Showing papers in "Drug Information Journal in 1995"

Assessment of Dose Proportionality: Report from the Statisticians in the Pharmaceutical Industry/Pharmacokinetics UK Joint Working Party

Abstract: There are a number of different approaches to the assessment of dose proportionality, but most of these are directed toward hypothesis testing. The analysis of dose proportionality studies, however, requires estimation rather than significance testing in order that the pharmacokinetic and clinical significance of any nonproportionality can be assessed.The methods of statistical analysis of these studies have been reviewed. An empirical model relating the log of the pharmacokinetic parameter linearly to the log of the dose (the “power model”) provides a readily interpreted measure of the degree of nonproportionality. The potential utility of this model has been demonstrated using a number of observed dataseis from different drugs. If there is doubt over the goodness of fit of the power model then analysis of variance (after log transformation), together with pairwise comparisons between doses, provides a suitable alternative approach.

In Vitro/In Vivo Correlations

Abstract: In vitro/in vivo correlations can and should be developed in many cases. This paper provides one approach to developing in vitro/in vivo correlations, along with examples, based upon the position of the United States Pharmacopeia (USP) Subcommittee on Bioavailability, Bioequivalence, and Dissolution (DBA). Although correlations should not be required, the Food and Drug Administration (FDA) must take a definitive position on the issue, accepting approaches which truly reflect in vivo performance.

Trends in Drug Development Costs, Times, and Risks:

Abstract: NEW DRUG DEVELOPMENT in the United States has been characterized by long development and regulatory review periods, high costs, and substantial scientific and financial risks. The factors that explain why the development and regulatory review processes are lengthy, costly, and risky are complex and vary in relative importance over time. Gathering reliable data on these processes and analyzing those data should precede and enhance evaluations of the factors that affect new drug development and regulatory review. This section surveys literature on the cost of drug development, the lengths of the development and regulatory review phases, and technical risks in new drug development for new chemical entities (NCEs). New results on clinical cost and clinical trial complexity for recent years are also presented. tures grew at about a 10% compound annual rate since 1979. On the other hand, new drug approvals in the United States have not yet increased at anywhere near such a rate. Without doubt, there is a substantial lag between R&D expenditures and marketing approval. Most of the expenditures at the end of the period shown should be associated with approvals in the future. Even so, it is hard not to at least suspect, and at most conclude, that R&D costs have increased over time. Several studies have averted the problems inherent in associating industry-level R&D expenditures with NCE approvals by estimating the cost of new drug development using detailed disaggregated data. Figure 2 shows comparative preclinical, clinical, and total costs per approved selforiginated NCE from two studies (1,2).*

Sparse-Sampling Optimal Designs in Pharmacokinetics and Toxicokinetics*:

Abstract: The population approach was developed to estimate population characteristics of the pharmacokinetics (PKs) of a drug from a sparse-sampling designed experiment in a set of individuals. This approac...

Large Differences between Prescribed and Dispensed Medicines Could Indicate Undertreatment

Abstract: The difference between prescribed and dispensed medicines in Sweden has been determined for the 20 most common diagnoses for all outpatients. For all diagnoses together, the value of dispensed medicines was 14% lower than for those prescribed. For some diagnoses a considerable number of the prescriptions never appeared at the pharmacies, for example, climactic symtoms—48%, allergic rhinitis—42%, glaucoma— 41%, and diabetes—39%. If the doctors intended that the medicines prescribed should also be consumed by the patients in order to obtain appropriate treatment, these data indicate that considerable undertreatment occurs for patients with certain diagnoses.

Current Issues in Bioequivalence Trials

Abstract: In recent years, as more generic drug products became available, the quality, safety, and efficacy of generic drugs became a great concern. As a result, the assessment of bioequivalence between the...

Information Overload with Written Prescription Drug Information

Abstract: The purpose of this study was to determine if increasing the scope and depth of information for written prescription drug information results in information overload Scope (number of topics) and depth (complexity of information) were varied in five information leaflets for a prescription drug Each of 150 patrons from a university medical clinic was given one of the leaflets randomly Patrons were asked to review the information and answer a pretested questionnaire upon completion to determine their degree of information overload Information overload was operationalized by a 15-item measure which included judgmental, emotional, and evaluative components A total of 94 individuals (63%) participated in the study Results of factor analysis suggested that three distinct components of information overload include: judgmental, emotional, and evaluative responses One-way ANOVA showed that respondents who received too much depth or too little scope of information were more likely to be confused, doubtful, an

Sample Size for Therapeutic Equivalence Based on Confidence Interval

Abstract: In this article, the sample size calculations pertaining to a therapeutic equivalence trial based on a confidence interval are described for both normally and dichotomously distributed data. Other issues regarding equivalence trials are also discussed.

A simple approach for the evaluation of individual bioequivalence

Abstract: The refinement of a procedure for assessing individual bioequivalence is presented. It is suggested that two drug products are inequivalent in individuals if a variation contrasting them substantia...

A Federal Perspective

Abstract: A Federal perspective is provided to the questions posed of the summary panel. Additionally, comments to presentations are provided. In general, unless the clinical trial is modified to collect the...

In Vitro-in Vivo Correlations — Quo Vadis

Abstract: During the last 25 years, there has been considerable interest in in vitro-in vivo relationships of oral dosage forms. The advantages are obvious in terms of cost, time, and safety. This paper considers the problems involved in establishing in vitro-in vivo relationships, the dimensions of the task, and the different perspectives that apply to in vitro-in vivo correlations. Two examples based on laboratory work on two compounds showing how in vitro data might be used to improve the efficiency and reduce the cost of dosage form development are included.

International Harmonization of Regulatory Requirements for Average Bioequivalence and Current Issues in Individual Bioequivalence

Abstract: International harmonization of regulatory requirements for average bioequivalence has made major progress during the last years, particularly with regard to the bioequivalence range and statistical analysis. The multiplicative model and hence the logarithmic transformation of the primary extent and rate characteristics AUC and Cmax and—consistent with this—the bioequivalence range of (0.80, 1.25) are now accepted by all major health authorities including the European Committee for Proprietary Medicinal Products (CPMP), the United States Food and Drug Administration (FDA), and the Canadian Health Protection Branch (HPB). Such a consensus is missing for the concept of individual bioequivalence. The selection of an appropriate methodology and suitable operative procedures for assessing individual bioequivalence must be addressed in the future by biostatisticians, biopharmaceutical scientists, and regulatory authorities.

Interpretation of Subgroup Analyses in Clinical Trials

Abstract: The reliability of subgroup analyses is frequently misunderstood. While pivotal clinical trials are usually designed to assess the global efficacy of a new therapy, there is often strong interest in performing exploratory subgroup analyses to allow for possible tailoring of patient care in a manner that depends on levels of one or more covariates. Estimates of treatment effects in subgroups tend to be highly variable. False-positive and false-negative conclusions from exploratory subgroup analyses are likely to occur, due to the unreliability of these estimates arising from this variability and due to the multiplicity of testing which is inherent in this exploratory setting. Prominent examples, as well as computer simulation studies for trials with time-to-event endpoints, are cited to provide scientific insight into the reliability of subgroup analyses, and into the proper interpretation of findings from these analyses. Exploratory subgroup analyses usually do not provide definitive conclusions, but rath...

A Review of the Source Document Verification Process in Clinical Trials

Abstract: Confirming that accurate and reliable information has been reported by the investigator to the sponsor during clinical trials is a fundamental requirement of good clinical practice (GCP), and there can be significant implications if this is not undertaken appropriately. Yet, there is still much uncertainty surrounding this process, generally referred to as source document verification (SDV). This paper attempts to identify and discuss the main considerations to enable an effective and appropriate SDV system to be implemented.The responsibilities of both the investigational team and the sponsor in SDV must be made clear at the outset of the trial. Considerations such as access to data and confidentiality must be fully addressed, so that there are no misunderstandings or surprises when SDV is undertaken. Records of what was done and found, including an evaluation of the findings, must be made, in the same way as for any other aspect of the trial. There must also be a recognition that SDV really adds value t...

A Drug Lag Update

Abstract: IN THE MID-l970s, Wardell’s pioneering drug lag studies revealed a therapeutically significant delay in the introduction of new drugs in the United States compared with the United Kingdom ( 1,2). These and later studies by other investigators demonstrated that the United States consistently lagged behind other industrialized countries in both the rate and timing of new drug introductions. Moreover, the impact of this delay on therapeutic practice in the United States was not offset by a significantly better safety record. Based on these findings, Wardell (3) concluded that the United Kingdom benefited from its less restrictive policies for approving new drugs and from its more developed program of postmarketing surveillance. At Congressional hearings in 1979, Wardell stated: “There is little doubt that for marketed drugs and approved therapeutic indications, the United States lags greatly, in the sense that new drugs are usually available abroad either exclusively or much earlier, and for a wider range of indications” (4). Although initially rejected by the FDA (5,6), the drug lag concept was eventually accepted as fact by policymakers in Concurrently focused on other concerns, such as health care reform, cost containment, and international competitiveness. Moreover, current efforts to standardize international regulatory practices for pharmaceuticals (eg, through the International Conference on Harmonization) and the increased globalization of the drug industry suggest that disparities among countries in the timing and rate of new drug introductions will eventually diminish. Nonetheless, recent reports in the academic literature and the lay press suggest that the drug lag continues to be a critical issue and that delays persist in the availability of important new therapies in the United States. In this report, the current status of the drug lag is examined. The first section reviews studies by the Tufts Center for the Study of Drug Development (CSDD) that show that the United States continues to lag behind other countries in the introduction of new pharmaceutical products. The next section examines recent data focusing on several specific therapeutic areas. The final section assesses the therapeutic implications of the drug lag.

A Health Services Approach for the Evaluation of Innovative Pharmaceutical and Biotechnology Products

Abstract: Recent advances in the field of biotechnology have created the potential for innovative therapies for the treatment of patients. These scientific innovations, however, have also created challenges in the assessment of efficacy in the clinical development process. Additionally, changes in the health care environment have led to increased demands on producers for information to be used in reimbursement decision making. Established methods of evaluation of more traditional therapies based on “clinical judgment” or the results of previous clinical trials may not meet these demands. This paper reviews the application of health services research techniques in the assessment of potential clinical endpoints and the time horizon of evaluation for clinical trials of innovative and more traditional clinical therapies.

Adverse Drug Reaction Reporting Part II: Evaluation of the Saskatchewan Pilot Project for a Regional Reporting Program in Canada:

Abstract: In October 1990, a regional center for reporting adverse drug reactions (ADRs) was established in Saskatchewan (SaskADR) as a pilot project for a revised national reporting system in Canada. SaskADR's development is described in this paper. During the first year of operation, SaskADR received 333 ADR reports, an approximately five-fold increase in the number of voluntary reports. In the four years preceding the pilot project, Canada's national ADR reporting program had received an average of 70 reports per year from Saskatchewan health care practitioners. The effect of regionalizing reporting was also assessed by comparing practitioners' responses to a questionnaire administered before (in 1990) and after (in 1991) SaskADR became operational; 355 pharmacists and 380 physicians responded to the questionnaire in both years. Based on questionnaire responses, the operation of SaskADR has had a positive impact, not only on the number of ADRs reported, but also on the familiarity of practitioners with procedure...

Metrics to Characterize Concentration-Time Profiles in Single- and Multiple-Dose Bioequivalence Studies

Abstract: In bioequivalence assessment, pharmacokinetic characteristics of concentration-time curves have traditionally been associated with rate and extent of absorption. In the actual context of bioequivalence, however, the similarity of the shapes rather than that of the absorption rates is essential. As a consequence, the following definition of bioequivalence was proposed during Bio-International ‘94 as a more appropriate one: “Two medicinal products are considered bioequivalent if their concentration-time profiles are so similar that they are unlikely to produce clinically relevant differences in therapeutic and/or adverse effects.” In order to quantify the similarity of concentration-time profiles, suitable shape characteristics (metrics) and appropriate bioequivalence acceptance limits (bioequivalence ranges) are needed. Whereas the majority of recent investigations dealt with indirect measures of rate of absorption and their sensitivity to simulated changes in the absorption rate, future research should fo...

Diabetes Mass Education for Patients, their Educators, and the General Public by the Pharmacies of Sweden

Abstract: Diabetes Mass Education for Patients, their Educators, and the General Public by the Pharmacies of Sweden

Strategies for Economic Assessment during the Development of New Drugs

Abstract: One of the fastest growing areas in the economic assessment of new drugs is the incorporation of economic analyses into Phase III clinical trials. These assessments quantify the cost of care for each treatment studied in the trial, evaluate whether the costs of each study treatment differ, and compare the differences in cost and patient outcome of each treatment. An economic assessment in a Phase III trial is one of the best ways to make an early decision about the economic viability of a new drug. The ideal assessment measures all of the health care costs of allpatients in the trial regardless of why the costs were incurred, but this approach is expensive; tradeoffs are often used to make the study more feasible. Several issues should be considered in the design and planning of an economic assessment, such as determining theproportion a f total costs to include, identifying which patients will contribute data, identifying care provided by nonstudy sites, determining the format of the collected economic data, and determining the definition of costs. Other issues involved in designing an economic assessment include procedures for implementing the study, analysis methods, and factors influencing the generalizability of the study’s findings.

Adverse Drug Reaction Reporting Part I: A Survey of Pharmacists and Physicians in Saskatchewan

Abstract: A survey was conducted to evaluate the awareness and understanding of adverse drug reaction (ADR) reporting by pharmacists and physicians in the province of Saskatchewan. Seventy-three percent of pharmacists and 54% of physicians responded to the survey. The importance of reporting serious ADRs was rated higher than for mild ADRs. Eighty-five percent of practitioners acknowledged their professional obligation to report ADRs, but only 20% of pharmacists and 15% of physicians indicated they had reported an ADR in the previous year. A relatively small proportion of practitioners (18% of physicians, 32% of pharmacists) were familiar with the procedures for reporting ADRs to the national adverse drug reaction reporting program (Health Protection Branch, Ottawa). Less than a third of practitioners cited the federal program as their preferred agency for reporting ADRs, whereas over half indicated a local agency (a hospital committee, a pharmacy, or medical association) as preferred.

Current Challenges and Future Regulatory Directions in In Vitro Dissolution

Abstract: In vitro dissolution is well established as a quality control technique to monitor the batch-to-batch quality and performance of a drug product. Dissolution is routinely used by most pharmaceutical...

Properties of Metrics Applied for the Evaluation of Bioequivalence

Abstract: Characteristics of metrics are defined in order to assist the effective assessment of bioequivalence as well as the evaluation of metrics and the development of new ones. Metrics should show specificity by reflecting only the kinetic quantity which they are expected to represent. An ideal metric should be linear with respect to the underlying kinetic quantity, and should exhibit high kinetic sensitivity and low statistical responsiveness. The area under the curve for the time course of plasma concentrations (AUC) is demonstrated to have features of an ideal metric. In contrast, Cmax (the maximum plasma concentration) is shown to deviate strongly, in all respects, from having ideal characteristics for the assessment of bioequivalence. Notably, the kinetic sensitivity of Cmax is not only very low but, as a consequence of nonlinearity, also uncertain.

Policy Implications of Modeling the Cost-Effectiveness of Health Care Technologies

Abstract: This paper covers the policy implications of modeling in cost-effectiveness analysis. Concerns about bias potential and validity are addressed. An historical perspective of cost-effectiveness analysis is provided. Cost-effectiveness modeling in the 1990s is covered, and future directions are outlined.

Health Care Reform and Pharmaceutical Innovation

Abstract: This paper discusses health care reform and its effects on pharmaceutical innovation. The percentage of health care costs spent on drugs in the United States has consistently been lower than in most other industrialized countries. To reduce health care costs, pharmaceutical companies must be encouraged, not penalized.

Assessment of Topical Corticosteroid-Induced Skin Blanching Response Using the Visual Mckenzie-Stoughton and Colorimetric Methods:

Abstract: The use of a portable noninvasive colorimeter is evaluated in the present studies for its ability to objectively assess the skin blanching response in vivo. Its correlation and application in differentiating the influence of vehicle, potency, circadian activity, and dose response of topical corticosteroid treatment in healthy subjects among various skin types is consistently high (r > 0.8) using the “a” scale values, which represent reflected light from the skin in the green-red color spectrum (low-to-high values). The colorimeter is most useful in bioequivalence studies where differences in subject skin pigment or sun exposure exist between designated test skin sites in the same individual. The “a” scale of the colorimeter is reproducible and demonstrates a lower intrasubject variability than the visual assessment of the skin blanching response (SBR). The colorimeter data suggest that it will be very useful in the objective and noninvasive assessment of topical corticosteroid bioequivalence.

Women in Bioavailability/Bioequivalence Trials — A Regulatory Perspective

Abstract: There has been a debate on the issue of inclusion of women in bioequivalence trials since the publication of a Federal Register notice by the Food and Drug Administration (FDA) in 1993 entitled “Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs.” Women are now generally not included in bioequivalence trials. A primary reason for the exclusion lies in the concern that hormonal fluctuation during different phases of the menstrual cycle in women might increase the intrasubject variability and thereby decrease the statistical power of the bioequivalence study.A comprehensive review of literature conducted by the FDA has revealed little or no evidence for a significant impact of the menstrual cycle on the intrasubject variance of pharmacokinetic parameters of drugs. In a small number of reports, an alteration in pharmacokinetics of the drug was noted in different phases of the menstrual cycle, which might suggest an increase in intrasubject variability in women co...

Current Issues of Individual Bioequivalence

Abstract: Since the concepts of switchability and individual bioequivalence were defined by Anderson and Hauck in 1990 (1), there have been numerous statistical criteria and methods developed to assess indiv...

Symptom Distress Check Lists as a Component of Quality of Life Measurement: Comparing Symptom Reports with Responses to Multiple Choice Questionnaires*:

Abstract: In order to capture both positive and negative aspects of the quality of life (QOL), clinicians and researchers commonly look to symptom inventories to supplement psychometric measures combining multiple-choice questionnaire items. While these two modalities clearly approach the broad concept of QOL from distinct directions, one wonders how much unique information —and, on the other hand, how much redundancy—each contributes to the overall picture.This retrospective study combined data from three randomized, double-blind, multicenter clinical comparisons of QOL under treatment with antihypertensive agents, in which 1,561 male patients responded concurrently to a Symptom Distress Check List (SDCJ administered at five office visits and to various multiple-choice measures of positive and negative aspects of QOL. The SDC required the respondent to state for each of 49 symptoms 1. whether he had experienced it during the past month, 2. if so, how often, and 3. with how much associated distress.For every sympto...