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Background A nivolumab dosage regimen of 480mg intravenously (i.v.) every 4weeks (Q4W) was approved by FDA for the majority of the approved indications for nivolumab. Methods The proposed new dosage regimen was supported by pharmacokinetic modeling and simulation, dose/exposure–response relationships for efficacy and safety in the indicated patient populations, and the clinical safety data with the 480mg Q4W dosage regimen. Pharmacokinetic exposures achieved with 480mg Q4W were predicted for 4166 patients in 21 clinical studies with various types of solid and hematological tumors. Exposure–response analyses were conducted to predict 480mg Q4W safety and efficacy across all FDA-approved indications for nivolumab. Results For the overall population, the geometric mean exposure achieved with 480mg i.v. Q4W was 5.2% higher for steady state Cavg and 15.6% lower for Ctrough than those with 3mg/kg i.v. Q2W, the approved dosage regimen. The simulated concentration–time course achieved with 480mg Q4W regimen was below the median concentration achieved with 10mg/kg i.v. Q2W that was also studied in clinical trials. The predicted probability of adverse events was similar between 480mg Q4W and that observed with the 3mg/kg Q2W regimen. Efficacy results were found to be similar between Q2W and Q3W dosage regimens in patients with renal cell carcinoma. The predicted efficacy for each indication suggested that the efficacy with 480mg Q4W is unlikely to be compromised compared with that observed with 3mg/kg Q2W. Conclusions The model-informed analyses of predicted exposure, efficacy and safety based on data from extensive clinical experience with nivolumab suggest that the benefit–risk profile of 480mg Q4W regimen is comparable to the approved 3mg/kg Q2W regimen, thus providing the regulatory basis for the approval of 480mg Q4W regimen in the absence of clinical efficacy data with this new dosage regimen.

Pembrolizumab is a monoclonal antibody that targets the programmed death-1 receptor to induce immune-mediated clearance (CL) of tumor cells. Originally approved by the US Food and Drug Administration in 2014 for treating patients with unresectable or metastatic melanoma, pembrolizumab is now also used to treat patients with non-small-cell lung cancer, classical Hodgkin lymphoma, head and neck cancer, and urothelial cancer. This paper describes the recently identified feature of pembrolizumab pharmacokinetics, the time-dependent or time-varying CL. Overall results indicate that CL decreases over the treatment period of a typical patient in a pattern well described by a sigmoidal function of time with three parameters: the maximum proportion change in CL from baseline (approximately Imax or exactly eImax − 1), the time to reach Imax/2 (TI50), and a Hill coefficient. Best overall response per response evaluation criteria in solid tumor category was found to be associated with the magnitude of Imax.

With the growing focus on translational research and the use of biomarkers to drive drug development and approvals, biomarkers have become a significant area of research within the pharmaceutical industry. However, until the US Food and Drug Administration’s (FDA) 2013 draft guidance on bioanalytical method validation included consideration of biomarker assays using LC-MS and LBA, those assays were created, validated, and used without standards of performance. This lack of expectations resulted in the FDA receiving data from assays of varying quality in support of efficacy and safety claims. The AAPS Crystal City VI (CC VI) Workshop in 2015 was held as the first forum for industry-FDA discussion around the general issues of biomarker measurements (e.g., endogenous levels) and specific technology strengths and weaknesses. The 2-day workshop served to develop a common understanding among the industrial scientific community of the issues around biomarkers, informed the FDA of the current state of the science, and will serve as a basis for further dialogue as experience with biomarkers expands with both groups.

BACKGROUND: Renal impairment (RI) is a common complication in patients with multiple myeloma (MM). Effective myeloma treatment can lead to reduction in urinary light-chain excretion and reversibility of RI. Our pooled analysis assessed the magnitude of improvement in renal function (RF) in patients with newly diagnosed (ND) or relapsed and/or refractory (RR) MM treated with novel agent induction therapies, including 3 immunomodulators, 3 proteasome inhibitors, 1 histone deacetylase inhibitor, 1 XP01 inhibitor and 2 monoclonal antibodies. METHODS: Seventeen registrational trials with 34 treatment arms that collected time profiles of RF during treatment with novel agent induction therapies in 3569 patients with NDMM and 7786 patients with RRMM at baseline were identified from various new drug applications submitted to the US FDA. Change in estimated glomerular filtration rate (eGFR, as estimated by Modification of Diet in Renal Disease formula) compared to baseline was summarized for each therapy. RESULTS: Increase in eGFR was observed in patients with MM and each category of RI (mild [eGFR 60 - Table 1:Improvement in eGFR in patients with MM and RI during the treatment of novel agent induction therapies between Month 3 and 6 as compared to baseline.PatientsTherapyMean (SD) increase in eGFR (mL/min/1.73 m2)% of patients with improvement in eGFR by at least 1 categoryRRMM (N=7786)Monotherapy A8.8 (15.3)33%Monotherapy B-1.5 (10.4)10%Monotherapy C5.9 (13.9)25%Combination D7.7 (15.4)30%Combination E8.9 (17.2)30%Combination F8.1 (14.9)33%Combination G7.6 (14.6)28%Combination H9.5 (16.1)34%Combination I6.5 (14.0)28%Combination J7.4 (14.6)27%Combination K7.6 (14.8)28%Combination L6.4 (12.0)17%Combination M3.1 (14.5)13%Combination N11.2 (17.1)38%NDMM (N-3569)Combination D7.8 (16.4)32%Combination J7.6 (16.0)29%Combination O6.0 (15.2)28%Combination P10.1 (16.7)38%Combination Q10.4 (17.5)37%Combination R11.5 (17.7)38% CONCLUSIONS: During the treatment with novel agent induction therapies for MM, frequent assessment of RF is needed in patients with RI to guide the proper dosing regimen. Citation Format: Liang Li, Shuai Hu, Hao Zhu, Yaning Wang, Lian Ma, Brian P. Booth, Nam Atiqur Rahman, Janice Schwartz, Gideon Blumenthal, Qi Liu. Improvement in renal function in patients with multiple myeloma and impaired renal function receiving novel agent induction therapies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 587.

Adequate dose selection for targeted oncology drugs can result in better efficacy and minimize the risk for toxicities that lead to high rates of treatment discontinuation and dose reductions. Less than optimal dose selection, in many cases, is likely due to tolerability-driven dose selection that was developed for cytotoxic chemotherapy drugs as far back as the early 1940s. This chapter addresses the following topics: (1) discusses the importance of optimal dose selection from the perspectives of different stakeholders, (2) highlights current dose selection approaches for targeted oncology drugs, and (3) provides proposed approaches for optimal dose selection. A few case studies are provided at the end of the chapter to highlight the different issues discussed in the main text.

Future of Medical Imaging Mark Nadeski and Gene Frantz Ultrahigh-Speed Real-Time Multidimensional Optical Coherence Tomography Kang Zhang and Jin U. Kang Molecular Imaging True Color Spectroscopic (METRiCS) Optical Coherence Tomography Adam Wax and Francisco E. Robles Spatial and Spectral Resolution of Semiconductor Detectors in Medical Imaging Bjorn Heismann Design and Assessment Principles of Semiconductor Flat-Panel Detector-Based X-Ray Micro-CT Systems for Small-Animal Imaging A. Sisniega, J.J. Vaquero, and M. Desco Dual-Energy CT Imaging with Fast-kVp Switching Baojun Li Four-Dimensional Computed Tomography Tinsu Pan Image Reconstruction Algorithms for X-Ray CT Ken Taguchi Portable High-Frequency Ultrasound Imaging System Design and Hardware Considerations Insoo Kim, Hyunsoo Kim, Flavio Griggio, Richard L. Tutwiler, Thomas N. Jackson, Susan Trolier-McKinstry, and Kyusun Choi Recent Advances in Capacitive Micromachined Ultrasonic Transducer Imaging Systems Albert I.H. Chen, Lawrence L.P. Wong, and John T.W. Yeow PET Detectors Alberto Del Guerra and Nicola Belcari Recent Developments of High-Performance PET Detectors Hao Peng and Craig S. Levin CT-SPECT/CT-PET R. Glenn Wells Multimodality Imaging with MR/PET and MR/SPECT Troy H. Farncombe Reducing Respiratory Artifacts in Thoracic PET/CT Greta S.P. Mok, Tao Sun, and Chi Liu Image Reconstruction for 3D PET Jinyi Qi Tracer Kinetic Analysis for PET and SPECT Jae Sung Lee and Dong Soo Lee Multicoil Parallel MRI Angshul Majumdar and Rabab Ward Brain Connectivity Mapping and Analysis Using Diffusion MRI Brian G. Booth and Ghassan Hamarneh T1rho MR Imaging: Principle, Technology, and Application Jing Yuan and Yi-Xiang J. Wang Brain Connectivity Assessed with Functional MRI Aiping Liu, Junning Li, Martin J. McKeown, and Z. Jane Wang Medical Image Registration: A Review Lisa Tang and Ghassan Hamarneh Medical Image Segmentation: Energy Minimization and Deformable Models Chris McIntosh and Ghassan Hamarneh Index

In September 2013, the FDA released a draft revision of the Bioanalytical Method Validation (BMV) Guidance, which included a number of changes to the expectations for bioanalysis, most notably the inclusion of biomarker assays and data. To provide a forum for an open, inclusive discussion of the revised draft BMV Guidance, the AAPS and FDA once again collaborated to convene a two-and-a-half day workshop during early December 2013 in Baltimore, MD, USA. The resulting format embodied extensive open discussion and each thematic session included only brief, concise descriptions by Agency and industry representatives prior to opening the floor discussion. The Workshop was built around four thematic sessions (Common Topics, Chromatographic, Ligand-Binding Assays, and Biomarkers) and a final session with international regulators, concluding with a review of the outcomes and recommendations from the thematic sessions. This Workshop report summarizes the outcomes and includes topics of agreement, those where the FDA will consider the Industry's perspective, and those where the workshop provided a first open dialogue. This article will be available to the bioanalytical community at http://www.aaps.org/BMV13 .

Nivolumab is a human monoclonal antibody that blocks the interaction between PD-1 programmed death-1 (PD-1) and its ligands, PD-L1 and PD-L2. Nivolumab demonstrated efficacy in clinical trials for various types of cancer. A time-varying clearance was identified for nivolumab. We show that the change of clearance over time is associated with the post-treatment effects: clearance decreases when disease status improves. This interaction between posttreatment effects and drug exposure may lead to a biased steep estimate of the exposure-response (E-R) relationship for efficacy. Under this scenario, simulations were performed to develop a proposed methodology to assess the causal effect of drug exposure upon clinical response. Data from nivolumab trials were subsequently used to verify the proposed methodology for E-R analysis. The results showed that E-R analysis results based on pharmacokinetic (PK) metrics derived from the first dose are more consistent with the true E-R or dose-response relationship than the steady-state PK metrics.

2569 Background: ICIs (anti-PD-L1/PD-1/CTLA-4) are approved in multiple cancers. The impact of organ dys on the pharmacokinetics of ICIs is known, but associated clinical outcomes are not well characterized. We compared real-world (rw) clinical outcomes in ICI-treated pts by liver and renal function. Methods: This retrospective study used longitudinal, patient-level data from community practices in the Flatiron Health electronic-health record (EHR)-derived database. We included pts diagnosed with advanced cancers (NSCLC, renal cell, melanoma, gastric/esophageal, or head and neck) on or after 1/1/2011, treated with an ICI with follow-up through 12/31/2018 and with baseline liver or renal function results in the EHR ≤30 days prior to ICI start. Organ function was stratified as normal, mild, moderate, or severe dys based on NCI CTCAE. We computed unadjusted median estimates for rw time to treatment discontinuation (rwTTD) for any reason and overall survival (OS) across baseline groups using the Kaplan-Meier method. Results: Of 15,979 pts, we identified 12,978/12,840 pts with evaluable renal/liver function, respectively; median follow-up was 5.1 mos and median age was 69.0 yrs (IQR: 61.0, 76.0) for both. Most pts had NSCLC (69.4/69.0%), were men (60.1/60.0%), white (73.5/73.6%), and diagnosed at stage IV (58.7%/58.6%). Most ICI was given in 1st-line (42.3/42.1%) (outcomes in Table). Conclusions: Pts with categorically worse baseline liver function had progressively worse on-treatment outcomes, including shorter OS, which differed from trends in renal dys. Whether baseline dys is prognostic or predictive of ICI outcomes should be further investigated in addition to reasons for discontinuation. Clinical outcomes (unadjusted median times, mos [95% CI]) by organ function. [Table: see text]

To reduce the bias introduced by confounding risk factors, a case-control comparison was incorporated in the exposure-response (ER) analysis to evaluate the recommended dosing regimen for trastuzumab in a pivotal trial. Results of Kaplan-Meier survival analysis suggest that patients with metastatic gastric cancer (mGC) in the lowest quartile trough concentrations of trastuzumab in cycle 1 (C(min 1) ) had shorter overall survival (OS) than did those in other quartiles. The result of the case-matched control comparison suggests that adjusting for these risk factors, patients with the lowest quartile of trastuzumab exposure did not benefit from addition of trastuzumab treatment to chemotherapy. The identified subgroup without survival benefit and the ER relationship support the recommendation on conducting clinical trials to identify a treatment regimen with greater exposure and acceptable safety profiles and to prospectively evaluate whether this treatment regimen will result in survival benefit for the identified subgroup.

There has been increased interest in optimizing dosing regimens for oncology products over the past decade. Investigations to refine dosing regimens often occur after new drug approval. There is growing focus on the use of exposure-response (ER) approaches to identify optimal dosing regimens for therapeutic biologics. Herein, we describe several recent observations that have informed our thinking on the use of ER analyses in the dose regimen optimization of therapeutic biologics developed to treat cancer.

On April 6, 2011, the U.S. Food and Drug Administration approved vandetanib (Caprelsa tablets; AstraZeneca Pharmaceuticals LP) for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable, locally advanced, or metastatic disease. Vandetanib is the first drug approved for this indication, and this article focuses on the basis of approval. Approval was based on the results of a double-blind trial conducted in patients with medullary thyroid carcinoma. Patients were randomized 2:1 to vandetanib, 300 mg/d orally (n = 231), or to placebo (n = 100). The primary objective was demonstration of improvement in progression-free survival (PFS) with vandetanib compared with placebo. Other endpoints included evaluation of overall survival and objective response rate. The PFS analysis showed a marked improvement for patients randomized to vandetanib (hazard ratio = 0.35; 95% confidence interval, 0.24–0.53; P < 0.0001). The objective response rate for the vandetanib arm was 44% compared with 1% for the placebo arm. The most common grade 3 and 4 toxicities (>5%) were diarrhea and/or colitis, hypertension and hypertensive crisis, fatigue, hypocalcemia, rash, and corrected QT interval (QTc) prolongation. This approval was based on a statistically significant and clinically meaningful improvement in PFS. Given the toxicity profile, which includes prolongation of the QT interval and sudden death, only prescribers and pharmacies certified through the vandetanib Risk Evaluation Mitigation Strategy Program are able to prescribe and dispense vandetanib. Treatment-related risks should be taken into account when considering the use of vandetanib in patients with indolent, asymptomatic, or slowly progressing disease. Clin Cancer Res; 18(14); 3722–30. ©2012 AACR.

Background Rivaroxaban is an oral Factor Xa inhibitor. The primary objective of this communication was to quantitatively predict changes in rivaroxaban exposure when individuals with varying degrees of renal impairment are co-administered with another drug that is both a P-gp and a moderate CYP3A4 inhibitor. Methods A physiologically based pharmacokinetic (PBPK) model was developed to simulate rivaroxaban pharmacokinetics in young (20–45 years) or older (55–65 years) subjects with normal renal function, mild, moderate and severe renal impairment, with or without concomitant use of the combined P-gp and moderate CYP3A4 inhibitor, erythromycin. Results The simulations indicate that combined factors (i.e., renal impairment and the use of erythromycin) have a greater impact on rivaroxaban exposure than expected when the impact of these factors are considered individually. Compared with normal young subjects taking rivaroxaban, concurrent mild, moderate or severe renal impairment plus erythromycin resulted in 1.9-, 2.4- or 2.6-fold increase in exposure, respectively in young subjects; and 2.5-, 2.9- or 3.0-fold increase in exposure in older subjects. Conclusions These simulations suggest that a drug–drug–disease interaction is possible, which may significantly increase rivaroxaban exposure and increase bleeding risk. These simulations render more mechanistic insights as to the possible outcomes and allow one to reach a decision to add cautionary language to the approved product labeling for rivaroxaban. Copyright © 2012 John Wiley & Sons, Ltd.

Four non-small-cell lung cancer (NSCLC) registration trials were utilized to develop models linking survival to risk factors and changes in tumor size during treatment. The purpose was to leverage existing quantitative knowledge to facilitate future development of anti-NSCLC drugs. Eleven risk factors were screened using a Cox model. A mixed exponential decay and linear growth model was utilized for modeling tumor size. Survival times were described in a parametric model. Eastern Cooperative Oncology Group (ECOG) score and baseline tumor size were consistent prognostic factors of survival. Tumor size was well described by the mixed model. The parametric survival model includes ECOG score, baseline tumor size, and week 8 tumor size change as predictors of survival duration. The change in tumor size at week 8 allows early assessment of the activity of an experimental regimen. The survival model and the tumor model will be beneficial for early screening of candidate drugs, simulating NSCLC trials, and optimizing trial designs.

To describe the U.S. Food and Drug Administration (FDA) review and approval of sorafenib (Nexavar; Bayer Pharmaceuticals Corp., Montville, NJ, and Onyx Pharmaceuticals Corp., Emeryville, CA), an oral kinase inhibitor, for the treatment of patients with unresectable hepatocellular carcinoma (HCC).The FDA independently analyzed an international, double-blind, placebo-controlled trial comparing the effect of best supportive care plus sorafenib or matching placebo on overall survival. Eligible patients had unresectable, biopsy-proven HCC and had not received prior systemic therapy.Among the 602 randomized patients (placebo, 303; sorafenib, 299), baseline characteristics were well balanced, and 97% were Child-Pugh score A. HCC was "advanced" in 70% overall, as defined by extrahepatic metastases or by tumor radiographically visible in venous structures outside the liver. Underlying liver diseases included hepatitis B (18%), hepatitis C (28%), and alcohol-related (26%). The trial was stopped following a prespecified second interim analysis showing a statistically significant survival advantage for sorafenib [median, 10.7 vs 7.9 months; hazard ratio, 0.69 (95% confidence interval, (0.55, 0.87)), p = 0.00058]. Adverse events in sorafenib-treated patients included diarrhea in 55% (grade 3, 10%), hand-foot syndrome in 21% (grade 3, 8%), rash in 19% (grade 3, 1%), and cardiac ischemia or infarction in 2.7% (versus 1.3% for placebo). On sorafenib, treatment-emergent hypertension occurred in 9% of patients (placebo, 4%) and was grade 3 in 4% (placebo, 1%); elevated serum lipase occurred in 40% (placebo, 37%); hypophosphatemia occurred in 35% (placebo, 11%).Sorafenib is the first systemic therapy to demonstrate a survival benefit in a randomized trial for unresectable HCC and has received FDA approval for this indication.

Purpose: To describe the Food and Drug Administration (FDA) review and approval of sunitinib malate (Sutent). Sunitinib received regular approval for the treatment of gastrointestinal stromal tumor (GIST) after disease progression or intolerance to imatinib mesylate (Gleevec). Additionally, sunitinib received accelerated approval for the treatment of advanced renal cell carcinoma. Experimental Design: For the GIST indication, FDA reviewed data from a randomized, placebo-controlled trial with supportive evidence from a single-arm study. For the advanced renal cell carcinoma indication, FDA reviewed data from two single-arm studies of patients with cytokine-refractory metastatic renal cell carcinoma. Results: In patients with imatinib refractory or intolerant GIST, time-to-tumor progression of sunitinib-treated patients was superior to that of placebo-treated patients. Median time-to-tumor progression of sunitinib-treated patients was 27.3 weeks, compared with 6.4 weeks for placebo-treated patients (P < 0.0001). Partial responses were observed in 6.8% of sunitinib-treated patients. In patients with metastatic renal cell carcinoma, partial responses were observed in 25.5% (95% confidence interval, 17.5, 34.9) and 36.5% (95% confidence interval, 24.7, 49.6) of patients treated with sunitinib. Median response durations were 27.1 and 54 weeks. The most common adverse events attributed to sunitinib included diarrhea, mucositis, skin abnormalities, and altered taste. Reductions in left ventricular ejection fraction and severe hypertension were also more common in sunitinib-treated patients. Conclusions: On January 26, 2006, the FDA approved sunitinib for the treatment of patients with imatinib refractory or intolerant GIST. Accelerated approval was granted for the treatment of advanced renal cell carcinoma.

Purpose: To describe the clinical studies, chemistry manufacturing and controls, and clinical pharmacology and toxicology that led to Food and Drug Administration approval of nelarabine (Arranon) for the treatment of T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma. Experimental Design: Two phase 2 trials, one conducted in pediatric patients and the other in adult patients, were reviewed. The i.v. dose and schedule of nelarabine in the pediatric and adult studies was 650 mg/m2/d daily for 5 days and 1,500 mg/m2 on days 1, 3, and 5, respectively. Treatments were repeated every 21 days. Study end points were the rates of complete response (CR) and CR with incomplete hematologic or bone marrow recovery (CR*). Results: The pediatric efficacy population consisted of 39 patients who had relapsed or had been refractory to two or more induction regimens. CR to nelarabine treatment was observed in 5 (13%) patients and CR+CR* was observed in 9 (23%) patients. The adult efficacy population consisted of 28 patients. CR to nelarabine treatment was observed in 5 (18%) patients and CR+CR* was observed in 6 (21%) patients. Neurologic toxicity was dose limiting for both pediatric and adult patients. Other severe toxicities included laboratory abnormalities in pediatric patients and gastrointestinal and pulmonary toxicities in adults. Conclusions: On October 28, 2005, the Food and Drug Administration granted accelerated approval for nelarabine for treatment of patients with relapsed or refractory T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma after at least two prior regimens. This use is based on the induction of CRs. The applicant will conduct postmarketing clinical trials to show clinical benefit (e.g., survival prolongation).

Purpose: To describe the Food and Drug Administration (FDA) review and approval of erlotinib (Tarceva, OSI Pharmaceuticals, Melville, NY) for treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen. Experimental Design: The FDA reviewed raw data in electronic format from a randomized controlled clinical trial comparing erlotinib with placebo in patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. Results: Patients were randomized in a 2:1 ratio (erlotinib, n = 488 and placebo, n = 243). Erlotinib was superior to placebo for survival, progression-free survival, and tumor response rate. Exploratory analyses indicate that epidermal growth factor receptor status may be an important predictor of the erlotinib survival effect. Rash (75% versus 17%) and diarrhea (54% versus 18%) in the erlotnib and placebo group respectively were the most common adverse events. Severe rash occurred in 9% and severe diarrhea in 6% of erlotinib-treated patients and each resulted in study discontinuation in 1% of patients. Dose reductions were required for 10% of patients with rash and 4% of patients with diarrhea. Conclusions: On November 18, 2004, the FDA granted erlotinib regular approval for treatment of patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. The applicant has committed to conduct post-marketing clinical trials to assess further the effect of epidermal growth factor receptor expression, measured with immunohistochemical staining, on erlotinib treatment effect.

The value of quantitative thinking in drug development and regulatory review is increasingly being appreciated. Modeling and simulation of data pertaining to pharmacokinetic, pharmacodynamic, and disease progression is often referred to as the pharmacometrics analyses. The objective of the current report is to assess the role of pharmacometrics at the US Food and Drug Administration (FDA) in making drug approval and labeling decisions. The New Drug Applications (NDAs) submitted between 2000 and 2004 to the Cardio-renal, Oncology, and Neuropharmacology drug products divisions were surveyed. For those NDA reviews that included a pharmacometrics consultation, the clinical pharmacology scientists ranked the impact on the regulatory decision(s). Of about a total of 244 NDAs, 42 included a pharmacometrics component. Review of NDAs involved independent, quantitative evaluation by FDA pharmacometricians, even when such analysis was not conducted by the sponsor. Pharmacometric analyses were pivotal in regulatory decision making in more than half of the 42 NDAs. Of the 14 reviews that were pivotal to approval related decisions, 5 identified the need for additional trials, whereas 6 reduced the burden of conducting additional trials. Collaboration among the FDA clinical pharmacology, medical, and statistical reviewers and effective communication with the sponsors was critical for the impact to occur. The survey and the case studies emphasize the need for early interaction between the FDA and sponsors to plan the development more efficiently by appreciating the regulatory expectations better.

Exposure-response (E-R) analyses for ado-trastuzumab emtansine (T-DM1, Kadcyla) were performed using data from a randomized, active control (lapatinib plus capecitabine) trial in patients with human epidermal growth factor 2-positive metastatic breast cancer. Kaplan-Meier survival analyses stratified by T-DM1 trough concentration on day 21 of cycle 1 (Cmin,C1D21) were performed for overall survival (OS) and progression-free survival (PFS). E-R analyses indicated that after adjusting for baseline risk factors, higher T-DM1 exposure is associated with improved efficacy. T-DM1-treated patients with Cmin,C1D21 lower than the median value had values of OS and PFS comparable to those of the active control arm. The percentage of patients who received T-DM1 dose adjustments was similar across the exposure range and was lower than that of the active control arm. Our findings suggest that there may be an opportunity to optimize Kadcyla dose in the patient subgroup with low T-DM1 exposure for improved efficacy with acceptable tolerability.

In the 2012 AAPS metabolites in safety testing (MIST) symposium held in Chicago, IL, USA, on October 15, 2012, regulatory experts and industrial scientists joined together to discuss their perspectives and strategies in addressing contemporary MIST recommendations (FDA 2008, International Conference on Harmonization (ICH) M3(R2), ICH M(R2) Q&A). Overall, these regulatory guidances indicate that metabolites identified in human plasma should circulate at similar or greater concentrations in at least one of the animal species used in nonclinical safety assessment of the parent drug. However, synthetic standards for the metabolites often do not exist or they are intractable to synthesize, thus introducing multiple challenges in drug development for the quantitative comparison of metabolites between human and animals. A tiered bioanalytical strategy for metabolite analysis is a prevalent approach to demonstrate coverage in animals. Recent developments in bioanalytical methodology have yielded several time- and resource-sparing strategies to provide fit-for-purpose approaches that can enable critical decisions related to metabolite quantification and monitoring in plasma. This report summarizes the presentations and panel discussions at the symposium.

e14121Background: On July 24, 2015, FDA approved Odomzo (sonidegib) for the treatment of patients with locally advanced basal cell carcinoma. At the recommended dose of 200mg once daily, 68% of pat...

Physiologically based pharmacokinetic (PBPK) modeling and simulation is a tool that can help predict the pharmacokinetics of drugs in humans and evaluate the effects of intrinsic (e.g., organ dysfunction, age, genetics) and extrinsic (e.g., drug-drug interactions) factors, alone or in combinations, on drug exposure. The use of this tool is increasing at all stages of the drug development process. This report reviews recent instances of the use of PBPK in decision-making during regulatory review. The examples are based on Center for Drug Evaluation and Research reviews of several submissions for investigational new drugs (INDs) and new drug applications (NDAs) received between July 2008 and June 2010. The use of PBPK modeling and simulation facilitated the following types of decisions: the need to conduct specific clinical pharmacology studies, specific study designs, and appropriate labeling language. The report also discusses the challenges encountered when PBPK modeling and simulation were used in these cases and recommends approaches to facilitating full utilization of this tool.

Purpose: On December 15, 2008, the US Food and Drug Administration approved plerixafor (Mozobil®; Genzyme Corp.), a new small-molecule inhibitor of the CXCR4 chemokine receptor, for use in combination with granulocyte colony-stimulating factor (G-CSF) to mobilize hematopoietic stem cells (HSC) to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM). This summary reviews the database supporting this approval. Experimental Design: The safety and efficacy of plerixafor were demonstrated by 2 multicenter, randomized, placebo-controlled studies in patients with NHL and MM who were eligible for autologous HSC transplantation. The primary efficacy end points were the collection of ≧5 × 106 CD34+ cells/kg from the peripheral blood in 4 or fewer apheresis sessions in patients with NHL or ≧6 × 106 CD34+ cells/kg from the peripheral blood in 2 or fewer apheresis sessions in patients with MM. Results: The 2 randomized studies combined enrolled 600 patients (298 with NHL and 302 with MM). Fifty-nine percent of patients with NHL who were mobilized with G-CSF and plerixafor had peripheral blood HSC collections of ≧5 × 106 CD34+ cells/kg in 4 or fewer apheresis sessions, compared with 20% of patients with NHL who were mobilized with G-CSF and placebo (p < 0.001). Seventy-two percent of patients with MM who were mobilized with Mozobil and G-CSF had peripheral blood HSC collections of ≧6 × 106 CD34+ cells/kg in 2 or fewer apheresis sessions, compared with 34% of patients with MM who were mobilized with placebo and G-CSF (p < 0.001). Common adverse reactions included diarrhea, nausea, vomiting, flatulence, injection site reactions, fatigue, arthralgia, headache, dizziness, and insomnia. Conclusions: This report describes the Food and Drug Administration review supporting the approval of plerixafor.

Purpose. Lenalidomide (CC-5013, Revlimid®; Celgene Corporation, Summit, NJ), a thalidomide analogue, was granted approval by the U.S. Food and Drug Administration (FDA) on June 29, 2006, for use in combination with dexamethasone in patients with multiple myeloma (MM) who have received at least one prior therapy. The FDA approved lenalidomide with a restricted distribution program, RevAssist®. Experimental Design. In two randomized, double-blind, multicenter studies, the combination of lenalidomide and dexamethasone (LD) was compared with placebo and dexamethasone (PD) in patients with MM who had received at least one prior therapy. The primary endpoint was time to progression (TTP). Results. Following a prespecified interim analysis of TTP, an independent data-monitoring committee advised the sponsor to halt the two studies. For both studies, the interim analysis for efficacy revealed a statistically significant longer TTP with LD than with PD. The most clinically relevant grade 3 and 4 adverse events that occurred more frequently in the LD arm were neutropenia, thrombocytopenia, deep vein thrombosis, pulmonary embolism, and atrial fibrillation. Thrombotic or thromboembolic events, including deep vein thrombosis, pulmonary embolism, thrombosis, and intracranial venous sinus thrombosis were reported more frequently in patients treated with LD than with PD. Conclusions. The FDA approved lenalidomide based on interim results from two multicenter, placebo-controlled, randomized trials comparing the combination of LD with PD that revealed a longer TTP with LD than with PD. The major toxicity observed during these trials was myelosuppression. The serious toxicities included thromboembolic events. Lenalidomide is only available under the RevAssist® Program.

Purpose: This Food and Drug Administration (FDA) approval report describes the data and analyses leading to the approval by the FDA of nilotinib (Tasigna, AMN-107; Novartis Pharmaceuticals Corporation), an inhibitor of Bcr-Abl tyrosine kinase, for the treatment of chronic-phase (CP) and accelerated-phase (AP) chronic myelogenous leukemia (CML) resistant to or intolerant of imatinib. Experimental Design: The FDA approval of the efficacy and safety of nilotinib was based on the results of an ongoing single-arm, open-label, phase 2 clinical trial. The primary end point for CML-CP was unconfirmed major cytogenetic response. The efficacy end point for CML-AP was confirmed hematologic response. Results: The major cytogenetic response rate in 232 evaluable CP patients was 40% (95% confidence interval, 33%, 46%). The hematologic response rate in 105 evaluable AP patients was 26% (95% confidence interval, 18%, 35%). The median duration of response has not been reached for both CML-CP and CML-AP responding patients. In CML-CP patients, the common serious drug-related adverse reactions were thrombocytopenia and neutropenia. In CML-AP patients, the common serious drug-related adverse reactions were thrombocytopenia, neutropenia, pneumonia, febrile neutropenia, leukopenia, intracranial hemorrhage, elevated lipase, and pyrexia. Nilotinib prolongs the QT interval and sudden deaths have been reported; these risks and appropriate risk minimization strategies are described in a boxed warning on the labeling. Conclusions: On October 29, 2007, the U.S. FDA granted accelerated approval to nilotinib (Tasigna) for use in the treatment of CP and AP Philadelphia chromosome positive CML in adult patients resistant to or intolerant of prior therapy that included imatinib.

Purpose: To describe the considerations leading to marketing approval of ixabepilone in combination with capecitabine and as monotherapy for the treatment of advanced breast cancer that is refractory to other chemotherapies. Experimental Design: Data from one randomized multicenter trial comparing combination therapy with ixabepilone and capecitabine to capecitabine alone were analyzed for support of the combination therapy indication. For monotherapy, a single-arm trial of ixabepilone was analyzed. Supporting data came from an additional single-arm combination therapy study and two single-arm monotherapy studies. Results: In patients with metastatic or locally advanced breast cancer who had disease progression on or following an anthracycline and a taxane, ixabepilone plus capecitabine showed an improvement in progression-free survival compared with capecitabine alone {median progression-free survival, 5.7 [95% confidence interval (95% CI), 4.8-6.7] versus 4.1 (95% CI, 3.1-4.3) months, stratified log-rank P < 0.0001; hazard ratio, 0.69 (95% CI, 0.58-0.83)}. As monotherapy for patients who had disease progression on or following an anthracycline, a taxane, and capecitabine, ixabepilone as monotherapy showed a 12% objective response rate by independent blinded review and 18% by investigator assessment. The major toxicities from ixabepilone therapy were peripheral neuropathy and myelosuppression, particularly neutropenia. Conclusions: On October 16, 2007, the Food and Drug Administration approved ixabepilone for injection in combination with capecitabine or as monotherapy for the treatment of patients with advanced breast cancer who have experienced disease progression on previous chemotherapies.

Purpose: On June 28, 2006, the U.S. Food and Drug Administration approved dasatinib (Sprycel; Bristol-Myers Squibb), a new small-molecule inhibitor of multiple tyrosine kinases, for the treatment of adults with chronic phase, accelerated phase, or myeloid or lymphoid blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy including imatinib. This summary reviews the database supporting this approval. Experimental Design: Four single-arm multicenter studies supported the efficacy and safety of dasatinib. The primary efficacy end point in chronic phase CML was major cytogenetic response. The primary end point in accelerated phase, myeloid phase, and lymphoid blast phase CML, and Ph+ ALL was major hematologic response. Results: The four studies combined enrolled 445 patients. In patients with chronic phase CML, the major cytogenetic response rate was 45% with a complete cytogenetic response rate of 33%. Major hematologic response rates in patients with accelerated phase CML, myeloid CML, lymphoid blast CML, and Ph+ ALL were 59%, 32%, 31%, and 42%, respectively. Median response durations in chronic phase, accelerated phase, and myeloid phase CML had not been reached. The median durations of major hematologic response were 3.7 months in lymphoid blast CML and 4.8 months in Ph+ ALL. Common toxicities with dasatinib included myelosuppression, bleeding, and fluid retention. Conclusions: This report describes the Food and Drug Administration review supporting the approval of dasatinib for CML and Ph+ ALL based on the rates and durability of cytogenetic and hematologic responses.

35S-labeled cells infected with herpes simplex virus type 1 (HSV-1), temperature-sensitive (ts) mutantts 1222 were used as a source of the large subunit of the viral ribonucleotide reductase (RR) to investigate the binding of the large (RR1) and small (RR2) subunits in the active enzyme. Mixing35S-labeled RR1 fromts 1222 with unlabeled RR1/RR2 complex from wild type (wt) infected cells resulted in the formation of a complex between35S-labeled RR1 and unlabeled RR2, indicating that the complex between the RR1 and RR2 subunits is dynamic and subunit dissociation/reassociation occurs during enzyme function. Similar results were obtained when unlabeled HSV-2 RR was substituted for HSV-1 RR, demonstrating that the holoenzyme can be formed from the large subunit of HSV-1 RR and the small subunit of HSV-2.

Purpose: To discuss vorinostat approval for treatment of cutaneous manifestations of advanced cutaneous T-cell lymphoma (CTCL). Experimental Design: Data from 1 single-arm, open-label, multicenter pivotal trial and 11 other trials submitted to support the new drug application for vorinostat in the treatment of advanced primary CTCL were reviewed. The pivotal trial assessed responses by changes in overall skin disease score using a severity-weighted assessment tool (SWAT). Vorinostat could be considered active in CTCL if observed response rate was at least 20% and the lower bound of the corresponding 95% confidence interval (95% CI) excluded 5%. Patients reported pruritis relief using a questionnaire and a visual analogue scale. Results: The pivotal trial enrolled 74 patients with stage IB or higher CTCL. Median number of prior treatments was 3, and 61 patients (82%) had stage IIB or higher disease. The objective response rate in the skin disease assessed by change in the overall SWAT score from the baseline was 30% (95% CI, 18.5 to 42.6) in patients with stage IIB or higher disease. Median response duration (end of response defined by 50% increase in SWAT score from the nadir) was 168 days. Median time to tumor progression was 148 days for overall population and 169 days for patients with stage IIB or higher disease. Assessment of pruritis relief was considered unreliable. Conclusions: Vorinostat showed activity in CTCL, and skin responses were a clinical benefit. Vorinostat was approved for treatment of cutaneous manifestations of CTCL. A nonblinded, single-arm trial did not allow a reliable assessment of pruritis relief.

I NTRODUCTION Bioanalysis, employed for the quantitative determination of drugs and their metabolites in biological fl uids, plays a signifi cant role in the evaluation and interpretation of bioequivalence, pharmacokinetic (PK), and toxicokinetic studies. The quality of these studies, which are often used to support regulatory fi lings, is directly related to the quality of the underlying bioanalytical data. It is therefore important that guiding principles for the validation of these analytical methods be established and disseminated to the pharmaceutical community. The fi rst American Association of Pharmaceutical Scientists (AAPS)/Food and Drug Administration (FDA) Bioanalytical Workshop in 1990 focused on key issues relevant to bioanalytical methodology and provided a platform for scientifi c discussions and deliberations. The workshop and the report 1 raised awareness of the need for validated bioanalytical methods for the regulatory acceptance of bioequivalence and pharmacokinetic data. Although the workshop addressed bioanalysis in general, it acknowledged the differences between chromatographic and ligand binding (nonchromatographic based) methods. The workshop identifi ed the essential parameters for bioanalytical method validation, ie, accuracy, precision, selectivity, sensitivity, reproducibility, limit of detection, and stability. The outcome of the fi rst workshop and its report resulted in improved quality of data submissions to regulatory agencies. Following the fi rst workshop report 1 and the experience

2578 Background: Ramucirumab was approved for the treatment of advanced gastric or gastro-esophageal junction adenocarcinoma in combination with paclitaxel based on an efficacy and safety trial tha...

2574 Background: On April 29 2014, the U.S. FDA approved ceritinib for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who hav...

2569 Background: Antibody-drug conjugates (ADCs) provide unique challenges during clinical development, as these products are a heterogeneous mixture of a monoclonal antibody and a small molecule p...

Irinotecan, an anticancer drug, is associated with severe and potentially fatal diarrhea and neutropenia. The objective of this analysis was to evaluate the role of SN-38 exposure, the active metabolite of irinotecan, UGT1A1 genotypes, and baseline bilirubin on the maximum decrease (nadir) in absolute neutrophil counts following irinotecan. This analysis extended the work of a previous study that examined the effect of UGT1A1 genotypes on the incidence of severe neutropenia in 86 advanced cancer patients following irinotecan treatment. Regression analysis showed that the absolute neutrophil count nadir depended on SN-38 exposure (AUC) and UGT1A1*28 homozygous 7/7 genotype. An increased SN-38 AUC and the 7/7 genotype were significantly associated with a lower absolute neutrophil count nadir (R2 = .49). An alternate model suggested that higher baseline bilirubin and the 7/7 genotype were also significantly associated with a lower absolute neutrophil count nadir, although with a lower coefficient of determination (R2 = .31). Based on these findings and other reports, the irinotecan label was modified to indicate the role of UGT1A1*28 polymorphism in the metabolism of irinotecan and the associated increased risk of severe neutropenia. The label modifications also included recommendations for lower starting doses of irinotecan in patients homozygous for the UGT1A1*28 (7/7) polymorphism.

Purpose: This report describes the U.S. Food and Drug Administration (FDA) review and approval of sorafenib (Nexavar, BAY43-9006), a new small-molecule, oral, multi-kinase inhibitor for the treatment of patients with advanced renal cell carcinoma (RCC). Experimental Design: After meeting with sponsors during development studies of sorafenib, the FDA reviewed the phase 3 protocol under the Special Protocol Assessment mechanism. Following new drug application submission, FDA independently analyzed the results of two studies in advanced RCC: a large, randomized, double-blinded, phase 3 international trial of single-agent sorafenib and a supportive phase 2 study. Results: In the phase 3 trial, 902 patients with advanced progressive RCC after one prior systemic therapy were randomized to 400 mg sorafenib twice daily plus best supportive care or to a matching placebo plus best supportive care. Primary study end points included overall survival and progression-free survival (PFS). A PFS analysis, pre-specified and conducted after a total of 342 events, showed statistically significant superiority for the sorafenib group (median = 167 days) compared with that for the controls (median = 84 days, log-rank P < 0.000001); the sorafenib/placebo hazard ratio was 0.44 (95% confidence interval, 0.35-0.55). Results were similar regardless of patient risk score, performance status, age, or prior therapy. The (partial) response rate to sorafenib was 2.1%. Overall survival results are preliminary. The principal toxicities in the sorafenib patients included reversible skin rashes in 40% and hand-foot skin reaction in 30%; diarrhea was reported in 43%, treatment-emergent hypertension was reported in 17%, and sensory neuropathic changes were reported in 13%. Grade 4 adverse events were uncommon. Grade 3 adverse events were hand-foot skin reaction (6%), fatigue (5%), and hypertension (3%). Laboratory findings included asymptomatic hypophosphatemia in 45% of sorafenib patients versus 11% in the placebo arm and elevation of serum lipase in 41% of sorafenib patients versus 30% in the placebo arm. Grade 4 pancreatitis was reported in two sorafenib patients, although both patients subsequently resumed sorafenib, with one at full dose. Conclusions: Sorafenib received FDA regular approval on December 20, 2005 for the treatment of advanced RCC based on the persuasive magnitude of improvement in PFS with acceptable safety. The recommended dose is 400 mg (two 200-mg tablets) twice daily taken either 1 h before or 2 h after meals. Adverse events were accommodated by temporary dose interruptions or reductions.

2600 Background: The implementation of the 2005 ICH E14 has included clinical evaluation of QTc prolongation for Therapeutic Biotechnology Products (TBPs). The ability of monoclonal antibodies (mAb...

2510 Background: On November 29 2012, the U. S. FDA approved cabozantinib (COMETRIQ) for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). Drug-related toxicity was common at a dose of 140 mg once daily across Phase 1 to Phase 3 trials submitted in this NDA. During the review of this application, these safety findings raised the question whether the optimal cabozantinib dose was selected for the treatment of MTC. Exposure-response (E-R) analyses were performed to assess the appropriateness of the cabozantinib dose. Methods: The data were obtained from an international, multi-center, randomized (2:1), placebo-controlled trial enrolling 330 patients with metastatic MTC. To account for variable exposure levels due to dose modification and inter-individual pharmacokinetic variability, average exposure (Starting Dose*Dose intensity/individual CL/F) was used as the exposure metric in the E-R analyses. The relationships between cabozantinib exposure and progression free survival (PFS), and selected safety endpoints including diarrhea, palmar-plantar erythrodysesthesia (PPE) syndrome and time to dose modification (TTDM) were evaluated. Results: Kaplan-Meier analyses of PFS for each quartile of average cabozantinib exposure suggest that patients with lower exposure and those with higher exposure may have equivalent PFS, comparatively. The multivariate Cox proportional analysis identified individual patient’s clearance as a significant covariate for prediction of TTDM with a hazard ratio of 1.95 (95% CI [1.47-2.59]), suggesting that patients with higher exposures required dose modification earlier than patients with lower exposures. The results of the E-R analyses may be difficult to interpret due to the high rate of dose modification. Nevertheless, these results indicate that a lower dose may be as effective with improved tolerability. Conclusions: The E-R analyses along with the observed safety and efficacy data in the clinical trials led to an FDA requirement to conduct a post marketing clinical trial to evaluate the safety and efficacy of a lower cabozantinib dose.

9550 Background: On October 29, 2010 the US FDA granted accelerated approval for the use of everolimus in the treatment of patients with SEGA associated with TS not amenable to curative surgical re...

4087 Background: In 2010, the FDA approved Herceptin (trastuzumab) as treatment for HER2-overexpressing metastatic gastric cancer. The purpose of this analysis was to further evaluate whether the a...

2597 Background: FDA drug approval requires demonstrated efficacy in adequate, well-controlled trials. In oncology, two key questions should be asked prior to initiation of “pivotal” efficacy trial...

Perception is based on the functional ability of the elderly person’s senses that influence behaviour; and sensory changes occur gradually with ageing. The purpose of this chapter is to provide the nurse with information to assist with developing nursing diagnoses and interventions in the area of health problems relating to vision and hearing, and with the promotion of the optimum use of remaining sensory function.

One of the most distressing health problems that the older person can face is incontinence. The healthy older adult tends to pass urine more frequently, with an increased degree of urgency; but other potential problems include urinary tract infections (UTIs), neurogenic disorders and amongst males, prostatic hypertrophy. Control of urinary elimination is vital to the older person, not just for social and hygienic reasons, but also for maintenance of self-esteem.

British-trained nurses who take up jobs in the United States are often struck by the extended range of nursing duties that they are expected to undertake — including many which they were previously used to seeing as falling within the domain of medical staff Physical examination comes into this category.

The following five case studies are designed to demonstrate implementation of the nursing process with older clients receiving nursing care in acute, continuing care, and community settings. The case studies are organised as in previous chapters using the format of nursing diagnosis and nursing interventions. Examples of goals and discussion of evaluations are also included.

The collection of the health history is the first step in assessment. The purposes of this procedure are to establish a rapport, aiding good communication, to determine the person’s expectations of what nursing will do for them, and to gather data for the formulation of nursing diagnoses [see the Introductions to Parts II and IV] and of a plan of care. In the case of a planned transfer from one ward to another (for example, from ‘acute’ to ‘rehabilitation’), discharge to a nursing home, or back into the community, the ideal is that the history is collected before transfer or discharge; members of the multidisciplinary team could visit the person beforehand, meeting later to draw up a preliminary plan of care, ready for the moment the person arrives in their area.

2601 Background: For many drugs, impaired renal function (RF) may alter pharmacokinetics (PK) to an extent requiring dosage adjustment. The CG is commonly utilized in approved product labeling (PI), but the MDRD is also used in clinical practice. The purpose of this study was to assess the relationship between the CG and MDRD equations to predict RF and concordance in the dose modification for oncology-related drugs. Methods: Demographic and pertinent laboratory data (presented as percentage [%] or median [25th, 75th percentile]) was pooled from renal dosing studies submitted to FDA in support 7 oncology related drugs. Four of these drugs ultimately required dose modification for renal impairment in the PI. Creatinine clearance (Clcr) and glomerular filtration rate (GFR) was estimated using the CG and MDRD equations, respectively. The relationship between these two estimates was determined by correlation analysis and a comparison of estimated RF to PK drug exposures for the 7 drugs. Additionally, the agre...