CDER Planning Guidance on Clinical Trial Modernization

CDER is planning a guidance document on the modernization of clinical trial conduct that is rooted in challenges to the clinical trial ecosystem brought on by the Covid-19 public health emergency. While Covid-19 disrupted traditional clinical trial infrastructures and operational activities, it also accelerated the adoption of modern clinical trial designs, operational approaches and data sources, CDER Office of Compliance director Don Ashley said in a compliance update at the FDA/PDA Joint Regulatory Conference in Washington, DC 9/13.

“Now, these modern approaches have the potential to increase the speed and efficiency of drug development,” he said. “However, the agency still needs to ensure that those trials are conducted in a manner that the data from those trials can be relied upon to make regulatory decisions.” As new trial approaches evolve, CDER’s Office of Scientific Investigations will be busy assessing clinical study data quality, integrity, and acceptability, as well as human subject protection measures. For example, Ashley said, “data collected remotely in a point of care or decentralized clinical trial need to be transferred securely as part of the record of the clinical investigation, and safety monitoring plans will need to ensure that patients with abnormal measurements that are collected outside of the clinical trials site are appropriately reviewed and managed.”

Some of the new trial approaches FDA is routinely seeing now include decentralized clinical trials and point-of-care trials. A decentralized trial may be designed as a traditional randomized, double blind clinical trial, but some or all of the elements of the trial occur away from the clinical trial site, he explained. “So it's really more about how the trial is operationalized, and a point of care trial integrates clinical research into routine health care delivery,” he said. “So operationally, it's also occurring away from a traditional clinical trial site and the data sources used for these point-of-care trials will also be different than a traditional clinical trial, and study data collection is accomplished by automatically extracting information from the electronic medical record. Now, this is something that has become more feasible with the widespread adoption of electronic health record systems.”

Real-world data and real-world evidence trials refer to the data source and can include a variety of sources like electronic medical records, claims and billing activities as well as product and disease registries, Ashley noted. And master protocols are also being explored more frequently to streamline and accelerate drug development. “So, in contrast to a traditional trial design where a single drug is tested in a single disease population in one clinical trial, master protocols use a single infrastructure, trial design and protocol to simultaneously evaluate multiple drugs and or disease populations in multiple sub-studies, which allows for efficient and accelerated drug development.” Master protocols have been popular during Covid and widely used in oncology studies.

Ashley told the conference that regardless of the modernized trial approach a sponsor may select, there are three main issues requiring consideration to ensure that the data can be relied on to make regulatory decisions right. The first is study design and making sure it uses principles of quality by design. Second is the study execution and whether the trial is operationalized effectively, including considerations for where data collection occurs, whether at the site or remote locations, and how the study design choices play out in real time while the trial is conducted. And third is the study assessment, and how to ensure accurate and consistent assessments that are aligned with the unique needs of the application, he said.

Additionally, Ashley placed emphasis on trial quality by design “because it’s so critically important as clinical trials continue to evolve.”  He noted the importance of applying a risk-based approach to the entire clinical trial lifecycle. “Quality in clinical trials isn’t the absence of error, rather it’s the absence of errors that matter, and that means identifying factors critical to the quality of the study, and then working to reduce risk associated with those factors,” he said.

Ashley acknowledged that while some of the different study designs and operational approaches he covered are not completely new, Covid presented a set of unique challenges that CDER had never seen before, and that led to the increased adoption of these modern approaches out of necessity.