Urgent Need for a More Aligned Regulatory Approach for Clinical Trials
Ginny Beakes-Read
Amgen Inc.

ll stakeholders involved in executing clinical trials during the pandemic faced enormous challenges, creating disruptions in clinical trial execution and delays in providing products to patients. The advice that global regulators provided to help address those issues was invaluable, and industry members are extremely grateful for that assistance. However, many different approaches were deployed by regulators across the globe. Those differences presented issues as industry tried to navigate the various requirements to continue clinical trials as safely as possible for patients. Many regulators are currently evaluating the impact of these flexible approaches and may continue to allow certain flexibilities in the future. This article highlights differences in regulatory guidance, suggests a deeper evaluation of the reasons for the various approaches, and advocates for appropriate alignment of guidances consistent with learnings from the pandemic.

The regulatory requirements for clinical trials are rooted in the principles of good clinical practices. Guidance from regulators, and flexible approaches to conducting trials, must ensure that risk to participants is mitigated and data integrity is maintained. Because the various guidances that regulators provided during the pandemic were clearly based on those principles, the different approaches may not have been obvious to those drafting the guidances. Some differences may be unavoidable, because regulatory authorities may have approaches that reflect their local healthcare systems or populations. However, when possible, they should be aligned so that we can collectively improve our global clinical trial system. This is particularly important because many early-stage and most late-stage clinical trials are conducted in more than one country. The experience of the last 18 months shows that there is a lot more work to do regarding harmonization (see examples below). This article shares our perspective related to those differences and suggests a dialogue to address these differences and minimize them in the future.

One positive outcome of the clinical trial disruptions that resulted from the pandemic is that we found new ways to reach patients, incorporating their needs and preferences. We all now recognize and appreciate the positive impact of patient-centered approaches to trials and want to foster them. Greater harmonization will support the use and adoption of innovative clinical trial designs and clinical trial approaches. These include decentralized trials (use of digital and other technologies to reach patients in a non-traditional trial model), or a hybrid of traditional and decentralized trials. Those types of designs and programs are promising for the future of drug development. In particular, they can promote inclusive clinical trial participation, helping to reach a more diverse population.

Appropriate remote operations became critically important, including remote monitoring and digital evidence collection. The pandemic required industry to implement advanced tools and analytics more broadly and demonstrated a clear need for improved clinical trials post-pandemic. However, new regulatory guidances must be aligned more closely to successfully advance innovative and patient-centered clinical trials. We also need to harness the creativity and energy that emerged during the pandemic over the past year and a half, and build a better, more modernized clinical trial system to serve our patients.

Examples of Varying Approaches

We created an internal tool that highlights differences in the regulatory approaches that were permitted by global health authorities during the pandemic. The initial goal of the tool was to capture global approaches and help internal teams navigate the differences. To that end, we included our interpretation of each health authority’s guidance, including what types of notifications are expected by each authority (Figure 1). Regulatory and clinical staff in each country collected and entered information in a Smartsheet database, which we used to generate charts that visually represent our interpretation.

The chart is not intended as legal or regulatory advice; rather, they are a visual aid to understand the challenges that clinical research teams may encounter in different countries or regions. The visual aid proved helpful for internal discussions, and we believe that it can facilitate external discussions as well. Ideally, regulators will engage in a dialogue regarding the rationale behind the varying regulatory approaches and identify where those differences can be minimized or eliminated in the future. The chart below highlights a few key topics, from eight countries, to illustrate the issue.

Key Health Authorities
Figure 1: Regulatory Flexibilities Chart. Overview of regulatory flexibilities across eight health authorities. The colors and shades vary from dark green (most permissive or flexible) to dark red (most restrictive, or most process required). Yellow indicates that no guidance is provided.
To give one example, when considering whether alternative methods of obtaining informed consent are permitted, we found that some regulators allow alternative approaches, some require advance notification or approval, and some have not yet addressed the issue. Another example relates to enrolment restart: We found that there were different submission requirements, ranging from no notification requirement to requiring a submission to request restart and obtaining approval of the submission prior to restart. Likewise, requirements related to the ability to use remote source data review or remote source data verification differed greatly, from allowed to not allowed, and with variations in between.

The chart above represents a sample of variations by country related to a few key guidance topic areas. We developed similar charts for over 50 health authorities that can help highlight the issues and support a dialogue.

We understand that regulators are working to align approaches where possible and to learn from regulatory flexibilities and agilities during the COVID-19 crisis. That includes the use and regulatory acceptance of digital tools, decentralized approaches, telemedicine, and modern statistical methods, among others. Consistent with the good clinical practices mandate, regulators will need to review data from clinical trials that were affected by the pandemic, to determine which flexible regulatory approaches are appropriate to maintain. Industry needs to provide information for regulators to make those evidence-driven decisions and help inform the future of clinical trials. All stakeholders express the desire to move forward in aligning regulatory approaches. To be successful, approaches must be global. Dialogue and understanding of the impact of varying approaches will go a long way toward achieving the goal of improved, innovative, patient-centered clinical trials for the future.