FDA Issues Draft Guidance on Developing Drug and Biological Products for MDS

The FDA has published draft guidance for sponsors in the clinical development of disease-modifying drugs for the treatment of myelodysplastic syndromes (MDS).

The document reflects the FDA’s recommendations for drug development, clinical trial designs, efficacy end points, and marketing applications for regulatory submissions to support an indication for the treatment of MDS.

General Drug Development Considerations

First, the FDA outlined general drug development considerations, including representation in clinical trials. Clinical trials should be representative of the US population, and the pharmacokinetics, pharmacodynamics, efficacy, and safety data should be applicable to patients with different ethnic and racial backgrounds. In addition, the FDA encourages sponsors to address pediatric patients early in the development plan for a drug, enroll adolescent patients with adults in clinical trials, represent older patients (65 years or older), and include pregnant patients after a thorough benefit-risk evaluation.

Efficacy End Points

The FDA provided definitions for common clinical trial efficacy end points in MDS. Complete remission (CR) is defined by marrow blasts greater than 5%, hemoglobin concentration less than 11 g/dL, platelet count greater than 100 × Gi/L, absolute neutrophil count greater than 1 Gi/L, absence of leukemic blasts in the peripheral blood as determined by morphologic examination, and responses that last for 4 weeks or more. Overall survival is defined as the time from randomization to the date of death, and the duration of CR is defined as the time from CR to relapse or death.

The FDA also determined that event-free survival and measurable residual disease (MRD) are not established clinical benefit end points for MDS. However, durable transfusion independence is an acceptable end point, as well as red blood cell transfusion independence in patients with lower-risk MDS.

“However, as technologies improve and new clinical findings emerge, MRD may be considered as supporting evidence of efficacy for new drugs that have demonstrated durable CR in patients with MDS,” the FDA wrote.

“I think the guidance, especially for high-risk MDS, did not incorporate some of the most recent patient centric end points such as the International Working Group [IWG] 2023 criteria which emphasized count recovery,” Amer Zeidan, MBBS, of Yale Cancer Center, told Blood Cancers Today. “There are responses that are close to complete response that are clinically meaningful because they involve recovery in the neutrophils, platelets, and hemoglobin, so there’s less of a chance of infection, bleeding, and less anemia symptoms.”

These responses have been shown to correlate with long-term outcomes in retrospective analyses, Dr. Zeidan explained.

“This is a draft guidance, and I’m hoping that it would be revised to emphasize IWG 2023 criteria, which I think are more clinically meaningful than the 2006 criteria that the guidance was based on for high-risk MDS,” he added.

Trial Considerations

The draft guidance also provides considerations for first-in-human, exploratory, and confirmatory trials in MDS. The FDA recommends avoiding first-in-human trials in patients with lower-risk MDS, a population with a longer life expectancy, for myelosuppressive or genotoxic drugs. In addition, these trials should be limited to one drug at a time rather than a combination regimen.

Dose-escalation trials should include patients whose disease has not responded to approved drugs, and sponsors should use nonclinical data to determine the slope of the dosage-toxicity curve, the anticipated dose range, and the maximal treatment exposure. The goal of dose-escalation trials is to determine the recommended phase 2 dose based on safety, tolerability, pharmacokinetic, pharmacodynamic, and efficacy data. However, because these trials have a limited sample size, varying drug dosages should be evaluated early in clinical development beyond the initial dose-escalation phase, the FDA noted.

To maintain patient safety, sponsors should include “stopping rules” for excessive toxicity in the expansion cohort plan of dose-escalating trials. For patients with higher-risk MDS, these rules may include treatment-related deaths, prolonged neutropenia or thrombocytopenia lasting more than 28 days, and high-grade nonhematologic adverse reactions.

For confirmatory trials, the drug dosage should be optimized before trial initiation, and tolerability should be considered when choosing a dose for long-term drugs administered for multiple cycles. Dose modification and discontinuations due to adverse reactions should be limited to less than 20% of patients.

To support the proposed recommended dosing regimen when submitting a marketing application, sponsors should include pharmacokinetic and exposure-response analyses for efficacy, safety, and pharmacodynamic biomarkers.

For confirmatory trials designed to support a marketing application, sponsors should enroll patients in the same risk group. However, enrollment across risk groups may be justified for targeted treatment based on early phase trial results.

In comparison trials, the FDA also maintains that the control arm should include the standard of care  and that “add-on” standard of care should be implemented when a placebo is used as a control. A blinded design should also be used to prevent bias.