Clinical Researcher—February 2025 (Volume 39, Issue 1)

RULES & REGULATIONS

Reid D’Amico

 

 

 

Real-world evidence (RWE) and externally controlled trials (ECTs) play increasingly critical roles in achieving marketing authorizations for drugs undergoing research and development, but sponsors must navigate a diverse body of regulatory guidance documents to prepare for successful regulatory engagements. While each application to the U.S. Food and Drug Administration (FDA) is specific and necessitates its own tailored approach, some key learnings for evidence planning have emerged that can help sponsors with managing expectations and enhancing real-world study execution.

Externally Controlled Trials Overview

As discussed in a recent white paper on “Best Practices for RWD/RWE Used in Regulatory Filings: Key Takeaways for Successful Regulatory Engagements,” ECTs should be strategically employed in specific contexts, such as trials of diseases with high and predictable mortality or progressive morbidity, or when conducting a randomized controlled trial may be ethically challenging.{1}

Key considerations for ECTs:

• Strategic use: Employ ECTs in situations where the natural history of the disease is well defined and the external control population closely mirrors the treatment group.
• Bias mitigation: Address potential biases, such as lack of randomization, selection bias, and confounding bias, during the design and implementation of ECTs.
• Regulatory alignment: Engage with the FDA early and align on the use of RWE for regulatory submissions for an ECT prior to the initiation of the single-arm trial.

ECTs can be a powerful tool in regulatory submissions, particularly in cases where traditional randomized controlled trials are not feasible. However, they come with their own set of challenges, including around bias and comparability. Sponsors must carefully design their ECTs to address these issues and ensure that the FDA is aligned with their approach from the outset. The following three best practices may be leveraged to assist the execution and acceptability of ECTs: early engagement, design robustness, and data quality.

Best Practice 1: Early Engagement

Early engagement with the FDA is paramount for successful regulatory submissions involving RWE. Sponsors should consult and ensure alignment with the FDA on study design and data management. This includes providing a clear rationale for the data source(s) intended to be used, the method of data collection, and the study design methodology.

Key steps for early engagement:

• Initial consultation: Engage with the FDA early to discuss the intended use of RWE in regulatory submissions. This should include the rationale for the data source and the study design concept.
• Feasibility assessments: Conduct feasibility assessments on all potential data sources and share the results with the FDA. Justify the final data source selection based on these assessments.
• Iterative process: Maintain ongoing communication with the FDA throughout the study design and execution phases. This iterative process ensures that the study design and data management plans are aligned with expectations.

Early engagement is not a one-time event but an ongoing dialogue. Sponsors should be prepared to discuss their study design, data sources, and methodologies in detail. This includes providing a comprehensive feasibility assessment of all potential data sources and justifying the final selection. The goal is to ensure that the FDA is fully informed and aligned with the sponsor’s approach from the outset.

Best Practice 2: Design Robustness

Ensuring the acceptability and robustness of the study design is crucial to prevent RWE from being excluded from regulatory review. Sponsors should engage with the FDA during the design phase to ensure that the data selection and study design meet the expectations.

Key considerations for design:

• Data selection: Provide a rationale for the selection of appropriate exposure and outcome variables. Consider whether these variables have been routinely used or are novel.
• Validation: Validate surrogate variables (e.g., for exposure or outcomes) prior to the initiation of the study. This validation should be conducted to ensure the variables are appropriate and reliable.
• Analytical approach: Demonstrate thoughtfulness in the analytical approach and study population selection. Ensure comparability of comparator groups prior to the modeling phase and engage with the FDA on the main analysis.

The robustness of the study design is critical for the acceptance of RWE in regulatory submissions. Sponsors should provide a clear rationale for their data selection and ensure that all variables are validated and reliable. The analytical approach should be well thought out, with a focus on ensuring comparability between comparator groups. Engaging with the FDA on these aspects early in the process can help prevent issues later on.

Best Practice 3: Data Quality

Applications containing data from non-interventional studies intended to support regulatory decision-making must follow several data quality guidelines regarding the design, conduct, and oversight of the study.

Key aspects of data quality:

• Compliance with study documents: Ensure compliance with final study documents, including the protocol and statistical analysis plan.
• Study monitoring: Implement appropriate study monitoring where applicable, particularly for additional data collection.
• Traceability and verification: Maintain traceability of study records and ensure that the FDA can access and verify study records. This includes maintaining a log of researchers involved in the study design and conduct.
• Data transformation: Transform data according to FDA standards, such as Clinical Data Interchange Standards Consortium formats, to ensure that the data are compliant and reliable.

Data quality is a cornerstone of successful regulatory submissions. Sponsors must ensure that their study documents are compliant with FDA guidelines and that appropriate monitoring is in place. Traceability and verification of study records are essential, as is the transformation of data into compliant formats. These steps help ensure that the data are reliable and can be easily reviewed by the FDA.

Real-World Case Studies: Lessons from the Field

Several marketing authorization applications have successfully incorporated RWE, providing valuable lessons for future submissions. Here are a few notable examples, as well as a look at a case where authorization was denied:

Lumakras® (sotorasib)

Amgen’s application for Lumakras (sotorasib) for the treatment of KRAS G12C-mutated non-small cell lung cancer (NSCLC) is a prime example of successful RWE use. Amgen conducted three retrospective cohort studies to characterize the patient population and outcomes, using data from the Flatiron Health Foundation Medicine Clinico-genomic Database and the American Association of Cancer Research Project GENIE database. The FDA found the studies to be well aligned with their understanding and provided a positive recommendation for accelerated approval.{2}

Key learnings:

• Use multiple data sources to characterize the patient population.
• Ensure data are fit-for-purpose and address unmet needs.
• Address methodological and statistical considerations, such as immortal time bias.

Vijoice® (alpelisib)

Novartis’s application for Vijoice (alpelisib) for PIK3CA-related overgrowth spectrum (PROS) utilized a retrospective single-arm cohort study. The study demonstrated compliance with FDA Good Clinical Practice standards and provided robust data that met the statutory evidentiary standards for accelerated approval.{3}

Key learnings:

• Engage early with the FDA to ensure alignment on study design and data selection.
• Use objective and appropriate endpoints.
• Ensure compliance with FDA Good Clinical Practice standards and be inspection-ready.

Prograf® (tacrolimus)

Astellas’s application for an expanded indication of Prograf (tacrolimus) for lung transplant recipients used RWE from the Scientific Registry for Transplant Recipients and historical controls from literature review. The FDA found the study to meet regulatory requirements and provided a positive review.{4}

Key learnings:

• Align early with the FDA on the suitability of RWE.
• Use national registry data for complete-case ascertainment.
• Supplement RWE with confirmatory evidence from previously approved indications.

Omblastys® (omburtamab)

Y-mAbs’s application for Omblastys (omburtamab) for neuroblastoma with central nervous system/leptomeningeal metastases faced challenges due to issues with the single-arm trial design and the external control arm. The FDA raised concerns about the use of time-to-event outcomes and the comparability of the control arm, ultimately leading to a negative recommendation.{5}

Key learnings:

• Ensure early alignment with the FDA and address regulatory recommendations.
• Demonstrate comparability of trial and control arms.
• Select appropriate outcomes for ECTs.

Conclusion

The successful use of RWE, including data from ECTs, in regulatory submissions requires careful planning, early and ongoing engagement with regulatory agencies, and adherence to data quality and study design standards. By following these best practices, sponsors can enhance their regulatory interactions and improve the chances of successful marketing authorization submissions.

The collective body of FDA guidance documents and case studies highlight six key themes for sponsors to consider in the adoption of RWE for regulatory submissions to the FDA when using RWE for substantial evidence. Focusing on these key points will help sponsors achieve regulatory acceptance:

1. Early engagement: Engage with the FDA early and often to ensure alignment on the intended use of RWE.
2. Fit-for-purpose data: Conduct thorough feasibility assessments, fit-for-purpose evaluations, and select data sources that are best suited to answer the research question.
3. Prespecified protocols: Ensure that study protocols and analysis plans are completed prior to the initiation of analysis to avoid preferential selection of results.
4. Patient-level data: Provide patient-level data in compliant formats to facilitate FDA review and analysis.
5. Internal validity: Implement rigorous methodologies to identify and mitigate biases, ensuring the internal validity of the study.
6. Data reliability: Demonstrate data accuracy, completeness, provenance, and traceability, and be prepared for potential audits.

By adhering to these best practices, sponsors can effectively navigate the regulatory landscape and leverage RWE to support their submissions. The journey to regulatory acceptance is a collaborative one, requiring ongoing dialogue and alignment with regulatory agencies. With careful planning and execution, RWE and ECTs can play a pivotal role in bringing new treatments to market and improving patient outcomes.

References

1. Cantoni C, Aggarwal S, Vitanova K, Raizada M, D’Amico R. 2024. Best Practices for RWD/RWE Used in Regulatory Filings: Key Takeaways for Successful Regulatory Engagements. IQVIA. https://www.iqvia.com/library/white-papers/best-practices-for-rwd-rwe-used-in-regulatory-filings
2. Sotorasib FDA Review. 2021. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/214665Orig1s000MultidisciplineR.pdf
3. Alpelisib FDA Approval. 2021. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2022/215039Orig1s000ltr.pdf
4. Tacrolimus FDA Review. 2021. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/050708Orig1s053;%20050709Orig1s045;%20210115Orig1s005.pdf
5. Omburtamab FDA Briefing Document. 2022. https://www.fda.gov/media/162614/download

Reid D’Amico, PhD, is the Principal and Co-Leader of IQVIA’s Regulatory Science and Strategy Team. Prior to IQVIA, he was a Life Sciences and Regulatory Specialist Master at Deloitte, managing teams addressing complex scientific and regulatory issues for the FDA’s Oncology Center of Excellence. He also served as a Biomedical Engineer Fellow at the FDA’s Center for Devices and Radiological Health, advising on policy and technical matters.