Clinically meaningful increases in blood pressure and cardiovascular risk
Severity: criticalJatenzo caused clinically meaningful increases in blood pressure, including a daytime average systolic blood pressure (SBP) increase of 5.0 mmHg, with larger increases in hypertensive subjects. This led to a higher rate of new or increased antihypertensive medication use compared to the comparator. The agency concluded these risks outweigh the benefits for many men due to increased risk of major cardiovascular adverse events.
Recommended response: Propose detailed strategies in labeling (Boxed Warning, Indication, Contraindication, Warnings and Precautions) and strategies beyond labeling, such as a Risk Evaluation and Mitigation Strategy (REMS) with elements to assure safe use, to mitigate risks and ensure a favorable benefit/risk profile.
Inaccurate and irreproducible total testosterone concentration measurements
Severity: majorThe proposed method of monitoring patients using total testosterone (T) concentrations from plasma in NaF/EDTA tubes is problematic. The extent to which NaF/EDTA tubes prevent TU to T ex vivo conversion is unknown, and observed differences between sample types may be due to varying temperatures and LC-MS/MS methods. Further investigation of ex vivo conversion and potential cross-reactivity of immunoassays with TU is warranted.
Recommended response: Conduct studies comparing T concentrations from serum in plain tubes and plasma in NaF/EDTA tubes under various conditions, prespecify acceptable overestimation, evaluate plasma without NaF, include bioanalytical method validation reports, ensure accurate and reliable T tests are available, and provide data on TU cross-reactivity with immunoassays. A new Phase 3 trial may be needed if accuracy cannot be confirmed.
Inadequate nonclinical studies for fertility and carcinogenicity
Severity: criticalThe submitted nonclinical studies are unacceptable. TU doses were inadequate to characterize chronic effects on male fertility and carcinogenicity, lacking sufficient exposure and toxicokinetic data. The 6-month carcinogenicity study in male Tg·rasH2 mice did not identify the maximally tolerated dose (MTD) and was insufficiently powered for one sex, failing to meet ICH guidance S1C(R2).
Recommended response: Provide justification for dose selection for the fertility study and conduct a new, adequately designed carcinogenicity study, submitting the protocol for review. Alternatively, classify the NDA as a 505(b)(2) application and provide appropriate nonclinical published literature references to address deficiencies.
