FDA COVID-19 Clinical Trial Guide: Welcome to Diverse Phase 2, Phase 3 Trial Designs

On May 11 this year, the FDA released the final version of the guidelines for the development of COVID-19 therapeutic drugs and preventive products, taking a flexible approach to the design of Phase 2 and Phase 3 clinical trials, demonstrating a willingness to consider options and urging the sponsors to discuss their clinical trial plans with the FDA as soon as possibleThe guidelines say the FDA is committed to supporting all scientifically sound ways to mitigate the clinical harm caused by COVID-19At the same time, however, the FDA continues to adhere to rigorous clinical evaluations that meet traditional regulatory standards, ideally using placebo-controlled, randomized groupings, and double-blindsEarly interaction with regulators The guidelines focus on drugs and biologics used to treat or prevent COVID-19 and do not cover rehabilitation plasma and preventive vaccinesThe Biologics Assessment and Research Guidelines, released on April 8 this year, cover the use of therapy for the extraction of plasma from recovered PATIENTs with COVID-19, while also encouraging potential vaccine manufacturers to seek the guidance of the Bioproduct Review and Research Centre (CBER) and actively seek regulatory guidanceThe guidelines state that the mechanisms of action of candidate drugs can have an important impact on the design elements of the study, from the relevant population and endpoint to safety evaluation and follow-up durationDiversity is one of the prominent features of the COVID-19 pipeline, which covers a wide range of mechanisms in the study of drugs, from attackvirus replication and entry, to neutralizing antibodies, anti-inflammatory agents, immunomodulators, stem cells, and RNA interferenceThe FDA said the guidelines' recommendations, while focused on the development of drugs with direct antiviral or immunomodulatory activity, "may be applicable" to other types of productsThe guidelines also caution: "For certain biological products, such as cells, gene therapy, and blood products, other considerations may also need to be taken into account." The wide coverage of the trial should start with a documented (preferably laboratory-confirmed) baseline classification of the severity of COVID-19 in a patient, using criteria based on objective measurementsThe guidelines include an example of sars-CoV-2 patients defined as asymptomatic, or mild, moderate, severe, or severe COVID-19 infectionsThe guidelines highlight the range of populations that should be evaluated in COVID-19 treatment trialsClinical trial sourcing environments include outpatient, inpatient, and the need to use mechanical ventilation to stay in the ICUDifferences in clinical environment, population and disease severity, in turn, affect the "relevance and appropriateness" of clinical endpoints for specific trial selectionsOn May 12, FDA Director DrStephen Hahn, at a Senate Health, Education, Labor and Pensions Committee hearing, said clinical development must reflect different clinical manifestations of COVID-19 diseaseDrHahn told the hearing that he hopes clinical trials will adapt to the clinical environment and the type of treatment you face "We do understand that in some cases, patients with severe COVID diseases already have thrombosis or clotattacks, so we prioritize the review of drugs that we believe may be beneficial .. Obviously, the clinical endpoint of these trials will be different from antiviral drugs We are studying the timing of recovery The guidelines say extending the criteria for patient admission in clinical studies is necessary to address such a wide range of public health crises, and urges sponsors to cover patients with complex or debilitating conditions in the group The FDA says clinical trials should be covered by people at high risk of complications, such as the elderly and immunocompromised, or potentially cardiovascular, respiratory or kidney disease or diabetes patients The guidelines recommend clinical trials in nursing homes and other aged care facilities Responses to clinical trial sites should also include "geographic locations where ethnic and ethnic minorities are more concentrated to recruit diverse research populations." Given the anticipated fluctuations in the frequency of SARS-CoV-2 infection in different regions, the bidders should focus on the need to open new clinical trial sites and possibly suspend existing sites The guidelines state that "children should not be explicitly excluded from clinical trials of COVID-19 products with direct benefits." The FDA is committed to working with the sponsors to reach agreement on the initial pediatric research plan and any pediatric trial options as soon as possible to avoid any unnecessary delays "The guidelines suggest that the bidders should specifically discuss the possibility of extrapolating adult efficacy data to children "For example, if the same recommendations are given for the administration of relevant drugs for adults and adolescents, and sufficient benefits are expected to be made to justify the risk, it may be appropriate to include adolescents in the initial Phase 3 clinical trial." The FDA strongly recommends that the applicant conduct random, placebo-controlled, double-blind trials and adopt an effective design Although the guidelines state that "in some cases, it may be appropriate to conduct decentralized and/or platform clinical trials." But the guidelines are cautious about the increasingly popular way of testing platforms The FDA recognizes the potential of these methods and the widespread concerns it has received, and as it learns more about these aspects of adoption, the FDA may make additional recommendations The bidder should, as always, discuss its plans with the FDA The National Institutes of Health (NIH) is supporting platform trials during the fight against the COVID-19 pandemic In mid-April, NIH, the NIH Foundation (FNIH), the CDC, the FDA, the European Medicines Agency (EMA) and 16 biopharmaceutical companies launched the Accelerated COVID-19 Therapeutic Interventions and Vaccines Partnership (The Accelerating COVID-19 Therapeutic Interventions and VaccinesIV), which is exploring a variety of options for different populations Dr David Wooley, senior vice president of partnerships at the NIH Foundation, said that all parties involved agreed that adopting a master approach structure while testing multiple therapies could be the only way to collaborate efficiently, adding weight to the platform if successful, and flexibility to uninstall developments that are not promising if progress is not going well The NIH Foundation is coordinating the ACTIV Partnership In February, adaptive platform trial designs were initiated in the first COVID-19 therapy study initiated by NIH The clinical trial, called ACTT, was used to test the efficacy of the antiviral drug Redsivir with a placebo control NiH adjusted the main endpoint of the ACTT clinical trial after reviewing the size of the results of 100 patients as originally planned THE NIH RECENTLY ANNOUNCED THAT IT WILL COMBINE REDSIVIR WITH LILLY'S ANTI-INFLAMMATORY DRUG OLUMIANT FOR A SECOND PHASE OF THE TRIAL, KNOWN AS THE ACTT2 TRIAL FDA guidelines identify a potential role in adaptive design With some data supporting the drug's efficacy potential, and when the data are limited, the bidders hope to produce some evidence before entering the group of large numbers of subjects, and adaptive design can work Trials with "the prospect of scaling up from the proof-of-concept phase to larger validation trials" could include "adjustments to forward-looking plans" and should also include a stop-to-view program stop for trials that may not result The guidelines emphasize the stop standardand and encourage bidders to "incorporate the criteria for a forward-looking plan and to stop all trials that do not result (lack effectiveness) or cause harm in a confirmed trial." Responding to the evolving environment FDA notes that in evolving COVID-19 therapies, "as other information, such as randomized controlled trials, emerges, standards of care are expected to change." "The FDA anticipates that events that occur outside of ongoing trials may provide important new information and may lead to revisions to the trial design." The Guide therefore notes that well-motivated changes based on information other than the experiment can be accepted In the presence of established medical care standards specific to specific populations, the FDA recommends a placebo-controlled benefit study to add candidate drugs or placebos to the standard of care The guidelines indicate that drugs with a systematic mechanism of action with the new standard siftles may be designed with active controls when there is positive evidence of preclinical and preliminary clinical trials For example, when direct-acting antiviral drugs become the standard of medical care, new direct-acting antiviral drug candidates can be controlled using active controls The guidelines, which allow for some flexibility in terms of efficacy endpoints, recommend that the sponsors evaluate candidate drugs against placebos against "clinically significant aspects of the disease" when conducting trials Depending on the patient population, the severity of the disease, and the clinical condition, different endpoints may need to be evaluated at different points in time Overall, however, "the time window should be long enough to ensure that important events related to patient status, treatment, and COVID-19 progression are captured." "Furthermore," the bidder should address the recurrence problems that may arise in its endpoint definition to ensure that the sustainability of the response is adequately assessed The guide provides examples of some important clinical outcome measurement indicators and highlights the overall requirements for cleardefinitions and specific clinical standards The guidelines recommend including respiratory failure measurements, mechanical ventilation or hospitalization needs, continuous clinical recovery (symptom resolution) and "continuous improvement of objective measurement indicators", such as recovery to the ability to breathe autonomously, or baseline oxygen delivery needs The FDA guidelines refer to the Grading Scale for measuring clinical conditions set out in the World Health Organization's COVID-19 Development Blueprint (R-D Blueprint and COVID-19) and lists "clinical status at the appropriate point in time for evaluation using the epitope table" as the endpoint of the trial in patients with severe or critical COVID-19 The guidelines note that the applicable scaleinclude includes a wide range of high-profile clinical outcomes "in order of clinical importance" The WHO grading scale scored from 0 (uninfected) to 8 (died) and tracked measurements including oxygen treatment and mechanical ventilation This is the most commonly used grading scale in industry and government-sponsored three-phase studies Outpatient trials may look at the proportion of patients admitted within a set time, such as 28 days, or the amount of time for continuous clinical rehabilitation The guidelines state that virology endpoints should not be the primary endpoint of Phase 3 trials because there is no established predictive relationship between "the magnitude and timing of the virus and the clinical benefit, function, or survival rate of the patient's self-perceived self-perception." Nor did the optimal sample size, timing, and calibration of clinically relevant virological measurements be determined However, the guidelines specifically point out that virological measurements can serve as a suitable secondary endpoint in Phase 3 studies and can be used as a primary endpoint in Phase 2 trials to support Phase 3 clinical endpoint studies "Collecting virological data and evaluating antiviral resistance is an important part of THE DEVELOPMENT OF COVID-19 drugs The urgency of fighting the COVID-19 pandemic has greatly accelerated the pace of drug development, but there is no compromise on the need for adequate safety evaluation Therefore, "if you want to get into the group quickly, additional safety data is necessary before a large number of subjects are given medication." FDA guidelines recommend establishing an "in-group pause key" in the trial "In this case, the admission will be temporarily suspended," the FDA said, after evaluating the data, recommendwhether to terminate the trial or administer the drug group, or to resume the group The guidelines also recommend the use of a standardized toxicity scale, a toxicity scale developed by the NIH's AIDS division (Division of AIDS, NIH) and the National Cancer Institute (NCI), in patients with severe COVID-19 or severe comorbidities Follow-up guidelines Unlike the usual practice, this final version of the COVID-19 Therapeutic Drugs and Preventive Product Development Guidelines did not seek advice and comments on the draft guidelines published first The FDA does not consider it feasible or inappropriate for the guidelines to be used in the usual way to solicit public advice and opinions before the final version is published The guidelines are limited to the COVID-19 public health emergency declared by the U.S Department of Health and Human Services (HHS) on January 31, 2020 But in the future, the end of the state of emergency does not mean the end of FDA guidance on the development of COVID-19 therapeutic drugs and preventive supplies The FDA expects that the experience gained in implementing the guidelines will help the FDA more broadly assist the sponsors in the clinical development of COVID-19 therapeutic drugs Therefore, within 60 days of the end of the public health emergency, the FDA plans to make appropriate changes to the revised and superseded guidelines based on the recommendations, comments, and internal discussions gathered.