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A Comparison of Post-marketing Measures Imposed by Regulatory Agencies to Confirm the Tissue-Agnostic Approach
Jorn Mulder1, Odile C van Stuijvenberg1, Paula B van Hennik1
1Dutch Medicines Evaluation Board, Utrecht, Netherlands.
Abstract:
There are currently four anti-cancer medicinal products approved for a tissue-agnostic indication. This is an indication based on a common biological characteristic rather than the tissue of origin. To date, the regulatory experience with tissue-agnostic approvals is limited. Therefore, we compared decision-making aspects of the first tissue-agnostic approvals between the Food and Drug Administration (FDA), European Medicines Agency (EMA) and Pharmaceuticals and Medical Devices Agency (PMDA). Post-marketing measures (PMMs) related to the tissue-agnostic indication were of specific interest. The main data source was the publicly available review documents. The following data were collected: submission date, approval date, clinical trials and datasets, and PMMs. At the time of data collection, the FDA and PMDA approved pembrolizumab, larotrectinib, and entrectinib for a tissue-agnostic indication, while the EMA approved larotrectinib and entrectinib for a tissue-agnostic indication. There were differences in analysis sets (integrated vs. non-integrated), submission dates and requests for data updates between agencies. All agencies had outstanding issues that needed to be addressed in the post-market setting. For pembrolizumab, larotrectinib and entrectinib, the number of imposed PMMs varied between one and eight, with the FDA requesting the most PMMs compared to the other two agencies. All agencies requested at least one PMM per approval to address the remaining uncertainties related to the tissue-agnostic indication. The FDA and EMA requested data from ongoing and proposed trials, while the PMDA requested data from use-result surveys. Confirmation of benefit in the post-marketing setting is an important aspect of tissue-agnostic approvals, regardless of agency. Nonetheless, each approach to confirm benefit has its inherent limitations. Post-marketing data will be essential for the regulatory and clinical decisions-making of medicinal products with a tissue-agnostic indication.
Insights
Regulatory agencies worldwide have limited experience with tissue-agnostic approvals for cancer drugs. Post-marketing measures are crucial for confirming the benefit of these targeted therapies.
Area of Science:
- Oncology
- Regulatory Science
- Pharmacovigilance
Background:
- Tissue-agnostic drug approvals represent a paradigm shift in oncology, targeting common molecular alterations rather than specific tumor locations.
- Regulatory experience with this novel approval pathway remains limited, necessitating comparative analysis of agency decision-making processes.
Purpose of the Study:
- To compare the regulatory decision-making processes for the initial tissue-agnostic approvals of anti-cancer drugs across major global health authorities.
- To specifically analyze and contrast the post-marketing measures (PMMs) imposed by regulatory agencies for tissue-agnostic indications.
Main Methods:
- A comparative analysis of publicly available review documents from the Food and Drug Administration (FDA), European Medicines Agency (EMA), and Pharmaceuticals and Medical Devices Agency (PMDA).
- Data collected included submission and approval dates, clinical trial datasets, and details of post-marketing measures (PMMs) for approved tissue-agnostic therapies.
Main Results:
- Differences observed in analysis sets, submission timelines, and data update requests among the FDA, EMA, and PMDA.
- The number of PMMs varied from one to eight per drug, with the FDA imposing the highest number.
- All agencies required at least one PMM to address post-approval uncertainties, with varying data requirements (e.g., ongoing trials, use-result surveys).
Conclusions:
- Confirmation of therapeutic benefit in the post-marketing setting is a universal requirement for tissue-agnostic approvals, despite differing agency approaches.
- Each agency's method for confirming benefit has inherent limitations, highlighting the need for robust post-marketing data.
- Post-marketing data are critical for informing future regulatory and clinical decisions regarding tissue-agnostic therapies.
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