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Investigating the Efficacy of Clinical Trial Monitoring Strategies: Design and Implementation of the Cluster Randomized START Monitoring Substudy
Background: Trial monitoring protects participant safety and study integrity. While monitors commonly go on site to verify source data, there is little evidence that this practice is efficient or effective. An ongoing international HIV treatment trial (START) provides an opportunity to explore the usefulness of different monitoring approaches. Methods: All START sites are centrally monitored and required to follow a local monitoring plan requiring specific quality assurance activities. In addition, sites were randomized (1:1) to receive, or not receive, annual on-site monitoring. The study will determine if on-site monito...
Source: Therapeutic Innovation and Regulatory Science - February 27, 2015 Category: Drugs & Pharmacology Authors: Hullsiek, K. H., Kagan, J. M., Engen, N., Grarup, J., Hudson, F., Denning, E. T., Carey, C., Courtney-Rodgers, D., Finley, E. B., Jansson, P. O., Pearson, M. T., Peavy, D. E., Belloso, W. H., for the INSIGHT START Monitoring Substudy Group Tags: Clinical Trials Source Type: research

ClinicalTrials.gov: An Underutilized Source of Research Data About the Design and Conduct of Commercial Clinical Trials
Since 2007, the US federal government has required that organizations sponsoring clinical trials with a least one site in the United States submit information on these clinical trials to an existing database: ClinicalTrials.gov. Over time, the number of mandatory variables has grown and will probably continue to grow. The database now represents an important source of descriptive information about the landscape for clinical trials. In addition, it constitutes a rich pool of data to test hypotheses—for instance, what variables are associated with an organization’s ability to correctly estimate study completion t...
Source: Therapeutic Innovation and Regulatory Science - February 27, 2015 Category: Drugs & Pharmacology Authors: Glass, H. E., Glass, L. M., DiFrancesco, J. J. Tags: Clinical Trials Source Type: research

The Challenge Is Translation
(Source: Therapeutic Innovation and Regulatory Science)
Source: Therapeutic Innovation and Regulatory Science - February 27, 2015 Category: Drugs & Pharmacology Authors: Spielberg, S. P. Tags: Editorial Source Type: research

The Wider Use of Fixed-Dose Combinations Emphasizes the Need for a Global Approach to Regulatory Guideline Development
A fixed-dose combination (FDC) is a drug product in which two or more separate drug components (active pharmaceutical ingredients) are combined in a single-dosage form. Interest in developing FDCs is increasing in a range of diseases. This project investigated the regulatory environment for FDCs in the EU and US. A review of the FDC guidelines set forth by the EMA, FDA, and ICH, followed by interviews of key informants in industry, identified 5 main industry concerns related to development of FDCs. These concerns were presented to key informants from both the EU and US regulatory authorities. It was clear from the results ...
Source: Therapeutic Innovation and Regulatory Science - January 8, 2015 Category: Drugs & Pharmacology Authors: Gautam, Y., Bjerrum, O. J., Schmiegelow, M. Tags: Regulatory Science Source Type: research

Interprofessional Authorship in Critical Care Journals
Interprofessional education and patient care have been endorsed by accrediting bodies because interprofessional health care teams improve outcomes while decreasing health care costs. Thus, there has been an increased focus in educating health professional students collectively. The purpose of this study was to investigate the frequency of interprofessional authorship of original research published in high-impact critical care journals. Physicians constituted 76.2% of authors, followed by 10.5% PhDs and 3.0% nonphysician health professionals. From 2001 to 2011, the frequency of physician and nonphysician authors increased s...
Source: Therapeutic Innovation and Regulatory Science - January 8, 2015 Category: Drugs & Pharmacology Authors: Suda, K. J., Torbett, A. L., Zarzaur, B. L. Tags: Product Development and Innovation Source Type: research

Analysis of the Current Situation of Antitumor Drug Use in China: A Hospital-Based Perspective
Conclusions: Plant alkaloids have become the most widely used antitumor drug for clinical medical treatment in China. In the future, monoclonal antibody and small-molecule compounds are expected to have wider usage in China. (Source: Therapeutic Innovation and Regulatory Science)
Source: Therapeutic Innovation and Regulatory Science - January 8, 2015 Category: Drugs & Pharmacology Authors: Lai, Y.-F., Lu, J.-J., Hu, H., Wang, Y.-T. Tags: Global Perspective Source Type: research

How Should a Globalized CTD Be Created? An Introduction to the Japanese 3-Layer Approach
This article is based on the consensus of a task force of the Data Science Expert Committee, Japan Pharmaceutical Manufacturers Association. Common Technical Documents (CTDs) need to be harmonized in all of the ICH regions to enhance the scientific value and efficiency of these documents. Region-specific CTDs often require modifications for submission in different countries—an urgent issue not only for Japan but also for the countries where participation in the ICH framework will expand. CTDs themselves should be globalized, which means they should use not only a common format but also common contents, by incorporati...
Source: Therapeutic Innovation and Regulatory Science - January 8, 2015 Category: Drugs & Pharmacology Authors: Yoshida, K., Awaji, N., Takenouchi, K., Asahara, Y., Hashigaki, S., Komiyama, O. Tags: Global Perspective Source Type: research

Exact Bayesian Inference Comparing Binomial Proportions, With Application to Proof-of-Concept Clinical Trials
The authors revisit the problem of exact Bayesian inference comparing two independent binomial proportions. Numerical integration in R is used to compute exact posterior distribution functions, probability densities, and quantiles of the risk difference, relative risk, and odds ratio. An application of the methodology is given in the context of randomized comparative proof-of-concept clinical trials that are driven by evaluation of quantitative criteria combining statistical significance and clinical relevance. A two-stage adaptive design based on predictive probability of success is proposed and its operating characterist...
Source: Therapeutic Innovation and Regulatory Science - January 8, 2015 Category: Drugs & Pharmacology Authors: Sverdlov, O., Ryeznik, Y., Wu, S. Tags: Biostatistics Source Type: research

Bayesian Design of Proof-of-Concept Trials
The proof-of-concept (PoC) decision is a key milestone in the clinical development of an experimental treatment. A decision is taken on whether the experimental treatment is further developed (GO), whether its development is stopped (NO-GO), or whether further information is needed to make a decision. The PoC decision is typically based on a PoC clinical trial in patients comparing the experimental treatment with a control treatment. It is important that the PoC trial be designed such that a GO/NO-GO decision can be made. The present work develops a generic, Bayesian framework for defining quantitative PoC criteria, agains...
Source: Therapeutic Innovation and Regulatory Science - January 8, 2015 Category: Drugs & Pharmacology Authors: Fisch, R., Jones, I., Jones, J., Kerman, J., Rosenkranz, G. K., Schmidli, H. Tags: Biostatistics Source Type: research

Characterization of Missing Data in Clinical Registry Studies
This study examined the magnitude of, and factors associated with, missing data across multiple observational studies. Missingness was evaluated for demographic, clinical, and patient-reported outcome (PRO) data from a procedure registry (TOPS), a rare disease (cystic fibrosis) registry (Port-CF), and a comparative effectiveness registry (glaucoma, RiGOR). Generalized linear mixed effects models were fit to assess whether patient characteristics or follow-up methods predicted missingness. Data from 156,707 surgical procedures, 32,118 cystic fibrosis patients, and 2373 glaucoma patients were analyzed. Data were rarely missi...
Source: Therapeutic Innovation and Regulatory Science - January 8, 2015 Category: Drugs & Pharmacology Authors: Mendelsohn, A. B., Dreyer, N. A., Mattox, P. W., Su, Z., Swenson, A., Li, R., Turner, J. R., Velentgas, P. Tags: Clinical Trials Source Type: research

Management of Clinical Trial Agreements: Current Practices of Investigators in the United States
The clinical trial agreement (CTA) is a key but often underappreciated document governing the relationship between a study site and a sponsor. Previous anecdotal materials have suggested that investigators may not often be involved in the review or negotiation of the CTA and may attach little importance to it. To provide more systematic current information, survey methods were used to explore the level of engagement, knowledge, and perceptions of investigators in the United States. The survey was distributed to more than 700 investigators—university affiliated and nonaffiliated—and/or related study staff, of wh...
Source: Therapeutic Innovation and Regulatory Science - January 8, 2015 Category: Drugs & Pharmacology Authors: Pfeiffer, J. P., Richmond, F. J. Tags: Clinical Trials Source Type: research

The Patient-Reported Outcome (PRO) Consortium: Lessons Learned Along the Path to PRO Instrument Qualification
Established in 2008, the Patient-Reported Outcome (PRO) Consortium is a collaboration among the US Food and Drug Administration’s Center for Drug Evaluation and Research, the Critical Path Institute, the pharmaceutical/biotechnology industry, and other stakeholders. The purpose of the consortium is to qualify PRO instruments through the Center for Drug Evaluation and Research’s drug development tool qualification process for use as clinical trial endpoints to support drug approval and product labeling claims. The PRO Consortium has made notable progress toward collaborative development of PRO instruments in the...
Source: Therapeutic Innovation and Regulatory Science - January 8, 2015 Category: Drugs & Pharmacology Authors: Hayes, R. P., Blum, S. I., Gordon, M. F., Piault, E., Burke, L. B., Slagle, A. F., Coons, S. J. Tags: Clinical Trials Source Type: research

Multivariate Common Language Effect Size
To find a common language effect size of multivariate outcomes, we convert the standardized multivariate effect size (Mahalanobis distance) to a probability of a randomly selected subject from one population having a larger discriminant function than a randomly selected subject from another population. This probability is simple to calculate and comprehensible to laypeople. It can serve as the multivariate common language effect size to compare not only two groups but also more than two groups. (Source: Therapeutic Innovation and Regulatory Science)
Source: Therapeutic Innovation and Regulatory Science - January 8, 2015 Category: Drugs & Pharmacology Authors: Liu, X. S. Tags: Clinical Trials Source Type: research

Smart Program Design Through a Common Information Model
Although much information is already available publically from information-sharing initiatives such as ClinicalTrials.gov, information about clinical programs is unstructured, inconsistent, and incomplete. Clinical research within bioscience companies, health care, academia, and governmental agencies could benefit from easier access to best practices, historical information, and improved information sharing. Facilitating information sharing requires a standardized information model. Information standards today focus on individual clinical trials and the representation of clinical trial data. Although work is ongoing to exp...
Source: Therapeutic Innovation and Regulatory Science - January 8, 2015 Category: Drugs & Pharmacology Authors: Vasko, L., Sundgren, M., Bachmann, P., Balinski, K., Bleich, N., Blom, T., Eriksson, H., Ferendo, R., Forsberg, K., King, D., Mordiva, A., Proeve, J., Thomas, L., Witch, E., Siman, M. Tags: Clinical Trials Source Type: research

Maximal Usage Trial: An Overview of the Design of Systemic Bioavailability Trial for Topical Dermatological Products
Dermatologic diseases can present in varying forms and severity, ranging from the individual lesion and up to almost total skin involvement. Pharmacokinetic assessment of topical drug products has previously been plagued by bioanalytical assay limitations and the lack of a standardized study design. Since the mid-1990's the US Food and Drug Administration has developed and implemented a pharmacokinetic maximal usage trial (MUsT) design to help address these issues. The MUsT design takes into account the following elements: the enrollment of patients rather than normal volunteers, the frequency of dosing, duration of dosing...
Source: Therapeutic Innovation and Regulatory Science - January 8, 2015 Category: Drugs & Pharmacology Authors: Bashaw, E. D., Tran, D. C., Shukla, C. G., Liu, X. Tags: Clinical Trials Source Type: research