An FDA analysis of clinical hold deficiencies affecting investigational new drug applications for oncology products.

A systematic analysis of new commercial investigational new drug applications (IND) submitted to the FDA's Office of Hematology and Oncology Products (OHOP) in the Center for Drug Evaluation and Research was conducted to quantify the most common reasons INDs for oncology indications go on clinical hold. In OHOP, less than 10% of INDs went on hold or were withdrawn within the 30-day safety review period. Of INDs that were placed on hold, deficiencies were mainly clinical, followed by concerns related to pharmaceutical quality and nonclinical development. INDs were also characterized based on phase of development, product type, sponsors' regulatory experience, and occurrence of a pre-IND meeting. INDs that were placed on hold were mostly for first-in-human trials or submitted by sponsors with limited regulatory experience. INDs that went on hold or were safe-to-proceed had pre-IND meetings with comparable rates but sponsors with substantial experience appeared to benefit more from pre-IND meetings compared to those with limited experience. The time interval between the pre-IND meeting and the IND submission was longer for INDs that went on hold. To obtain useful FDA feedback on product development, it is essential to provide focused questions and supporting information in pre-IND meeting packages.

FDA Approval: Palbociclib for the Treatment of Postmenopausal Patients with Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer.

On February 3, 2015, the FDA granted accelerated approval to palbociclib (IBRANCE, Pfizer Inc.), an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. The approval is based on a randomized, multicenter, open-label phase I/II trial (PALOMA-1) in 165 patients randomized to palbociclib (125 mg orally daily for 21 consecutive days, followed by 7 days off treatment) plus letrozole (2.5 mg orally daily) or letrozole alone. The phase II portion of the trial was divided into two cohorts: cohort 1 enrolled 66 biomarker-unselected patients and cohort 2 enrolled 99 biomarker-positive patients. The major efficacy outcome measure was investigator-assessed progression-free survival (PFS). A large magnitude of improvement in PFS was observed in patients receiving palbociclib plus letrozole compared with patients receiving letrozole alone (HR, 0.488; 95% confidence interval, 0.319-0.748). Multiple sensitivity analyses were supportive of clinical benefit. The most common adverse reaction in patients receiving palbociclib plus letrozole was neutropenia. This article summarizes the FDA thought process and data supporting accelerated approval based on PALOMA-1 that may be contingent upon verification and description of clinical benefit in the ongoing and fully accrued confirmatory trial PALOMA-2.