How have regulatory agencies looked at RWE studies in the past?
Regulatory agencies have used traditionally used RWD and RWE studies for post-marketing monitoring of safety and adverse events. Passage of the 21st Century Cures Act in the US in 2016 called for a focus on how RWD and RWE studies could be used more broadly, including approval of new indications for approved drugs. In response, FDA and other regulatory agencies have issued multiple guidance documents which emphasize issues such as transparency and documentation of data management, study design and analysis plans, and fitness of the data for the purpose under study.
How and why is this perspective changing?
The regulatory change in perspective has been influenced by several factors. First, the amount of electronic health information that is available – from health records, claims data, wearable devices and other sources has been increasing at a rapid rate. Second, new analytic tools are continually being developed that improve the ability to extract meaningful information from the data evaluated. Third, increasingly therapeutics are under development for diseases in which in is not feasible, or unethical, to conduct a traditional RCT. Examples include rare diseases affecting small populations and serious diseases with no existing treatments.
RWE studies are not a substitute for RCT but can contribute to the totality of evidence for evaluating a therapy. The hurdle for regulatory acceptance of RWE studies is much lower when it is presented as supporting evidence rather than as major evidence for deciding the efficacy and safety of a product.
What are some examples of RWE used in regulatory decisions?
Approval: Avelumab (Bavencio) was approved in 2017 for treatment of Merkel Cell Carcinoma (MCC), a rare disease for which a RCT was not feasible. Approval was based on a Phase 2 study comparing an active treatment arm and a matched RW historical control arm of MCC patients treated with chemotherapy identified via retrospective analysis of electronic health records.
Label expansion: In 2019, approval of palbociclib (Ibrance) for female breast cancer was expanded to include male breast cancer. This approval considered a number of RWD sources, including EHR records and claims data of males with breast CA who received palbociclib, and several safety data sources (global safety database, two Phase 1 studies of palbociclib in males with other solid tumors, and FDA’s AE reporting system).
New dosing regimen: Cetuximab (Erbutix) was originally approved in 2000 for weekly administration for the treatment of Colorectal CA and Squamous Cell CA of Head and Neck. In 2021 a bi-weekly dosing regimen was approved based on RWD in CRC which showed consistent Overall Survival results for patients who received weekly or bi-weekly treatments, supported by pooled efficacy analyses from the literature for patients with the two types of cancer.
References:
1) Wedam, S. et al, FDA Approval Summary: Palbociclib for Male Patients with Metastatic Breast Cancer. Clin Cancer Res 26 (6): 1208–1212, 2020.
2) Feinberg, B.A., et al, Use of Real-World Evidence to Support FDA Approval of Oncology Drugs. Value Health, 23(10):1358–1365, 2020. https://doi.org/10.1016/j.jval.2020.06.006
3) FDA approves new dosing regimen for cetuximab