New FDA Guidance Addresses the Need for Data-Generation Strategies Across the Drug Development Lifecycle

Over the past decade, there has been a proliferation of real-world data (RWD) sources that sponsors can use to generate real-world evidence (RWE) for a wide range of purposes across the product development lifecycle. In addition to traditional claims and administrative data, they now have access to even higher-quality patient-level and regulatory-grade data generated by healthcare systems. Legislation and regulatory guidances have also proliferated. The use of RWD and RWE in support of drug development and regulatory submissions has steadily gained traction globally, with regulatory agencies in the U.S., E.U., and Asia-Pacific promulgating guidance. For example, in late 2021, the U.S. Food & Drug Administration (FDA) issued a series of draft guidances for industry on aspects of RWD and RWE in regulatory decision-making. The FDA guidances released to date cover topics related to data sources, data standards, and regulatory considerations and are summarized in this article.

These FDA guidances are essential for understanding agency expectations when submitting applications for regulatory approval. The systematic prosecution of product lifecycle management requires a proactive early-engagement strategy for generating RWE and corresponding RWD strategy. Sponsors should have both.

The Diverse Value of RWE

RWD has historically been used to address evidence gaps to support market sizing, inform clinical development, augment regulatory submissions focusing on safety rather than efficacy, address payer requirements, and solve market access challenges. Randomized clinical trials (RCTs) remain the gold standard for clinical research to establish evidence for efficacy. However, there has been an increase in the number of NDA and BLA submissions augmented or supplemented with high-quality data RWD sources and RWE in support of efficacy evaluations. In a recent review of FDA approvals between January 1, 2019, and June 2021, authors reported that 116 approvals incorporated RWE in any form, with year-over-year increases in the proportion of applications, including RWE1. Among those 116 approvals, 76% included RWE studies providing supporting evidence for safety or effectiveness. Among those RWE studies, 74% influenced FDA decision-making, with 43% being referenced in the product label.

Thus, increased regulatory consideration of RWE in NDA/BLA submissions has been a key driver for the trend seen within pharmaceutical and biotechnology companies in establishing their own RWD/RWE functions or outsourcing their RWE generation needs to trusted third-party intermediaries. A drug development model that best incorporates all relevant available data can help sponsors make informed decisions and bring new therapies to patients in need more quickly. RWE can answer key questions in clinical research and promote a better understanding of patient experiences and outcomes. It can also help broaden the focus, better represent the patient population, and address clinical homogeneity and exclusion issues.

A Systematic Approach

Every company, regardless of size and scope, needs a roadmap to:

• Build the right business model or internal infrastructure that establishes a way to determine the best sources and ensure confidence in the reliability and integrity of the data
• Develop a strategy for proper data management, analysis, and governance to support effective utilization and collaboration
• Utilize technology most effectively within the context of data-privacy regulations in different regions of the world

Mapping a sound strategy requires a thorough understanding of data science and the technology tools and systems needed to develop the right infrastructure.

The Importance of Governance

Governance is critical for ensuring scientific integrity and data reliability. Processes and procedures must be in place to frame research questions, establish evidence objectives, and specify data collection methods. Additionally, processes and procedures must be in place for data curation, management, storage, access control, and to address availability to patients, researchers, and clinicians. Staff education and training on RWD best practices should be foremost in your planning initiatives.

Three Key Guidelines

Let’s take a look at the latest regulatory guidance. Three key guidelines from the U.S. Food & Drug Administration (FDA) address important aspects of the use of RWE in regulatory decision-making.

Assessing Electronic Health Records and Claims Data

Real-World Data: Assessing Electronic Health Records and Medical Claims Data to Support Regulatory Decision-Making for Drug and Biological Products, released in September 2021

This guidance was released in response to the mandate under the 21st Century Cures Act for a framework for evaluating the potential use of RWD relative to approval of a new indication for an already-approved drug. Specifically, it addresses considerations for the inclusion of data sources for research and regulatory purposes, including electronic health records (EHR) and insurance claims. These considerations encompass the relevance of the data source, data capture, information content, and missing data. Further, the guidance covers questions of maintaining data quality during accrual, curation, and transformation into the final study-specific data set.

Assessing Registries

Real-World Data: Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products Guidance for Industry, released in November 2021

Registries follow a standardized format for a predefined population and organize a specific type of health-related data for each patient. Registry data can be used to help determine sample size, selection criteria, and endpoints for an interventional study, for example, or to inform the design of an observational study. The data can also be used in both cases to identify biomarkers or clinical characteristics associated with relevant clinical outcomes.

Supplementing registries with other sources of RWD can be a useful means of filling in evidence gaps. For example, interlinked healthcare registries of aggregated data enable the identification of common characteristics of a disease and target populations and on-the-fly natural history studies, which can inform more efficient development paths.

The FDA also addresses the concept of a natural history study in the Rare Diseases: Natural History Studies for Drug Development | FDA. It covers the strengths and weaknesses of various types of natural history study designs, common data elements, and research plans. The draft also offers a framework for the conduct of such a study, including information on data collection, storage, dissemination, and human subject protections.

Using RWD and RWE in Regulatory Decision-Making

Considerations for the Use of Real-World Data and Real-World Evidence, released in December 2021

This guidance was published in response to a specific mandate under the 21-Century Cures Act regarding the applicability of the FDA’s IND regulation to various study designs using RWD. It also clarifies FDA expectations concerning clinical studies using RWE in support of the effectiveness and safety of a drug, focusing primarily on non-interventional clinical study designs. Crucially, the evidence submitted by a sponsor in a marketing application must satisfy the applicable legal standards for the application to be approved. This guidance covers transparency relative to data collection and analysis, data access and agreements with third parties, and study monitoring and safety reporting.

What’s Next? A Real-World Evidence Generation Roadmap for Corresponding RWD Strategy

As sponsors rethink long-held principles on clinical development, Parexel offers strong expertise and guidance. Parexel can support you in developing a roadmap for generating RWE and a corresponding RWD strategy to help you make crucial lifecycle decisions. We work with small and mid-sized biopharma companies, including those that lack specific expertise in this area and support internal teams needing additional support.

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^{1 Purpura CA, Garry EM, Honig N, Case A, Rassen JA. The Role of Real-World Evidence in FDA-Approved New Drug and Biologics License Applications. Clin Pharmacol Ther. 2022 Jan;111(1):135-144.}

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