FDA issues draft guidance on study designs using real-world data
The US Food and Drug Administration (FDA) has issued draft guidance to industry on how real-world data (RWD) could be used in clinical trials and how it could be incorporated into the design of non-interventional studies.The draft guidance, released Thursday, outlines the applicability of FDA’s investigational new drug application (IND) regulations to clinical study designs that use RWD and clarifies the agency’s expectations on new drug applications (NDAs) or biologics license applications (BLAs) using RWD to support drug safety or effectiveness in clinical studies not subject to IND regulations. The bulk of the guidance document focuses on clinical study design for non-interventional, or observational, studies.
The guidance is part of a series of documents the FDA has issued spelling out regulatory considerations around RWD and real-world evidence. (RELATED: FDA offers draft guidance for registries as RWD, Regulatory Focus 29 November 2021; FDA issues draft guidance on RWD sourced from EHRs, claims data, Regulatory Focus 29 September 2021)
IND applicability
The guidance discusses the applicability of IND regulations (part 312) to studies involving the use of RWD. The agency highlighted the potential for the use of RWD in interventional studies, including to identify potential participants for a randomized controlled trial, to ascertain endpoints or outcomes in a randomized controlled trial, or to serve as a comparator arm in an externally controlled trial, including historically controlled trials.
Non-interventional study designs
In the draft guidance, FDA recommends that sponsors contact FDA in the early stages of designing a non-interventional study that will be used to support a marketing application. Sponsors can request a Type C meeting to discuss study design elements. FDA recommends that sponsors provide draft versions of their proposed study protocol and statistical analysis plan (SAP) for agency review before finalizing the documents.
The protocol and SAP should be finalized before conducting prespecified analyses to ensure that specific data sources were not selected to favor a particular conclusion. Additionally, revisions to the protocol should be date stamped and the rationale for each change should be provided.
The study protocol should include a description of all the data sources accessed when designing the study and a justification for selecting or excluding certain sources from the study. FDA recommends that sponsors generate audit trails in their datasets that track access to analyses. Sponsors should also describe the patient characteristics of the source and study populations and note any differences between them that could impact the final study findings, FDA advised.
The agency also recommended posting study protocols on a publicly available website, such as clinicaltrials.gov, to promote transparency.
Non-interventional studies that do not include ancillary activities can focus study monitoring on maintaining reliability of the RWD and data integrity. If a study includes additional protocol-specified activities and procedures, monitoring needs to ensure that human subject protections are in place and that data integrity is maintained, according to FDA.
“FDA encourages sponsors to use a risk-based quality management approach to study oversight,” the agency wrote in the draft guidance. “This approach focuses sponsor oversight activities on preventing or mitigating important and likely risks to study quality in most instances, and on processes critical to human subject protection that are relevant when ancillary protocol-specified activities or procedures are included in a non-interventional study.”
In the draft guidance, FDA also advises sponsors of non-interventional studies, which examine the use of a drug in routine practice, to report relevant adverse events to FDA as specified by postmarketing safety reporting regulations.
The draft guidance spells out that sponsors submitting non-interventional studies for regulatory review should take responsibility for all activities related to the design, conduct, and oversight of the studies. This includes selecting qualified researchers, ensuring the study is conducted according to the final protocol and SAP, maintaining adequate study records and providing them to the FDA, and ensuring appropriate study monitoring and data collection.
FDA: Draft guidance on RWD
