SURF: A Screening Tool (for Sponsors) to Evaluate Whether Using Real-World Data to Support an Effectiveness Claim in an FDA Application Has Regulatory Feasibility.

Based on recent guidance and publicly available approvals, the US Food and Drug Administration (FDA) has demonstrated its openness to considering evidence of effectiveness from real-world data (RWD) and nonrandomized studies (or "real-world evidence (RWE)") in its decision making. Through analysis of the FDA approvals, several authors have identified methodologic issues commonly discussed by FDA reviewers. However, in our analysis of FDA guidance and use cases, acceptability of RWE also critically depends on whether the characteristics of the clinical development program align with circumstances in which the FDA may have flexibility in considering evidence from real-world study designs relative to more robust designs. Successful use of RWD requires advance planning to allocate the necessary resources and time to undertake principled epidemiology approaches to study design, data selection, and implementation of analyses as well as address regulatory feedback. Thus, sponsors benefit from early identification of programs in which successful RWD use is more likely, to ensure efficient use of resources required for the next steps of scientific feasibility assessment. We developed SURF, a screening tool intended to help a sponsor decide whether to prioritize resources for further exploring the feasibility of using an RWD approach to meet the FDA's effectiveness evidentiary standards for a particular clinical development program. Here, we provide an analysis of FDA guidance, highlighting the circumstances in which RWD approaches may be most acceptable, and demonstrate the use of this screening tool, including the rationale for its construction, types of evidence needed, and application to publicly available approvals as support of concept.

The Role of Real-World Evidence in FDA-Approved New Drug and Biologics License Applications.

The US Food and Drug Administration (FDA) is open to accepting real-world evidence (RWE) to support its assessment of medical products. However, RWE stakeholders lack a shared understanding of FDA's evidentiary expectations for the use of RWE in applications for new drugs and biologics. We conducted a systematic review of publicly available FDA approval documents from January 2019 to June 2021. We sought to quantify, by year, how many approvals incorporated RWE in any form, and the intended use of RWE in those applications. Among approvals with RWE intended to support safety and/or effectiveness, we classified whether and how those studies impacted FDA's benefit-risk considerations, whether those studies were incorporated into the product label, and the therapeutic area of the medical product. Finally, we qualified FDA's documented feedback where available. We found that 116 approvals incorporated RWE in any form, with the proportion of approvals incorporating RWE increasing each year. Of these approvals, 88 included an RWE study intended to provide evidence of safety or effectiveness. Among these 88 approvals, 65 of the studies influenced FDA's final decision and 38 were included in product labels. The 88 approvals spanned 18 therapeutic areas. FDA's feedback on RWE study quality included methodological issues, sample size concerns, omission of patient level data, and other limitations. Based on these findings, we would anticipate that future guidance on FDA's evidentiary expectations of RWE use will incorporate fit-for-purpose real-world data selection and careful attention to study design and analysis.

Addressing Pharmaceutical Injuries: The US Landscape.

The legal landscape for addressing an injury related to the use of a pharmaceutical product varies from country to country. Approximately 10 countries have adopted some form of no-fault compensation, in which an individual must establish that they sustained an injury caused by the medicine, but need not demonstrate that the manufacturer acted negligently in order to recover. This commentary compares and contrasts the approach taken in Japan with that in the United States.

Activation of mutant enzyme function in vivo by proteasome inhibitors and treatments that induce Hsp70.

Missense mutant proteins, such as those produced in individuals with genetic diseases, are often misfolded and subject to processing by intracellular quality control systems. Previously, we have shown using a yeast system that enzymatic function could be restored to I278T cystathionine beta-synthase (CBS), a cause of homocystinuria, by treatments that affect the intracellular chaperone environment. Here, we extend these studies and show that it is possible to restore significant levels of enzyme activity to 17 of 18 (94%) disease causing missense mutations in human cystathionine beta-synthase (CBS) expressed in Saccharomyces cerevisiae by exposure to ethanol, proteasome inhibitors, or deletion of the Hsp26 small heat shock protein. All three of these treatments induce Hsp70, which is necessary but not sufficient for rescue. In addition to CBS, these same treatments can rescue disease-causing mutations in human p53 and the methylene tetrahydrofolate reductase gene. These findings do not appear restricted to S. cerevisiae, as proteasome inhibitors can restore significant CBS enzymatic activity to CBS alleles expressed in fibroblasts derived from homocystinuric patients and in a mouse model for homocystinuria that expresses human I278T CBS. These findings suggest that proteasome inhibitors and other Hsp70 inducing agents may be useful in the treatment of a variety of genetic diseases caused by missense mutations.