Clinical Drug Safety Research Articles

Satisfaction surveys: do we really need new questionnaires?

Before introducing a new intervention in the health care setting, whether it is a technology, a new drug, or an evaluative tool, its validity must be fully tested as the final goal is to improve patients (quality of) care, as any change in patients care is potentially associated with benefits, risks, and costs. ‘Validity’ is not a yes/no attribute, but the results of the accumulation of evidence were produced through a long process where hypotheses are formulated and then sequentially challenged with several empirical testings. A good example is the process of development and validation of new drugs. The regulatory agencies that are responsible for the first evaluation of the scientific and clinical value of new drugs, generally require information on the intrinsic quality and clinical safety and efficacy of drugs before approving their introduction in the market. After an exhaustive pre-clinical evaluation, phase I and II studies on small samples of patients give information about the toxicity and activity of the new compounds. Later phase III and IV studies provide data on safety and efficacy, either in an ideal and real setting. The cornerstone of this evaluation is a formal comparison of the new drug with an appropriate control. This approach derives from the experience that some drugs have been shown to have good intrinsic pharmacological properties in early phase studies but when they were tested in more carefully controlled research …

Accuracy of popular automatic QT Interval algorithms assessed by a 'Gold Standard' and comparison with a Novel method: computer simulation study

BackgroundAccurate measurement of the QT interval is very important from a clinical and pharmaceutical drug safety screening perspective. Expert manual measurement is both imprecise and imperfectly reproducible, yet it is used as the reference standard to assess the accuracy of current automatic computer algorithms, which thus produce reproducible but incorrect measurements of the QT interval. There is a scientific imperative to evaluate the most commonly used algorithms with an accurate and objective 'gold standard' and investigate novel automatic algorithms if the commonly used algorithms are found to be deficient.MethodsThis study uses a validated computer simulation of 8 different noise contaminated ECG waveforms (with known QT intervals of 461 and 495 ms), generated from a cell array using Luo-Rudy membrane kinetics and the Crank-Nicholson method, as a reference standard to assess the accuracy of commonly used QT measurement algorithms. Each ECG contaminated with 39 mixtures of noise at 3 levels of intensity was first filtered then subjected to three threshold methods (T1, T2, T3), two T wave slope methods (S1, S2) and a Novel method. The reproducibility and accuracy of each algorithm was compared for each ECG.ResultsThe coefficient of variation for methods T1, T2, T3, S1, S2 and Novel were 0.36, 0.23, 1.9, 0.93, 0.92 and 0.62 respectively. For ECGs of real QT interval 461 ms the methods T1, T2, T3, S1, S2 and Novel calculated the mean QT intervals(standard deviations) to be 379.4(1.29), 368.5(0.8), 401.3(8.4), 358.9(4.8), 381.5(4.6) and 464(4.9) ms respectively. For ECGs of real QT interval 495 ms the methods T1, T2, T3, S1, S2 and Novel calculated the mean QT intervals(standard deviations) to be 396.9(1.7), 387.2(0.97), 424.9(8.7), 386.7(2.2), 396.8(2.8) and 493(0.97) ms respectively. These results showed significant differences between means at >95% confidence level. Shifting ECG baselines caused large errors of QT interval with T1 and T2 but no error with Novel.ConclusionThe algorithms T2, T1 and Novel gave low coefficients of variation for QT measurement. The Novel technique gave the most accurate measurement of QT interval, T3 (a differential threshold method) was the next most accurate by a large margin. The objective and accurate 'gold standard' presented in this paper may be useful to assess new QT measurement algorithms. The Novel algorithm may prove to be more accurate and reliable method to measure the QT interval.

Clinical Pharmacology and Drug Safety

Clinical Pharmacology and Drug Safety

In Response to Diel I, Bergner R. Letter to the Editor of The Oncologist Re: Safety and Convenience of a 15-Minute Infusion of Zoledronic Acid

The Oncologist 2005;10:84-87 www.TheOncologist.com Diel and Bergner take objection to some of the statements that were made in our manuscript [1]. In their letter, these two authors propose that we did not appropriately address renal safety concerns, especially with zoledronic acid (Zometa®; Novartis Pharmaceuticals Corporation, East Hanover, NJ, http://www.pharma.us.novartis.com) in comparison with ibandronate (Bondronat®; Hoffmann-La Roche Inc., Nutley, NJ, http://www.rocheusa.com). While we share their concern of the nephrotoxicity of i.v. bisphosphonates, we respectfully disagree with several imprecise remarks made by Diel and Bergner. In the manuscript, we reviewed in detail the renal safety findings from prospective, randomized, controlled clinical trials, which is the accepted gold standard for the determination of clinical efficacy and safety of medicinal drugs. Those trials, which included more than 3,000 patients, have demonstrated the superior efficacy of zoledronic acid in the treatment of hypercalcemia of malignancy (HCM), exceeding that of pamidronate (Aredia®; Novartis Pharmaceuticals Corporation, East Hanover, NJ, http://www.pharma.us.novartis. com), and in the prevention of skeletal-related events (SREs) in patients with multiple myeloma or documented bone metastases from solid tumors [2–5]. Zoledronic acid is approved for the treatment of all these conditions and, hence, has the broadest U.S. Food and Drug Administration (FDA) approval among all i.v. bisphosphonates. In contrast, i.v. ibandronate is not FDA approved, and data on the efficacy and safety of this bisphosphonate in patients with bone metastases are available only from one published prospective, randomized clinical trial, which enrolled 466 patients [6]. Moreover, clinical trial data providing a direct comparison of the efficacy and/or safety of i.v. ibandronate with those of pamidronate show only equivalent efficacy of ibandronate (4 mg) to pamidronate (60 mg) in the treatment of HCM [7]. In contrast, 4 mg zoledronic acid has been examined in two randomized, prospective trials in direct comparison with 90 mg pamidronate [2, 3]. In patients with HCM, the efficacy of zoledronic acid surpasses that of pamidronate in normalizing serum calcium [2]. In patients with breast cancer and documented bone metastases, 4 mg zoledronic acid was significantly more effective than 90 mg pamidronate in reducing the overall risk of developing an SRE [8, 9]. Neither ibandronate nor any other i.v. bisphosphonate has, to date, been shown to have greater or, in the least, similar overall efficacy. Safety comparisons between two bisphosphonates are only meaningful when balanced for efficacy. As reviewed in our manuscript (page 322), 4 mg zoledronic acid was associated with slightly lower incidences of National Cancer Institute Common Toxicity Criteria (CTC) grade 4 (0% versus 1%) and grade 3 (2% versus 3%) serum creatinine levels in comparison with pamidronate in a pooled analysis of patients with HCM [2]. In patients with skeletal lesions from breast cancer or multiple myeloma, the incidence of stringently defined increases in serum creatinine levels with 4 mg zoledronic acid via a 15-minute infusion (8.9%) is similar to that of 90 mg pamidronate via a 2-hour infusion (8.2%) [3]. These data were also described in detail in the manuscript (page 324). In a large, randomized, placebo-controlled trial of patients with bone metastases The Oncologist Letter to the Editor

Gender differences in the prescribing of antipsychotic drugs.

The aim of this article is to offer recommendations and rationale for gender-specific antipsychotic treatment. The author summarizes reviews of recent literature in psychiatric clinical trials, pharmacology, drug safety, toxicology, obstetrics and gynecology, and pediatrics. The pharmacokinetics and pharmacodynamics of antipsychotic drugs differ in women and men and are influenced by gender-specific factors such as body build, diet, smoking, concurrent medication, exercise, substance use, and hormonal transitions. In general, and for some drugs in particular, women require lower doses in order to stay well. Because preliminary drug testing is not done in pregnant women, the issue of effective dosing during pregnancy is unstudied, and safety for fetuses and nursing infants may not become evident until a drug is widely used. Specific adverse effects on issues crucial to women (e.g., parenting) have not been well studied, but some side effects, such as weight gain, passivity, hypotension, and hyperprolactinemia, are reported to be particularly problematic for women. Some serious side effects are more often seen among women than among men. Optimal maintenance regimens of antipsychotics for women and men are not the same.

Electronic Reporting for Clinical Drug Safety and Pharmacovigilance

The 31 January 2003 deadline for electronic reporting to the European Agency for the Evaluation of Medicinal Products has helped to focus industry and regulator attention alike. This conference provided a wide perspective on background and scope, recent successes, and possible future developments by specialists from regulators, pharmaceutical industries, software vendors and more. Organised by IIR Conferences Ltd, attendees had the opportunity to gain an overview of all major aspects of electronic reporting of individual case safety reports, to broaden their knowledge, and to network with individuals concerned by these issues.

Update on Glycoprotein IIb/IIIa Blockade in Endovascular Interventions

Platelet aggregation plays a central role in the ischemic complications of percutaneous coronary interventions (PCI) and the acute coronary syndromes (ACS). Although aspirin and heparin have been effective at decreasing adverse events in these settings, the perceived need for more potent inhibition of platelet aggregation has led to targeting of the platelet surface membrane glycoprotein IIb/IIIa (GP IIb/IIIa) receptor. Several agents have been developed; four: abciximab, tirofiban, eptifibatide, and lamifiban have been tested in clinical trials. Overall, the positive findings of these studies have supported the hypothesis that enhanced platelet blockade leads to improved clinical outcomes in the settings of PCI and ACS. In this article, an overview of the various GP IIb/IIIa receptor inhibitors is presented. The clinical trials of these agents as adjunctive therapy for patients undergoing PCI and in treatment of acute myocardial infarction are reviewed. Practical considerations relating to clinical efficacy, drug safety, and economic issues are discussed.

The role of Italy in development: [formula omitted] — Head of International Clinical Research and Drug Safety, Roche, Milan

The role of Italy in development: [formula omitted] — Head of International Clinical Research and Drug Safety, Roche, Milan

Clinical pharmacology and drug safety: lessons from hirudin.

Clinical pharmacology and drug safety: lessons from hirudin.

A primer of drug safety surveillance: an industry perspective. Part III: Managing adverse-event data.

To place the fundamentals of clinical drug safety surveillance in a conceptual framework that will facilitate understanding and application of adverse drug event data to protect the health of the public and support a market for pharmaceutical manufacturers' products. Part III of this series describes management of adverse-event data. This process involves an interplay of regulations, labeling, and product knowledge. Types of databases are defined and the scope of paper files and computerized files is discussed. Database management is discussed in terms of four processes: receipt, retention, retrieval, and review of adverse-event reports. A summary of the application of the fundamentals to the incident described in the scenario shows that knowledge of the fundamentals may be sufficient to make a substantial contribution to the health of patients and the commercial well-being of manufacturers. This review uses primary sources from the federal laws (regulations), commentaries, and summaries. Very complex topics are briefly summarized in the text and additional readings are listed in the appendix. Secondary sources, ranging from newspaper articles to judicial summaries, illustrate the interpretation of adverse drug events and opportunities for drug safety surveillance intervention. The reference materials used were articles theoretically or practically applicable in the day-to-day practice of drug safety surveillance. The role of clinical drug safety surveillance in product monitoring and drug development is described. The process of drug safety surveillance is defined by the Food and Drug Administration regulations, product labeling, product knowledge, and database management. Emphasis is placed on the dynamic interaction of the components of the process. Suggestions are offered to facilitate communication of a review of adverse-event data for various audiences. Careful drug safety surveillance is beneficial to the health of the public and the commercial well-being of manufacturers. Attention to the basic principles is essential and, as illustrated, may be sufficient to resolve some problems.

A primer of drug safety surveillance: an industry perspective. Part II: Product labeling and product knowledge.

To place the fundamentals of clinical drug safety surveillance in a conceptual framework that will facilitate understanding and application of adverse drug event data to protect the health of the public and support a market for pharmaceutical manufacturers' products. Part II of this series discusses specific issues regarding product labeling, such as developing the labeling, changing the labeling, and the legal as well as commercial ramifications of the contents of the labeling. An adverse event report scenario is further analyzed and suggestions are offered for maintaining the product labeling as an accurate reflection of the drug safety surveillance data. This article also emphasizes the necessity of product knowledge in adverse event database management. Both scientific and proprietary knowledge are required. Acquiring product knowledge is a part of the day-to-day activities of drug safety surveillance. A knowledge of the history of the product may forestall adverse publicity, as shown in the illustration. This review uses primary sources from the federal laws (regulations), commentaries, and summaries. Very complex topics are briefly summarized in the text. Secondary sources, ranging from newspaper articles to judicial summaries, illustrate the interpretation of adverse drug events and opportunities for drug safety surveillance intervention. The reference materials used were articles theoretically or practically applicable in the day-to-day practice of drug safety surveillance. The role of clinical drug safety surveillance in product monitoring and drug development is described. The process of drug safety surveillance is defined by the Food and Drug Administration regulations, product labeling, product knowledge, and database management. Database management is subdivided into the functions of receipt, retention, retrieval, and review of adverse event reports. Emphasis is placed on the dynamic interaction of the components of the process. Suggestions are offered to facilitate communication of a review of adverse event data for various audiences. Careful drug safety surveillance is beneficial to the health of the public and the commercial well-being of the manufacturer. Attention to the basic principles is essential and, as illustrated, may be sufficient to resolve some problems.

A Primer of Drug Safety Surveillance: An Industry Perspective

To place the fundamentals of clinical drug safety surveillance in a conceptual framework that will facilitate understanding and application of adverse drug event data to protect the health of the public and support a market for pharmaceutical manufacturers' products. Part I of this series provides a background for the discussion of drug safety by defining the basic terms and showing the flow of safety information through a pharmaceutical company. The customers for adverse drug event data are identified to provide a basis for providing quality service. The development of a drug product is briefly reviewed to show the evolution of safety data. Drug development and safety are defined by federal regulations. These regulations are developed by the FDA with information from pharmaceutical manufacturers. The intent of the regulations and the accompanying guidelines is described. An illustration from the news media is cited to show an alternative, positive approach to handling an adverse event report. This review uses primary sources from the federal laws (regulations), commentaries, and summaries. Very complex topics are briefly summarized in the text and additional readings are presented in an appendix. Secondary sources, ranging from newspaper articles to judicial summaries, illustrate the interpretation of adverse drug events and opportunities for drug safety surveillance intervention. The reference materials used were articles theoretically or practically applicable in the day-to-day practice of drug safety surveillance. The role of clinical drug safety surveillance in product monitoring and drug development is described. The process of drug safety surveillance is defined by the Food and Drug Administration regulations, product labeling, product knowledge, and database management. Database management is subdivided into the functions of receipt, retention, retrieval, and review of adverse event reports. Emphasis is placed on the dynamic interaction ;of the components of the process. Suggestions are offered to facilitate communication of a review of adverse event data for various audiences. Careful drug safety surveillance is beneficial to the health of the public and the commercial well-being of the manufacturer. Attention to basic principles is essential and, as illustrated, may be sufficient to resolve some problems.

Worldwide Regulations for Manufacturers on Clinical Safety Surveillance of Drugs

It has become increasingly difficult, especially for multinational pharmaceutical companies, to remain current and comply efficiently with the multiplicity of regulations and guidelines in various countries throughout the world governing clinical drug safety surveillance and reporting. In order to obtain a better understanding of current and pending obligations for manufacturers, a questionnaire was completed with input from medical, legal, and regulatory personnel in Pfizer's 47 subsidiaries covering some 100 countries outside the United States. Twenty-seven countries, including the United States, have some formal regulations which cover: (a) expedited reporting of serious or other special adverse events (20 countries); (b) periodic safety update reports (13 countries); and (c) post-marketing surveillance studies (a few countries). Details by country are discussed on the various determinants for expedited reporting (seriousness; expectedness; causality; timing; local or foreign origin; investigational or...

The clinical evaluation of antibacterial drugs: Guidelines of the british society for antimicrobial chemotherapy

Anti-infective agents differ in several respects from other classes of therapeutic drugs. They are aimed at the treatment or prevention of infection which can occur at several body sites and be caused by a wide range of microorganisms. The infectious process frequently modifies metabolic behaviour which in turn may affect the pharmacology of an agent. In addition, the issue of drug resistance raises concerns in individual patients, hospital units and the broader community. The difficulties in scientifically validating the clinical efficacy and safety of anti-infective drugs led to the Report on the Clinical Evaluation of Antibacterial Drugs of the British Society for Antimicrobial Chemotherapy. The report identifies general principles relevant to the study of these drugs in man and identifies the major microbiological and clinical considerations. Detailed comments on the conduct of pharmacokinetic studies and therapeutic trials are provided with particular emphasis on design, definitions, execution and analysis. Adverse event monitoring, assessment of severity and determination of causality are also reviewed. Pharmaco-economic considerations are identified as a significant issue for the future. The revision of the 1977 FDA guidelines on anti-infective drug development provides the opportunity to harmonise these issues, particularly within the major markets of North America, Europe and Japan.

Current Recommendations and Future Prospects in the Treatment of Toxoplasmosis

Toxoplasma infection is highly prevalent throughout the world and causes disease in diverse populations. Effective treatment regimens are available for each clinical entity of toxoplasma, but problems of incomplete clinical efficacy, drug potency, drug safety, and length of treatment remain. No well-controlled clinical trials in humans have been performed to evaluate the efficacy and safety of treatment. Primary treatment of toxoplasmosis is with the synergistic combination of pyrimethamine and sulphonamide. This is considered the treatment of choice for severe disease, disease in immunocompromised patients, and congenital toxoplasmosis. Spiramycin, a macrolide antibiotic, is frequently used alone or alternately with pyrimethamine and sulphonamide for pregnant women with the acute acquired infection to prevent congenital toxoplasmosis. Clindamycin is used frequently to treat acute flares of toxoplasmic chorioretinitis and as second-line therapy for toxoplasmic encephalitis in patients with the acquired immunodeficiency syndrome (AIDS). Inadequacies in the treatment of toxoplasmosis in immunosuppressed patients, exemplified by experience with AIDS patients, should provide the impetus for well-designed trials to find and evaluate more potent and better-tolerated agents. Classes of new drugs that have been investigated and show some promise include: (a) macrolides (roxithromycin, azithromycin); (b) folic acid antagonists (piritrexim and trimetrexate), and (c) purine analogues (arprinocid). Immunomodulators have attracted interest, and interferon-gamma alone and in combination with roxithromycin is effective in murine models. Interleukin-2 is also effective in the murine model.

A Clinical Pharmacologic Perspective on the Detection and Assessment of Adverse Drug Reactions

The study of a new drug includes the assessment of its pharmacologic effects, benefits (efficacy), and risks (safety). Most recent drug discontinuations in the United States and the United Kingdom have been associated with problems of safety. The assessment of clinical drug safety is difficult. Those assessing drug safety are confronted with the need to make causality assessment judgments of drug-related events. Several procedures for assessing causality of adverse reactions have been proposed; however, none of them is completely satisfactory. Global introspection (the unaided judgment based on knowledge and experience) and the currently available standardized decision aids (questionnaires or algorithms) have serious limitations that hamper their use. There is a need for better procedures.

非ステロイド性抗炎症剤の安全性の評価に関する文献的考察

In the past decade, many new non-steroidal anti-inflammatory drugs (NSAIDs) havebeen introduced into Japan and they are now widely used to treat inflammatory andrheumatic disorders. NSAIDs have recently received a great deal of attention because ofreports of various adverse reactions. However, the frequency of the adverse reactions to NSAIDs has varied among the clinical studies. Special caution should be taken wheninterpreting the data on adverse reactions in clinical studies carried out in different patientsby different physicians. It is the purpose of this study to evaluate accurately theclinical safety of NSAIDs. Twelve acidic NSAIDs were examined for which clinicaldata were published in comparison with indometacin in double blind trials in patientswith rheumatoid arthritis. The ratio of the test drug to the standard drug indometacin inthe frequency of adverse reactions in each trial was used as an index of the frequency ofadverse reactions to each NSAID. Discussion of the comparative frequency of adversereactions among the various NSAIDs was possible by using this index. The severity ofadverse reactions was estimated by observing the number of patients for whom themedication was withdrawn because of adverse reactions . The ratio of the test drug to thestandard drug in the frequency of withdrawal from each trial was used as an index of theseverity of the adverse reactions to each NSAID . The safety of drugs must be evaluatednot only by the frequency of the adverse reactions but also by their severity . It is suggested that the procedure described in this paper may be useful for evaluating the clinical safety of drugs.

Technology Assessment: Differing Perspectives

As a concept, term medical technology assessment * is interpreted differently by different intellectual disciplines. To physician, essence of medical technology assessment is focus on clinical safety and efficacy of drugs, medical devices, and technical procedures; medicine's raison d'etre is improved patient care and enhanced of patients' lives. In contrast, an economist's assessment of medical technology will use that discipline's evaluation tools, which include an emphasis on a variety of cost-accounting approaches. These have very real potential to create conflict in a variety of areas central to practice of medicine. Where generally accepted medical credo strives for greatest good for individual patient, new economic imperative calls for the greatest good for greatest number, within clearly defined limits on available resources. This can readily create a cost v access and quality imbalance, and some patients may pay dearly. One