Showing papers in "Drug Information Journal in 1999"

Some Issues in the Design and Analysis of Equivalence Trials

Abstract: Given the number of approved drugs, it is increasingly the case that the comparison arm for a new drug or combination product is another drug or combination, that is, the trial uses an “active-control.” Such active-controlled trials raise issues not seen in placebo-controlled trials. This note reviews and discusses some issues associated with the design and analysis of equivalence trials. Included are discussions of the choice of the equivalence allowance in designing the trial, and the roles of confidence intervals and intent-to-treat analyses.

Design Issues in Noninferiority/Equivalence Trials*:

Abstract: When designing a noninferiority/equivalence trial, the sponsor intends to show efficacy by demonstrating that a new treatment is as good as or not worse than a known effective treatment by a small predefined margin. To confirm noninferiority/equivalence of the new treatment to an active control, “sensitivity-to-drug-effects” and “assay sensitivity,” as defined in the International Conference on Harmonization (ICH) E10 Guideline (1, 2) must be supported. Otherwise, a finding of mere nonsignificant difference between treatments in the traditional setting of significance testing leaves the question unanswered: Would the trial have concluded noninferiority while the new treatment was, in fact, inferior?This paper first reviews the choice of control and the crucial issues of sensitivity-to-drug-effects and assay sensitivity. Then, it discusses the choice of the noninferiority/equivalence margin and the forms of the null and alternative hypotheses and confidence intervals. Finally, it addresses the inherent dif...

Using Conjoint Analysis to Evaluate Health State Preferences

Abstract: Quality of life dimensions are important considerations when patients evaluate pharmaceutical products with respect to personal benefits. Traditionally, standard gamble, time trade-off, and rating scale techniques are used to obtain preference (utility) estimates for various quality of life dimensions. This study examines three objectives to determine the feasibility of using conjoint analysis to elicit patient preferences for a particular health state. For the first objective, patients with multiple myeloma were asked to select quality of life conditions for 18 hypothetical patients with cancer and to indicate which conditions were the easiest and hardest to live with. Second, patients were asked to rate several cancer-related and general symptoms using visual analog scales. Third, comparisons were made between the two techniques to determine similarity and validity. Results revealed that conjoint analysis is useful for health-related quality of life research, and that conjoint analysis results compare favorably with values obtained from visual analog scales.

Nonparametric Analysis of Covariance and its Role in Noninferiority Clinical Trials

Abstract: Some randomized clinical trials are conducted to compare test treatment, an active reference control, and placebo with the objectives of demonstrating that test treatment is not inferior to referen...

Some Developments on the International Index of Erectile Function (IIEF)

Abstract: This manuscript covers two complementary topics. For both topics, data from clinical studies and control samples were used. The first topic provides an overview of the development and validation of the International Index of Erectile Function (IIEF), a 15-item questionnaire, for male erectile and sexual function. A principal components analysis revealed five factors (erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction). The IIEF demonstrated reliability, validity, and sensitivity and specificity with regard to treatment effect. The second topic presents, among men who reported having had sexual intercourse, the methodology and results on the evaluation of the erectile function (EF) domain of the IIEF, which has a range of scores from 6–30 for these men, as a diagnostic tool to help discriminate between men with and without erectile dysfunction (ED). For a prevalence rate of ED equal to 0.5 in a clinical population, the Classification and Regression Trees program gave a cutoff score of 25: men with EF scores of 25 or less were retrospectively classified as having ED, while those with scores above 25 were classified as not having ED (sensitivity = 0.97, specificity = 0.88). The IIEF has been developed and validated as a scale that is reliable, brief, self-administered, and psychometrically sound. Its EF domain showed desirable diagnostic properties. More research is encouraged in this area.

Issues in adjusting for covariates arising postrandomization in clinical trials

Abstract: While there is broad consensus on analytic techniques for adjusting for covariates at baseline, the situation for covariates arising postrandomization is considerably more difficult. Examples include the level of patient “compliance” measured through pill counts and other biochemical markers, the occurrence of missing data over patient followup, and early withdrawal from medication. The “intention-to-treat” (ITT) principle requires that all randomized patients be included in all analyses irrespective of their confounder experience. This approach, however, seems at odds with good scientific method and is a considerable source of friction with medical investigators. In this paper, we review the interpretation of this analysis strategy and suggest that the statistical community has been careless in its interpretation of these results. We outline a conservative strategy that is consistent with ITT principles. Nevertheless, any analysis that adjusts for these covariates must be considered speculative in nature and followed by a properly designed confirmatory study. For this reason, we argue that these analyses are of greater relevance early in a drug development program.

Exploring heterogeneity in randomized trials via meta-analysis

Abstract: Meta-analysis of clinical trials with heterogeneous results provides an opportunity to learn a great deal about variations in treatment effectiveness. Rather than computing a single summary estimate of a series of trials, it may be more informative to explore the effect that different study characteristics may make on treatment efficacy. Regression analysis offers a tool for these analyses. This paper outlines and applies hierarchical Bayesian models for this purpose, presenting two examples of meta-regression using summary data, in one of which results are compared with those from analysis of complete individual patient data. When covariates are not readily available, the event rate in the control group can become a surrogate covariate. An empirical study of 115 meta-analyses shows that this control rate is significantly correlated with the odds ratio about 15% of the time. This suggests that investigators should search for the causes of heterogeneity related to patient characteristics and treatment protocols to determine when treatment is most beneficial and that they should plan to study this heterogeneity in clinical trials.

Overview of Herbal Quality Control

Abstract: This paper outlines the importance of quality control of herbal remedies by providing an overview of the types of toxic and pathogenic contaminants which may OCCUK These include toxic boranicals, micro-organisms, microbial toxins, pesticides, fumigation agents, radioactivity, toxic metals, synthetic pharmaceuticals, and animal substances. Academia, government, the herbal industry, and the pharmaceutical industry must work together to develop practical methods of improving the safety of herbal remedies.

One Large, Well-Designed, Multicenter Study as an Alternative to the Usual Fda Paradigm

Abstract: This article considers when a single study presents both: 1. The same strength of evidence for a drug or biologic effects as the usual Food and Drug Administration (FDA) two-study paradigm, and 2. Also gives sufficient evidence of replicability as in two studies done at disjoint sets of institutions. It is argued that 1. holds if the two-sided significance level is 0.00125 and 2. holds if the clinical sites are divided into two subsets that maximize the smaller sample size that each is statistically significant at the 0.05 significance level. Other approaches to satisfying 2. are also addressed. The approach is illustrated with data from the Condylox® Gel 0.5% (podofilox gel) versus vehicle control.

A model for understanding patient attribution of adverse drug reaction symptoms

Abstract: The study addressed issues surrounding the patient's recognition of whether a symptom is drug- or disease-related. Studies have demonstrated that the information the lay population has about illness can be organized into five categories: identity (symptoms and label), cause, time course, consequences, and cure. These elements, termed illness representations or prototypes, facilitate patient interpretation and response to symptoms as they occur. Theoretically, patients may have such a framework for interpretation of symptoms that they considered adverse drug reactions. The purpose of this study was to explore whether an adverse drug reaction (ADR) prototype exists. A self-administered questionnaire was used to elicit the subject's perceptions and awareness of adverse drug reactions. Subjects were also asked to make judgments about severity of ADRs and frequency of particular symptoms as drug-related effects. The study population was a sample of 338 adults visiting a family practice clinic over a four-week ...

The European Agency for the Evaluation of Medicinal Products’ Centralized Procedure for Product Approval: Current Status

Abstract: The European Agency for the Evaluation of Medicinal Products (EMEA) was established in July 1993 to unify regulatory practices and improve market access within the European Union (EU). In February 1995, the EMEA implemented the centralized procedure for drug approval within the EU. The current study explores the history, goals, and implementation of the centralized procedure. We examine the time to obtain product marketing authorization for products that have gone through the process relative to the goals set for the program at its inception, and we compare approval times for a group of products that have been approved by both the EMEA and the United States Food and Drug Administration (FDA). Our data indicate that the goals established by the EMEA for the timeliness of application review have generally been met. Moreover, mean approval times for products approved by both the EMEA and the FDA were similar.

A household survey of source, availability, and use of antimalarials in a rural area of tanzania

Abstract: The source, availability, and use of antimalarial drugs in a rural community in the Kibaha district of Tanzania were assessed. Using questionnaires, the heads of households and mothers/guardians of children under five years of age in 1000 randomly selected households were interviewed, and an inventory of antimalarials at all drug stores and shops in the area was carried out. The majority of the drugs stocked by both households and mothers/guardians were antimalarials, exclusively chloroquine. Only 20.1% of the mothers/guardians knew the correct pediatric dose regimen of the chloroquine syrup which they stocked the most. In contrast, 70.4% of the mothers/guardians stated the correct adult dose of chloroquine tablets. They had significantly (p < 0.025) higher mean ages than those who stated the dose incorrectly. Similarly, 78.6% of heads of households stated the correct adult dose of chloroquine tablets, and those with more education had better knowledge of dose regimens (p < 0.001). Drug stores were the main sources of malaria treatment for both the heads of households (72.2%) and the mothers/guardians (89.4%). Lack of drugs at public health facilities, as stated by more than 85.6% of the mothers /guardians, is a possible reason for this. Only four of the drug store sellers had professional training. Most malaria treatment in children occurs in the home and, thus, poor knowledge of pediatric chloroquine regimen by the mothers/guardians is of great concern. A simplified dose regimen, particularly the pediatric formulation for mothers/ guardians with limited education, should be developed. As these caregivers interact with the public and private health facilities, the quality of malaria management, including instructions given to them, needs to be assessed.

Individual Bioequivalence—A Review of the FDA Draft Guidance:

Abstract: As more generic drugs become available in the marketplace, it is a public concern whether the quality, safety, and efficacy of generic drugs are the same as the brand name drug. Under current regulation, the United States Food and Drug Administration (FDA) only requires that evidence of bioequivalence in average bioavailability be provided for assessment of bioequivalence. FDA, however, does not require that bioequivalence among generic copies of the same brand name drug be demonstrated. As a result, it is a concern whether these generic drugs can be used interchangeably. To address this question, the concepts of population bioequivalence for drug prescribability and individual bioequivalence for drug switchability have been proposed. In this paper, we provide a comprehensive review of the draft FDA guidance on “In Vivo Bioequivalence Studies Based on Population and Individual Bioequivalence Approaches” which was distributed for comment in October 1997. The discussion will be primarily on the FDA proposed criteria, design, statistical methods, and interpretations on the assessment of individual bioequivalence from the pharmaceutical industry perspective.

Sensitivity Analysis by Worst and Best Case Assessment: Is it Really Sensitive?:

Abstract: The question of how to perform an analysis according to intention-to-treat in the presence of missing information is of major importance. Several procedures have been suggested, but there is no generally accepted rule. Sensitivity analysis has been recommended as one solution. Extreme case analysis, consisting of worst case and best case analysis, has been widely requested to assess the sensitivity of results to the method of handling missing values.In a simulation study the consequences of worst case and best case analysis on type I error and power of clinical trials with continuous endpoints are evaluated. The strategies of worst case and best case analysis are too extreme for a meaningful sensitivity analysis. Only for very small dropout rates are the two strategies able to discriminate at all between different situations. The demand for sensitivity analysis is no satisfactory solution to the intention-to-treat problem unless its methods and application are evaluated carefully, it is specified in advan...

A Health-Related Quality of Life Measure in Patients with Deep Vein Thrombosis: A Validation Study*

Abstract: This study was conducted to test the psychometric properties of a newly developed health-related quality of life (HRQOL) questionnaire. One hundred eleven individuals identified through a registry and medical records who experienced an acute iliofemoral deep vein thrombosis (DVT) more than six months ago completed the questionnaire (containing the Health Utilities Index and Short Form-12, and DVT-specific scales). Respondents were primarily female, Caucasian, and married with an average age of 54 years. Internal-consistency reliability was acceptable (Cronbach’s alpha: 0.69–0.95). Interscale correlations were as expected. In general, patients with no symptoms reported the highest functioning, those with severe symptoms the lowest, and those with moderate symptoms reported values between the two. Guyatt’s statistic values for the majority of scales were ≥|0.20|, demonstrating acceptable responsiveness to change. Psychometric testing indicated that the measure is reliable, valid, and responsive in this group. Future research will focus on further evaluating its use in studies of patients receiving different therapies for acute DVT.

Using the Readability Assessment Instrument to Evaluate Patient Medication Leaflets

Abstract: Seven phenytoin information leaflets were evaluated for their readability using the Singh Readability Assessment Instrument (RAIN). These evaluations were performed to ascertain if the variable criteria of the RAIN, developed to assess the readability of patient information brochures, were appropriate for evaluating the readability of medication information leaflets. Leaflets were scored in terms of eight variables identified by reading researchers as facilitating comprehension: global coherence, local coherence, unity, audience appropriateness, adjunct questions, writing style, illustrations, and typography. A scoring criterion of 80% adherence on most variables was considered acceptable. The American Association of Retired Persons leaflet was found to be acceptable. Five of the leaflets failed to meet RAIN criteria for audience appropriateness, adjunct questions, illustrations, and typography. Results support the RAIN as a useful tool for evaluating and optimizing the readability of medication information leaflets.

Mixed-Model Imputation of Cost Data for Early Discontinuers from a Randomized Clinical Trial:

Abstract: For studies with appreciable attrition in which one expects not only differences between individual patients but also time trends in repeated measures, a “sophisticatedly simple” approach to imputation of missing values is illustrated. A linear model having random patient intercept and slope terms as well as fixed effects for treatment, investigator, time, and interactions between both treatment-investigator and treatment-time is used. In contrast to a purely fixed effects approach, mixed-model estimation then optimally shrinks patient-specific differences toward zero. This shrinkage moves the predictions for each patient toward the average time line for the corresponding investigator and treatment. Using a variety of sensitivity analyses, it is established that imputation of missing values using these mixed-model predictions provides a “benchmark” lower limit for cost differences between treatments. To illustrate concepts, supplementary analyses of selected cost and effectiveness outcomes from a randomized, double-blind trial of olanzapine versus haloperidol for the treatment of schizophrenia are presented.

Medical Affairs and Drug Information Practices within the Pharmaceutical Industry: Results of a Benchmarking Survey

Abstract: Pharma or biotech companies that are looking to develop and implement a medical affairs department, or current directors who are looking for ways to assess the performance of their department, find...

New and Integrated Approaches to Successful Accelerated Drug Development

Abstract: Traditionally, the development of a new drug from discovery to market takes 10 to 15 years and costs hundreds of millions of dollars. Accelerated drug development, therefore, is of critical importance to both maximizing return on this investment and bringing drugs for unmet medical needs to patients as rapidly as possible. New structure-based development strategies are being combined with integrated, multidisciplinary approaches to speed the processes of physicochemical and pharmacological characterization, toxico-logical investigation, and clinical testing. The process of accelerated drug development, however, presents unique challenges as well as opportunities.

Global Two-Group Multiple Endpoint Adjustment Methods Applied to Clinical Trials

Abstract: Often, clinical trial results are reported and used for claiming a treatment effect without adjusting for the multiplicity arising from the presence of multiple endpoints. It is well recognized that this practice is likely to inflate the type I error rate unless the endpoints are highly correlated. To control such an inflation of the type I error rate, two approaches, both appropriate on their own grounds, are in use. One is the ’global’ approach which aims at demonstrating overall treatment effect and considers all given endpoints simultaneously. The other approach, often called the ’endpoint-speciftc’ approach, assesses significance for each endpoint separately, assuring meaningful control of the overall type I error rate. This paper addresses and discusses some of these global multiple endpoint adjustment methods in the context of clinical trial applications where two treatments are being compared (for example, active treatment with a placebo), and gives some simulation results to assess their performance regarding the a-level protection and power.

Qualified Statisticians in the European Pharmaceutical Industry: Report of a European Federation of Statisticians in the Pharmaceutical Industry (EFSPI) Working Group: EFSPI Working Group,* Isleworth, United Kingdom

Abstract: Regulatory guidelines assume that the responsibility for all statistical work associated with clinical trials will lie with a statistician who should be qualified by education, training, and experience to perform this task. As different European countries have widely differing educational systems and varied experiences of applying statistics in the pharmaceutical industry, it is difficult to develop a clear, unambiguous Europe-wide definition of the desired profile of such a statistician. There is a broad consensus, however, that an appropriate background would include a university degree in statistics or equivalent qualification, plus more than three years of experience in medical statistics. An example of an equivalent qualification would be a degree in mathematics or a related subject, involving more than one year (full-time equivalent) of courses in statistics.It is hoped that this outline definition will give guidance to companies, to regulatory authorities, and to individual statisticians in terms o...

Pricing and Reimbursement Regulation in Europe: An Update on the Industry Perspective

Abstract: Health costs, including the cost of pharmaceuticals, have been rising throughout the world for 35 years. Governments are determined to reduce public expenditure on health; pharmaceuticals are an obvious if frequently an inappropriate target. Cost containment measures include positive and negative lists, permission for more over-the-counter drugs, reference pricing and other price and profit controls, generic substitution, patient copayments, and drug budgets for general practitioners. These methods have been tried in various European countries and their experiences are reviewed. The advantages and drawbacks of the methods to patients, physicians, and the pharmaceutical industry are discussed. The question of elasticity of demand for pharmaceuticals is reviewed in an Appendix and a value varying between −0.44 and about −1.3 is obtained. The industry response to cost containment has been mixed. Some of the research-based companies have followed confrontational policies with their governments; others have tried collaborating. Companies aim at “satisficing” the market, that is, making the best profits they can consistent with not generating adverse publicity. The generics companies, which appear at first sight to profit from cost-cutting measures, are actually vulnerable to competition in generics from the research-based companies. Most companies are following policies of risk minimization and this is reflected in the large number of mergers in recent years. One change that has come about is that policy makers are collaborating internationally. The idea that multinationals can confront governments in Europe is now seen to be untrue, although it may be successful in the United States. The best prospect for pharmaceutical companies is to reach agreements with governments which enable them to flourish if they are innovative and to survive if they are not. This policy has so far been successful, and the industry seems to have emerged largely undamaged from the pressures of the early 1990s.

Sequential Designs for Monitoring Two Endpoints in a Clinical Trial

Abstract: When more than one response is of primary interest in a clinical trial, use of univariate stopping rules for allowing interim analyses is inappropriate. This paper considers the case where two endpoints are of interest and presents general methodology for the design, monitoring, and analysis of such trials. Two examples are presented of situations in which the technique could be implemented; the first is a trial in Alzheimer’s patients, the second concerns women with osteoporosis. The appropriate application of the procedure can lead to the same ethical and economic benefits of univariate sequential designs, and so carries the potential to lead to more efficient clinical trials.

Regulatory Status of Excipients in Japan

Abstract: Regulations governing excipients in Japan do not differ remarkably from those in other countries. The general notice in the Japanese Pharmacopoeia states that excipients must be harmless at the administration levels and must not interfere with the therapeutic efficacy or testing of the preparations. Thus, the evaluation of excipients requires an understanding of the preparation as a whole in addition to the inherent quality and safety of the excipients.General procedures involved in application for approval of excipients in Japan are introduced. The precedent of approval is of critical importance. Several points which should be considered describing the entries on quality attributes and safety in an application are explained. Future trends on Good Manufacturing Practice (GMP) and safety guidelines in Japan are also discussed.

Evaluation of Spontaneous Adverse Event Reports by Primary Reporter—A 15-Year Review (1983 to 1997)

Abstract: We conducted a study to explore whether the type of reporter has any impact on the quality and type of adverse event reports collected. One thousand spontaneous reports each from seven major reporter categories (primary care physicians, consultant/specialist physicians, psychiatrists, nurses, pharmacists, other health care providers, and consumers) were randomly generated from our safety database. Among the 7000 reports reviewed, serious reports were most commonly reported by consultant/specialist physicians (30.4% of the 1000 reports) with the lowest number reported by consumers (5.7%). Allergic reactions/anaphylaxis cases were reported most commonly by both pharmacists and other health care providers (2.9% each). Interestingly, other health care providers reported more cases about drug interaction than pharmacists (3.4% vs. 1.9%) although pharmacists remained the most common type of reporter to report lack of drug effect cases (14.6%). Psychiatrists (5.2%) and pharmacists (4.6%) reported the most incidences of overdose. Addiction/drug dependence reports were rarely reported, but were most commonly reported by primary care physicians and consumers (0.7% each). Completed reports were highest among primary care physicians. The current study is limited to our experience and further research by other investigators to confirm these findings is warranted.

Drugs in pregnancy : The dilemma of labeling

Abstract: The paper discusses the problems with pregnancy labeling of drugs. The Swedish, United States, and Australian labeling systems are briefly summarized. Data on drug use in early pregnancy in Sweden (1996) are presented according to pregnancy labeling category and with details on drugs thought to be teratogenic or where animal data suggest hazards. The various situations when drug teratogenicity are of interest are reviewed and the difficulties in presenting detailed pregnancy warnings valid for all situations are stressed. The amount of data needed for information in the different situations is discussed and exemplified. Finally, suggestions are made on how texts referring to drug use during pregnancy can be structured for different drug categories.

Monitoring Response to Treatment in the Development of Anti-Cancer Drugs Using Positron Emission Tomography (PET)

Abstract: Current assessment of the effect of anticancer drugs relies on measurement of tumor volume using structural imaging modalities such as CT/MRI. Functional imaging allows assessment of tumor physiology and metabolism in vivo. These measurements are more directly related to the anticancer drug target and may provide more specific and sensitive methods of assessing anticancer drug activity and response. Positron emission tomography (PET) is a sensitive, quantitative method of imaging radiotracers labeled with biologically important radionuclides. PET can be used to measure alterations in perfusion in response to pharmacological manipulation of tumor vasculature to improve drug delivery and in the future to assess novel therapeutic agents targeted directly at the tumor vasculature. 2-[IIC]-thymidine, a marker of proliferation, and [18F]-FDG, a marker of glucose metabolism reflecting tumor cell viability, may provide more sensitive methods of assessing anticancer drugs for in vivo activity for Phase I and II trials. In addition, 2-[IIC]-thymidine may be used to demonstrate the pharmacodynamic effects of specific enzyme inhibitors. Improved identification and measurement o/in vivo activity in Phase I/II trials may assist drug selection prior to commencement of very costly Phase HI assessment.

Hoffmann-La Roche Ltd. Drug Information & Safety Department Survey of Customer Needs and Satisfaction

Abstract: The purpose of this survey was to evaluate customer satisfaction with the services provided by the Hoffmann-La Roche Ltd. (Roche) Drug Information and Safety Department, and to identify the department’s strengths and areas for improvement. Bilingual surveys (English or French) were sent to 100 hospital pharmacists, 100 community pharmacists, 100 physicians, and 30 drug information centers randomly selected from a list of all inquiries made between November 1, 1996 and February 27, 1997. A slightly different version of the survey was sent to 125 Roche sales representatives. The response rate was 51.2%. Respondents reported a high level of overall satisfaction with Roche drug information services. In general, there was a good correlation between customer needs and customer satisfaction with the services offered. Areas of strength were identified as courtesy of personnel, accuracy, and relevance to the inquiry. The major area for improvement was found to be response time. Strategies for improvement include expanding the range of topics available through the “Fax on Demand” system, raising customer awareness of this system, streamlining the process of handling information requests, and using a drug information website with an externally accessible database to reduce the workload of the Roche Drug Information and Safety Department.

Clinical Equivalence—A Clarification

Abstract: Despite the increasing use of randomized clinical trials to investigate clinical equivalence between regimens, a misunderstanding concerning the design and analysis of such trials continues to exist. We, therefore, prepared this paper, hoping to clarify some fundamental issues concerning equivalence trials. We begin by reviewing the definition of clinical equivalence and discussing two common approaches to making decisions concerning clinical equivalence. We contrast the hypothesis testing approach to establish equivalence with that to show superiority. We argue that should the right kind of decision rules be used for equivalence determination, statements such as “equivalence trials promote sloppiness in trial design and conduct” can never be held against such trials. We conclude by giving some suggestions to help dispel common misconceptions about equivalence trials.

Interim analyses : An update of an FDA reviewer's experience and perspective

Abstract: Food and Drug Administration (FDA) clinical and statistical guidelines request that sponsors document considerations which will govern the conduct of interim analyses in clinical trials. These considerations include clearly stating the reasons for such interim analyses, the planned number of or the (information/calendar) times when the interim analyses will be carried out, adequate stopping rules, and measures taken to minimize bias.