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

One of the outstanding features of the COVID-19 pipeline is diversity, which covers a wide range of drug action mechanismsUnder the premise of adhering to adequate safety evaluation, the phase 2 and 3 tests are encouraged to adopt targeted and diversified test designMay 11 this year, the FDA released the final version of the COVID-19 therapeutic drug and preventive product development guidelines, taking a flexible approach to the design of Phase 2 and Phase 3 clinical trials, indicating 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-blindsThe guidelines focus on drugs and biological products used to treat or prevent COVID-19 and do not cover plasma and preventive vaccines during rehabilitationThe 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 interferenceFDA said the guidelines' recommendations, while focused on the development of drugs with direct antiviral or immunomodulatory activity, "may apply" 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." "
trials 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 infectionsguidelines 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 selectionsmay, on 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 drugsWe are studying the timing of recoveryguidelines say that expanding 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 frail conditions in the groupThe 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 patientsThe guidelines recommend clinical trials in nursing homes and other aged care facilitiesResponses 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"
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 for drug administration for adults and adolescents are the same, 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."FDA strongly recommends that the applicant conduct random, placebo-controlled, double-blind trials and adopt an effective designAlthough 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 platformsthe FDA recognizes the potential of these methods and the widespread concern seisacs that it may make additional recommendations as it learns more about these aspects of adoption 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 this year, in the first COVID-19 therapy study initiated by the NIH, adaptive platform trial design was initiated 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 to 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 "prospects for scaling from the proof-of-concept phase to larger validation trials" could include "adjustments to forward-looking plans" and forward-looking program severance criteria for discontinuation of 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." The FDA notes that in evolving COVID-19 therapy, "with the emergence of other information, such as randomized controlled trials, the standard of care is 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 for specific populations, the FDA recommends a placebo-controlled benefit study to add candidate drugs or placebos to medical care standards guidelines indicate that drugs with a systematic mechanism of action with the new standard scant can be designed using active control stakes 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 allow for some flexibility in terms of efficacy endpoints, it is recommended that the sponsors evaluate candidate drugs against placebos against "clinically significant aspects of the disease" in 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 guidelines provide examples of some important clinical outcome measurement indicators, highlighting the overall requirements for clear definitions 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 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 state that virological measurements can serve as a suitable secondary endpoint in Phase 3 studies and 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, greatly accelerating 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 FDA said, "In this case, the intake will be temporarily suspended," and the Clinical Trial Data Board will recommend whether to terminate the trial or administer the drug group or resume the group after evaluating the data 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 , unlike the usual practice, this final version of the COVID-19 Guidelines for the Development of Therapeutic Drugs and Prevention products has not been pre-published with recommendations and comments 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 emergency does not mean the end of FDA guidance on the development of COVID-19 therapeutic drugs and preventive products 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