ABSTRACT Digital health technologies can support remote acquisition of clinical investigation data and may facilitate more flexible clinical trial designs. In March 2023, FDA revised Forms FDA 1571 and FDA 356h to include a structured yes/no field asking whether a submission contains DHT data or a proposal to collect DHT data. This change created a mechanism for identifying submissions involving DHT‐based remote data acquisition. Following implementation of these fields, the Office of Medical Policy in FDA's Center for Drug Evaluation and Research developed and implemented a systematic process to track, identify, and adjudicate DHT‐related submissions. This analytical report presents a descriptive, aggregated, de‐identified analysis of submissions that were flagged through this operational process from March 2023 through December 2025. Operational inclusion criteria were applied to identify submissions involving DHTs used for remote data acquisition intended to support regulatory decision‐making. Of 2318 flagged submissions, 277 (12%) were confirmed for inclusion in this analysis. Confirmed submissions were predominantly associated with investigational applications (237/277, 86%). When classified by the nature of data collected, submissions reflected a range of remote data acquisition approaches, including patient reported data and sensor‐based measurements, with some submissions combining more than one modality. Electronic diary and electronic patient‐reported outcomes were most common, exclusively appearing in 161 submissions (58%), followed by data captured from general objective sensors in 92 submissions (33%) and continuous glucose monitoring data in 24 submissions (9%). These findings establish a quantitative baseline for DHT‐based remote data acquisition in CDER submissions and the implementation of FDA's corresponding guidance.
ABSTRACT MK‐1942 is a negative allosteric modulator of the metabotropic glutamate receptor 2 that was investigated for the treatment of Alzheimer's disease and depression. Nonclinical studies with recombinant human CYPs and genotyped human hepatocytes suggested that CYP2C19 is involved in the metabolism of MK‐1942. Given the high incidence of different CYP2C19 polymorphisms in the Japanese population, a Phase 1 single and multiple dose study in healthy Japanese participants provided an opportunity to determine the involvement of CYP2C19 phenotype on the clinical PK of MK‐1942. Also, since a first‐in‐human study in non‐Japanese showed a decrease in exposures after administration with high‐fat meal, we further tested an effect of low‐fat meal on PK in the Japan study. The study was designed with flexibility which enabled dose selection for the multiple dose panels, based on the totality of safety and PK data. Oral administration of single and multiple doses of MK‐1942 in Japanese participants was generally well tolerated. AUC 0‐inf was comparable between fasted and fed (low‐fat meal) state. Following a single dose of MK‐1942, AUC 0‐inf was ~70% increased in CYP2C19 poor metabolizer (PM) vs. extensive metabolizer (EM). Therefore, a decision was made to test the multiple dose separately for each CYP2C19 phenotype, rather than grouping them into a single panel. As opposed to the expectation from the single dose result, steady state exposures were similar among CYP2C19 phenotypes. These data supported the subsequent global Phase 2 study to permit a low‐fat meal around dosing and no dose adjustment for any CYP2C19 phenotype.
ABSTRACT Brain metastases (BMs) represent a major clinical challenge due to their high incidence in cancers such as non‐small cell lung cancer (NSCLC) and breast cancer, and the limited efficacy of systemic therapies resulting from inadequate drug penetration across the blood–brain barrier. Although several brain‐penetrant tyrosine kinase inhibitors (TKIs) have been developed, the quantitative relationship between intracranial drug exposure and intracranial clinical response has not been well established, leaving an important gap in dose selection strategies. In this study, we systematically evaluated the intracranial exposure‐response relationship across brain‐penetrant small‐molecule TKIs. Fourteen TKIs were identified based on guideline‐recommended therapies for BMs. For each drug, plasma and cerebrospinal fluid (CSF) pharmacokinetic profiles were simulated using published population pharmacokinetic models, with CSF exposures extrapolated using known unbound plasma fractions and CSF‐to‐plasma unbound concentration ratios ( K p,uu,CSF ) in humans. Key intracranial exposure metrics, including the CSF steady‐state trough and average concentrations relative to IC 50 ( C min,ss /IC 50 and C ave,ss /IC 50 ) and the percentage of the steady‐state dosing interval during which CSF concentrations remained above IC 50 (T% > IC 50 ), were derived and correlated with intracranial outcomes from published clinical studies. Overall, significant positive correlations were observed between intracranial exposure metrics and both intracranial objective response rate (ORR) and complete response rate (CR). Greater exposure coverage above IC 50 was associated with improved intracranial efficacy. This work demonstrates a positive intracranial exposure‐response relationship across brain‐penetrant TKIs and provides a quantitative benchmark to inform dose selection beyond traditional plasma exposure metrics. These findings highlight the importance of achieving sufficient CNS drug concentrations to optimize the therapeutic effect in patients with BMs.
ABSTRACT To advance drug product development, regulatory decision making, and improve patient care, FDA has committed to the quantitative medicine paradigm that involves, among others, quantitative in silico methodologies and tools developed based on nonclinical, clinical, and real‐world sources. In this Perspective, Model Master File (MMF) submissions as Type V Drug Master Files (DMF) are discussed as a path towards this commitment.
ABSTRACT Fruquintinib is a highly selective, oral inhibitor of all three vascular endothelial growth factor receptors (‐1, ‐2, and ‐3) that was approved, including in China, the United States, and the European Union, for the treatment of previously treated metastatic colorectal cancer (mCRC). The efficacy of fruquintinib for mCRC has been consistently demonstrated in randomized, double‐blind, Phase 3 clinical studies, including FRESCO (NCT02314819), which enrolled patients in China, and FRESCO‐2 (NCT04322539), which enrolled patients across 14 countries in North America, Europe, Asia, and Australia. In both studies, patients were randomized 2:1 to receive oral fruquintinib 5 mg or a matching placebo once daily, 3 weeks on, 1 week off, in 28‐day cycles, plus best supportive care, until progression or unacceptable toxicity. Both FRESCO and FRESCO‐2 met their primary endpoints, demonstrating significant improvements in overall survival (OS) with fruquintinib versus placebo: in FRESCO (fruquintinib: n = 278; placebo: n = 138), median OS was 9.3 with fruquintinib versus 6.6 months with placebo (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.51–0.83; p < 0.001); in FRESCO‐2 (fruquintinib: n = 461; placebo: n = 230), median OS was 7.4 with fruquintinib versus 4.8 months with placebo (HR, 0.66; 95% CI, 0.55–0.80; p < 0.001). The most common any‐grade treatment‐emergent adverse events with fruquintinib (incidence ≥ 20% in either study, excluding laboratory abnormalities) were hypertension, palmar‐plantar erythrodysesthesia, proteinuria, dysphonia, diarrhea, asthenia, decreased appetite, hypothyroidism, and fatigue. This mini‐review summarizes the mechanism of action, pharmacokinetics, key clinical trials, and clinical efficacy and safety data for fruquintinib.
