FDA Expands COVID-19 Clinical Trial Guidance, Offers New Guidance on Developing Treatment and Prevention Products
The FDA expanded its guidance on conducting clinical trials during the COVID-19 pandemic to include information on considerations for using alternate laboratories or imaging centers, holding trial participant visits via video conference, and conducting required postmarketing clinical trials.
The FDA also released guidance to assist sponsors in the clinical development of drugs and biological products for the treatment or prevention of COVID-19.
The expanded question and answer guidance also updates information about managing protocol deviations saying that they should be included in final study reports and that they also may be included in annual reports.
The guidance also emphasizes that the requirement to gain prior FDA approval before implementing changes to the investigational plan does not apply to changes “made to protect the life or physical well-being of a subject in an emergency, including study-wide changes.” However, those changes must be reported to the FDA within five working days.
In addition, the answer about consulting with the FDA regarding the administration of investigational product infusions at home rather than at the clinical trial site now states: “If a sponsor is considering providing alternative arrangements for administration of the investigational product (e.g., home nursing or alternative sites by trained but non-study personnel), the sponsor is expected to perform a risk assessment that considers the nature of the investigational product and the potential risks to both the trial participants and the health care providers responsible for administering the product at the alternative site.”
According to the FDA, the risk assessment should include assessment of risk mitigation strategies and, based on this risk assessment, sponsors should consider whether to consult the appropriate FDA review divisions regarding plans for alternative arrangements.
The revised guidance added three questions:
- We are instituting trial participant visits remotely through video conferencing. Are there recommendations regarding best practices?
- How does the COVID-19 public health emergency affect drug and biological product clinical trials required as postmarketing requirements (PMRs)? What about for required postmarket device studies?
- I am a sponsor and would like to use an alternate laboratory or imaging center for protocol assessments. What should I consider regarding when this approach would be appropriate and the selection of alternate laboratories or imaging facilities?
Guidance Discusses Video Conferencing
The guidance noted that while the FDA “does not endorse any particular telemedicine best practices,” there are several important considerations for conducting trial visits through video conferencing from a regulatory perspective:
- The investigator or study personnel who will conduct remote visits should be trained on how to conduct real-time video conferencing visits (e.g., training on the use of telemedicine for remote clinical trial visits)
- Procedures should be put in place to maintain a trial participant’s privacy, as would be done for a clinical visit.
- Both the investigator and the trial participant should confirm their respective identities with one another before engaging in a real-time video conference visit according to an identity verification plan developed by the sponsor.
The guidance noted that the date and time of the real-time video interaction, the location of the trial subject, and the location of the investigator or personnel conducting the remote visit should be documented in the case report form, as would be done for face-to-face interactions.
The “FDA considers real-time video interactions, including telemedicine, as a live exchange of information between the trial personnel and trial participants. These interactions are not considered electronic records and therefore are not subject to 21 C.F.R. Part 11,” the guidance said.
The FDA also noted that the guidance “applies to all clinical trials, including those postmarketing clinical trials that FDA requires an applicant to conduct for drugs and biological products. Many of the considerations outlined in this guidance may also be relevant to postmarket device studies.”
The FDA noted applicants who are required to complete postmarketing clinical trials must follow a timetable that includes due dates for completing certain milestones in the trial. The agency “encourages applicants to inform FDA as soon as possible if they experience COVID-19-related delays that may affect the applicant’s ability to meet the applicable interim, trial completion, and/or final report submission milestone(s).” The applicants should propose feasible revised milestones for interim, trial completion, and/or final report submission milestones, the guidance said.
Applicants for post-market device studies “should similarly inform FDA as soon as possible of COVID-19-related delays that may affect the applicant’s ability to meet those milestones and propose feasible revised milestones. Applicants with PMRs or required postmarket device studies should also provide an explanation to FDA of how COVID-19 impacts the ability to meet the original milestones,” the guidance said.
The agency “will evaluate the facts and circumstances of the explanation provided, as well as the conduct of the applicant, in determining whether the applicant is in compliance with the applicable authority requiring the postmarketing trial or postmarket device study after the milestone has been missed,” the guidance said.
Additional considerations for drug and biological product PMRs include:
- PMRs under section 505(o)(3) of the Act – The FDA will continue to make “good cause” determinations on a case-by-case basis for all missed milestones, including those where the applicant asserts that its failure to meet a PMR interim, trial completion, and/or final report submission milestone(s) is related to the current public health emergency.
- Deferred Pediatric Study PMRs under the Pediatric Research Equity Act (PREA) – If circumstances involving COVID-19 have affected an applicant’s ability to complete a PREA PMR, applicants may request a deferral extension for the final report submission milestone. If an applicant has not obtained a deferral extension and fails to submit required PREA studies by the final report submission date listed in the PREA PMR, the FDA is required to issue a non-compliance letter to the applicant.
- PMRs under Accelerated Approval – For confirmatory trials, if an applicant misses an interim, trial completion, and/or final report submission milestone, the FDA will review the applicant’s explanation for the delay, as well as assess the trial’s progress prior to the current public health emergency, before determining whether or not the applicant has been compliant with its milestone obligations.
- Annual Status Reports of PMRs – Applicants must continue to follow the annual reporting requirements for PMRs and should document in their annual status report the COVID-19-related reason(s) for missing interim, trial completion, and/or final report submission milestone(s), and any steps taken to address COVID-19-related factors.
Guidance Examines Use of Alternative Labs
As to the use of alternative laboratories and imaging centers, the guidance said “the
suitability of such alternative arrangements may vary depending on whether the protocol-specified procedures are related to eligibility criteria, safety evaluations, or endpoint assessments. In general, if trial participants cannot access a clinical trial site, alternative sites may be used for laboratory tests or imaging assessments that focus on the safety of trial participants when such tests and assessments are routinely performed in those settings (e.g., routine chemistries, blood counts, chest radiographs),” the guidance said.
“However, if the results of laboratory tests or imaging assessments are the basis for formal hypothesis testing, including primary or secondary efficacy endpoints and some safety endpoints, sponsors should consult with the relevant FDA review division,” the guidance said.
The guidance noted that “disparities in laboratory measurements or imaging protocols will introduce increased variability and thus can affect type I and type II error rates.”
In addition, when baseline tests are needed to characterize the eligible study population, “potential variation in test performance or precision related to use of an alternative laboratory or imaging center may also warrant discussion with the FDA review division. For example, an inclusion criterion based on a commonly available, routine test performed as a safety screen (e.g., renal function on a metabolic panel) might be amenable to alternative laboratory collection with minimal impact on study results,” the guidance said.
However, “using an alternative laboratory for tests related to other eligibility factors could be more likely to affect study integrity (e.g., laboratory tests to identify a tumor biomarker required for inclusion, genetic test to identify a marker that is a critical inclusion criterion). It may be important for such assessments to be standardized at a single site or at most a few sites. Based on the nature of laboratory tests conducted for the purpose of protocol assessments, the alternative laboratory conducting such tests for investigational purposes will likely be subject to certification and other requirements under the Clinical Laboratory Improvement Amendments (CLIA). Alternative laboratory and imaging centers may also be subject to additional laws governing their operations,” the guidance noted.
Recommendations Given for Late Stage Trials
The new guidance – COVID-19: Developing Drugs and Biological Products for Treatment or Prevention – provides FDA recommendations on later stage clinical trials intended to establish safety and effectiveness for COVID-19 products. The guidance outlines critical sponsor considerations for trial population, trial design, efficacy endpoints, safety, and statistical assessment.
In regard to trial population, sponsors should consider:
- A range of populations is appropriate for evaluation and may include outpatient, inpatient, or inpatient on mechanical ventilation populations.
- For treatment trials, sponsors should document diagnosis of COVID-19. Laboratory-confirmed disease is preferred.
- For treatment trials, the agency recommends that sponsors categorize the baseline severity of the enrolled population. The criteria used to describe baseline severity should incorporate objective measures.
- For prevention trials, sponsors should conduct trials in communities with documentation of circulating SARS-CoV-2 infection. Populations including the following may be considered: pre-exposure prophylaxis trials in persons at high risk for SARS-CoV-2 exposure with no symptoms (e.g., health care workers and first responders); post-exposure prophylaxis trials in health care workers; or household contacts with no symptoms and with a documented exposure to a definite or clinically presumed case.
- Given the expected fluctuation in regions in the frequency of SARS-CoV-2 infection, sponsors should address the need to open new sites and potentially suspend existing sites.
- Clinical trials should include persons at high risk of complications such as the elderly, persons with underlying cardiovascular or respiratory disease, diabetes, chronic kidney disease, or other comorbidities, and immunocompromised persons (e.g., HIV-infected patients, organ transplant recipients, or patients receiving cancer chemotherapy).
- COVID-19 disproportionately affects adults, including older individuals. The geriatric population should be appropriately represented in clinical trials. Sponsors should consider conducting trials in nursing homes or other elder care facilities.
- Racial and ethnic minority persons should be represented in clinical trials. Sponsors should ensure that clinical trial sites include geographic locations with a higher concentration of racial and ethnic minorities to recruit a diverse study population.
- Patients with renal or hepatic impairment should be enrolled in clinical trials provided the pharmacokinetics of the drug have been evaluated in these patients and appropriate dosing regimens have been identified.
- The FDA encourages the enrollment of pregnant and lactating individuals in the Phase 3 (efficacy) clinical trials if appropriate.
- Children should not be categorically excluded from clinical trials of investigational COVID-19 products in which there is a prospect for direct benefit.
- Sponsors are encouraged to discuss pediatric drug development with FDA early in the course of clinical development, including the potential for extrapolation of adult efficacy data, appropriate pharmacokinetic trials in pediatric subjects to support dose selection, and the recommended size of the preapproval safety database in children. In addition, disease severity classification should reflect age appropriate norms, as applicable. Decisions on the timing of initiating pediatric studies depend on several factors, including but not limited to the amount of available clinical and/or nonclinical safety data for the drug. For example, if dosing recommendations for a drug are the same for adults and adolescents and there is sufficient prospect of benefit to justify the risks, then it may be appropriate to include adolescents in the initial Phase 3 clinical trials.
- Sponsors are encouraged to submit an initial pediatric study plan as soon as practicable.
- Under the Pediatric Research Equity Act, all applications for new active ingredients (which includes new salts and new fixed combinations), new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication or indications in pediatric populations unless this requirement is waived, deferred or inapplicable. The agency intends to work with sponsors to reach agreement on the initial pediatric study plan and any pediatric trial protocols as quickly as possible to avoid any unnecessary delays in the initiation of trials or submission of any marketing application.
In regard to trial design, sponsors should consider:
The FDA strongly recommends that drugs to treat or prevent COVID-19 be evaluated in randomized, placebo-controlled, double-blind clinical trials using a superiority design.
Background standard of care should be maintained in all treatment arms. Sponsors should address anticipated off-label use of any other drugs, devices or interventions that might be used to manage COVID-19.
The standard of care is expected to change as additional information, such as from randomized controlled trials, emerges. Where treatments become standard of care for specific COVID-19 populations (e.g., severely ill hospitalized patients), trials in these populations should generally be designed as placebo-controlled superiority studies with an add-on design (i.e., the investigational agent or placebo added on to the standard of care agent). For agents with a similar mechanism of action as the standard of care (e.g., direct antiviral agent as the investigational agent when the new standard of care is also a direct antiviral agent), an active-comparator controlled study design may be considered if there is sufficient preclinical and initial clinical evidence of activity of the investigational agent. Sponsors should plan early discussion with the appropriate clinical division.
Under certain circumstances it may be appropriate to conduct decentralized and/or platform clinical trials. Sponsors considering these approaches should discuss their plans with the agency. FDA recognizes the potential of, and significant interest in, such approaches, and may provide additional recommendations as the agency gains more experience regarding their use in this context.
Given the infection control concerns associated with COVID-19, sponsors should limit in-person data collection to those measurements intended to ensure safety and establish effectiveness or influence the benefit-risk assessment.
The trial should be of sufficient duration to evaluate safety and effectiveness reliably (i.e., the duration should be adequate to capture the vast majority of COVID-19-related outcomes that are relevant for the population under study). For example, a four-week duration would likely be sufficient to capture most important outcomes (e.g., mortality) in a trial of mechanically ventilated patients. Longer durations would potentially be appropriate for trials of patients who are less ill at baseline and for trials of preventive treatments. In some cases, longer follow-up should be considered to assess safety.
When there is compelling preclinical or preliminary clinical evidence, it may be appropriate to move directly to conduct a trial of sufficient size and appropriate design to provide substantial evidence of effectiveness and adequate characterization of safety.
In instances where there is some limited information supporting the potential for efficacy, approaches where an initial assessment of potential benefit can be made before enrolling a large number of subjects are appropriate. These approaches may include: conducting an initial small, controlled trial to assess for drug activity (proof-of-concept) that suggests the potential for clinical benefit; or conducting a trial that incorporates prospectively planned criteria to stop the trial for futility (i.e., with the prospect of expanding from a proof-of-concept phase to a larger confirmatory trial). Such a trial might also incorporate additional prospectively planned adaptations.
The FDA encourages sponsors to use an independent data monitoring committee (DMC) to ensure subject safety and trial integrity. Sponsors should submit the DMC charter as early as possible. Sponsors should ensure there will be appropriate DMC monitoring to safeguard the welfare of subjects, accounting for important factors such as the expected enrollment rate, the expected lag time to analyze interim data for DMC meetings and the frequency of DMC meetings. If enrollment is anticipated to be rapid, but additional safety data are needed before dosing a large number of subjects, an enrollment pause could be built into the trial. In this case, enrollment would be temporarily halted, and the DMC would assess the data and then recommend that the trial or dosing group either terminate or resume enrollment.
The FDA encourages sponsors to incorporate prospectively planned criteria to stop the trial for futility (lack of efficacy) or harm in any confirmatory trial. The stopping criteria should aim to ensure a high probability of halting the trial if the drug is harmful (e.g., associated with a higher risk of death), a reasonable probability of halting the trial if the drug is ineffective, and a high probability of continuing the trial if the drug is effective. If accrual in such a trial is expected to be rapid, an enrollment pause may be considered to support stopping for futility.
If a trial incorporates the possibility of early stopping for evidence of benefit or any adaptations to the sample size, dosing arms, or other design features, sponsors should prospectively plan the design in a manner to ensure control of the type I error rate and reliable treatment effect estimation. An independent committee, such as a DMC, should be tasked with providing any recommendations for early termination or design adaptations based on unblinded interim data.
The FDA anticipates events that occur outside of an ongoing trial may provide important new information relevant to the ongoing trial (e.g., changes to the standard of care) and may motivate revisions to the trial design. Well-motivated changes based on information external to the trial can be acceptable and sponsors are encouraged to discuss these changes with the FDA.