Bridging blinded and unblinded analysis for ongoing safety monitoring and evaluation

Abstract

In order to better characterize the safety profile of investigational new drugs (INDs) during clinical development, more interest and attention have been paid to ongoing safety monitoring and evaluation. The 2015 US FDA IND safety reporting draft guidance compels sponsors to periodically evaluate unblinded safety data. However, maintaining the trial blind is necessary to avoid jeopardizing the validity of study findings. In this article, we propose an innovative new approach which includes analyzing both blinded and unblinded data. The proposed two-stage framework incorporates periodic analyses of blinded safety data to detect and flag adverse events that may have potential risk elevation related to experimental treatment, as well as planned unblinded analyses to quantify associations between the drug and adverse events, and to determine thresholds for referring adverse events for medical review and safety reporting.

Introduction

Evaluating patient safety is an integral and essential part of the clinical trial process. Safety monitoring and evaluation from ongoing clinical trials has a direct impact on the safety and clinical care of patients enrolled during and after completion of these trials. Goals of ongoing safety evaluation from clinical trials include early detection of important safety signals, protecting patients from unnecessary risks, and developing the safety profile of the experimental treatment. The regulatory landscape for safety monitoring of health care products has changed considerably in recent years. The US FDA published a final rule amending the safety reporting requirements under 21 CFR part 312 and 21 CFR part 320 in September 2010. The final rule has placed strong emphasis on expediting reports of serious events with a reasonable possibility of being associated with the experimental treatment, so that safety evaluations are not confounded with excessive noise and product safety can be assessed more meaningfully [1]. In particular, the 2012 final guidance on IND safety reporting (Safety Reporting Requirements for Investigational New Drug (IND) and Bioavailability/Bioequivalence (BA/BE) Studies) recommends that sponsors conduct ongoing safety evaluations, including periodic review and analysis of the entire safety database, not only for IND safety reporting purposes, but also to update the investigator brochure (IB), protocol, and consent forms with new safety information [2].

Moreover, the 2015 draft guidance (Safety Assessment for IND Safety Reporting) provides recommendations on the composition and role of a safety assessment committee (SAC), how it differs from a data monitoring committee (DMC), and how and when to unblind safety data. Specifically, the US FDA recommends “unblinding to allow a comparison of event rates and detection of numerical imbalances across treatment groups to identify important safety information.” [3]. It is generally agreed that unblinding during ongoing clinical trials, by an independent expert committee (such as a DMC or SAC), is needed to identify and evaluate important imbalances in serious adverse events while studies are ongoing [3,4]. With randomized and blinded clinical trials, it is also necessary to maintain the blind of study personnel to treatment assignment in order to avoid jeopardizing the validity of study findings. Auspiciously, ongoing analysis of blinded safety data can be used to inform relationships between the drug and adverse events. With an expected range of event rates from internal and/or external data sources, we can assess whether there is a possible risk elevation due to experimental treatment. Furthermore, evidence from a blinded safety analysis could be used to evaluate the need for performing an unblinded safety analysis [5,6]. Therefore, it is feasible and potentially advantageous to combine the strength of both periodic blinded analyses and planned unblinded analyses for monitoring and evaluation of accumulating safety data.

In this article, we propose a two-stage framework for ongoing safety monitoring and evaluation. In the first stage, we periodically analyze blinded safety data to detect and flag adverse events that may have potential risk elevation related to experimental treatment. In the second stage, we conduct planned unblinded analyses to quantify associations between the drug and adverse events, and to determine thresholds for referring adverse events for medical review and possible safety reporting. The remainder of this article is organized as follows: In Section 2, we describe the proposed two-stage framework for ongoing safety monitoring and evaluation. Extensive simulations are presented in Section 3 to evaluate the performance of the proposed approach, in comparison to a single-stage approach with only an unblinded analysis. Practical considerations and related issues are discussed in Section 4.