FDA Releases Draft Guidance for MDS Drug Development

This article was originally published on Targeted Oncology™.

The FDA has issued comprehensive draft guidance for the development of novel drugs and biologics targeting myelodysplastic syndromes (MDS).1

A cornerstone of the proposed guidance is the emphasis on robust clinical trial design and appropriate patient selection. | Image Credit: wladimir1804 - stock.adobe.com

This document, titled "Myelodysplastic Syndromes: Developing Drugs and Biological Products for Treatment," outlines the agency's current thinking on clinical trial design, patient selection, safety reporting, and efficacy end points for these complex hematologic disorders. The guidance is a critical resource for pharmaceutical sponsors, clinicians, and researchers involved in bringing new therapeutic options to patients with MDS.1,2

MDS represents a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective blood cell production (hematopoiesis), cellular abnormalities (myeloid dysplasia), low blood cell counts (cytopenias), and a significant risk of progression to acute myeloid leukemia. The FDA's draft guidance specifically addresses disease-modifying therapies, distinct from supportive care interventions such as erythropoiesis-stimulating agents and does not extend to drug development for MDS/myeloproliferative neoplasm overlap syndromes, like chronic myelomonocytic leukemia.

A cornerstone of the proposed guidance is the emphasis on robust clinical trial design and appropriate patient selection. Sponsors are advised to ensure study populations are representative of the diverse MDS patient landscape. This includes careful consideration for vulnerable populations such as pediatric patients, older adults, individuals with organ impairment, and pregnant patients, acknowledging the unique challenges and ethical considerations associated with including these groups in clinical research. The aim is to generate data that is broadly applicable to the real-world patient population.

Safety reporting is another key area addressed, recognizing the inherent complexities of managing adverse events (AEs) in MDS patients who often present with underlying comorbidities. The guidance acknowledges that many myelosuppressive MDS therapies are anticipated to induce cytopenic complications. To streamline reporting while maintaining regulatory oversight, the FDA suggests that sponsors may propose alternative arrangements for reporting anticipated serious adverse events that are not individually expedited.

However, an investigational new drug safety report remains mandatory if aggregate analysis reveals an increased frequency of events in the investigational drug arm compared with the control group. This pragmatic approach seeks to balance the need for comprehensive safety data with the operational burden on investigators, particularly when a high incidence of certain AEs is expected.

The guidance delves into the nuances of efficacy end points, offering detailed perspectives on both time-to-event and binary measures. Overall survival and event-free survival are highlighted as crucial time-to-event end points, providing direct measures of patient benefit and disease progression. For binary end points, complete remission (CR) and partial remission are emphasized as established measures of therapeutic response.

The FDA also acknowledges the evolving role of minimal residual disease (MRD) as a potential end point. While not yet a fully established primary end point in MDS, MRD may be considered for drugs demonstrating durable CR in these patients as advancements in technology and understanding of MDS pathogenesis continue to mature.

Furthermore, patient-reported outcome (PRO) measures are recognized as potentially critical efficacy end points, provided they are well defined, reliable, and demonstrably reflect a direct impact on MDS.

“While achievement of remission and improvement in survival remain standard end points in measuring the effectiveness of drugs for MDS, the palliation of symptoms or reduction in treatment burden may be considered meaningful in certain circumstances,” the guidance states.

The guidance stresses the importance of adequate enrollment of US patients to ensure the reliable interpretation and generalizability of PRO data.

Beyond specific end points, the draft guidance also addresses broader aspects of clinical development, including the design and execution of both exploratory and confirmatory clinical trials. This holistic approach underscores the FDA's commitment to fostering a clear and consistent regulatory environment for MDS drug development.

The release of this draft guidance represents a significant step forward in clarifying the regulatory expectations for MDS therapies, aiming to facilitate the development of more effective and safer treatments for patients battling these challenging blood disorders. Stakeholders within the pharmaceutical industry, clinical community, and patient advocacy groups are encouraged to provide comments on the draft guidance via www.regulations.gov under docket no. FDA-2025-D-0649, with a submission deadline of September 2, 2025.

References

1. Myelodysplastic syndromes: Developing drug and biological products for treatment. US FDA. July 2, 2025. Accessed July 8, 2025. https://tinyurl.com/22xb8zes

2. Al-Faruque F. FDA proposes clinical trial, endpoint considerations in MDS drug development guidance. News release. Regulatory Focus. July 7, 2025. Accessed July 8, 2025. https://tinyurl.com/26swthd4