Stakeholders seek changes to FDA’s MDS drug development guidance

Stakeholders have asked the US Food and Drug Administration (FDA) to consider genetic markers and biomarkers when recruiting clinical trial participants to develop myelodysplastic syndromes (MDS) treatments. They also want the agency to allow patients with the human immunodeficiency virus (HIV) to participate in the studies and to consider the difficulty in recruiting children.

In July, FDA published a draft guidance detailing its thinking when developing MDS drugs and biologics. Several stakeholders have commented on the proposed guidance, stating that while they agree with the agency's objective, they want to see significant changes that can encourage MDS treatment development. (RELATED: FDA proposes clinical trial, endpoint considerations in MDS drug development guidance, Regulatory Focus 7 July 2025)

The proposed guidance states that sponsors should select clinical trial participants who are representative of the patient population. It includes details for specific groups such as children, older patients, patients with organ impairment, and pregnant patients. The American Society of Hematology (ASH) asked FDA to also recommend including HIV patients in MDS clinical trials.

"People living with HIV have increased cancer incidence and cardiovascular diseases compared to the general population; as such, this epidemiology needs to be better studied in the context of MDS trials," said ASH. "By excluding patients with well-controlled HIV, MDS clinical trials are selecting out these important populations that are reflective of the US real-world population."

ASH said that while it also agrees with FDA that children should be considered in the early clinical development stage, it is important to remember that the disease is rare in children and is often hypocellular. The group highlighted that finding children with MDS to include in clinical trials can be a challenge for researchers, and regulators should narrow their recommendations for including them.

"The Society recommends inclusion of pediatric MDS populations in cases of pediatric MDS that mimic adult disease with comparable genetic mutations and phenotypes," said ASH. "In such situations, it is critical that these pediatric patients be included in early phase trials to benefit from targeted therapies."

While overall survival (OS) may be the appropriate endpoint for most patients, AHS also asked FDA to consider allowing other clinically meaningful endpoints, including partial response (PR) or complete response (CR), or transfusion independence endpoints for children in some instances. The group also recommended convening stakeholders to discuss potential secondary and surrogate endpoints for developing MDS treatments.

"This is important because overall survival as a core primary endpoint may require large sample sizes and follow-ups over several years, which may limit the development of novel therapies and could be further confounded by cross over designs and sequential therapies being studied, especially for low risk MDS," ASH added.

Drugmaker Regeneron asked FDA to include genetic markers and biomarkers as factors to consider when researchers are recruiting patients for exploratory clinical trials. The company said the agency should recognize the ongoing advances in understanding how the markers may be used to identify potential trial participants.

“Genetic markers and biomarkers may complement or serve as alternatives to the more conventional disease risk classification based on other factors such as peripheral blood parameters, medullary blasts, and standard cytogenetics,” said Regeneron. “Including information in the guidance document about genetics and biomarkers will make recommendations in the guidance durable over time and will also help to facilitate development of new therapies that are targeted to patient populations identified by genetic characteristics or biomarkers.

“The identification of genetic markers or biomarkers that impact patient outcomes or disease progression are factors that should be considered in identifying appropriate patient populations for early phase studies,” the company added.

FDA defines MDS as "a heterogenous group of clonal hematologic disorders characterized by ineffective hematopoiesis, myeloid dysplasia, cytopenias, and potential transformation into acute myeloid leukemia (AML)." Furthermore, it notes that the International Agency for Research on Cancer uses morphological, clinical, and genomic parameters to classify the disease.

Servier Pharmaceuticals asked the FDA to update the scope and definition of the guidance to state that it only applies to treatments for patients who meet the most recent MDS diagnostic criteria, such as the disease's classification by the World Health Organization. The company notes that patients may progress to acute myeloid leukemia (AML), and sponsors should refer to a separate FDA guidance for AML in such cases to avoid confusion.

“Our suggestions retain the important biological context, such as risk of transformation, and clearly separate the scopes of different concepts to avoid endpoint confusion,” said Servier. “MDS and AML now carry different, FDA-endorsed primary endpoints (e.g., durable transfusion independence or OS for MDS vs. CR/CRh ± MRD, EFS or OS for AML).

“If the guidance implies it ‘applies to both,’ sponsors could misassign endpoints, power calculations and estimates, complicating review and post-hoc pooling,” the company added. “Directing baseline AML cases to the FDA’s final AML guidance (Oct 2022) preserves consistency and leverages the endpoint framework already accepted.”

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Stakeholders seek changes to FDA’s MDS drug development guidance

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