Therapeutic Innovation & Regulatory Science

A recent article in the Drug Information Journal argued that sloppy study conduct would not affect the rate of false positive conclusions in noninferiority trials. We demonstrate by means of a simulation study that this is not universally true. In fact, whether an analysis is conservative may depend on: 1. The objective of the trial, 2. The population analyzed and the mechanism for imputation of nonevaluable measurements, 3. The mechanism generating nonevaluable measurements, and 4. The selected measure for the treatment effect. We suggest that simulation studies be routinely performed to investigate the effect of these often counteracting influencing factors in practical situations.

This paper discusses an algorithm to calculate information about the trial that is needed at the design stage implemented as an S-plus function. The function allows the user to specify arbitrary length of accrual, control, and treatment survival distributions; number and timing of interim analyses; stopping boundaries or an alpha-spending function; and which member of the Harrington-Fleming Gρ class of statistics it is. Three examples from real treatment protocols are presented.

To study whether clinical trial consent forms comply with international guidelines, the deficiencies of 71 clinical trial consent forms reviewed by the Center for Drug Evaluation in Taiwan were analyzed. Two hundred and twenty seven deficiencies in 15 categories were found. The most frequent deficiency was inadequate description of the worldwide regulatory status of the study drug, which was not specifically required by the international guidelines. The second most frequent deficiency was inadequate information regarding the person to contact in case of an emergency. It was concluded that consent forms, in general, do comply with international guidelines. However, the quality and hence, the protection of clinical trial subjects, can be further improved by monitoring deficiencies not required by the international guidelines but deemed significant.

Multiple issues concerning the assent process for adolescent female participation in clinical trials are present in a process that has historically been based on an adult developmental and cognitive perspective. Adolescents are experiencing physiological and psycho-social, sexual growth and, therefore, should not be approached as though they are adults. This paper addresses important assent elements from the unique developmental perspective of female adolescents including sexual activity, birth control, privacy rights, confidentiality, and pregnancy. A proposed assent process and model assent form addressing these important issues are presented.

There is a pressing need to reconsider clinical drug development and distribution of medicines in a truly global sense. The majority of people who desperately need medicinal products get only an inadequate portion of all that is manufactured. This paper is an appeal to those in the international drug development arena to include some of the poorest countries in their drug development programs. It is also a challenge to health professionals and regulatory authorities in those countries to upgrade clinical trial procedures in order to meet international standards and to provide other incentives that attract clinical trials from international drug companies. As a case study, the status of clinical research in Kenya is documented. It is shown that the framework for conducting clinical trials exists. Potential sponsors are challenged to seek out clinical trial opportunities in this region in order to benefit from the impressive number of excellent health research professionals and large pools of drug-free patient populations.

Clinical trials, by their very nature, are a kind of second choice involving uncertainty from the beginning. The inherent characteristics of clinical trials necessitate ethical considerations. Ethical analysis emphasizes the importance of medical indications, patient preferences, trial quality, and contextual features. Instances of clinical trial misconduct are usually due to insufficient analysis of medical indications, which ignore patient preferences and the way in which investigators assess clinical trial results. These problems are universal concerns. In the context of clinical trials, these are subjective needs in every society. For clinical trials conducted in Asia, ethics must consider the specific needs and benefits of Asian people.

This article provides an overview of legislative differences among countries. There are two basic types of legal systems: common-law (also called Anglo-American legal systems) and civil law. A nation's culture is reflected in its law. In most countries, laws and regulations include a preamble, a dictum, and an explanatory memorandum. The dictum, which contains the articles, is the most important part. The dictum includes definitions, realm or scope, and the rules in stricto sensu.

Closely reading the definitions is important. For example, in the European Union, it is important to know the definition of herbal products in order to determine whether the herbal regulations apply. Determining the scope of the regulation is also necessary in order to determine whether a regulation is applicable.

In many countries, little attention was paid to herbal medicines during the second half of the twentieth century, when most pharmaceutical legislation and licensing procedures were developed. Thus, many countries have less specific regulations for herbal medicines than for pharmaceuticals. Today, there is renewed interest in herbal medicines. Many countries are preparing new legislation on herbal medicines.

In Germany in 1995 an intercompany expert working group was formed to define a flexible structure for a modern database system, named the Pharmacokinetic/Pharmacodynamic RESearch TOol (PRESTO), which handles pharmacokinetic/pharmacodynamic (PK/PD) results of entire research and development (R&D) projects, thus going beyond the information available in laboratory or clinical data systems generally present in most companies. PRESTO consists of two main modules: a database and an analysis system. The database part of PRESTO is designed for storing and managing PK and PD study data. Associated information such as biochemistry, toxicokinetic, physico-chemistry, and clinical chemistry data can also be handled to aid the interpretation of results, if necessary. The database will be used as a source for all kinds of pharmacokinetic, pharmacodynamic, and biometric evaluations. The extraction of data across studies to prepare meta-analyses is an essential feature of this system. The analysis system part of PRESTO provides uniform graphical interfaces to the database and to commercially available and proprietary data analysis programs (noncompartmental, compartmental PK, effect modeling, population PK/PD) as well as statistical software packages. The database part is then additionally used as a repository of the results from these evaluations. PRESTO is designed to a modular concept and a flexible data model, and offers configuration to site-specific needs. The concept supports filfillment of Good Clinical Practice/Good Laboratory Practice requirement

A well-written project scope or statement of work is the cornerstone for any outsourced work. An effective scope document is written from the perspective of both the sponsor and the provider. Understanding and defining this mutual perspective requires considerably more effort, discussion, and internal alignment at the sponsor than is often done. The work itself needs to be defined not only in the context of the specific project, but also in the context of the sponsor's overall project objectives, project management expectations, and commercial philosophy. A project for which these objectives and expectations are clearly stated in a Request for Proposal (RFP) is far more likely to lead to success than a project in which objectives and expectations are not clearly defined. This article outlines those factors that should be considered in developing scope and other aspects of the RFP, and offers suggestions for how this should be accomplished.

There is an opportunity to take the contract research organization (CRO)/sponsor relationship to a new level of performance with the implementation of a comprehensive outsourcing strategy that becomes part of a corporate culture. The strategy starts with macro choices that drill down to determine micro processes. If a sponsor company can answer the why, how, and what questions for outsourcing and train internal staff accordingly, then a formula is created to optimize CRO relationships. Performance metrics are then closely aligned with corporate goals and driven by a tactical level modeled for the future. With a cohesive plan, the organizational, cultural, and management differences at all levels within a company become secondary to the focus on corporate results.

GlaxoSmithKline (formerly Glaxo Wellcome Genetics Directorate) undertook a descriptive study to elicit volunteers' perceptions of a pharmacogenetic research consent form, an educational brochure, and a video; and to identify modifications in these materials that would enhance their usefulness. Face-to-face interviews were conducted to obtain feedback on the material and assess volunteer understanding of the basic components of the study. Although repeated exposure to key information in different formats resulted in improved comprehension, almost one-third of respondents could not accurately describe the two options for participating in the pharmacogenetic research. Almost all of the respondents reported that they would like to have the brochure, video, or both, in addition to the consent form. These results underscore the importance of providing volunteers with the opportunity for discussion with the study physician. They also support the use of supplementary aids to accommodate different styles of processing information. The respondents' suggestions will be considered when the materials are revised.

Drug discovery operations in pharmaceutical companies are often required to decide if it is better to commit resources to the development of novel, first-in-class compounds (“prototypes”) or to use the same resources to develop “backups” that can be brought forward to replace a prototype that fails during development. By examining the probabilistic dependency between the failure of a prototype and its backups, we find that adding backup compounds to a development program enhances the chances that a program will result in the development of one or more marketable products. The benefit of developing backup compounds is subject to the law of diminishing returns. Thus, the most cost-effective strategies will involve creating a limited number of backups for each prototype. Despite the existence of inherent similarities between a prototype and its backups, continuing to pursue backups after the prototype has failed can still be an attractive development opportunity.

CONCLUSIONS

The detection of fraud and other systematic data irregularities in clinical trials is an important issue. While awareness of the problem is growing and willingness to combat it is clear, there still appears to be a lack of detection procedures suitable for routine implementation by trial coordinators. The shortage is particularly acute for discrete data, since the majority of methods which are available have been developed for continuous responses. In this paper, we examine the suitability of existing methods for discrete outcomes and propose a new technique for questionnaire data in both an informal graphical mode and as a randomization test. This method exploits the underlying correlation structure of a questionnaire and the difficulty in fabricating such details. A data set concerning a trial of a novel drug for treatment of schizophrenia, in which the Brief Psychiatric Rating Scale was used to assess patient mental health, is used for illustration.

Integrated summaries of safety and efficacy have long been used for regulatory purposes in clinical drug development, where the main objective is to summarize the results of a drug development program as outlined in the International Conference on Harmonization (ICH) E9 guideline. Curiously, the use of meta-analytical techniques seems to be restricted to the submission process and little use of cumulative data is made for life cycle management of drugs. In this paper, we will explore options for a comprehensive approach to support the development, registration, and life cycle management of pharmaceuticals for human use.

Drawing upon more than 30 years of experience in the drug industry, the author suggests how quality control principles proposed by W. Edwards Deming can be applied to case report form (CRF) processing. The transfer of information from patient visit to writing a final report is broken into 16 distinct steps. It is proposed that time to process be taken as a measure of quality. The author identifies a specific step—follow-up on queries to investigator sites—as the most variable of these steps in many programs and suggests methods for reducing the time involved. The author then identifies other steps that have high variability and suggests methods for improving them.

In this paper we discuss a behavioral Bayes approach to the sample size question in clinical trials with binary responses for which the central limit theorem cannot be applied to provide an adequate approximation of the size of a trial. A fully Bayesian framework is considered. The optimal sample size is obtained by maximizing the expected net benefit, which is the benefit from subsequent use of the new treatment under consideration minus the cost of the trial. The regulatory requirements for granting a licence to the new treatment are discussed. It is shown, not surprisingly, that the optimal sample size depends strongly on the expected benefit from a conclusively favorable outcome, and on the strength of the evidence required by the regulator. Conventional approaches to the question ignore the trade-off between costs and benefits.

When two drug products are combined together, the traditional design of a trial to investigate the efficacy of the combination product usually includes four arms: a placebo arm, both monotherapy arms, and the combination arm. For ethical reasons, it is sometimes not possible to include a placebo arm in the study when one drug has already been shown to be effective. In this article, we will specifically look at the case when drug A has already been shown to have a mortality effect relative to placebo from an historical study. A new drug is believed to have a similar effect to drug A, and the effect of the combination of the two drugs is believed to be more effective than drug A alone. A clinical trial is designed with three arms to show these conclusions, but no placebo arm is present.

An analysis of combined safety data from cardiology, pulmonology, and bioequivalence studies collected at the Central Register of Clinical Trials in Poland was conducted. The number of serious adverse events, adverse events, and patient withdrawals is lower in combined data from trials than in individual published studies. In some acute and severe conditions, more adverse events are reported in placebo-treated patients than in the treatment arm.

This article reviews the value and importance of the World Health Organisation Certificate of Pharmaceutical Product (CPP) scheme. The scheme has largely streamlined a part of the registration procedure associated with imported medicines. It provides a significant assurance to regulatory authorities that imported medicines have been evaluated against rigorous and publicly-defined standards of quality, safety, and efficacy and have been approved for marketing. It also provides confirmation that the product is manufactured in accordance with the requirements of Good Manufacturing Practice.

A more effective use of the scheme may provide drug regulatory authorities with an opportunity to deploy their resources to other areas of medicines regulation to the greater benefit of the public health. Six recommendations are made regarding how use of the scheme could be enhanced to improve patients' access to new medicines more rapidly: 1. CPPs should be required at the regulatory approval stage rather than at submission of the application; 2. Regulatory agencies should develop goals to approve products within one month after receiving the CPP; 3. CPPs should be acceptable from nonsource countries, that is, a selection of issuing authorities recognized for their highly developed regulatory review processes; 4. CPPs should be accepted from recognized authorities regardless of marketing status in that country; 5. Health authorities with limited resources should consider approving the product on the basis of a CPP alone; and 6. Legalization of CPPs should not be required.

Facing serious challenges, the industry is looking for ways to shorten the drug discovery cycle without taking additional risks. Techniques such as high throughput screening, genomics, and proteomics generate enormous amounts of data. However, they impose an even bigger challenge to process that flood of information without delaying the drug development process. If both context-based models and data-driven methods are used for the knowledge discovery process then these new scientific techniques could be utilized in a much more structured way. By definition, these technologies require close cooperation between information technology experts and research scientists, enabling more creative project management. This will lead directly to a scenario in which leads, targets, and drug candidates are selected with much higher quality.

Objectives: This study used Rogers' model of adoption of innovation to investigate consumers' adoption of herbal therapies. Methods: Data were collected from up to 100 surveys at each of eight family practice clinics and a mail survey of a random sample of 500 Iowa residents. Independent variables measured consumer characteristics, social systems, communication channels, and herbal characteristics. The number of herbal products reported being used was the measure of adoption. For those respondents reporting herbal use, multiple regression assessed the associations between adoption and the modeled influences on adoption. Results: Of the 794 respondents, 276 (34.8%) reported using herbal products. The regression was performed using the 236 cases with complete data. The overall regression model was significant (R-square = 0.406). Significant positive influences included getting information about herbs from an herb professional and from the news, and obtaining herbal products from health food stores and from mail order sources. A belief that herbs improve health was a significant influence as well. Conclusions: The absence of health care practitioners from many consumers' decisions to use herbals draws attention to the importance of understanding the variety of influences on consumers' adoption of herbal products.

Objectives: To determine whether the reading level of health information printouts and the inclusion of commercial information varied in a statistically significant manner in printouts obtained from a retail pharmacy. Methods: A total of 31 different health information printouts were evaluated for reading level using the Simplified Measure of Gobbledygook (SMOG) readability analysis. Chi-square was used to determine differences in the presence or absence of four commercial content parameters: mention of a health organization, mention of a manufacturer, mention of a drug, or mention of a dose. Results: A single-sample t-test revealed a statistically significant difference in reading level among the health information printouts, t(30) = 47.91, p < 0.000, two-tailed. Chi-square analysis found no significant difference in whether a health organization, χ²(1, n = 31) = 1.58, p = 0.21, or a manufacturer, χ²(1, n = 31) = 2.61, p = 0.11, were mentioned. There was a statistically significant difference in whether a drug, χ²(1, n = 31) = 9.32, p = 0.002, or a dose, χ²(1, n = 31) = 20.16, p = 0.000, was mentioned. Conclusions: The fact that reading levels and the mention of a drug or dose was significantly different among the printouts suggests that these were not random events. It is thought that printouts, which have strong commercial overtones, are prepared in a manner to influence consumers to seek these products from their health care provider and not to strictly provide information on a particular health condition or disease state.

The purpose of this study was to assess pharmacy students' attitudes toward the use of Web-based pharmacy reference guides. Reference guides exist to assist the user to quickly locate the desired information through defined search strategies. Web-based guides have several distinct advantages over a printed format. One major advantage is that they can be easily edited and posted on an Internet server. A Likert-type rating scale was developed to assess pharmacy students' attitudes toward the usefulness and effectiveness of the pharmacy reference guides. A total of 270 students from four drug information/literature evaluation pharmacy school courses were surveyed; 182 (67%) students returned the survey. Percentages from five questions with the assigned rating of one through five (strongly disagree to strongly agree) indicated that most students either agree or strongly agree that the Web-based guides were easy to use and effective in locating pertinent drug information resources. In summary, the results indicate that the guides are performing the intended purpose.

Objective: To explore the impact of the inclusion of a benefit message in a patient package insert on knowledge about medicines and on subjective benefit/risk perception. Setting: Female members of community social organizations, female relatives of psychology students, and caregivers to psychotic patients. Nature of the study: Randomized, controlled healthy human volunteer study with three parallel experiments, involving the inserts of cisapride, itraconazol, and risperidon. Design: Subjects were recruited in a convenience sample and randomized to one control and two intervention groups (one with a normal insert and one with an insert with a benefit message). Material and methods: Subjects were asked to read the inserts (using mock text in the control group) in 5 to 15 minutes. Knowledge of the medication was tested with 20 simple questions (to be answered Yes/No/Don't know) and benefit/risk perception with a five-point bipolar Likert scale. Results: In the three experiments respectively 89, 102, and 83 subjects were recruited. The provision of inserts increased the knowledge about medication in all the intervention groups. Thirty-one percent, 41%, and 54% of the subjects who read a normal insert agreed that the benefit of the medicine was greater than its risks, compared to 62%, 64%, and 70% of subjects who read an insert with a benefit message included (P <0.05 in all 3 experiments). Discussion: A hypothesis for further research is formulated: adding a section on benefit information within a patient package insert helps to integrate increased knowledge about medication into a more balanced benefit/risk perception.

The added value for assessing the health-related quality of life (HRQOL) in chronic conditions is now well documented for evaluation of treatment effectiveness in clinical trials and as a criterion for licensing new medications and in policy decisions. However, European standards still need to be developed for the measurement and reporting of HRQOL in clinical trials. This is one of the objectives of the European Regulatory Issues on Quality of Life Assessment (ERIQA) Working Group. This document reviews the major issues arising from the selection of an HRQOL instrument; the integration of HRQOL assessment into the research protocol (methodological design, practicalities of HRQOL administration and collection, prevention and handling of missing data); the statistical analysis plan; and the presentation and interpretation of the results. Finally, to gain wider acceptance, whether HRQOL is considered as a primary or secondary endpoint, the scientific principles of clinical trial design should apply to HRQOL.

This paper describes an organization, The Institute of Health Economics in Alberta, Canada, that has been created by multisectoral collaboration and is engaged in pharmacoeconomics and outcomes research and applications. Since its establishment, a number of academic researchers have been attracted to Alberta from elsewhere. A multisectoral process (that incorporates both quality and relevance) of developing research programs has been implemented. Multidisciplinary and multicenter groups are being put together to undertake research programs in disease-specific areas. Some of these will provide help to government decision makers regarding the introduction of new, expensive health technologies. Studies are abo underway to try and improve drug compliance, particularly among the elderly.

Challenges faced include the different time frames that decision makers and researchers have for research projects. It has also been a challenge translating expressed research needs of “users” to meaningful research questions. However, the structure of the institute has enabled such obstacles to be clearly defined and addressed.