Volume 41, No. 2/2003(February)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Editorial
Clinical trials, industrial sponsoring, and ethics – A never ending story?
T. Sudhop and K. von Bergmann
Abstract
T. Sudhop and K. von Bergmann
Department of Clinical Pharmacology
University of Bonn, Germany
The recent revision of the Declaration of Helsinki and the ongoing discussion on placebo use in clinical trials has pushed ethical aspects into the focus of scientific debates again. In the current issue of the Journal Cleophas & Cleophas raise the question whether clinical trials are in jeopardy. The authors pointed out 8 major common procedures which they estimate as potential flaws jeopardizing the reliability and acceptance of clinical trial results. They point their finger at the role of independent ethical committees (IEC) and institutional review boards (IRB) and criticize the data management which is almost completely under the control of the pharmaceutical sponsor. This concerns the trial monitors who are mostly employees of sponsor and includes both safety and interim analysis, which is often not in the hand of a real independent scientific committee, and sponsor-influenced publications signed by “ghosts” and “graphters”. Is this the reality?
The issue of credibility of clinical trial results is not a new one and not only restricted to sponsored scientific work as has been shown by the many cases of scientific fraud in the past. At least in post-marketing trials many physicians do not believe trial results, especially when they show that the sponsor’s product is superior to that of the direct competitor. The reader should maintain a healthy portion of mistrust in regard to such trials since Thomas et al. [2002] detected a clear bias in sponsored trials comparing topical glucocorticosteroids in the treatment of asthma and allergic rhinitis. The issue of “sponsorship, authorship and accountability” has been recently discussed by the editors of the mainstream medical journals and is clearly in the mind of the scientific audience [Davidoff et al. 2001]. Not only the issue of reporting favorable results but, even more, the problem of not reporting unfavorable results in sponsored trials may bias public opinion. Trial protocols and more often investigator contracts – which are not usually accessible to the public – sometimes restrict the right of authors to publish their results and this attitude of course enhances the mistrust in clinical trial results [Anonymous 2001, Mann 2002]. Cleophas & Cleophas suggest 7 criteria for independent trial surveillance which, in their opinion, should help to solve some of these issues. Some of the suggestions made are already part of international guidelines such as the revised Declaration of Helsinki and the international harmonized guidelines on Good Clinical Practice (ICH-GCP). Others are very difficult to implement; in particular, the need for independent monitoring of trial conduct, data management and statistical analysis. Who has the capability and competence to carry out such a review and surveillance of multicenter/multinational trials? At least in regulatory trials, some of this work is done by the regulatory authorities – sometimes satisfactorily – sometimes in a less impressive manner as illustrated by the withdrawal of mibefradil and the withdrawal and reapproval of alosetron. However, such events are usually based on data gathered and presented by the sponsor after conducting the trial. Systematic independent data inspection during trial conduct would require an enormous amount of manpower. This would clearly increase the costs of performing multicenter trials but, at the same time, it would help to increase the degree of trust in the results obtained.
Although independent trial inspection by IEC/IRBs is already now implemented in the ICH-GCP guidelines, very few IEC/IRBs perform such “live” inspections. Despite international guidelines the role of the IEC/IRB varies in different countries throughout the western world because of differences in the legal framework. At least in the European Community (EC) the legal basics will be harmonized by the EC directive 2001/20/EC by 2004 at the latest. The directive will clarify and to some extent strengthen the role of the IEC/IRB in clinical trials especially in the review process during the conduct of the trial. On the other hand the same directive will weaken the position of the local IEC/IRB by implementation of a master IEC approval for multicenter trials which will be effective for an entire country. Until now it is common practice in major parts of the western world that every trial center or regional trial center has its own IEC/IRB which grants approval for each trial. These IEC/IRBs may be hospital-based or situated in the local chambers of medicine or in universities. In some cases local IEC/IRBs only confirm prior approvals granted to the principal investigator by the IEC/IRB responsible without further review. Nevertheless many other local IEC/IRBs perform a complete review sometimes leading to changes in the informed consent form and even general or local trial amendments. Although these local reviews, especially in the case of Phase III/IV trials, are often considered as a time- and money-consuming burden by pharmaceutical sponsors, such procedures may help to safeguard rights and the well-being of trial subjects and are common practice in large scale multicenter/multinational trials. For example the OVERTURE trial was performed in 42 counties and 704 IEC/IRB approvals had to be obtained [Packer et al. 2002]. A reduction in the number of national IEC/IRBs involved to a single master IEC/IRB approval, as implemented in the EC directive, might bear the risk of becoming “special IEC/IRBs” with a less critical mandate and these would be preferred by some sponsors. Under these conditions the risk for all trial participants, including trial physicians, would increase significantly. Scientific and clinical competence and accuracy must be a strict requirement for every IEC/IRB, especially those serving as master review institution.
Despite all criticisms, clinical trials – especially those for drug development – need to be sponsored by pharmaceutical manufacturers. Only industrial sponsors and national institutions have the capability of financing large scale trials and giving investigators the chance to conduct trials in larger populations. Both, sponsor and investigator should keep in mind that they are responsible for accurate and unbiased results, not only to shareholders, but also to the public. Sponsors and investigators must find the courage to publish unfavorable results and, if they are successful in this, they will increase the credibility of sponsored trials substantially.
References
Anonymous 2001 The tightening grip of big pharma (Editorial). Lancet 357: 1141
Davidoff F, DeAngelis CD, Drazen JM, Hoey J, Hojgaard L, Horton R, Kotzin S, Nicholls MG, Nylenna M, Overbeke AJ, Sox HC, Van Der Weyden MB, Wilkes MS 2001 Sponsorship, authorship, and accountability. Lancet 358: 854-856
Mann H 2002 Research ethics committees and public dissemination of clinical trial results. Lancet 360: 406-408
Packer M, Califf RM, Konstam MA, Krum H, McMurray JJ, Rouleau JL, Swedberg K 2002 Comparison of Omapatrilat and Enalapril in patients with chronic heart failure: the Omapatrilat versus Enalapril randomized trial of utility in reducing events (OVERTURE). Circulation 106: 920-926
Thomas PS, Tan KS, Yates DH 2002 Sponsorship, authorship, and accountability [Letter]. Lancet 359: 351
T. Sudhop and K. von Bergmann
Department of Clinical Pharmacology
University of Bonn, Germany
Viewpoint
Clinical trials in jeopardy
G.C.J.M. Cleophas and T.J. Cleophas
Abstract
G.C.J.M. Cleophas and T.J. Cleophas
1Faculty of Law, Department of Health Affairs, Erasmus University, Rotterdam, Netherlands, 2European College of Pharmaceutical Medicine, Lyon, France
Background: The controlled clinical trial, the gold standard for clinical research, is in jeopardy. The pharmaceutical industry is rapidly expanding its command over clinical trials but scientific rigor requires independence and objectivity. Safeguarding such criteria is hard because industrial sponsors, benefit directly from favorable results and are virtually in complete control. Objective: To review flawed procedures jeopardizing the credibility of trials and to look for possible solutions to the conflict between sponsored industry and scientific independence. Results: Flawed procedures jeopardizing current clinical trials can be listed as follows. Industries, at least in Europe, are allowed to choose their own independent protocol review board prior for approval. The independent protocol review board approves protocols even when the research is beyond the scope of its expertise. Health institutions hosting multicenter trials are requested to refrain from scientific or ethic assessment of the trial. Trial monitors are often employees of industry. Data control is predominantly in the hands of the sponsor. Interim analyses are rarely performed by independent groups. The scientific committee of the trial consists largely of prominent but otherwise uninvolved physicians attached to the study. The analysis and report of the trial is generally provided by clinical associates of the pharmaceutical companies and, after a brief review, co-signed by prominent physicians attached to the study. Possible solutions: Possible solutions to the conflict between sponsored industry and scientific independence could include the following. Surveillance by independent observers during each stage of the trial is desirable. In contrast, tight control of study data, analysis, and interpretation by the commercial sponsor is undesirable. If, instead, the pharmaceutical industry allows the profession to more actively participate in different stages of the trial, scientific research will be better served, reasonable biological questions will be better answered, and, because the profession will be more convinced of the objective character of the research, it will not be counterproductive to the sales.
Review
Bupropion: pharmacological and clinical profile in smoking cessation
K.-O. Haustein
Abstract
K.-O. Haustein
Institute for Nicotine Research and Smoking Cessation, Erfurt, Germany
Chemistry, pharmacokinetics, pharmacology, clinical efficacy, adverse effects and dosage of bupropion hydrochloride (BP), an aminoketone antidepressant used in smoking cessation, are reviewed. The nicotinergic acetylcholine receptors are inhibited at clinically relevant concentrations of BP. BP does not inhibit monoamine oxidase, and it has minimal inhibitory effects on presynaptic noradrenaline and dopamine uptake. BP is rapidly absorbed after oral administration and demonstrates biphasic elimination with an elimination half-life of 11 – 14 hours. BP is extensively metabolized by oxidation and reduction to at least 6 metabolites, 2 of which may be active. The plasma levels of the erythro-amino alcohol of BP correlate with several side effects such as insomnia and dry mouth. Efficacy of BPSR in smoking cessation has been examined in several double-blind, randomized trials in which daily doses of 150 or 300 mg have been administered for 7 or 9 weeks. In addition, 1 study examined the combination of BPSR plus nicotine patch. The point prevalences of stopping smoking reached values between 21.2 and 38%, but they did not exceed those after nicotine replacement therapy alone. Long-term administration (52 weeks) of BP did not improve abstinence compared with placebo after a 2-year follow-up period. Thus, the efficacy of BP in smoking cessation is comparable to that of nicotine replacement therapy. However, BP possesses a broad spectrum of infrequent adverse effects and interferes with the degradation of several drugs such as tricyclic antidepressants, b-recpetor blocking agents, class Ic-antiarrhythmics etc. As the risk-benefit ratio of BP is smaller than that of nicotine replacement, BP should be considered as a second-line treatment in smoking cessation.
Therapeutics
Prospective observational cohort safety study to monitor the introduction of a non-CFC formulation of salbutamol with HFA134a in England
P.M. Craig-McFeely, L.V. Wilton, J.B. Soriano, W.C. Maier and S. A.W. Shakir
Abstract
P.M. Craig-McFeely, L.V. Wilton, J.B. Soriano, W.C. Maier and S. A.W. Shakir
1Drug Safety Research Unit, Southampton, 2Hillbrow Surgery, Liss, 3GlaxoSmithKline, Greenford, and 4London School of Hygiene and
Tropical Medicine, London, UK
Objective: To monitor the safety of a salbutamol MDI with a hydrofluoroalkane propellant (Ventolin Evohaler) during its introduction into primary care use in England. Methods: Prospective observational cohort study. 1,365 GPs in England submitted data on 10,472 regular users of Ventolin MDI, over five 3-month periods of observation between October 1, 1998 and December 31, 1999. The primary aim was to compare event rates occurring before and after the introduction of Ventolin Evohaler. The secondary aim was a comparison of event rates between users of Ventolin Evohaler and Ventolin MDI. The main outcome measures were: indication for use of Ventolin MDI, assessment of disease severity, event rates during each period of observation; deaths, pregnancies, reported adverse drug reactions and reasons for discontinuation of MDI. Event rates were adjusted using a ratio for under-reporting derived from a validation study on 4.6% of the study population and stratified by severity of indication. Results: The primary indication was asthma in 94%, distributed by severity as 47% mild, 44% moderate and 9% severe; 13% were children. By October 1999, 52.7% of the 8,973 remaining patients had transitioned to Ventolin Evohaler. There was no increase in major or minor events observed following the introduction of Ventolin Evohaler. No serious adverse events, abnormal pregnancy outcomes or deaths have been related to Ventolin MDI or Ventolin Evohaler. The validation study showed a degree of under-reporting. Conclusion: These results on a large cohort of community patients in England indicate that Ventolin Evohaler is well tolerated among asthmatics.
Drug Utilization
Frequency and predictors of drug therapy interruptions after hospital discharge under physician drug budgets in Germany
K. Taxis and S. Schneeweiss
Abstract
K. Taxis and S. Schneeweiss
1Pharmazeutische Biologie, Pharmazeutisches Institut, Universität Tübingen, Germany, and 2Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA
Objective: We sought to study how frequently prescription drug therapy at hospital discharge was discontinued or changed by general practitioners under physician drug budgets in Germany and explore reasons and predictors for such discontinuations. Methods: This cohort study was part of a larger project on clinical outcomes of acute hospital care in patients with 5 groups of medical diagnoses, including conditions of the heart, lung and brain, gastroduodenal ulcer disease and diabetes. Patients entered the study cohort at hospital admission and were followed throughout their stay until they had their first encounter with a primary care physician responsible for follow-up treatment after hospital discharge. Nurse practitioners and physicians assessed patient characteristics at admission and discharge. A 1-page questionnaire on continuity of care, including drug therapy, was provided to primary care physicians at the first patient encounter. The primary study endpoint was discontinuation of drug therapy by the primary care physician. Data were analyzed by multivariate logistic regression. Results: A total of 3,267 patients in 22 primary care hospitals were eligible for the study. Standardized questionnaires on continuation of drug therapy were returned by 890 patients (27%); 846 patients (95%) used prescription drugs at discharge. Of those, drug therapy was interrupted in 122 (14%). Reasons for discontinuations included excessive costs of drugs in 66 patients (54%), excessive number of drugs prescribed (32, 26%) and differences in judgment on the clinical appropriateness of a drug (23, 19%). In a multivariate logistic regression, gastroduodenal ulcer disease was a significant predictor for discontinuation (OR = 3.1; 95% CI 1.5 – 6.5). Discontinuation tended to be more likely in older patients (69 – 76 years vs. £ 58: OR = 2.0; 1.0 – 3.9) but slightly less likely in male patients (OR = 0.7; 0.4 – 1.1). Conclusion: Discontinuation of drug therapy after hospital discharge is common. The high costs of prescription drugs were the most common reason. Elderly patients seem to be particularly affected.
AAPP-Report
Introduction
A.W. Fox
AAPP-Report
Keynote Address
The Hon. H.A. Waxman
Abstract
The Hon. H.A. Waxman
AAPP-Report
Keynote Address
D. Romza-Kutz
AAPP-Report
The Biotechnology Spectrum: Where we’ve been and where we are going
J. Kurth, J. Panetta, G. Yakatan and D. Senyei
Abstract
J. Kurth, J. Panetta, G. Yakatan and D. Senyei
AAPP-Report
Biotech Clinical Research: Issues for clinical investigators
S. Garbus, R. Pellegrino, J. Nicklas, A. Esteban and B. Miskin
Abstract
S. Garbus, R. Pellegrino, J. Nicklas, A. Esteban and B. Miskin
AAPP-Report
Current issues in clinical investigation: HIPAA and FDA inspections
T. Haverty, S. Bernstein and J. Mackenzie
Abstract
T. Haverty, S. Bernstein and J. Mackenzie
AAPP-Report
Biotech case studies: Building collaborative relationships
S. Dychter, M.N. Krupp and P.J. Pokros
Abstract
S. Dychter, M.N. Krupp and P.J. Pokros
AAPP-Report
Research Presentation: A Phase Ib study of a potential anti-sickling agent
K.I. Ataga
AAPP-Report
Research Presentation: Medical imaging in pharmaceutical research
B. Kuo
AAPP-Report
Human cloning and stem cell research
G. Shangold, M.D. West, W.B. Hurlbut and W.J. Smith
Abstract
G. Shangold, M.D. West, W.B. Hurlbut and W.J. Smith
AAPP-Report
Clinical research: An international
perspective
C.P. Allen, D. Criscuolo, D. Hurley, D. Harle and A. Kalali
Abstract
C.P. Allen, D. Criscuolo, D. Hurley, D. Harle and A. Kalali
AAPP-Report
Human research protection: New developments in the governmental and private sectors
G. Noble, M.A. Speers, J. Beach and G. Poppristo
Abstract
G. Noble, M.A. Speers, J. Beach and G. Poppristo
