Six Pivotal Studies Investigating the Efficacy of Remdesivir: Does Calling it Phase II or III Matter?

During the Covid-19 pandemic, people are desperate to find effective treatments to combat the coronavirus. One promising drug is Gilead's Remdesivir. Although Gilead developed remdesivir for Ebola (and did not get FDA's approval though), which belongs to a different family of viruses than SARS-CoV-2, the viral machinery has elements in common. The remdesivir has been repurposed to be used to treat the Covid-19 infected patients under compassionate use or expanded access program and to be used in the clinical trials.

While there are individual cases and anecdotal experience, the efficacy and safety still need to be demonstrated through the pivotal clinical trials - the adequate, well-controlled clinical trials.

There are currently six pivotal clinical trials involving Remdesivir (summarized below). If the information provided in clinicaltrials.gov is accurate, we should be able to get a readout about Remdesivir's efficacy in the coming weeks. The first study to have the efficacy readout is the phase III study in China for severe Covid-19 patients (estimated primary completion date: Apri 3, 2020). Given that the Covid-19 outbreak in China has been under control and very few new cases are reported in China, two studies in China should be wrapped up even though there may be short of the required sample sizes.

The largest trial in Covid-19 is the French study with 3100 patients to be enrolled. In this study, Remdesivir will be compared with standard of care, also head-to-head compared with three other treatments: Lopinavir/ritonavir, interferon Beta-1A, Hydroxychloroquine. The projected study completion date is March 2023 - by that time, the Covid-19 should be long gone.  

Protocol Title	Study Features	Primary Efficacy Endpoints
A Phase 3 Randomized Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants With Severe COVID-19	Gilead Sciences Phase III, 400 Subjects Three arms: Remdesivir for 5 days, Remdesivir for 10 days, Standard of care Multi-national： US, Hong Kong, Italy, South Korea, Singapore, Spain, Taiwan Estimated Primary Completion Date: May 2020	Proportion of Participants With Normalization of Fever and Oxygen Saturation Through Day 14 This is a composite outcome measure. Criteria for fever normalization: Temperature < 36.6 °C armpit, < 37.2 °C oral, or < 37.8 °C rectal sustained for at least 24 hours and criteria for oxygen normalization: peripheral capillary oxygen saturation (Sp02) > 94% sustained for at least 24 hours.
A Phase 3 Randomized Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants With Moderate COVID-19 Compared to Standard of Care Treatment	Gilead Sciences Phase III, 600 Subjects Three arms: Remdesivir for 5 days, Remdesivir for 10 days, Standard of care Multi-national： US, Hong Kong, Italy, South Korea, Singapore, Spain, Taiwan Estimated Primary Completion Date: May 2020	Proportion of Participants Discharged by Day 14
A Phase 3 Randomized, Double-blind, Placebo-controlled Multicenter Study to Evaluate the Efficacy and Safety of Remdesivir in Hospitalized Adult Patients With Mild and Moderate 2019-nCoV Respiratory Disease.	Capital Medical University/Chinese Academy of Medical Sciences Phase III, 308 Subjects Two arms: Remdesivir, placebo Mainland China only Estimated Primary Completion Date: April 10, 2020	Time to Clinical recovery (TTCR)  TTCR is defined as the time (in hours) from initiation of study treatment (active or placebo) until normalisation of fever, respiratory rate, and oxygen saturation, and alleviation of cough, sustained for at least 72 hours. Normalisation and alleviation criteria: Fever - ≤36.9°C or -axilla, ≤37.2 °C oral, Respiratory rate - ≤24/minute on room air, Oxygen saturation - >94% on room air, Cough - mild or absent on a patient reported scale of severe, moderate, mild, absent.
A Phase 3 Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Efficacy and Safety of Remdesivir in Hospitalized Adult Patients With Severe 2019-nCoV Respiratory Disease.	Capital Medical University Phase III, 453 Subjects Two arms: Remdesivir, placebo Mainland China only Estimated Primary Completion Date: April 3, 2020	Time to Clinical Improvement (TTCI) [Censored at Day 28] TTCI is defined as the time (in days) from initiation of study treatment (active or placebo) until a decline of two categories from status at randomisation on a six-category ordinal scale of clinical status which ranges from 1 (discharged) to 6 (death). Six-category ordinal scale: 6. Death; 5. ICU, requiring ECMO and/or IMV; 4. ICU/hospitalization, requiring NIV/ HFNC therapy; 3. Hospitalization, requiring supplemental oxygen (but not NIV/ HFNC); 2. Hospitalization, not requiring supplemental oxygen; 1. Hospital discharge or meet discharge criteria (discharge criteria are defined as clinical recovery, i.e. fever, respiratory rate, oxygen saturation return to normal, and cough relief).
A Multicenter, Adaptive, Randomized Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 in Hospitalized Adults	National Institute of Allergy and Infectious Diseases (NIAID) Phase II, 440 Subjects Two arms: Placebo, Remdesivir with additional arms to be added Multi-National: US, Japan, South Korea, Singapore Estimated Primary Completion Date: April 3, 2020	Percentage of subjects reporting each severity rating on an 8-point ordinal scale. The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or ECMO; 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitation on activities.
Multi-centre, Adaptive, Randomized Trial of the Safety and Efficacy of Treatments of COVID-19 in Hospitalized Adults	Institut National de la Santé Et de la Recherche Médicale, France Phase III, 3100 Subjects Four arms: Remdesivir, Lopinavir/ritonavir, Interferon Beta-1A, Hydroxychloroquine, Standard of care France Only Estimated Primary Completion Date: March, 2023	Percentage of subjects reporting each severity rating on a 7-point ordinal scale a. Not hospitalized, no limitations on activities b. Not hospitalized, limitation on activities; c. Hospitalized, not requiring supplemental oxygen; d. Hospitalized, requiring supplemental oxygen; e. Hospitalized, on non-invasive ventilation or high flow oxygen devices; f. Hospitalized, on invasive mechanical ventilation or ECMO; g. Death.

While five of these pivotal trials are labeled as Phase III study, only the NIH study (with 440 subjects) is labeled as Phase II study. Several weeks ago, I attended a seminar and three statistical professors discussed the Remdesivir clinical trials and the difficulties in patient recruitments. One professor spent quite some time discussing why two trials in China were labeled as Phase III while the NIH trial was labeled as Phase II - he mistakenly thought that only studies labeled as phase III could be used to support the product approval/registration.

Traditionally, clinical trials are phased: pre-marketing: phase I, phase II, and phase III studies; post-marketing: phase IV study. However, nowadays, these phases are blurred. A clinical trial labeled as phase II can still be sufficient to support the product approval/registration as long as the study is adequate and well-controlled. With adaptive design, some of the different phases of clinical trials are combined - seamless design. In the oncology area, a phase I study with cohort expansion may be sufficient for product approval (see FDA's guidance "Expansion Cohorts: Use inFirst-In-Human Clinical Trialsto Expedite Development ofOncology Drugs and Biologics" and Prowell et al "Seamless Oncology-Drug Development".

21CFR part 314 section 126 defined Adequate and Well-Controlled Studies to provide substantial evidence to demonstrate the efficacy of an investigational drug - there is no mention of the phase of the study.

Sec. 314.126 Adequate and well-controlled studies.

(a) The purpose of conducting clinical investigations of a drug is to distinguish the effect of a drug from other influences, such as spontaneous change in the course of the disease, placebo effect, or biased observation. The characteristics described in paragraph (b) of this section have been developed over a period of years and are recognized by the scientific community as the essentials of an adequate and well-controlled clinical investigation. The Food and Drug Administration considers these characteristics in determining whether an investigation is adequate and well-controlled for purposes of section 505 of the act. Reports of adequate and well-controlled investigations provide the primary basis for determining whether there is "substantial evidence" to support the claims of effectiveness for new drugs. Therefore, the study report should provide sufficient details of study design, conduct, and analysis to allow critical evaluation and a determination of whether the characteristics of an adequate and well-controlled study are present.

Similarly, in FDA's guidance (very important one) "Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products Guidance for Industry", there is no mention of the phases of clinical trials.

If a clinical trial is qualified for 'adequate and well-controlled', it can be used to demonstrate the substantial evidence of effectiveness regardless of the study phase.