If licensed establishments implement DHQ and accompanying material revisions prepared by the AABB Donor History Task Force or Plasma Protein Therapeutic Association, which revisions have been found acceptable by FDA, the change may be reported in an annual report. Unlicensed establishments are not required to report changes to FDA.
- Revised Recommendations to Reduce the Risk of Transfusion-Transmitted Malaria (April 2020)—Through this guidance, FDA updates its recommendations for screening donors of blood and blood components, except source plasma, for malaria risk by reducing certain deferral periods to three months. Like the above HIV guidance, this guidance also includes recommendations with respect to DHQs, product retrieval and quarantine, consignee notification, and product disposition and labeling. Licensed establishments must report DHQ and accompanying material revisions as a Changes Being Effected Supplement. If licensed establishments implement DHQ and accompanying material revisions prepared by the AABB Donor History Task Force or Plasma Protein Therapeutic Association, which revisions have been found acceptable by FDA, the change may be reported in an annual report. Unlicensed establishments are not required to report changes to FDA.
- Notifying FDA of a Permanent Discontinuance or Interruption in Manufacturing under 506C of the FD&C Act (March 2020) – FDA summarizes its notice requirements for manufacturing interruptions and discontinuations with respect to drugs that are life supporting, life sustaining, or intended for debilitating diseases or conditions. These notice requirements are only applicable to application sponsors and, for drugs that are not subject to approved applications, the product manufacturer. Accordingly applicants and manufacturers should ensure that contractors and licensed partners report issues up, so that the responsible entity may timely make any necessary FDA notifications. FDA also expects strict compliance with statutory notification timelines (e.g., FDA should not learn of a disruption from a purchaser whose order could not be filled). Additionally, while not a statutory requirement, FDA requests notification if product demand cannot be met. Companies also should refer to the heightened shortage reporting requirements that were implemented as part of the Coronavirus Aid, Relief, and Economic Security (CARES) Act, which we summarized in our March 31 LawFlash.
- Policy for Certain REMS Requirements during the COVID-19 Public Health Emergency (March 2020) – As described in our March 26 LawFlash, FDA is exercising enforcement discretion with regard to laboratory testing and imaging prerequisites for prescribing and dispensing products subject to Risk Evaluation and Mitigation Strategies (REMS), so long as accommodations are made based on the independent medical judgement of a healthcare professional.
In addition to the above FDA guidances, other relevant administrative agencies are also continuing to make COVID-19 regulatory adjustments. By example, the Drug Enforcement Administration issued a number of regulatory modifications to ensure an adequate supply of controlled substances to meet medical needs.
Law clerk Angela M. Silva provided helpful contributions to this article.
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 In addition to the discussed guidances, FDA also issued guidances related to compounded drugs, hand sanitizers, and specific drug products (e.g., convalescent plasma) that are not addressed here.