Approval Letter Other (Nov 13, 2025)

Summary

The FDA issued a Complete Response letter for NDA 022561 for cladribine tablets, indicating that the application cannot be approved in its current form. While cladribine was found effective for relapsing remitting multiple sclerosis (RRMS), significant safety concerns, particularly an increased risk of malignancy and lymphopenia, outweigh its benefits. The letter details specific deficiencies in clinical safety data, product quality, and labeling, requiring the applicant to provide additional analyses, studies, and information before resubmission.

Key points

• Provide an improved understanding of the malignancy risk through additional analyses or by conducting additional studies.
• Provide additional information on the methods used in calculating the standardized incidence ratios (SIRs) described in the Integrated Summary of Safety.
• Clarify whether risk factors for malignancy were documented in all study subjects and whether an imbalance in pre-existing risk factors has been documented in cladribine-treated subjects as compared to placebo-treated subjects.
• Provide additional information on the PREMIERE long-term prospective follow-up safety registry, including information to be collected and planned methods for analysis, specifically how expected rates of adverse events will be determined.
• Ascertain the time to resolution of lymphopenia in cladribine-treated subjects in the CLARITY study.
• Clarify and justify the intended maximum dosing duration of cladribine in clinical use.
• Submit analyses of malignancy risk and changes in hematologic laboratory measurements for the subgroup of patients with a history of taking disease-modifying drugs for multiple sclerosis.
• Submit analyses of malignancy risk stratified by age, especially for subjects over age 40.

Cited reasons

• Unacceptable Increased Risk of Malignancy
• Insufficient Understanding of Lymphopenia Resolution
• Vague Long-term Dosing Plans
• Need for Additional Safety Analyses for Specific Subgroups
• Insufficient Information on Additive Lymphocyte Effects with Concomitant Medications
• Unacceptable Dissolution Specification
• Carton and Container Labeling Revisions Required
• The application for cladribine Tablets cannot be approved in its present form due to significant safety concerns, primarily an unacceptable increased risk of malignancy associated with its use, which outweighs its demonstrated effectiveness for relapsing remitting multiple sclerosis. Additional deficiencies include insufficient understanding of lymphopenia resolution, vague long-term dosing plans, the need for further safety analyses in specific subgroups, inadequate information on potential drug-drug interactions affecting lymphocytes, an unacceptable dissolution specification, and required revisions to carton and container labeling.

Recommended actions

• Provide an improved understanding of the malignancy risk through additional analyses or by conducting additional studies.
• Provide additional information on the methods used in calculating the standardized incidence ratios (SIRs) described in the Integrated Summary of Safety.
• Clarify whether risk factors for malignancy were documented in all study subjects and whether an imbalance in pre-existing risk factors has been documented in cladribine-treated subjects as compared to placebo-treated subjects.
• Provide additional information on the PREMIERE long-term prospective follow-up safety registry, including information to be collected and planned methods for analysis, specifically how expected rates of adverse events will be determined.
• Ascertain the time to resolution of lymphopenia in cladribine-treated subjects in the CLARITY study.
• Clarify and justify the intended maximum dosing duration of cladribine in clinical use.
• Submit analyses of malignancy risk and changes in hematologic laboratory measurements for the subgroup of patients with a history of taking disease-modifying drugs for multiple sclerosis.
• Submit analyses of malignancy risk stratified by age, especially for subjects over age 40.

Deficiency summary

The application for cladribine Tablets cannot be approved in its present form due to significant safety concerns, primarily an unacceptable increased risk of malignancy associated with its use, which outweighs its demonstrated effectiveness for relapsing remitting multiple sclerosis. Additional deficiencies include insufficient understanding of lymphopenia resolution, vague long-term dosing plans, the need for further safety analyses in specific subgroups, inadequate information on potential drug-drug interactions affecting lymphocytes, an unacceptable dissolution specification, and required revisions to carton and container labeling.

Findings

Regulatory context

Submission stage

final decision

Regulatory pathway

NDA 505(b)

Impact

Impact score

0.95

Estimated delay

730 days

Estimated rework cost

$0

Subsequent action

resubmission

Strategic insights

The primary theme is the unacceptable safety risk of malignancy associated with cladribine, which outweighs its demonstrated effectiveness for RRMS, necessitating further extensive safety characterization and risk mitigation strategies before approval can be considered. Secondary themes include insufficient data on lymphopenia management, unclear long-term dosing, and minor product quality and labeling issues.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%