Recommendations for the Bioanalytical Method Validation of Ligand-Binding Assays to Support Pharmacokinetic Assessments of Macromolecules

PURPOSE: With this publication a subcommittee of the AAPS Ligand Binding Assay Bioanalytical Focus Group (LBABFG) makes recommendations for the development, validation, and implementation of ligand binding assays (LBAs) that are intended to support pharmacokinetic and toxicokinetic assessments of macromolecules. METHODS: This subcommittee was comprised of 10 members representing Pharmaceutical, Biotechnology, and the contract research organization industries from the United States, Canada, and Europe. Each section of this consensus document addresses a specific analytical performance characteristic or aspect for validation of a LBA. Within each section the topics are organized by an assay's life cycle, the development phase, pre-study validation, and in-study validation. Because unique issues often accompany bioanalytical assays for macromolecules, this document should be viewed as a guide for designing and conducting the validation of ligand binding assays. RESULTS: Values of +/- 20% (25% at the lower limit of quantification [LLOQ]) are recommended as default acceptance criteria for accuracy (% relative error [RE], mean bias) and interbatch precision (%coefficient of variation [CV]). In addition, we propose as secondary criteria for method acceptance that the sum of the interbatch precision (%CV) and the absolute value of the mean bias (%RE) be less than or equal to 30%. This added criterion is recommended to help ensure that in-study runs of test samples will meet the proposed run acceptance criteria of 4-6-30. Exceptions to the proposed process and acceptance criteria are appropriate when accompanied by a sound scientific rationale. CONCLUSIONS: In this consensus document, we attempt to make recommendations that are based on bioanalytical best practices and statistical thinking for development and validation of LBAs.     

Excipient Taxonomy for the 21st Century

The performance of pharmaceutical dosage forms relies heavily on the characteristics of the excipients that are incorporated into the drug product during the manufacturing process. Therefore, it is imperative that formulators are able to accurately and completely specify the key chemical and physical properties of those excipients. Current approaches to describing excipients are outdated and inadequate for the needs of the 21^st century and in this article we highlight the benefits of a more systematic and comprehensive approach to specifying and controlling excipient properties. We hope that this will prompt the users, suppliers, and manufacturers of excipients to take a careful look at current approaches and develop tangible proposals for attaining an enhanced future state.     

Monitoring Trends in Drug Use: Strategies for the 21st Century

Since the 1970s the United States and other nations have conducted regular statistical monitoring of the prevalence and patterns of drug use in their populations. Given the importance of such surveys for policymaking, their quality is a critical issue, and the biases that may affect their measurements become a major concern. An increasing volume of empirical evidence shows that the mode of administration of a survey can strongly influence the validity of respondents' reports. Compared with interviewer-administered questionnaires, self-administered forms appear to elicit more complete reporting of drug use, but the challenges they pose to the literacy skills of respondents may result in measurement biases. In addition, processes of social change may confound true shifts in drug use with changes in the willingness of respondents to report such use. The authors propose several strategies to improve monitoring of trends in drug use. Those approaches include 1) more frequent use of a survey technology—audio computer-assisted self-interviewing—that ensures full privacy for all survey respondents but does not require literacy; 2) increased use of time-series of indicators of drug use consequences built from blinded surveys of medical records; and 3) population-based surveys that collect biological specimens (e.g., hair samples). Data from the latter two sources are not subject to the same constellation of biases that afflict self-reports of drug use. Time-series of those data can be integrated with self-reports to provide a better understanding of changes over time in the prevalence and patterns of drug use.

RESUMEN

Desde la década de los 70s, los Estados Unidos y otras naciones han conducido regularmente el monitoreo estadístico de la prevalencía y patrones del uso de drogas dentro de sus poblaciones. En base de la importancia de estas encuestas para la toma de decisión política, la calidad de los datos y los sesgos que afectan las medidas son asuntos críticos. La cantidad de pruebas empíricas muesta que el modo de realizar una encuesta puede influir la validez de las respuestas. Relacionado con instrumentos administrados a través de encuestadores, los instrumentos contestados por si mismo sacan datos más completos sobre el uso de drogas, pero los desafíos que tienen hacia la capacidad de leer del encuestado pueden resultar en sesgos de medición. También, los procesos de cambio social pueden confundir cambios verdaderos en el uso de drogas con cambios en la disposición a reportar tal uso. Los autores proponen varias estrategias para mejorar el monitoreo de patrones en el uso de drogas. Entre las estrategias son: (1) el uso más frecuente de una tecnología que asegura la privacidad completa del encuestado y que no requiere la capacidad de leer-autoentrevista con asistencia audio de la computadora (A-CASI); (2) el uso aumentado de indicadores de serie de tiempo obtenidos a través de encuestas anónimas de historias médicas sobre las consecuencias del uso de drogas; (3) encuestas en base de la población que recogen especimenes biológicos (como pelo humano). Datos obtenidos a través de las dos últimas fuentes no tienen los mismos sesgos que afectan los datos sobre el uso de drogas como los reportados por la persona misma. Serie de tiempo puede estar integrada con datos reportados por la persona misma para conseguir una comprensión mejor de los cambios longitudinales en la prevalencia y los patrones del uso de drogas.

RÉSUMÉ

Depuis les années soixante-dix, les Etats-Unis et d'autres pays ont conducté des surveillances de statistiques regulières des fréquences et des modèles de l'utilisation des drogues dans leurs populations. Donné l'importance de telles enquětes pour faire les déclarations de principe, la qualité est un sujet crucial et les préjugés qui peuvent affecter les résultats deviennent une affaire importante. L'évidence empirique de plus en plus grande montre que la façon de l'administration d'une enquěte peut influencer fortement la validité des réponses. En comparaison des enquětes passés avec un enquěteur, les questionnaires completés à soi-měme semblent obtenir des reportages plus complets de l'usage des drogues, mais le degré d'alphabetisation des sujets pose des problèmes de préjugés dans ces résultats. De plus les processus de changements socials peuvent confondre les vrais changements de l'utilisation des drogues avec une diminuation dans le volonté des sujets de rapporter ces nouvelles utilisations. Les auteurs proposent plusieurs moyens d'améliorer la surveillance des nouveaux mouvements dans l'usage des drogues. Ces moyens sont (1) l'utilisation plus fréquent d'une mode d'enquěte qui s'appelle—audio computer-assisted self-interviewing—Audio-CASI—(l'entretien à soi-měme assisté à l'ordinateur et acoustique) où la vie privée de chaque sujet est assurée, mais où il ne faut pas savoir lire ni écrire; (2) l'utilisation plus fréquent des séries de temps des indications des conséquences de l'usage des drogues avec les enquětes masquées des dossiers médicals; et (3) les enquětes de la population où des spécimens biologiques sont collectionés (par exemple des échantillons de cheveux). Les données collectés par la deuxième et troisième moyens ne sont pas sujet aux měmes préjugés qui peuvent avoir un effet sur les reportages à soi-měme de l'usage des drogues. Les séries de temps de ces données peuvent ětre integrées avec les reportages à soi-měme pour obtenir une meilleure compréhension des changements au cours de temps des fréquences et des modèles de l'usage des drogues.

Charles F. Turner is director of the Program in Health and Behavior Measurement at the Research Triangle Institute (RTI), a nonprofit research organization established in 1958 by Duke University, North Carolina State University, and the University of North Carolina. Prior to joining RTI, Dr. Turner was a scholar-in-residence at the US National Academy of Sciences (NAS), and he served from 1987 to 1991 as director of the NAS Committee on AIDS Research and the Behavioral, Social, and Statistical Sciences. Among his publications, Dr. Turner is coauthor and coeditor of three recent books on AIDS research and policy: AIDS, Sexual Behavior, and IV Drug Use; AIDS: The Second Decade; and Evaluating AIDS Prevention Programs. Outside of the AIDS arena, he is coeditor of a two-volume reference work on survey measurement, Surveying Subjective Phenomena, and of the monograph Survey Measurement of Drug Use: Methodological Issues.     

Statisticians in the Pharmaceutical Industry: The 21st Century

Pharmaceutical statisticians have come a long way during the past 50 years in supporting product discovery, development, manufacturing, and commercialization. Statisticians are either equal partners or are consultants in all areas of pharmaceutical research and development. While statistics is enjoying a greater role in the current environment, our industry is facing unprecedented challenges. The number of approved new molecular entities has decreased in recent years. The public is expecting medicines that are more effective and have fewer side effects. Many of our customers are demanding greater data disclosure, greater transparency, and higher standards of evidence. At the same time, public trust in our industry and regulators is at its lowest point since the 1970s. To face this unfavorable external environment and to take advantage of the rapidly emerging information to drive innovations, many companies have joined forces to form collaborative partnerships. The collaborations cover not only scientific pursuits, but also operational efficiency. In this article, we discuss the changing landscape of the 21st century. More importantly, we discuss what statisticians should do to rise to the challenges and take advantage of the opportunities in an environment where “openness” is a major consideration that will govern many public and private decisions.     

21世纪的临床药理学：趋向个体化

传统的临床药理学注重于指导药物开发和应用在一个“典型”的病人身上，所以在研究数据的时候，我们偏重于“平均值”。到了21世纪，FDA、医药公司、生物工程公司、学术界、医生以及病人团体等逐步认识到，并不是“一个尺寸适合于每个人”。根据每个人的内在因素，比如年龄、性别、种族、身高、体重、器官功能障碍、遗传的多态性（genetic polymorphism）等等，以及环境、饮食、同时使用的药物、是否吸烟和饮酒等外在因素，每个人对药物的反应和药量的需求是不同的。关键是要建立药物的暴露-效应之间的关系（exposure—response relatjonship）以及研究人的内在因素和外在因素对它的影响，才能确定有效及安全地使用药物。     

Preventing Cardiovascular Disease in the 21st Century

Cardiovascular disease (CVD), particularly coronary heart disease (CHD), remains a major cause of mortality, morbidity, and disability in the US and other Westernized societies. As a result of therapeutic and preventive measures to control the CVD/CHD epidemic, mortality has declined steadily during the last several decades with a consequent gain in life expectancy, but the 1990s witnessed a slowing of this decline. In response to these trends, a range of therapeutic regimens were developed to address adverse CVD risk factor levels and their deleterious effects. The scientific evidence regarding the efficacy, cost effectiveness, strengths, and limitations of a range of pharmacologic and lifestyle approaches to CVD prevention--both primary and secondary--are reviewed in depth. Clinical trials aimed at primary and secondary prevention of CVD have documented the efficacy and cost effectiveness of various drugs in lowering individual risk factor levels and in reducing clinical CVD events. More recently, the idea of a 'polypill' containing low doses of multiple drugs has generated much interest, with proponents arguing that, given the high prevalence of CVD risk factors and the effectiveness of pharmacologic interventions, such a drug combination would reduce CHD mortality by 88% if taken by all individuals aged > or = 55 years. However, current treatments to control high BP and serum cholesterol, while effective, do not typically reduce morbidity and mortality to levels observed in low-risk individuals, i.e. those with favorable levels of all readily measured major risk factors. Rather, primary prevention of all major risk factors starting early in life is critical. Prospective population-based research has delineated multiple long-term benefits associated with low-risk status in young adulthood and middle age, i.e. markedly lower age-specific CVD and total mortality rates, increased life expectancy, lower healthcare costs, lower medication use and prevalence of chronic diseases, and higher self-reported quality of life at older ages. Unfortunately, despite declines in the prevalence of most major CVD risk factors, low-risk status remains rare among US adults. Data have also demonstrated that adverse levels of one or more major risk factors precede clinical CHD in 90% or more of all cases, undermining the assertion that major CVD risk factors account for 'no more than 50%' of CHD cases. Hence, while numerous treatment options exist for secondary prevention of CVD, strategies that focus on progressively increasing the proportion of low-risk individuals could greatly reduce the need for secondary prevention in the first place. Public health policies must focus on prevention of all major risk factors simultaneously, using lifestyle approaches from early ages onwards to reduce population CVD risk to endemic levels, rather than current epidemic levels.     

21世纪生物技术和生物制药二、生物技术药物的研究开发

根据最新信息资料，分析了21世纪生物技术发展的趋势；评价生物技术产业在国民经济发展中的重要地位，并对我国生物技术药物的发展方向及有关问题提出了建设性意见，可供国家宏观指导部门及生物制药科技工作决策时参考。     

Risk Management for the 21st Century: Current Status and Future Needs

Drug Safety - Global adoption of risk management principles outlined in the International Conference on Harmonisation (ICH) E2E guideline and the Council for International Organizations of Medical...     

21世纪生物工程药物的发展与展望

中愉钱搂后徨物药物和产业化蓬毂发展的现状，总结了当代生物工程药物取得的成就；展示了近年来生物技术进步的轨迹；描述了２１世纪第一个１０年生物制药的前景；总结和提出了２１世纪生物制药的发展趋势。为发展我国生物制药产业提供了咨询意见。     

Rectal route in the 21st Century to treat children

The rectal route can be considered a good alternative to the oral route for the paediatric population because these dosage forms are neither to be swallowed nor need to be taste-masked. Rectal forms can also be administered in an emergency to unconscious or vomiting children. Their manufacturing cost is low with excipients generally regarded as safe. Some new formulation strategies, including mucoadhesive gels and suppositories, were introduced to increase patient acceptability. Even if recent paediatric clinical studies have demonstrated the equivalence of the rectal route with others, in order to enable the use of this promising route for the treatment of children in the 21st Century, some effort should be focused on informing and educating parents and care givers. This review is the first ever to address all the aforementioned items, and to list all drugs used in paediatric rectal forms in literature and marketed products in developed countries.