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Introduction: This research aims to characterize and evaluate the potential of two novel tandem peptides for their ability to mediate the delivery of CD44 siRNA into HER2+ breast cancer cell lines. HER2+ cancer accounts for 20%-25% of invasive breast cancers and shows overexpression of HER2 protein. The tandem peptides examined consist of P51 or P25 targeting peptide sequences that bind to the HER2 protein, and DIV3W, a fusogenic peptide that allows for siRNA protection, cellular internalization, and endosomal escape. We hypothesize that delivery of tandem peptide will result in the observation of mRNA knockdown of CD44, a reduction of CD44 protein expression, and a decrease in metastatic properties of breast cancer cells. Methods: Western blot analysis was used to determine the basal expression of CD44 in HER2+ breast cancer cell lines, SKBR3 and BT474, and breast epithelial cell line MCF10A. Tandem targeting/fusogenic peptides termed P51-DIV3W and P25-DIV3W were electrostatically complexed with non-targeting siRNA (siNT) at increasing N:P ratios to determine the minimum ratios needed to complex free siRNA. Various ratios of peptide-siRNA complexes were also treated with FBS and RNase A to determine whether the peptides protected siRNA from degradation. MTS assays were performed in SKBR3, BT474, and MCF10A cells to determine cytotoxicity using increasing peptide concentrations. Dynamic light scattering was performed using a Zetasizer to determine the size of the peptide-siRNA nanocomplexes. Results: Western Blot data of the three cell lines showed that CD44 protein was present in cancerous and normal cells, whereas HER2 protein was only present in SKBR3 and BT474 cells. Peptide-siRNA complexes for both P51-DIV3W and P25-DIV3W formed at a minimum N:P ratio of 20:1. Both peptide complexes protected siRNA from degradation in FBS and RNase A at N:P ratios ranging from 20:1 to 60:1. DLS results showed that P25-DIV3W-siRNA complexes had an average diameter of 200.23 nm and a zeta-potential of 24.7 mV. Conclusions: The data collected shows that the tandem peptides successfully complex with siNT and protect siNT from degradation. The peptide complexes formulate at a size that serves as an effective carrier for siRNA to breast cancer cells. Future work will focus on evaluating the ability of the tandem peptides to target HER2 and effectively silence CD44 in HER2+ breast cancer cells. Acknowledgements: This research was supported in part by the Dabo Swinney All In Foundation and Materials Assembly and Design Excellence in South Carolina (MADE in SC) under the National Science Foundation EPSCoR Program under NSF Award # OIA-1655740. We also thank SC BioCRAFT, NIH award P30 GM131959, for the use of core equipment and facilities. Citation Format: James W. Kalogeros, Audreanna Miserendino, Angela Alexander-Bryant, Brian Booth. Tandem peptides targeting HER2 for delivery of CD44 siRNA into HER2+ breast cancer cells in vitro. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3979.

In this chapter, we describe the importance of bioanalytical methods to drug development. These assays, measuring the active drug and metabolites, provide critical information on the exposure of the drug that is used to correlate with safety and efficacy data to demonstrate the appropriate selection of the dosage strength and frequency. Technologies discussed include those supporting small molecule drugs (chromatographic assays (LC-MS/MS)), biologics (immunoassays), and gene therapies (polymerase chain reaction assays (PCR)). This chapter reviews the predominant technologies and critical features in their use to provide reliable data, the characteristics of the assays that must be demonstrated during validation, and case studies highlighting many of these aspects.

The 2019 13th Workshop on Recent Issues in Bioanalysis (WRIB) took place in New Orleans, LA on 1–5 April 2019 with an attendance of over 1000 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day, week-long event – a full immersion week of bioanalysis, biomarkers, immunogenicity and gene therapy. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small- and large-molecule bioanalysis involving LCMS, hybrid LBA/LCMS, LBA cell-based/flow cytometry assays and qPCR approaches. This 2019 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2019 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 2) covers the recommendations on the 2018 FDA BMV guidance, 2019 ICH M10 BMV draft guideline and regulatory agencies' input on bioanalysis, biomarkers, immunogenicity and gene therapy. Part 1 (Innovation in small molecules and oligonucleotides and mass spectrometry method development strategies for large molecules bioanalysis) and Part 3 (New insights in biomarker assay validation, current and effective strategies for critical reagent management, flow cytometry validation in drug discovery and development and CLSI H62, interpretation of the 2019 FDA immunogenicity guidance and gene therapy bioanalytical challenges) are published in volume 10 of Bioanalysis, issues 22 and 24 (2019), respectively.

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.

The microsampling workshop generated recommendations pertaining to blood sampling site (venous blood versus capillary blood), when to conduct a bridging study, statistical approaches to establish correlation/concordance and deciding on sample size, opportunities and challenges with patient-centric sampling, and how microsampling technology can enrich clinical drug development. Overall, the goal was to provide clarity and recommendations and enable the broader adoption of microsampling supporting patients’ needs, convenience, and the transformation from clinic-centric to patient-centric drug development. The need and adoption of away-from-clinic sampling techniques has become critical to maintain patient safety during the current COVID-19 pandemic.

Over the last decade, several regulatory guidelines on bioanalytical method validation (BMV) have been issued by regulatory agencies around the world. This has left the bioanalytical community struggling with regional differences in regulatory expectations when preparing for global pharmaceutical submissions. The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) has the mission to achieve greater harmonization worldwide to ensure that safe, effective, and high-quality medicines are developed and registered in the most resource-efficient manner. Following calls for harmonization, ICH-selected bioanalytical method validation and sample analysis among its topics for guidance development and earlier this year released a draft guideline (M10) on BMV for public consultation. In response, the American Association of Pharmaceutical Scientists (AAPS) held a 3-day workshop to provide a forum for regulatory, industry, and academic scientists to discuss the guideline and hear various points of view on key aspects. While there was agreement that the draft guideline is generally well written and comprehensive, specific topics generated considerable discussion and, in some cases, revision recommendations for consideration by the expert working group (EWG) responsible for the guideline content. This report provides a summary of the workshop proceedings.

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.

Bioanalysis in biosimilar biological product development (BPD) plays a critical role in demonstrating pharmacokinetic (PK) similarity across products. The 2018 FDA Bioanalytical Method Validation guidance for industry provides general principles in the development, validation, and conduct of bioanalytical assays. Given that the PK similarity assessment in BPD programs involves two or more non-identical products, there are additional considerations for bioanalytical methods. Here in, we provide our perspectives on the definition of (1) a single bioanalytical method in the context of BPD in supporting a PK similarity study, (2) bioanalytical method comparability during accuracy and precision experiments to determine the potential bias difference prior to assessing other validation parameters, and (3) bioanalytical method validations that support PK similarity assessments.

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.

A PRESCRIBER'S GUIDE TO DRESSINGS AND WOUND MANAGEMENT MATERIALS CLAYTON'S ELECTROTHERAPY 10th edition

THE DIAGNOSIS AND MANAGEMENT OF LEG ULCERS IN THE COMMUNITY NO STANDARD FOR SKIN CARE IN PATIENTS WITH INCONTINENCE PROBLEMS ASSESSING PRESSURE SORE RISK

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]

The 2013 7th Workshop on Recent Issues in Bioanalysis was held in Long Beach, California, USA, where close to 500 professionals from pharmaceutical and biopharmaceutical companies, CROs and regulatory agencies convened to discuss current topics of interest in bioanalysis. These ‘hot’ topics, which covered both small and large molecules, were the starting point for fruitful exchanges of knowledge, and sharing of ideas among speakers, panelists and attendees. The discussions led to specific recommendations pertinent to bioanalytical science. Such as the previous editions, this 2013 White Paper addresses important bioanalytical issues and provides practical answers to the topics presented, discussed and agreed upon by the global bioanalytical community attending the 7th Workshop on Recent Issues in Bioanalysis.

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.

This University of Wisconsin School of Pharmacy bioanalytical conference is presented each year by the Extension Services in Pharmacy, the professional development department within the School. The purpose of this 4-day conference is to provide an educational forum to discuss issues and applications associated with the analysis of xenobiotics, metabolites, biologics and biomarkers in biological matrices. The conference is designed to include and encourage an open exchange of scientific and methodological applications for bioanalysis. To increase the interactive nature of the conference, the program was a mixture of lectures, poster sessions, round table discussions and workshops. This article summarizes the presentations at the 13th Annual Conference.

Over 400 professionals representing pharmaceutical companies, CROs, and multiple regulatory agencies participated in the 6th Workshop on Recent Issues in Bioanalysis (WRIB). Like the previous sessions, this event was in the format of a practical, focused, highly interactive and informative workshop aiming for high-quality, improved regulatory compliance and scientific excellence. Numerous ‘hot’ topics in bioanalysis of both small and large molecules were shared and discussed, leading to consensus and recommendations among panelists and attendees representing the bioanalytical community. The major outcome of this year’s workshop was the noticeable alignment of multiple bioanalytical guidance/guidelines from different regulatory agencies. This represents a concrete step forward in the global harmonization of bioanalytical activities. The present 2012 White Paper acts as a practical and useful reference document that provides key information and solutions on several topics and issues in the constantly evolving world of bioanalysis.

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.

The 2011 annual conference of the American Association of Pharmaceutical Scientists, held in Washington DC, USA, hosted a roundtable entitled: ‘Update of the US FDA/European Medicines Agency (EMA) harmonization of their bioanalytical guidance – Global Bioanalytical Consortium activity and impact on small and large molecules.’ The roundtable was initiated with a presentation from CT Viswanathan on the history of the revision of the FDA guideline on bioanalytical method validation. It was followed by a presentation by Jan Welink who presented an update on the final European Medicines Agency guideline on bioanalytical method validation with relevance to ongoing harmonization efforts. The final presentation was by Fabio Garofolo on the progress of the Global Bioanalytical Consortium harmonization teams for small and large molecules. Brian Booth and Sam Haidar of the FDA updated the audience on the status of the revision of the FDA bioanalytical guidance. The roundtable was moderated by Stephen Lowes.

The 5th Workshop on Recent Issues in Bioanalysis (WRIB) was organized by the Calibration and Validation Group as a 2-day full immersion workshop for pharmaceutical companies, CROs and regulatory agencies to discuss, review, share perspectives, provide potential solutions and agree upon a consistent approach to recent issues in the bioanalysis of both small and large molecules. High quality, better compliance to regulations and scientific excellence are the foundation of this workshop. As in the previous editions of this significant event, recommendations were made and a consensus was reached among panelists and attendees, including industry leaders and regulatory experts representing the global bioanalytical community, on many ‘hot’ topics in bioanalysis. This 2011 White Paper is based on the conclusions from this workshop, and aims to provide a practical reference guide on those topics.

The 4th Calibration and Validation Group Workshop on Recent Issues in Regulated Bioanalysis, a 2-day full immersion workshop, was organized by the Calibration and Validation Group. Contract research organizations, pharmaceutical companies and regulatory agencies came together to discuss several ‘hot’ topics concerning bioanalytical issues and regulatory challenges and to reach a consensus among panelists and attendees on many points regarding method validation of small and large molecules.

ISSN 1757-6180 Bioanalysis (2010) 2(9), 1547–1552 10.4155/BIO.10.127 © 2010 Future Science Ltd Over the past year, Bioanalysis has featured profiles of eight young bioanalysts [1–8] from around the world, nominated by their supervisors. The Young Investigators are given the opportunity to highlight their bioanalytical work to date, discuss their future career aspirations and give their thoughts on the future evolution of the field of bioanalysis. The Bioanalysis Young Investigator 2010 was decided on the basis of votes cast by our international editorial advisory board.

This conference was arranged by the Extension Services in Pharmacy at the University of Wisconsin School of Pharmacy. The purpose of this annual 4-day conference is to provide an educational forum to discuss issues and applications associated with the analysis of xenobiotics and metabolites in biological matrices. The conference is designed to include and encourage an open exchange of scientific and methodological applications for bioanalysis. To increase the interactive nature of the conference, the program will be a mixture of lectures, poster sessions, round table discussions and workshops. This paper summarizes the presentations at the Tenth Annual Conference.

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.

The Third AAPS/FDA Bioanalytical Workshop, entitled "Quantitative Bioanalytical Methods Validation and Implementation: Best Practices for Chromatographic and Ligand Binding Assays" was held on May 1-3, 2006 in Arlington, VA. The format of this workshop consisted of presentations on bioanalytical topics, followed by discussion sessions where these topics could be debated, with the goal of reaching consensus, or identifying subjects where addition input or clarification was required. The discussion also addressed bioanalytical validation requirements of regulatory agencies, with the purpose of clarifying expectations for regulatory submissions. The proceedings from each day were reviewed and summarized in the evening sessions among the speakers and moderators of the day. The consensus summary was presented back to the workshop on the last day and was further debated. This communication represents the distillate of the workshop proceedings and provides the summary of consensus reached and also contains the validation topics where no consensus was reached.

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.

A novel format was introduced at the recent AAPS NBC Workshop on Method Development, Validation and Troubleshooting in San Diego on 18th May 2014. The workshop format was initiated by Binodh De Silva; Marie Rock and Sherri Dudal joined the initiative to develop and chair the workshop. Questions were solicited by a variety of avenues, including a Linked-In Discussion Group. Once collated and clarified, the topics covered assay development, validation, and analysis of PK, Immunogenicity, and Biomarkers with an additional topic on alternative bioanalytical technologies. A panel of experts (workshop report co-authors) was assigned to each topic to bring forward thought-provoking aspects of each topic. The format of the workshop was developed to target the needs of bioanalytical scientists with intermediate to advanced experience in the field ranging to enable robust discussion and to delve deeper into the current bioanalytical hot topics. While the new format allowed for an interactive session with the topical discussion driven by the audience members, it did not foster equal discussion time for all of the proposed topics, especially Biomarkers and alternative LBA technologies.

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.