Statistical Considerations for Clinical Trials During COVID-19: Phase 1 Cancer Trials

Qing Liu, Ph.D., ASA Fellow

Success in Gene Therapy and Rare Disease Drug Development with Innovation

Published Apr 20, 2020

Authors: Michael H. Tirgan, MD, Phase1Oncology, attending physician at Mount Sinai St. Luke’s Hospital , Qing Liu, Ph.D. ASA Fellow, Quantitative and Regulatory Medical Science, LLC., and Karl Peace, Ph.D. ASA Fellow, Jiann-Ping Hsu College of Public Health, Georgia Southern University

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Introduction

It is well-recognized that the COVID-19 pandemic has hit many ongoing clinical trials hard in many different ways, including but not limited to:

Government interventions including suppression and non-pharmaceutical interventions (NPIs) such as social distancing, lockdown, or quarantine.
Supplies of study medications and availability of healthcare professionals and facilities for clinical and/or laboratory evaluations, treatment administration according to scheduled clinical visits typically specified in Table 1 of study protocols.

In response to the impacts of COVID-19 pandemic on ongoing clinical trials, the March 17, 2020 FDA Guidance on Clinical Trials during COVID-19 states that

“FDA recognizes that protocol modifications may be required, including unavoidable protocol deviations due to COVID-19 illness and/or COVID-19 control measures. Efforts to minimize impacts on trial integrity, and to document the reasons for protocol deviations, will be important.”

And

“Prior to locking the database, sponsors should address in the statistical analysis plan how protocol deviations related to COVID-19 will be handled for the prespecified analyses.”

COVID-19 affects ongoing clinical trials in many different ways, which in turn affects many aspects of statistical inference. To comprehensively describe and capture the multitudes of COVID-19 impacts, Liu and Peace (2020a) describe ongoing clinical trials with substantial data collection as minimally affected, moderately affected and substantially affected. An ongoing trial is severely affected if the trial has to be put on hold. This article outlines mitigation strategies of phase 1 cancer trials with a dose escalation scheme to identify maximum tolerated dose (MTD) for continuation to phase 2 trials. As a majority of cancer patients are above the age of 50 and are immune compromised, and at very high risk for developing the severe form of COVID-19 that carries high morbidity and mortality, we propose a two-stage adaptive design following a pause-analysis-redesign-restart (PARR) strategy (Liu and Peace, 2020b).

Phase 1 Cancer Trials

Oncology drug discovery and proper conduct of cancer clinical trials are essential to our battle against cancer. According to a 2015 Center for Disease Control and Prevention (CDC) report, the expected cancer cases and deaths in 2020 are 1.9 million and 630,000. While the world is fighting COV-19 pandemic, it is also important to be more creative than ever to continue anti-cancer drug development in a safe manner - without exposing cancer patients to unnecessary COVID-19 risks while maintaining the integrity of cancer clinical trials.

Phase 1 oncology trials are the steppingstone for every potential anti-cancer drug, a major step in drug development that cannot be bypassed. Proper conduct of phase 1 clinical trials in oncology indications serves several purposes, but most importantly it leads to:

1) establishing the maximally tolerated dose (MTD) and the recommended phase 2 dose (RP2D) and

2) studying the pharmacokinetics (PK) of the drug.

Conducting phase 1 studies in COVID-19 era, however, poses numerous practical challenges. Since almost all phase 1 studies are conducted at tertiary care centers, with overwhelming numbers of COVID-19 patients, if not all, a great majority of these centers are busy providing care to COVID-19 patients, displacing the focus from oncology research to providing acute medical care.

Furthermore, a majority of cancer patients are above the age of 50, are immune compromised and at very high risk for developing severe form of COVID-19 that carries a very high morbidity and mortality (Liu and Peace, 2020b). Extreme care must be exercised to prevent development of COVID-19 in cancer patients, including minimizing the number visits, blood draws, radiology tests as well as minimizing the time that patients spend inside healthcare facilities.

Traditional Phase 1 studies, by their nature, are very demanding and require excessive numbers of patients’ visits to the healthcare facilities for scheduled evaluations, PK, other blood draws, tumor biopsies, etc. This in turn results in prolongation of the time that patients are inside clinical facilities.

The increased number of prolonged visits in the COVID-19 era will simply increase the risk of acquiring the illness while on study, requiring additional medical and possibly supportive care. All these will add to the number of adverse events and serious adverse events on study, all of which have to be properly documented, analyzed and reported.

To protect patient safety and maintain trial integrity, it is necessary to adopt accurate test for SARS-CoV-2 at baseline and during the study (Ogenstad and Peace, 2020c). This allows effective implementation of the two-stage adaptive design following the PARR strategy (Liu and Peace, 2020a).

Review of the research program with patients, obtaining informed consent, copying the signed consent form and providing a copy to the patients, meeting with research staff, all increase the amount of time patients have to spend in a healthcare facility.

Mitigation Strategies

Enrolling new patients during the COVID-19 is quite challenging. Being cognizant of various challenges and trying to maintain scientific integrity of the phase 1 clinical studies, requires us to adapt strategies that would allow enrollment into phase 1 studies, yet without imposing excess risks on the study subjects. The first author is aware of study cancellations and lack of recruitment for existing studies. This is known as the pause where a trial is put on hold. During the pause, analysis of the COVID-19 impacts on the trial design is performed and necessary changes to the trial design are made, including a new section for COVID-19 mitigation in the study protocol as well as in the informed consent form, before resuming the trial with currently enrolled patients and prior to restarting the trial during or post COVID-19.

Following the two-stage adaptive design with the PARR strategy, a phase 1 trial consists of three patient groups:

Group 1: those who have completed the trial prior COVID-19,

Group 2: those who are enrolled during COVID-19 and are potentially affected by COVID-19, and

Group 3: those yet to be enrolled after restart during or post COVID-19.

Patients in group 1 are unaffected by COVID-19. As patients in group 2 are enrolled during COVID-19, protecting their safety is of the primary concern. To maximize information from these patients, accurate testing for SARS-CoV-2 during the study is important to identify patients who are infected, and those who are not infected. This goal can only be achieved with maximizing the usage of telemedicine. Below are several examples of creative ways to reduce the risk of contracting COVID-19:

1. Conduct the informed consent process by telemedicine, preferably via video consultation,

2. Allow patients to either electronically sign the study consent forms or implement and accept a verbal consent process,

3. Establish a drive through research process where research subjects can drive through, have their vital signs, blood or other tests performed without having to enter the healthcare facility, and

4. Perform SARS-CoV-2 by RT-PCR once every two weeks via a drive-through research station.

To maintain integrity of MTD determination, patients in group 2 who test positive for SARS-CoV-2 will be excluded and the protocol will be updated such that the remaining patients will be used for assessing the next dose or cohort for new patients to be enrolled in group 3 following the original dose escalation scheme. Depending on the specifics of the study, other mitigation steps or changes may be made in the updated protocol to accommodate new norms of clinical practice after trial restart during or post COVID-19. This may include various mitigation strategies of patient protection and testing for SARS-CoV-2.