Drug makers usually put in rigorous efforts to fast-track and reduce the cost burden of regulatory decision-making by regulatory authorities like USFDA and EMA. As a part of these efforts, the interest in utilizing real-world evidence (RWE) for the approval process has considerably increased in the past few years.(1) Even though data from randomized controlled trials (RCTs) are still regarded as the standard for new drug evaluations, at times RCT findings may not be practicable. For instance, prospects of low patient enrollment (e.g., for rare diseases), high anticipated costs and resource needs, or ethical prohibition (e.g., the absence of an established standard of care [SoC] and unethical nature of an RCT).(2, 3) RCTs are also time and resource intensive, and over-dependence on RCTs may delay the entry of new effective treatments into the market. All these factors have resulted in the increasing usage of real-world data (RWD) to help address unmet medical needs and report the efficacy, tolerability, and care patterns of a given drug/device in real-life settings and populations.(3) In this context, it becomes important to understand the nuances of regulatory requirements surrounding RWD and RWE.

The USFDA guidance on submitting RWD and RWE for regulatory approval, published in December 2018, is useful for sponsors and applicants for regulatory submission. This guidance provides details about using RWE for safety and efficacy details for the purpose of regulatory decisions in submissions for investigational new drug applications (INDs), new drug applications (NDAs), and biologics license applications (BLAs).(4) Between January 2019 and June 2021, the USFDA has approved a total of 116 submissions out of 136 (85%) NDAs and BLAs, which included RWE.(5)

Traditionally, the role of RWE in the regulatory process has been relatively limited to supplementing existing approvals (e.g., for indication expansion). However, there are several recent examples of RWE applications in supporting new drug approvals, especially in the rare disease and oncology settings. Regulators in Europe and the USA have begun to establish frameworks and industry guidance on using RWE in regulatory submissions. Nonetheless, what constitutes ‘regulatory-grade’ RWD is still unclear. Moreover, there is a growing need for increased communication between regulatory bodies and those submitting data packages concerning what exactly is required from the RWD for the related evidence to inform their decisions.(3)

According to the International Council of Harmonization’s (ICH) strategic goals, a “structured template for planning and reporting on RWE study implementation” (STaRT-RWE) has been introduced for reporting of the safety and effectiveness of treatments in RWE studies. This template guides in designing and conducting consistent RWE studies; sets standards for transparency in RWE methods; enhances specificity; enables reviewers to adapt and find important information quickly; and expedites reproducibility, assessment of validity, and evidence generation. It is aimed to be used in the effectiveness and safety studies of medical products. It applies to multiple study designs, data sources, reporting recommendations, checklists, and bias assessment tools.(6)

RWE studies are multidisciplinary, multi-database, and collective in nature. Their conduct and design can be improved with clearer communication of vital details. The need of clear communication is relevant for common protocol studies that involve multiple group collaborations, where different interpretation by the different protocol executors can significantly influence results. Clear documentation of a research team’s intended parameters for the conduct of study can improve the communication within the multidisciplinary study team as well as between research teams and decision makers.(6)

More work is necessary to complement protocol and reporting standards for regulatory submissions and coverage decisions. This can include:

  • Reaching STaRT-RWE to a broader group of regulators and other stakeholders, including health technology assessment (HTA) agencies;
  • Creating training modules;
  • Using the template for protocols in study registries, such as EU-PASS or other governance processes;
  • Managing study registration sites to allow electronic uploading of the completed template when pre-registering an RWE study; and
  • Engaging with medical journal editors.

Feedback collected from this broad stakeholder group will then be critical to inform updates.(6)

RWE preparation for regulatory decision-making is subject to several challenges that are not only data-related but also operational and methodological. However, regulators realise the need to address these challenges. As a result, various initiatives are underway in Europe and the USA to develop innovative real-world study designs and endpoints and improve and standardise methods and statistical approaches.(3)

Become A Certified HEOR Professional – Enrol yourself here!


  1. Framework for FDA’s real-world evidence program. 2018. Available at: https://www.fda.gov/media/120060/download
  2. Martin L, et al. How much do clinical trials cost? Nat. Rev. Drug Discov 2017; 16(6):381-382.
  3. O’Donnell J, et al. Evolving use of real-world evidence in the regulatory process: a focus on immuno-oncology treatment and outcomes. Future Oncol 2021; 17(3):333-347.
  4. Submitting Documents Using Real-World Data and Real-World Evidence to FDA for Drugs and Biologics – Guidance for Industry. 2018. Available at: https://www.fda.gov/media/124795/download
  5. Rassen J. The role of RWE in FDA approvals. November 2021. Available at: https://www.ema.europa.eu/en/documents/presentation/presentation-role-rwe-fda-approvals-j-rassen_en.pdf
  6. Wang S, et al. STaRT-RWE: structured template for planning and reporting on the implementation of real world evidence studies. BMJ 2021; 372:m4856.

Related Posts