ICH/FDA Draft Guidance on RWD Safety Studies Highlight Their Increased Importance

The evaluation of drug safety is a critical aspect in the development and marketing of pharmaceutical therapies. Throughout the lifecycle of drug development, the safety of a novel therapy is continuously evaluated and monitored via early-phase randomized controlled trials (RCTs), regulatory-mandated pharmacovigilance commitments, and spontaneous reporting of post-marketing adverse events. Although RCTs provide the earliest insights into the safety profile of a drug and are considered the gold standard for evaluating safety, their limitations, including the short duration and highly restricted study population, often lead to an incomplete picture of a drug's safety profile. There is an increasing recognition of the importance of observational studies using real-world data (RWD) to generate real-world evidence (RWE) to assess drug safety. Despite their own limitations and complexities, RWD studies can help mitigate some of the drawbacks seen with RCTs. Their increasing importance is evidenced by recent decisions by the FDA to approve some drugs and medical procedures using results from RWD studies in addition to, or in place of, clinical trials.

FDA and Real-World Evidence

The FDA has a long history of using RWD/RWE to monitor and evaluate the post-market safety of approved drugs. Most recently, the agency contributed to a draft guidance document¹ released by an Expert Working Group (a team of experts appointed from Member and Observer organizations/countries to develop harmonized guidelines for selected technical topics) from the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) in July 2024, recommending international standards and outlining general principles on planning, designing, and analyzing noninterventional pharmacoepidemiologic studies on drug safety using RWD. Referencing over 30 global regulatory and non-regulatory guidelines, this guidance document is intended to streamline the methods of designing and implementing these studies and improve their chances of acceptance across various health authorities. Several important factors when conducting a safety study using RWD were highlighted, including:

• Formulating the research question/rationale and explaining the types of data available/required to answer the question
• Determining whether the identified data source(s) is suitable, and identifying the pros and cons of these sources
• Selecting the most appropriate study design to answer the research question
• Ensuring that the study population is representative of the target population for which the inference will be made
• Creating conceptual definitions of the exposure, outcome, and covariates, and determining the best way to develop these conceptual definitions into operational definitions that can extract the most complete/accurate data from the data source
• Anticipating and addressing any potential sources of bias and confounding
• Creating a plan of data management and/or data curation
• Describing the statistical analysis plan as well as any assumptions and conditions

UBC and RWD/RWE

UBC is globally recognized for generating RWE to support biopharma in all phases of the drug development process, with over 20 years of world-class observational research. Our expert, multi-disciplinary evidence generation teams have been pioneers in the use of diverse real-world data sources to obtain insights for better understanding characteristics of disease populations, treatment patterns, and especially in the assessment of drug safety. Importantly, many of the principles outlined in the ICH/FDA draft guidance have already been incorporated into UBC's processes and research practices. In addition to reinforcing our existing practices, the guidance offers further approaches that UBC will incorporate to generate reliable and meaningful evidence as UBC continues to support our clients' regulatory commitments to assess drug safety.

UBC routinely supports various pharmacovigilance and safety evaluation processes such as post-authorization safety studies (PASS) for post-marketing safety requirements, risk evaluation and mitigation strategies (REMS), and risk management plans (RMP).

For more information on UBC's comprehensive approach to drug safety, get in touch with us HERE.

About the Author

Samuel Igweokpala is an Associate Epidemiologist at UBC. He contributes to UBC's cross-functional expertise that powers the design and conduct of modernized observational studies using databases, registries, and patient medical charts. He also has a pharmacy degree and combines his pharmaceutical knowledge and epidemiology skills to support public health research.

References

1. U.S. Food & Drug Administration, M14 General Principles on Plan, Design and Analysis of Pharmacoepidemiological Studies That Utilize Real-World Data for Safety Assessment of Medicines, July 2024. Accessed 10 July 2024. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/m14-general-principles-plan-design-and-analysis-pharmacoepidemiological-studies-utilize-real-world

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