Statistical Considerations for Clinical Trials During COVID-19: Natural History Controls for Survival Analysis (Part I)

Co-author: 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:

1. Government interventions including suppression and non-pharmaceutical interventions (NPIs) such as social distancing, lockdown, or quarantine.
2. 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 (2020) 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.

For severely affected clinical trials in patients with serious diseases, we present a virtual matched control (VMC) methodology to overcome challenges of existing epidemiological methods (e.g., the IPTW propensity score method) which have questionable validity or limited statistical power due to small sample size. It also provides the foundation for assessing treatment efficacy when the trial enrolls only 1 or very few patients for individualized therapies such as an antisense oligonucleotide (ASO) therapy.

For COVID-19 affected ongoing clinical trials in patients with serious diseases, a practical and immediate mitigation action is to pause enrolling new patients and restart enrollment after COVID-19 due to massive interruptions of healthcare systems worldwide. Usually the primary superiority efficacy analyses for these trials are based on short-term clinical endpoints or biomarkers, and patients are followed for long-term clinical events such as death even after patients have completed the study. For randomized controlled trials, patients would switch over to the new treatment when the primary superiority objectives with the short-term clinical endpoints or biomarkers are met. This leads to the well-known difficulty of demonstrating superiority of the new treatment over the control with respect to the long-term clinical endpoint following the intent-to-treatment (ITT) principle.

To address this general difficulty, as well as various difficulties specific to impacts of COVID-19, we describe the approach of using natural history studies for comparative effectiveness analysis used in rare disease drug approval applications. This article is divided in three parts: substantial evidence standards, virtual matched control methodology, and inappropriateness of existing methods such as propensity score methods.

Substantial Evidence Standards

Section 355(d) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) requires substantial evidence for drug approval.

“The term ‘substantial evidence’ means evidence consisting of adequate and well controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.”

Following the 21st Century Cures Act, a recent (February 2019) FDA revision of the draft guidance for rare diseases states that

“One of the statutory requirements for drug marketing approval is substantial evidence that the drug will have its claimed effect. This requirement is the same for all drugs regardless of whether they are for common or rare diseases.”

To address challenges in rare disease drug development, Section 3021 (b)(2)(A) of the Cures Act specifically requires that the FDA issues guidance on

“the use of complex adaptive and other novel trial designs, including how such clinical trials proposed or submitted help to satisfy the substantial evidence standard under section 505(d) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(d))”

Furthermore, Section 3022 (a) of the Cures Act requires that

“The Secretary shall establish a program to evaluate the potential use of real world evidence (1) to help to support the approval of a new indication for a drug approved under section 505(c); and (2) to help to support or satisfy post approval study requirements.”

Section 3022 (b) defines

“... the term real world evidence means data regarding the usage, or the potential benefits or risks, of a drug derived from sources other than randomized clinical trials.”

Section 3022 (c)(2)(A) specifically requires the FDA to setup a program framework that includes information describing

“the sources of real world evidence, including ongoing safety surveillance, observational studies, registries, claims, and patient-centered outcomes research activities;”

To provide additional flexibility, Section 3022 (f) states that

“... nothing in this section prohibits the Secretary from using real world evidence for purposes not specified in this section, provided the Secretary determines that sufficient basis exists for any such nonspecified use.”

Pursuant to the Cures Act on the use of real-world evidence (RWE), the FDA issued its “Framework to FDA’s Real-World Evidence Program” to support

1)     a new indication for drug and biological products already approved under section 505(c),

2)     post approval study requirements, and

3)     biological products licensed under the Public Health Service Act.

On past use of RWE for effectiveness determinations, the Framework states that

“In limited instances, FDA has accepted RWE to support drug product approvals, primarily in the setting of oncology and rare diseases. When approval is based on a single-arm interventional trial - often when using a parallel assignment control arm is unethical or not feasible and usually when the effect size is expected to be large, based on preliminary data - the supportive RWE has consisted of data on historical response rates drawn from chart reviews, expanded access, and other practice

settings.”

In conclusion, the 21st Century Cures Act and FDA’s real-world evidence framework provide the legal foundation and a regulatory pathway for using real-world evidence for effectiveness determinations in developing drug and biological products for rare diseases. These are especially relevant to mitigate challenges of ongoing clinical trials severely affected by COVID-19 in patients with serious diseases.

Links to Part II and III

Part II https://lnkd.in/emZ6Z_k

Part III https://lnkd.in/eZffAS8

References

1.      2020 FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic. https://www.fda.gov/media/136238/download

2.      Liu and Peace (2020). Blinded data review for adaptive estimands. Statistical Considerations for Clinical Trials During COVID-19. Media | QRMedSci. Links to Part I and II https://lnkd.in/dw-Ag-4 and https://lnkd.in/dezxHS3

3.      2019 FDA Guidance on Rare Diseases: Common Issues in Drug Development https://www.fda.gov/media/119757/download

4.      2019 Framework to FDA’s Real-World Evidence Program" https://www.fda.gov/media/120060/download

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