Therapeutic Innovation & Regulatory Science

The purpose of this study was to assess whether the use of verbal descriptors, such as “common” and “rare” affects peoples perceptions of the risks involved in clinical trials as well as their likelihood of entering into the trial. Participants were required to imagine that they had a serious skin condition and being asked if they would take part in a clinical trial for a new drug. They were provided with some information about the trial and drug, in which the probability of side effects occurring was described using either verbal labels alone or verbal labels with associated numerical values. The results showed that those given just the verbal descriptors were significantly less satisfied with the information, perceived risk to be higher (by a factor of three) and benefit to health to be lower, and indicated that they would be significantly less likely to enter the trial. We recommend that patients are informed about the likelihood of potential risks using verbal terms linked with indicative frequency ranges

Introduction: The literature supports the use of electronic diaries (e-diaries) in a variety of populations, including different disease and age groups. However, there has been little discussion of cross-cultural preferences. The aim of this study was to compare acceptability of paper and electronic diaries to collect symptom data from patients with benign prostatic hyperplasia (BPH) in the United States and Slovakia. Methods: Participants were 28 US and 20 Slovak men aged 49–83 years with moderate-to-severe BPH. All were randomly assigned to complete a paper or electronic urinary symptom diary for 7 consecutive days, then complete the alternate version for another 7 days. Participants' experiences with the diaries were assessed via ease of use and preference questions and patient interview. Site issues were assessed via tracking of technical problems and investigator feedback. Results: The US men preferred the electronic version, whereas men in Slovakia had equal preference between the formats. Most men in both countries felt they could continue using the e-diary for another 2 weeks and still provide accurate information. Technical issues at the Slovakian site included incompatibility with power supplies, loss of battery power, and problems downloading data. Conclusion: The use of e-diaries is feasible with BPH populations, although this may vary by country. When including in clinical trials patients who are less familiar with technology, careful consideration should be given to diary design, training, and technical issues in that country that may have an impact on the data collection process.

A statistical problem of primary interest in a thorough QT/QTc study is that of deciding if a drug is noninferior to placebo in terms of QT/QTc prolongation. A standard way of approaching this problem is to construct a 90% two-sided (or a 95% one-sided) confidence interval, using the t distribution, at each time point in the study for the difference in mean QTc between drug and placebo and to conclude that the drug is noninferior to placebo if the upper end points of all of these confidence intervals is less than a prespecified constant, such as 10 ms. Under standard normality assumptions, this procedure corresponds to both an intersection-union test and the likelihood ratio test of size .05. It is not without its drawbacks, however. It is conservative in that the probability of a type I error may be smaller than the intended level .05. It is also biased, which means that the power function, for some values of parameters in the alternative space, takes values less than .05. The May 12, 2005, draft of the International Conference on Harmonisation E14 guidance states: “a negative ‘thorough QT/QTc study’ is one in which the upper bound of the 95% one-sided confidence interval for the largest time-matched mean effect of the drug on the QTc interval excludes 10 ms.” In this article, we show how an approximate confidence interval can be constructed for the largest difference in population mean QT/QTc between drug and placebo. The interval is approximate in the sense that, as sample sizes increase, the asymptotic probability of coverage is at least as large as intended. The results of simulations on a proposed one-sided 95% confidence interval are provided and discussed. Situations in which this interval works well, and does not work well, are delineated.

QT prolongation is frequently associated with proarrhythmia, including torsade de pointes (TdP). At the same time, prolongation of action potential duration (APD) is widely recognized as a primary antiarrhythmic mechanism. This paradox results from linking an accidental association (APD prolongation) to the cause of proarrhythmia: triangulation, reverse use dependence, and instability of the cardiac action potential, which result in dispersion (TRIaD). Thus, prolongation of APD can occur without TRIaD (antiarrhythmic) or with TRIaD (proarrhythmic). Human ether-à-go-go related gene (hERG) blockers are more often than not associated with TRIaD and proarrhythmia. When associated with prolongation of APD, their average proarrhythmia does increase and is frequently TdP. But, when associated with APD shortening, proarrhythmia increases more steeply and frequently becomes ventricular fibrillation. For hERG blockers that change the APD little or not at all, proarrhythmia increases with increasing TRIaD, while TRIaD reduction can lead to antiarrhythmic action. In the absence of TRIaD, prolongation of the APD becomes increasingly antiarrhythmic. In conclusion, (a) rejection of drugs that lengthen the APD without TRIaD may unnecessarily withhold safe and valuable therapeutic agents from needy patients; (b) acceptance of drugs that shorten the APD but possess TRIaD may result in proarrhythmic agents. These will not be stopped by QT prolongation tests, even when thorough. Thus, banning drugs solely on the QT interval is counterproductive.

The pharmaceutical industry is facing an unprecedented challenge to restore public confidence in the contribution of pharmaceuticals to health care and the value of new drug innovation. Without this confidence, the very fabric of the pharmaceutical and biotech industries and the future of new drug innovation are at risk. The potential long-term impact on patient welfare is enormous. During the 2005 DIA Annual Conference, a panel discussion was held entitled “Medicines and Healthcare: Rebuilding the Trust, Reshaping the Future.” Several key issues affecting public perception and confidence regarding the development and approval of new therapeutic agents were discussed by the panelists. This article represents a compilation of the major topics and concepts discussed during the session as well as the perspective of the authors.

This article is the continuation of a discussion about the utility of the Medical Dictionary for Regulatory Activities (MedDRA) in the analysis of adverse event data. This topic was initiated by the Biometry Subgroup of the German Association of Research-Based Pharmaceutical Companies. They pointed out issues within the MedDRA terminology that physicians and scientists are facing in safety and statistical analysis. These issues include multiaxiality in standard adverse event tabulation; lack of connection between laboratory results and disease/diagnosis, between patient social back-ground and disease classification; and more. Similar issues have been brought to the attention of the MedDRA Maintenance and Support Services Organization by MedDRA subscribers. In response to subscribers' requests, the MedDRA Maintenance and Support Services Organization conducted a feasibility study on potential modifications to MedDRA's hierarchy terms to better facilitate analytical requirements while considering the potential impacts of these changes on users of MedDRA. Changes to the MedDRA terminology were proposed and discussed.

This first part of a two-part series provides background information about the US Pharmacopeia (USP) and reviews key elements of the organization and its activities during the 2000-2005 cycle, a period of exciting expansion and transformation. This article is divided into five parts: Background and State of the Pharmacopeia; USP Volunteers; USP Staff; USP Products and Services; and the Future. The report focuses on the who, the what, and the how of USP. A second article provides insights into the standards-setting activities of the Council of Experts—the core work of USP. Both articles are abridgements of larger reports presented at the USP Convention 2005.

The first part of this two-part series provided management information about the US Pharmacopeia (USP) and reviewed key elements of the organization and its activities during the 2000–2005 cycle. This second portion of the series examines the standards-setting activities undertaken by the USP Council of Experts and Expert Committees and other bodies, together with outreach activities of Stakeholder Forums and Quality Communications Groups. Both articles are abridgements of larger reports presented at the USP Convention 2005.

The development of analysis-ready data for clinical trials is a complicated process that is often problematic. Not only are the data inherently complex, but also analytical and reporting requirements tend to evolve over a period of time. Additional difficulties arise because of the number of individuals working with the data and the varied uses of the data. A new approach is described that greatly facilitates the creation, maintenance, and documentation of these data. Results are encouraging and include contributing to high quality and improved productivity.

Applications of process analytical technology (PAT) are currently attracting wide interest. One of the potential applications of PAT is large-scale (hundreds or thousands of tablets), real-time evaluation of tablet content uniformity. An issue associated with this situation is which acceptance criteria the obtained large sample should meet. Traditionally, a sample of 10-30 tablets is assessed against criteria specified in the harmonized pharmacopeial specification for uniformity of dosage units (UDU). These criteria, however, are not directly applicable to large sample sizes as application of the acceptance criteria in the harmonized pharmacopeial specification in these situations results in an overly restrictive requirement. Industry has highlighted this issue as a potential deterrent for extended applications of PAT in this area. A one-tiered counting test for UDU with associated acceptance criteria is proposed as an alternative to the harmonized pharmacopeial specification for UDU. The proposed test is applicable to large sample sizes yet provides the same assurance of uniformity of the batch as the harmonized pharmacopeial specification.

The design of a randomized, controlled, confirmatory efficacy clinical trial is influenced by multiple competing factors, including ethical, scientific, economic, and regulatory interests. Design elements, including choice of end points, study duration, and interim monitoring plans, need to be adapted to specific circumstances. The Weekly Intervention With Zithromax for Atherosclerosis and Its Related Disorders (WIZARD) study design was initially intended to meet the sponsor's scientific goals while being subject to practical constraints. In response to changing circumstances, modifications to the study design were required. The WIZARD trial demonstrates the substantial flexibility in the design and conduct of group-sequential randomized trials not only during the design stage but also after the trial is under way, effectively satisfying evolving and competing demands while preserving the statistical and scientific validity of the study.