FDA Grants

The digital sharing and storage of medical claims and electronic health records has produced volumes of real-world data (RWD) that could advance the production of real-world evidence (RWE) to evaluate in silico the efficacy and safety of biosimilar products. Big-data analysis of RWD has not yet been leveraged in the regulatory evaluation of biosimilars because biosimilars are fairly new, past biosimilar research has focused on new products (and thus RWD was very limited), the quality of RWD for biosimilars has not been established, and no validated, standard set of analytic tools for RWE exist. For new biosimilars, RWD/RWE could be used as supplementary evidence to clinical trials, as an external control arm to interventional studies, or to narrow the scope or population to only that necessary for answering pertinent clinical and safety questions. There is a particular opportunity for RWD/RWE to supplement or supplant evidence needs around product switching to demonstrate biosimilar interchangeability. While clinical trials are considered the gold-standard for developing initial evidence, incorporating RWD/RWE offers evaluation of populations that are likely more reflective of the patients who are receiving the products in usual care and could be used to predict real-world outcomes more accurately. The use of RWD/RWE to improve the efficiency of clinical trials for biosimilar products will speed the development of new biosimilars, speed the process of granting the regulatory designation of interchangeability, and encourage more rapid uptake of biosimilars.

The lack of evidence on the quality of RWD and on the relevance of RWE for regulatory decision-making about biosimilars is a major obstacle to using big-data analyses of RWD/RWE for interchangeability evaluations. The question of RWD quality addresses the availability and completeness of RWD. The question of RWE relevance addresses the ability of RWE to capture meaningful clinical endpoints for use in biosimilar regulatory decisions, such as interchangeability. Previous work has demonstrated that RWD is reliable (ClinicalTrials.gov [NCT03259373]; FDA, 2021) for small molecule drugs or very narrow questions about biosimilars. A meta-analysis of RWE found that it is feasible to emulate clinical trials with RWE (Anglemyer et al., 2014). Our own preliminary work has determined that RWD/RWE can reliably identify cohorts and exposures of interest for conducting observational research with biosimilars; and, while there are known limitations to using claims data for research, we have also developed solutions and strategies to address many of those gaps (Lockhart et al. 2019, He et al. 2019, Zhang et al. 2019, Desai et al. 2019).

Our long-term goal is to advance the use of RWD/RWE in biosimilars by providing the research community with tools they can re-use for their own tests of interchangeability and other regulatory questions. The purpose of this study is to assess RWD/RWE and determine its potential to streamline the pre-market regulatory approval process for biosimilars. Our study will advance the development of interchangeable products by applying RWD/RWE to biosimilar development and developing new analytics for the interchangeability evaluation. This study will examine whether the current in silico data and methods are ready to use to improve the efficiency of clinical trials for biosimilar products or whether more work must be done to improve the quality and rigor of this new avenue for research before it can be applied in the biosimilar regulatory process. In the proposed study, we will:

Aim 1: Determine the quality of RWD and the relevance of RWE for biosimilars regulatory decision-making. We will conduct a literature review and convene an expert panel to measure availability and completeness of RWD. We will measure the availability—or ability to impute—clinically relevant endpoints to indicate the relevance of RWE.

Aim 2: Use RWD/RWE to emulate an FDA evaluation of interchangeability of a biosimilar drug. We will conduct a target trial emulation of a switching study using RWD/RWE from multiple deidentified datasets representing over 180 million patient lives. We will compare outcomes produced from the emulation to those obtained from the FDA’s evaluations of interchangeability of adalimumab.

Impact. These aims are expected to yield validated, re-usable tools and a replicable example for the use of RWD/RWE in a biosimilar regulatory study. Our findings will foster the use of RWD/RWE in the design and implementation of clinical trials to increase the efficiency of trials.

Update – December 2024: Activities related to Aim 1 are complete and reports are in preparation. We have at least two abstracts and two manuscripts planned or in preparation for Aim 1 work. A protocol is has been prepared for Aim 2 activities to conduct a trial emulation. We have selected pegfilgrastim used in patients with breast cancer as the test case.

We have presented three posters related to this work:

Pithua P, Djibo DA, DeFor T, Myers S, Lockhart CM. Evaluating the Feasibility of Claims Databases for Emulating Interchangeability and Switching Trials: A Multi-Therapeutic Evaluation of Originator Biologics and Biosimilars. Poster presentation at ISPOR Europe 2024, Barcelona, Spain, November 17-20, 2024.

Lockhart CM, Bosco J, Li E, Ling Y, McCabe D, McDermott CL, McMahill-Walraven CN, Roth J. The Potential of Real-World Data (RWD) for Informing FDA Biosimilar and Interchangeable Biosimilar Regulatory Decisions: Recommendations from a Multi-Stakeholder Expert Panel. Poster presentation at ISPOR Europe 2024, Barcelona, Spain, November 17-20, 2024.

Lockhart CM, Anyoha AN, McDermott CL. Use and potential of real-world data (RWD) and real-world evidence (RWE) to inform pre-market regulatory decisions: a scoping review. Poster presentation at ISPOR Europe 2023, Copenhagen, Denmark, November 12-15, 2023.

Protocol and Reports Status:

• Final Protocol
• Final Regulatory Assessment Report
• Expert Panel Report: Developing Draft for BBCIC Review

Manuscripts Status:

• Literature Review Manuscript: Under BBCIC Review
• Data Assessment Report: Developing Draft for BBCIC Review

Partners:

CVS Health, HealthPartners Institute, Pearldiver

Research Team:

• Principal Investigator: Cate Lockhart, PharmD, PhD, Executive Director, BBCIC 
• Steve Asche, HealthPartners Institute
• Jaclyn Bosco, PhD, MPH, Senior Director, Global Head, Epidemiology & Outcomes Research, IQVIA
• Tigwa Davis, Inovalon
• Teri DeFor, MS, HealthPartners Institute
• Mitch DeKoven, MHSA, Practice Leader – US Retrospective Research, IQVIA
• Audrey Djibo, PhD, Lead Epidemiologist, CVS Health Clinical Trial Services
• Adam Hoye-Simek, Devoted
• Argentina Servin, Global Biosimilar Lead, Amgen
• Ed Li, Head, HEOR and Oncology, Sandoz
• Sam Li, PhD, Assistant Professor, Health Outcomes and Policy Research, University of Tennessee
• Nancy Lin, ScD, Principal, Epidemiology and Drug Safety, Real World Evidence Solutions, IQVIA
• Jake Milliron, Inovalon
• Scott Myers, Senior Research Scientist, PearlDiver Technologies™
• Darren Toh, Harvard Pilgrim

To address the inefficiencies inherent in clinical biosimilar switching studies, observational methodologies hold promise as an alternative approach for demonstrating biosimilar interchangeability. If utilized to examine interchangeability, observational approaches could reduce or eliminate the need for clinical trials and expedite the approval and adoption of interchangeable biosimilars in the U.S. healthcare system, ultimately increasing access to therapy, controlling costs, and improving the quality of care for patients with chronic diseases.

Observational studies using real-world data (RWD) can be enhanced by using multiple databases, including databases from outside the United States (OUS). OUS data can add the experiences of a larger number of patients than a U.S.-data-only study. The wider range of patient demographics in OUS data could increase the generalizability of findings. Therefore, the use of OUS data can inform U.S. regulatory decisions for interchangeability, significantly improving the efficiency of approving interchangeable biologics.

To improve the efficiency of regulatory science in the United States, we propose to develop alternatives to clinical biosimilar switching studies. Our long-term goal is to develop tools and guidance for U.S. regulatory research to access OUS RWD for demonstrating interchangeability. The purpose of the proposed study is to determine the potential of OUS RWD to improve the power and generalizability of U.S. regulatory studies. In the proposed study, we will expand upon U.S. data sources with the addition of large, rich datasets from Italy and Denmark. Using harmonized data and a shared study protocol, we will use both U.S. and OUS RWD datasets to conduct a non-interventional retrospective cohort study, using a distributed dataset to emulate a clinical switching study. We will compare the results of those emulations among sites and with the target clinical trial. We will use a distributed data set; our raw data will not be pooled all together into a single database. The data stays under the control of the source and can satisfy different privacy and security policies. Only code analytical scripts and aggregate results will be shared between sites; the data itself will not be moved. Based on the results of our emulation and analyses, we will also develop practical recommendations for the U.S. Food and Drug Administration (FDA) on the future use of OUS RWD in regulatory decision-making.

The proposed study builds on the track record of our organization, the Biologics & Biosimilars Collective Intelligence Consortium, of advancing the field of RWD research and generating reliable evidence on the safety and effectiveness of biologics to improve public health. We will address the following specific aims:

Aim 1: Evaluate the feasibility and validity of a biosimilar interchangeability (e.g., switching) study using real-world data from the United States and sources from outside the United States. We will assess the quality (availability, completeness, and standardization) of RWD from two OUS sources. We will develop an ad hoc common data model to harmonize the data, identifying and addressing any barriers to harmonization. We will design and implement a shared protocol for the study and will select a clinical switching study of a biosimilar product as a target trial. We will design and conduct emulations of the target trial at US, Italian, and Danish sites, with each site using its own database to run the emulation. We will also conduct a detailed comparison of the results at each site to the other sites and with an existing study to validate the study’s findings.

Aim 2: Develop recommendations for the FDA on how to address the challenges of using real-world data from outside the United States in its regulatory decision-making processes. Based on learnings from Aim 1, we will propose guidance for the FDA to consider. The guidance will recommend strategies to address the unique challenges associated with collecting, standardizing, and validating real-world data from international sources.

Impact. Our study will show how using foreign RWD can significantly improve the efficiency of the FDA regulatory process, leading to increased adoption of safe and effective biosimilar products. This innovative approach could also serve as a model for using RWD from outside the U.S. in regulatory decision-making across different therapeutic areas. This study will help the FDA advance its mission of making safe and effective drugs available to patients.

Update – October 2024: We have completed an initial data assessment to evaluate data quality and completeness from each partner site, and a protocol is in development to design a switching study to be conducted at each site.

Partners:

University of Verona, University of Southern Denmark, PearlDiver

Research Team:

• Principal Investigator: Cate Lockhart, PharmD, PhD, Executive Director, BBCIC 
• Chiara Bellitto, University of Verona
• Jesper Hallas, University of Southern Denmark
• Ylenia Ingrasciotta, University of Verona
• Morten Olesen, University of Southern Denmark
• Giorgia Pellegrini, University of Verona
• Mette Reilev, University of Southern Denmark
• Julie Rudbech Krumborg, University of Southern Denmark
• Andrea Spini, University of Verona
• Gianluca Trifirò, University of Verona