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Clinical trials: Deliberations on their essence and value
Abstract
In the context of the evidence-based medicine (EBM) movement, the clinical trial has come to be hailed as the ultimate source of medical knowledge, and especially of clinical pharmacology. By subjecting the premises of this procedure to a thorough analysis, the author hopes to achieve a sound rating of its epistemological significance in the context of medical research.
Current claims on the basic importance of the evidence provided by standardized clinical trials are confronted with conflicting observations concerning their current application in medical practice. The stereotyped trials of present research in multiple sclerosis serve as an example to illustrate this point.
Traditional assumptions concerning the validity of standardized clinical trials are based on an illusion of absolute objectivity and reliability. Apart from being subject to tough publish (conveniently)-or-perish and commercial influences, the results of clinical trials, especially drug trials, are of limited informative value in diverse respects, such as (i) clinical trials do not identify every possible drug reaction for every instance of a disease; (ii) their results never allow the prediction of the efficacy of a specific drug in any given individual; (iii) clinical trials have no inherent potential to provide concrete insights into the nature and cause(s) of a definite morbid condition; and (iv) extensions of clinical drug trials to ever-larger study groups indicate serious problems in basic theoretical respects.
A clinical trial cannot indicate a certain prevention or cure for any particular instance of a disease, and the correctness of its individual predictions is always only contingent. This can be explained by the fact that the correspondence between the nature of each of all pathological conditions presented by the different members of a clinical trial population and by the individual patients being treated according to the results of the trial is never complete.
... For example, Zimmerman et al. [10] found that most patients with a diagnosis of major depressive disorder who had presented for treatment in a clinic would be excluded from research trials. Given that there may be important differences between clinical and research populations, clinicians tend to be cautious when generalizing research findings to daily practice and avoid turning evidence-based medicine into 'evidence-biased medicine' [11] . Other critiques of RCTs include: insensitive measures, problems with research raters and the use of designs meant for medication registration rather than for guiding clinical practice [12,13] . ...
Systematic biases in decision-making have been well characterized in medical and nonmedical fields but mostly ignored in clinical psychopharmacology. The purpose of this paper is to sensitize clinicians who prescribe psychiatric drugs to the issues of the psychology of risk, especially as they pertain to the risk of side effects. Specifically, the present analysis focuses on heuristic organization and framing effects that create cognitive biases in medical practice. Our purpose is to increase the awareness of how pharmaceutical companies may influence physicians by framing the risk of medication side effects to favor their products.
A review of:
Haynes, R. Brian, K. Ann McKibbon, Nancy L. Wilczynski, Stephen D. Walter, and Stephen R. Were. “Optimal search strategies for retrieving scientifically strong studies of treatment from Medline: analytical survey.” BMJ 330.7501 (21 May 2005): 1179.
Objective – To develop and test search strategies for retrieving clinically sound studies from the MEDLINE database on the prevention or treatment of health disorders.
Design – Analytical survey.
Subjects – The data sources were articles about treatment studies selected from 161 journal titles indexed for MEDLINE in the year 2000.
Setting – MEDLINE database searches performed at the Health Information Research Unit, McMaster University, in Ontario, Canada.
Methods – Researchers hand searched each issue of 161 journal titles indexed in MEDLINE in the year 2000 to find treatment studies. Journal content included internal medicine, family practice, nursing, and mental health titles. Selected studies met the following criteria: randomisation of subjects, outcome assessment for at least 80% of who entered the study, and an analysis consistent with study design. Of 49,028 potential articles, 6,568 were identified as being treatment or prevention related, and 1,587 met the evaluation criteria. The study authors then created search strategies designed to retrieve articles in MEDLINE that met the same criteria, while excluding articles that did not. They compiled a list of 4,862 unique terms related to study criteria, and tested them using the Ovid Technologies search platform. Overall, 18,404 multiple-term search strategies were tested. Single terms with specificity greater than 75% and sensitivity greater than 25% were combined into strategies with two or more terms. These multiple term strategies were tested if they yielded sensitivity or accuracy greater than 75% and specificity of at least 50%.
Main Results – Of the 4,862 unique terms, 3,807 retrieved citations from MEDLINE that researchers used to assess sensitivity, specificity, precision, and accuracy. The single term that yielded the best accuracy while keeping sensitivity greater than 50% was ‘randomized controlled trial.pt.’.The single term that yielded the best precision while keeping sensitivity greater than 50% was also ‘randomized controlled trial.pt.’.This term also gave the greatest balance of sensitivity and specificity. Combination strategies varied. Some two-term combinations outperformed single term strategies and three-term combinations. Tables in the article provide the top three search strategies yielding the highest sensitivity, specificity, accuracy, and balance between sensitivity and specificity.
Search strategies with sensitivity greater than 50% and specificity greater than 95% were evaluated further by adding search terms using logistic regression techniques. The best strategies for maximizing sensitivity had sensitivity greater than 99% and specificity higher than 70%. The best strategies for maximizing specificity had sensitivity greater than 93% and specificity more than 97%.
Conclusion – In addition to providing the best strategies developed in this study, authors compared their results with the results from 19 other published strategies. The published strategies had a sensitivity range of 1.3% to 98.8% on the basis of the hand searched articles. These were all lower than this study’s best sensitivity of 99.3%. Two strategies published by Dumbrigue, with specificities of 98.1% and 97.6%, outperformed this study’s most specific strategy of 97.4%.
To review clinical trials in natural products and mind-body therapies for oncology symptom management, to discuss issues related to developing clinical trials in this area, and outline examples of rigorous and innovative study design.
Peer reviewed literature.
Most of the evidence for the integrative therapies reviewed is derived from phase II trials, and is considered preliminary. More research is needed in these therapies to clearly articulate their role in the management of oncology symptoms. Innovative strategies and methodologies for studying integrative therapies have been demonstrated.
It is necessary to critically evaluate the literature to be able to educate patients about integrative therapies. Investigators should expand on well-designed studies that demonstrate clinically important effects. Dissemination trials may be a good strategy, once data exists, to move integrative therapies into the care of patients.
The Contribution of Clinical Trials in Psychiatry: A Basic Science of Clinical Care - Volume 14 Issue 10 - Andrew A. Nierenberg
Objective – To develop and test search strategies for retrieving clinically sound studies from the MEDLINE database on the prevention or treatment of health disorders.
Design – Analytical survey.
Subjects – The data sources were articles about treatment studies selected from 161 journal titles indexed for MEDLINE in the year 2000.
Setting – MEDLINE database searches performed at the Health Information Research Unit, McMaster University, in Ontario, Canada.
Methods – Researchers hand searched each issue of 161 journal titles indexed in MEDLINE in the year 2000 to find treatment studies. Journal content included internal medicine, family practice, nursing, and mental health titles. Selected studies met the following criteria: randomisation of subjects, outcome assessment for at least 80% of who entered the study, and an analysis consistent with study design. Of 49,028 potential articles, 6,568 were identified as being treatment or prevention related, and 1,587 met the evaluation criteria. The study authors then created search strategies designed to retrieve articles in MEDLINE that met the same criteria, while excluding articles that did not. They compiled a list of 4,862 unique terms related to study criteria, and tested them using the Ovid Technologies search platform. Overall, 18,404 multiple‐term search strategies were tested. Single terms with specificity greater than 75% and sensitivity greater than 25% were combined into strategies with two or more terms. These multiple term strategies were tested if they yielded sensitivity or accuracy greater than 75% and specificity of at least 50%.
Main Results – Of the 4,862 unique terms, 3,807 retrieved citations from MEDLINE that researchers used to assess sensitivity, specificity, precision, and accuracy. The single term that yielded the best accuracy while keeping sensitivity greater than 50% was ‘randomized controlled trial.pt.’. The single term that yielded the best precision while keeping sensitivity greater than 50% was also ‘randomized controlled trial.pt.’.This term also gave the greatest balance of sensitivity and specificity. Combination strategies varied. Some two term combinations outperformed single term strategies and three‐term combinations. Tables in the article provide the top three search strategies yielding the highest sensitivity, specificity, accuracy, and balance between sensitivity and specificity. Search strategies with sensitivity greater than 50% and specificity greater than 95% were evaluated further by adding search terms using logistic regression techniques. The best strategies for maximizing sensitivity had sensitivity greater than 99% and specificity higher than 70%. The best strategies for maximizing specificity had sensitivity greater than 93% and specificity more than 97%.
Conclusion – In addition to providing the best strategies developed in this study, authors compared their results with the results from 19 other published strategies. The published strategies had a sensitivity range of 1.3% to 98.8% on the basis of the hand searched articles. These were all lower than this study’s best sensitivity of 99.3%. Two strategies published by Dumbrigue, with specificities of 98.1% and 97.6%, outperformed this study’s most specific strategy of 97.4%.
Definition of the problem: In Germany, the dissection rate of the deceased is distinctly lower than in many other European countries. Although critics of autopsies use to put forward ethical objections and religious scruples, neither the Christian church nor piety stand opposite to the practise of autopsies.
Arguments: From an ethical point of view, there are numerous arguments for an increase in the number of autopsies. It can be shown that not only the deceased, his relations and the physicians but also the population as a whole could take advantage of a higher percentage of dissections. In Germany, law authorities put much more emphasis on the regulation of birth and origin of life than on problems concerning dying and death of human beings. Legal obstacles and tendentious reporting by the mass media are serious reasons for the poor popularity of dissections of the corpse.
Conclusion: For many reasons, comprehensive and unbiassed information about autopsies, fundamental legislative reforms and an increase of the dissection rate have to be claimed.
This work provides an introduction to ethics, conceptual analysis, critical thinking and rational decision making, in relation to healthcare management. It strips away the mythology behind the rhetoric of contemporary management theory.
Recombinant interferons have been approved by many national regulatory agencies for treatment of relapsing remitting multiple sclerosis, but widespread discussion continues about their true effectiveness, benefits, side-effects, and costs.
With the Cochrane Collaboration methodology, we reviewed all published, randomised, placebo-controlled trials of recombinant interferons undertaken in patients with relapsing remitting multiple sclerosis between 1993 and 2002. Our primary aim was to find out whether recombinant interferons reduced the number of patients who had clinical exacerbations and disease progression, compared with placebo.
The seven trials that met our criteria included 1215 randomised patients: data from 667 (55%) were available for analysis at 1 year's and from 919 (76%) at 2 years' follow-up. Interferon seemed to reduce the number of patients who had exacerbations during the first year of treatment (relative risk 0.73, 95% CI 0.54-0.99), but results at 2 years' follow-up were not robust and were difficult to interpret because of the many dropouts. Although the number of patients who had exacerbations (0.81, 0.74-0.89) or progressed (0.70, 0.55-0.88) during the first 2 years fell significantly in the protocol analysis, results were inconclusive after sensitivity analyses for exacerbations (1.11, 0.73-1.68) and disease progression (1.31, 0.60-2.89). Data were insufficient to establish whether steroid use and admissions to hospital were reduced in the interferon group. Similarly, MRI outcome data could not be analysed quantitatively. Side-effects were common, and acute toxic effects adversely affected quality of life.
Recombinant interferons slightly reduce the number of patients who have exacerbations during first year of treatment. Their clinical effect beyond 1 year is uncertain and new trials are needed to assess their long-term effectiveness and side-effects.
Autopsy as an outcome and performance measure; evi-dence report, technology assessment The patho-genesis of multiple sclerosis revisited
- Healthcare Research Agency
- Quality
Agency for Healthcare Research and Quality (2002) Autopsy as an outcome and performance measure; evi-dence report, technology assessment. AHRQ publication No. 03-E001, Rockville, MD. October 2002. [http://www.ahrq.gov/clinic/epcsums/autopsum.htm] Behan P.O., Chaudhuri A. & Roep B.O. (2002) The patho-genesis of multiple sclerosis revisited. Journal of the Royal College of the Physicians of Edinburgh 32, 244– 265.
Multiple Sclerosis: The Image and Its Message
- A Schellingf
Schelling F.A. (2002) Multiple Sclerosis: The Image and Its Message. [http://www.multiple-sclerosis-abc.org] US National Library of Health (ClinicalTrials.gov, a service of the National Institutes of Health) (2003) An introduc-tion to clinical trials. 30 June 2003. [http://clinicaltrials.gov/ct/info/resources]