FDA proposes clinical trial, endpoint considerations in MDS drug development guidance

The US Food and Drug Administration (FDA) has issued draft guidance for sponsors of drugs and biologics intended to treat myelodysplastic syndromes (MDS). It outlines the agency’s thinking on requirements for developing MDS products, including considerations for clinical trial designs and efficacy endpoints.

“MDS are a heterogenous group of clonal hematologic disorders characterized by ineffective hematopoiesis, myeloid dysplasia, cytopenias, and potential transformation into acute myeloid leukemia (AML),” FDA explains in its draft guidance published 2 July.

“This guidance is specific to the development of drugs that are considered disease-modifying, and not drugs that are considered as supportive therapy (e.g., erythropoiesis-stimulating agents),” the agency added. “Furthermore, the guidance will not address drug development for MDS/myeloproliferative neoplasm overlap syndromes, such as chronic myelomonocytic leukemia, which are considered a separate class of myeloid neoplasms.”

The proposed guidance states that sponsors should select clinical trial participants representative of the patient population, and includes details for specific groups such as children, older patients, patients with organ impairment, and pregnant patients. It also details safety reporting considerations during the trials.

FDA notes that MDS patients may have underlying diseases that cause adverse events, and many MDS products intended to be myelosuppressive are also expected to have cytopenia complications. The agency said some preclinical studies may also show expected toxicities from using the MDS drug.

“Sponsors should inform FDA of the anticipated serious adverse events that the Sponsor does not plan to report individually in an expedited manner,” said the guidance. “An [investigational new drug (IND)] safety report must be submitted to FDA if an aggregate analysis indicates that the events are occurring more frequently in the investigational drug treatment group.”

“Although investigators are required to report all serious adverse events to the sponsor immediately, this requirement may be burdensome and not useful when several serious adverse events are expected at a high rate, such as might occur with the cytopenic complications of treatment of MDS,” the agency added. “Under such circumstances, sponsors may propose an alternative reporting arrangement for Investigators in the protocol or in a specific waiver request to FDA, and FDA will provide comment on whether the alternative reporting arrangement is acceptable.”

The guidance lays out FDA's thinking on the efficacy endpoints that sponsors should consider when developing MDS products. Some of the key issues to consider include time-to-event endpoints such as overall survival (OS) and event-free survival (EFS). It also details the agency's thinking on binary endpoints such as complete remission (CR) and partial remission (PR).

FDA also provides insights into other potential efficacy measures that sponsors can consider. While minimal residual disease (MRD) is not currently accepted as an established endpoint, the agency said it may be considered an endpoint in drugs that have proven durable CR in MDS patients as technology improves and a better understanding of the disease from new clinical findings.

“Key efficacy endpoints may also include well-defined and reliable patient-reported outcome measures,” said FDA. “When sponsors propose to use such measures as the basis of a claim for MDS drugs, such endpoints should be supported by data showing that the treatment also has a direct effect on the MDS.

“Furthermore, adequate enrollment of patients from the United States should be included for reliable interpretation of patient-reported outcome data,” the agency added.

The guidance also outlines FDA’s thinking on exploratory and confirmatory clinical trials. Throughout the guidance, the agency also heavily recommends sponsors look to other guidances to get more detail on its recommendations depending on the topic.

Stakeholders can comment on the draft guidance on www.regulations.gov under docket no. FDA-2025-D-0649 through 2 September.

Draft guidance

FDA proposes clinical trial, endpoint considerations in MDS drug development guidance

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