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1.  Meeting Report: Metabolites in Safety Testing (MIST) Symposium—Safety Assessment of Human Metabolites: What’s REALLY Necessary to Ascertain Exposure Coverage in Safety Tests? 
The AAPS Journal  2013;15(4):970-973.
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.
doi:10.1208/s12248-013-9502-6
PMCID: PMC3787210  PMID: 23821354
MIST; safety assessment of human metabolites; metabolite exposure coverage in safety test; ICH M3(R2); LC/MS/MS
2.  Therapeutic Protein Drug–Drug Interactions: Navigating the Knowledge Gaps–Highlights from the 2012 AAPS NBC Roundtable and IQ Consortium/FDA Workshop 
The AAPS Journal  2013;15(4):933-940.
The investigation of therapeutic protein drug–drug interactions has proven to be challenging. In May 2012, a roundtable was held at the American Association of Pharmaceutical Scientists National Biotechnology Conference to discuss the challenges of preclinical assessment and in vitro to in vivo extrapolation of these interactions. Several weeks later, a 2-day workshop co-sponsored by the U.S. Food and Drug Administration and the International Consortium for Innovation and Quality in Pharmaceutical Development was held to facilitate better understanding of the current science, investigative approaches and knowledge gaps in this field. Both meetings focused primarily on drug interactions involving therapeutic proteins that are pro-inflammatory cytokines or cytokine modulators. In this meeting synopsis, we provide highlights from both meetings and summarize observations and recommendations that were developed to reflect the current state of the art thinking, including a four-step risk assessment that could be used to determine the need (or not) for a dedicated clinical pharmacokinetic interaction study.
doi:10.1208/s12248-013-9495-1
PMCID: PMC3787234  PMID: 23794076
cytochrome P450s; drug–drug interactions; pro-inflammatory cytokines; small molecule; therapeutic protein
3.  Effect of Censoring Due to Progressive Disease on Tumor Size Kinetic Parameter Estimates 
The AAPS Journal  2013;15(3):832-839.
Tumor growth profiles were simulated for 2 years using the Wang and Claret models under a phase 3 clinical trial design. Profiles were censored when tumor size increased >20% from nadir similar to clinical practice. The percent of patients censored varied from 0% (perfect case) to 100% (real-life case). The model used to generate the data was then fit to the censored data using FOCE in NONMEM. The percent bias in the estimated model parameters determined with censored data was compared to the true values. A total of 100 simulation replicates was used. For the Wang model, under clinical conditions (100% censoring), the parameter related to tumor reduction SR was underpredicted by 30% and the parameter related to tumor growth PR was underpredicted by ∼45%. Most of the variance components in the model were within ±20% of the true values. However, biased parameter estimates in the Wang model did not translate to biased tumor size predictions as the mean percent prediction error between true and model predicted tumor size never exceeded 10%. For the Claret model, at 100% censoring, the tumor growth parameter KL was unaffected by censoring. Both tumor shrinkage parameters, KD and λ, were overestimated by ∼20% in both cases. Future research needs to be directed to develop less empirically based models and to use simulation as a way to improve clinical oncology trials designs.
doi:10.1208/s12248-013-9487-1
PMCID: PMC3691421  PMID: 23605951
Claret model; growth model; Monte Carlo simulation; NONMEM; Wang model
4.  Summary Workshop Report: Facilitating Oral Product Development and Reducing Regulatory Burden Through Novel Approaches to Assess Bioavailability/Bioequivalence 
The AAPS Journal  2012;14(3):627-638.
This summary workshop report highlights presentations and over-arching themes from an October 2011 workshop. Discussions focused on best practices in the application of biopharmaceutics in oral drug product development and evolving bioequivalence approaches. Best practices leverage biopharmaceutic data and other drug, formulation, and patient/disease data to identify drug development challenges in yielding a successfully performing product. Quality by design and product developability paradigms were discussed. Development tools include early development strategies to identify critical absorption factors and oral absorption modeling. An ongoing theme was the desire to comprehensively and systematically assess risk of product failure via the quality target product profile and root cause and risk analysis. However, a parallel need is reduced timelines and fewer resources. Several presentations discussed applying Biopharmaceutics Classification System (BCS) and in vitro–in vivo correlations in development and in post-development and discussed both resource savings and best scientific practices. The workshop also focused on evolving bioequivalence approaches, with emphasis on highly variable products (HVDP), as well as specialized modified-release products. In USA, two bioequivalence approaches for HVDP are the reference-scaled average bioequivalence approach and the two-stage group-sequential design. An adaptive sequential design approach is also acceptable in Canada. In European Union, two approaches for HVDP are a two-stage design and an approach to widen Cmax acceptance limits. For some specialized modified-release products, FDA now requests partial area under the curve. Rationale and limitations of such metrics were discussed (e.g., zolpidem and methylphenidate). A common theme was the benefit of the scientific and regulatory community developing, validating, and harmonizing newer bioequivalence methodologies (e.g., BCS-based waivers and HVDP trial designs).
doi:10.1208/s12248-012-9376-z
PMCID: PMC3385831  PMID: 22684402
5.  Harmonization of Regulatory Approaches for Evaluating Therapeutic Equivalence and Interchangeability of Multisource Drug Products: Workshop Summary Report 
The AAPS Journal  2011;13(4):556-564.
Regulatory approaches for evaluating therapeutic equivalence of multisource (or generic) drug products vary among different countries and/or regions. Harmonization of these approaches may decrease the number of in vivo bioequivalence studies and avoid unnecessary drug exposure to humans. Global harmonization for regulatory requirements may be promoted by a better understanding of factors underlying product performance and expectations from different regulatory authorities. This workshop provided an opportunity for pharmaceutical scientists from academia, industry and regulatory agencies to have open discussions on current regulatory issues and industry practices, facilitating harmonization of regulatory approaches for establishing therapeutic equivalence and interchangeability of multisource drug products.
doi:10.1208/s12248-011-9294-5
PMCID: PMC3231855  PMID: 21845486
bioequivalence; harmonization; interchangeability; regulatory standards; therapeutic equivalence
6.  AAPS Workshop Report: Strategies to Address Therapeutic Protein–Drug Interactions during Clinical Development 
The AAPS Journal  2011;13(3):405-416.
Therapeutic proteins (TPs) are increasingly combined with small molecules and/or with other TPs. However preclinical tools and in vitro test systems for assessing drug interaction potential of TPs such as monoclonal antibodies, cytokines and cytokine modulators are limited. Published data suggests that clinically relevant TP-drug interactions (TP-DI) are likely from overlap in mechanisms of action, alteration in target and/or drug-disease interaction. Clinical drug interaction studies are not routinely conducted for TPs because of the logistical constraints in study design to address pharmacokinetic (PK)- and pharmacodynamic (PD)-based interactions. Different pharmaceutical companies have developed their respective question- and/or risk-based approaches for TP-DI based on the TP mechanism of action as well as patient population. During the workshop both company strategies and regulatory perspectives were discussed in depth using case studies; knowledge gaps and best practices were subsequently identified and discussed. Understanding the functional role of target, target expression and their downstream consequences were identified as important for assessing the potential for a TP-DI. Therefore, a question-and/or risk-based approach based upon the mechanism of action and patient population was proposed as a reasonable TP-DI strategy. This field continues to evolve as companies generate additional preclinical and clinical data to improve their understanding of possible mechanisms for drug interactions. Regulatory agencies are in the process of updating their recommendations to sponsors regarding the conduct of in vitro and in vivo interaction studies for new drug applications (NDAs) and biologics license applications (BLAs).
doi:10.1208/s12248-011-9285-6
PMCID: PMC3144367  PMID: 21630127
drug interactions; question based; regulatory; risk based; therapeutic proteins
7.  Translational Biomarkers: from Preclinical to Clinical a Report of 2009 AAPS/ACCP Biomarker Workshop 
The AAPS Journal  2011;13(2):274-283.
There have been some successes in qualifying biomarkers and applying them to drug development and clinical treatment of various diseases. A recent success is illustrated by a collaborative effort among the US Food and Drug Administration, the European Medicines Agency, and the pharmaceutical industry to provide a set of seven preclinical kidney toxicity biomarkers for drug development. Other successes include, but are not limited to, clinical biomarkers for cancer treatment and clinical management of heart transplant patients. The value of fully qualified surrogate endpoints in facilitating successful drug development is undisputed, especially for diseases in which the traditional clinical outcome can only be assessed in large, multi-year trials. Emerging biomarkers, including chemical genomic or imaging biomarkers, and measurement of circulating tumor cells hold great promise for early diagnosis of disease and as prognostic tests for managing treatment of chronic diseases such as osteoarthritis, Alzheimer disease, cardiovascular disease, and cancer. To advance the success of treating and managing these diseases, efforts are needed to establish the temporal relationship between changes in inflammatory or imaging biomarkers with the progression of the chronic disease, and in the case of cancer, between the extent of circulating cancer cells and tumor progression or remission.
doi:10.1208/s12248-011-9265-x
PMCID: PMC3085704  PMID: 21448748
biomarkers; diagnostic; diseases; gene expression; imaging
8.  Meeting Report: Applied Biopharmaceutics and Quality by Design for Dissolution/Release Specification Setting: Product Quality for Patient Benefit 
The AAPS Journal  2010;12(3):465-472.
A biopharmaceutics and Quality by Design (QbD) conference was held on June 10–12, 2009 in Rockville, Maryland, USA to provide a forum and identify approaches for enhancing product quality for patient benefit. Presentations concerned the current biopharmaceutical toolbox (i.e., in vitro, in silico, pre-clinical, in vivo, and statistical approaches), as well as case studies, and reflections on new paradigms. Plenary and breakout session discussions evaluated the current state and envisioned a future state that more effectively integrates QbD and biopharmaceutics. Breakout groups discussed the following four topics: Integrating Biopharmaceutical Assessment into the QbD Paradigm, Predictive Statistical Tools, Predictive Mechanistic Tools, and Predictive Analytical Tools. Nine priority areas, further described in this report, were identified for advancing integration of biopharmaceutics and support a more fundamentally based, integrated approach to setting product dissolution/release acceptance criteria. Collaboration among a broad range of disciplines and fostering a knowledge sharing environment that places the patient's needs as the focus of drug development, consistent with science- and risk-based spirit of QbD, were identified as key components of the path forward.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-010-9206-0) contains supplementary material, which is available to authorized users.
doi:10.1208/s12248-010-9206-0
PMCID: PMC2895441  PMID: 20517660
biopharmaceutics; dissolution; product performance; quality by design; quality target product profile
9.  AAPS Workshop Report: Strategies to Address Therapeutic Protein–Drug Interactions during Clinical Development 
The AAPS Journal  2011;13(3):405-416.
Therapeutic proteins (TPs) are increasingly combined with small molecules and/or with other TPs. However preclinical tools and in vitro test systems for assessing drug interaction potential of TPs such as monoclonal antibodies, cytokines and cytokine modulators are limited. Published data suggests that clinically relevant TP-drug interactions (TP-DI) are likely from overlap in mechanisms of action, alteration in target and/or drug-disease interaction. Clinical drug interaction studies are not routinely conducted for TPs because of the logistical constraints in study design to address pharmacokinetic (PK)- and pharmacodynamic (PD)-based interactions. Different pharmaceutical companies have developed their respective question- and/or risk-based approaches for TP-DI based on the TP mechanism of action as well as patient population. During the workshop both company strategies and regulatory perspectives were discussed in depth using case studies; knowledge gaps and best practices were subsequently identified and discussed. Understanding the functional role of target, target expression and their downstream consequences were identified as important for assessing the potential for a TP-DI. Therefore, a question-and/or risk-based approach based upon the mechanism of action and patient population was proposed as a reasonable TP-DI strategy. This field continues to evolve as companies generate additional preclinical and clinical data to improve their understanding of possible mechanisms for drug interactions. Regulatory agencies are in the process of updating their recommendations to sponsors regarding the conduct of in vitro and in vivo interaction studies for new drug applications (NDAs) and biologics license applications (BLAs).
doi:10.1208/s12248-011-9285-6
PMCID: PMC3144367  PMID: 21630127
drug interactions; question based; regulatory; risk based; therapeutic proteins
10.  Challenges and Opportunities in Establishing Scientific and Regulatory Standards for Assuring Therapeutic Equivalence of Modified Release Products: Workshop Summary Report 
The AAPS Journal  2010;12(3):371-377.
Modified release products are complex dosage forms designed to release drug in a controlled manner to achieve desired efficacy and safety. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity. This workshop provided an opportunity for pharmaceutical scientists from academia, industry, and regulatory agencies to discuss current industry practices and regulatory expectations for demonstrating pharmaceutical equivalence and bioequivalence of MR products, further facilitating the establishment of regulatory standards for ensuring therapeutic equivalence of these products.
doi:10.1208/s12248-010-9201-5
PMCID: PMC2895434  PMID: 20440588
bioequivalence; interchangeability; modified release; pharmaceutical equivalence; therapeutic equivalence
11.  AIDS Treatment with Novel Anti-HIV Compounds Improved by Nanotechnology 
The AAPS Journal  2010;12(3):272-278.
The first International Symposium of Nanomedicine on AIDS “AIDS Treatment with Novel Anti-HIV compounds Improved by Nanotechnology” was held November 19–20, 2009 in Beijing, China. This symposium provided an international forum for presentation and discussion of exciting new advances in the emerging research area of nanobiomedical research on AIDS treatment as the focus point, as well as some issues in relevant fields such as nanobiomedical research on tumor treatment and safety evaluation of nanomedicines. Key highlights of the symposium include (1) reviewing current status of nanobiotechnology programs and their relations, more or less, with AIDS treatment; (2) reviewing current AIDS epidemiology in China and examining effectiveness and efficiency of current prevention and treatment strategies; (3) highlighting the obstacles to improve AIDS prevention and treatment, and (4) exploring innovative ways for nanotechnology to advance AIDS treatment, especially to combat HIV resistance to drugs.
doi:10.1208/s12248-010-9187-z
PMCID: PMC2895444  PMID: 20373061
AIDS treatment; anti-AIDS drug development; nanomedicine; nanotechnology
12.  Successes Achieved and Challenges Ahead in Translating Biomarkers into Clinical Applications 
The AAPS Journal  2010;12(3):243-253.
Biomarkers are important tools for identifying and stratifying diseases, predicting their progression and determining the effectiveness, safety, and doses of therapeutic interventions. This is important for common chronic diseases such as diabetic nephropathy, osteoporosis, and rheumatoid arthritis which affect large numbers of patients worldwide. This article summarizes the current knowledge of established and novel biomarkers for each of these diseases as presented at the 2008 AAPS/ACCP joint symposium “Success Achieved and Challenges Ahead in Translating Biomarkers into Clinical Applications,” in Atlanta, Georgia. The advantages and disadvantages of various proteomic, metabolomic, genomic, and imaging biomarkers are discussed in relation to disease diagnosis and stratification, prognosis, drug development, and potential clinical applications. The use of biomarkers as a means to determine therapeutic interventions is also considered. In addition, we show that biomarkers may be useful for adapting therapies for individual needs by allowing the selection of patients who are most likely to respond or react adversely to a particular treatment. They may also be used to determine whether the development of a novel therapy is worth pursuing by informing crucial go/no go decisions around safety and efficacy. Indeed, regulatory bodies now suggest that effective integration of biomarkers into clinical drug development programs is likely to promote the development of novel therapeutics and more personalized medicine.
doi:10.1208/s12248-010-9182-4
PMCID: PMC2895431  PMID: 20232184
biomarkers; bone; diabetic nephropathy; drug development; genetic; inflammation; osteoporosis; proteomics; rheumatoid arthritis
13.  Workshop Report and Follow-Up—AAPS Workshop on Current Topics in GLP Bioanalysis: Assay Reproducibility for Incurred Samples—Implications of Crystal City Recommendations 
The AAPS Journal  2009;11(2):238-241.
The Conference Report of the 3rd AAPS/FDA Bioanalytical Workshop (Crystal City III) endorsed the concept that assay methods supporting bioanalytical data in submissions must demonstrate assay reproducibility by using incurred samples. The present Workshop was convened to provide a forum for discussion and consensus building about incurred sample assay reproducibility for both nonclinical and clinical studies. Information about current regulatory perspectives on incurred sample reanalysis (ISR) was presented, implications of ISR for both large and small molecules were discussed, and the steering committee put forth recommendations for performing ISR. These recommendations from the Workshop, along with the subsequent evolution of approaches leading to a robust ISR program, may be used by scientists performing bioanalytical assays for regulated studies to provide additional confirmation of assay reproducibility for incurred samples.
doi:10.1208/s12248-009-9100-9
PMCID: PMC2691460  PMID: 19381839
bioanalytical; confirmatory analysis; incurred sample(s); reanalysis
14.  AAPS–FIP Summary Workshop Report: Pharmacogenetics in Individualized Medicine: Methods, Regulatory, and Clinical Applications 
The AAPS Journal  2009;11(2):214-216.
The workshop “Pharmacogenetics in Individualized Medicine: Methods, Regulatory, and Clinical Applications” was held November 15–16, 2008 in Atlanta, Georgia, USA. This workshop provided an opportunity for pharmaceutical scientists, clinical practitioners, clinical laboratory scientists, and FDA to discuss methods, regulatory, and the application of pharmacogenetics in clinical practice and drug discovery. Key highlights of the workshop were: (a) the use of genetic information in individualized medicine has significant potential in advancing drug development and human health by optimizing drug response, drug efficacy, and preventing adverse drug reactions; (b) various barriers exist preventing the advance of the individualized medicine in the society, industry, and clinical practice; and (c) the barriers may be overcome by integrated approaches; the education of researchers, clinical practitioners, and patients and fostering interactive communication among stakeholders. By targeting the AAPS audience, this workshop was one step among many steps that AAPS–FIP is intending to take towards removing the barriers to widespread uptake of pharmacogenetics in drug discovery and clinical practice.
doi:10.1208/s12248-009-9097-0
PMCID: PMC2691457  PMID: 19319689
clinical pharmacology; drug discovery; drug metabolism; individualized medicine; pharmacogenetics; pharmacogenomics
15.  Antidrug Antibody Assay Validation: Industry Survey Results 
The AAPS Journal  2009;11(1):133-138.
Immunogenicity of biopharmaceutical products has attracted considerable attention from the industrial, academia, and regulatory organizations. Many methods exist to detect and characterize level of antidrug antibody response in patients. Still, additional work is required to harmonize various approaches used throughout the industry. This review presents results of a survey sponsored by the American Association of Pharmaceutical Scientists that was designed to collect relevant information and to understand various methods used throughout the bioanalytical field for the detection and evaluation of antidrug antibody responses.
doi:10.1208/s12248-009-9091-6
PMCID: PMC2664891  PMID: 19255857
antidrug antibody; antiproduct antibody; biopharmaceutics; immunogenicity
16.  Summary Workshop Report: Bioequivalence, Biopharmaceutics Classification System, and Beyond 
The AAPS Journal  2008;10(2):373-379.
The workshop “Bioequivalence, Biopharmaceutics Classification System, and Beyond” was held May 21–23, 2007 in North Bethesda, MD, USA. This workshop provided an opportunity for pharmaceutical scientists to discuss the FDA guidance on the Biopharmaceutics Classification System (BCS), bioequivalence of oral products, and related FDA initiatives such as the FDA Critical Path Initiative. The objective of this Summary Workshop Report is to document the main points from this workshop. Key highlights of the workshop were (a) the described granting of over a dozen BCS-based biowaivers by the FDA for Class I drugs whose formulations exhibit rapid dissolution, (b) continued scientific support for biowaivers for Class III compounds whose formulations exhibit very rapid dissolution, (c) scientific support for a number of permeability methodologies to assess BCS permeability class, (d) utilization of BCS in pharmaceutical research and development, and (e) scientific progress in in vitro dissolution methods to predict dosage form performance.
doi:10.1208/s12248-008-9040-9
PMCID: PMC2751390  PMID: 18679807
bioavailability; bioequivalence; biopharmaceutics classification system (BCS); oral absorption; permeability; regulatory science; solubility

Results 1-19 (19)