- Email: [email protected]
Industry-sponsored research
CORRESPONDENCE
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Djulbegovic B, Lacevic M, Cantor A, et al. The uncertainty principle and industrysponsored research. Lancet 2000; 356: 635–38. DeMets DL. Distinctions between fraud, bias, errors, misunderstanding, and incompetence. Control Clin Trials 1997; 18: 637–50. Hagmann M. Cancer researcher sacked for alleged fraud. Science 2000; 287: 1901–02. Stehman FB, Blessing JA, Fowler WC, Park RC. Quality assessment and assurance programs in the gynecologic oncology group. Obstet Gynecol 1994; 84: 1059–62.
Authors’ reply Sir—Scott Halpern and Jason Karlawish contend that no relation exists between the ethical and scientific principles of randomised controlled trials and their outcomes. We disagree. We believe it is reasonable to assume that there exists some relation between equipoise (a fundamental premise on which randomised controlled trials are established) and ultimate outcomes of clinical trials. There are three possible relations between this fundamental premise and the outcomes observed: innovative treatments are on average better; standard treatments are on average better; and, on average, there is no difference in oucomes between innovative and standard treatments. In light of our hypothesis we postulate that the third possibility is most likely. It is important to understand that we have not focused on the confirmation of equipoise for each individual trial, but on a group of trials over time. If the uncertainty principle plays a part in undertaking randomised controlled trials we would expect to see the distribution of belief probabilities averaging out around 50/50 split between preference for standard and innovative therapies. If this were not the case, patients might be expected to be cautious about entering into clinical trials of innovative therapies and would request treatments that are expected to be superior. However, if the uncertainty principle is applied, there is no a priori reason to be cautious about entering a clinical trial, either because innovative therapies are generally beneficial or harmful on average. Thus, by preserving the uncertainty principle we are in fact preserving the system of clinical trials in medicine! This is the main reason that we also called for improvement in empirical techniques in assessment of this essential principle, on which nearly the entire system of human experimentation stands. Our study should be seen only as the first
2194
empirical step towards further comprehension of this important principle in the design and undertaking of clinical trials. Halpern and Karlawish also state that much of the reported difference between private and public trials might be attributable to the differential use of the inferior controls and that we must stratify our analysis by the type of control used. We could not agree more. That it is exactly what violation of the uncertainty principle means and what we have discussed in our paper. We agree with Reto Nuesch and Thomas Dieterle that there are many sources for potential bias in clinical research.1 However, one should also note that real or potential bias related to the sponsorship2 has also been acknowledged by the World Medical Assocation Declaration Of Helsinki’s Ethical Principles for Medical Research Involving Human Subjects. This declaration states that, in research on human beings, full information about funding, sponsors, institutional affiliations, and other potential conflicts of interest and incentives for participants must be disclosed (information available at www.wma.net/e/policy/17-c_e.html accessed on Dec 20, 2000). *Benjamin Djulbegovic, Charles L Bennett, Jared R Adams, G H Lyman *Divisions of Blood and Bone Marrow Transplantation, H Lee Moffitt Cancer Center and Research Institute, South Florida University, Tampa, FL33612, USA; Division of Haematology and Oncology, Northwestern University Medical School, Chicago, IL; and Division of Haematology and Oncology, Albany Medical College, Albany, NY 1 2
Horton R. The less acceptable face of bias. Lancet 2000; 356: 959–60. Angell M. Is academic medicine for sale? N Engl J Med 2000; 342: 1516–18.
Myopia and its mechanisms Sir—The report by David Goss (Oct 28, p 1456)1 presents a good review of the symptoms and some immediate antecedents of the two principal human refractive errors of myopia and hypermetropia. A word or two can, however, be added on potential causative mechanisms. For myopia, an elongated or ellipsoidal eye remains an embryonic characteristic up to the 215 mm stage, v as described by O Les er2 and confirmed by E Blechschmidt.3 Only at this stage does the eye appear as a
globe. Despite this original tubularity, most people, including Asian babies who grow up as myopes, are born hypermetropic. The initial hypermetropia is probably due to the lens increasing its transverse diameter but not its thickness at, and for some time after, birth. Since hypermetropia is commonly overcome by the accommodation of the lens (at times leading to strabismus), the development of accommodation may be viewed as an evolutionary result of the initial hypermetropia: neonates do not seem to accommodate since they have no need for this faculty in the earliest months. In normal emmetropic eyes, therefore, lenticular changes finely balance potential remnants of the earlier tubularity, with anomalies resulting when this tenuous equilibrium is disturbed. Goss reports that minus or concave correcting lenses generally promote myopia, whereas plus or convex lenses accentuate hypermetropia. On a developmental basis, this effect seems to apply only to normally sized eyes, the anterior segments of which have anomalies. The acquisition of myopia seems to coincide only with the duration of the function of accommodation (ie, to end with the onset of presbyopia)4 no matter whether a corrective lens is worn afterwards. The eyes do not seem to have lost the ability to elongate after presbyopia has set in, since Horner’s syndrome, when the pupil is partly or wholly occluded, can be accompanied by this refractive anomaly even in later years.5 Finally, many have considered the practicality of emmetropic children wearing reading glasses so that the need for accommodation and the degree of acquired myopia can be kept to a minimum. Considerations of vanity make this solution unfeasible. As for parental exhortation, also recommended by Goss, heeding is, these days, hardly fashionable. R A Weale Age Concern Institute of Gerontology, Waterloo Bridge Wing, Franklin-Wilkins Building, London SE1 8WA, UK 1 2
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Goss DA. Nearwork and myopia. Lancet 2000; 356: 1456–57. v Leser O. Développement de la forme de l’oeil humain. Arch Ophthalmol 1925; 42: 81–109. Bleschschmidt E. The stages of human development before birth. Basel: S Karger, 1961: 149. Kent PR. Acquired myopia of maturity. Am J Optometry 1963; 40: 247–56. O’Leary DJ, Millodot M. Eyelid closure causes myopia in humans. Experientia 1979; 35: 1478–79.
THE LANCET • Vol 356 • December 23/30, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
1
2
3 4
Djulbegovic B, Lacevic M, Cantor A, et al. The uncertainty principle and industrysponsored research. Lancet 2000; 356: 635–38. DeMets DL. Distinctions between fraud, bias, errors, misunderstanding, and incompetence. Control Clin Trials 1997; 18: 637–50. Hagmann M. Cancer researcher sacked for alleged fraud. Science 2000; 287: 1901–02. Stehman FB, Blessing JA, Fowler WC, Park RC. Quality assessment and assurance programs in the gynecologic oncology group. Obstet Gynecol 1994; 84: 1059–62.
Authors’ reply Sir—Scott Halpern and Jason Karlawish contend that no relation exists between the ethical and scientific principles of randomised controlled trials and their outcomes. We disagree. We believe it is reasonable to assume that there exists some relation between equipoise (a fundamental premise on which randomised controlled trials are established) and ultimate outcomes of clinical trials. There are three possible relations between this fundamental premise and the outcomes observed: innovative treatments are on average better; standard treatments are on average better; and, on average, there is no difference in oucomes between innovative and standard treatments. In light of our hypothesis we postulate that the third possibility is most likely. It is important to understand that we have not focused on the confirmation of equipoise for each individual trial, but on a group of trials over time. If the uncertainty principle plays a part in undertaking randomised controlled trials we would expect to see the distribution of belief probabilities averaging out around 50/50 split between preference for standard and innovative therapies. If this were not the case, patients might be expected to be cautious about entering into clinical trials of innovative therapies and would request treatments that are expected to be superior. However, if the uncertainty principle is applied, there is no a priori reason to be cautious about entering a clinical trial, either because innovative therapies are generally beneficial or harmful on average. Thus, by preserving the uncertainty principle we are in fact preserving the system of clinical trials in medicine! This is the main reason that we also called for improvement in empirical techniques in assessment of this essential principle, on which nearly the entire system of human experimentation stands. Our study should be seen only as the first
2194
empirical step towards further comprehension of this important principle in the design and undertaking of clinical trials. Halpern and Karlawish also state that much of the reported difference between private and public trials might be attributable to the differential use of the inferior controls and that we must stratify our analysis by the type of control used. We could not agree more. That it is exactly what violation of the uncertainty principle means and what we have discussed in our paper. We agree with Reto Nuesch and Thomas Dieterle that there are many sources for potential bias in clinical research.1 However, one should also note that real or potential bias related to the sponsorship2 has also been acknowledged by the World Medical Assocation Declaration Of Helsinki’s Ethical Principles for Medical Research Involving Human Subjects. This declaration states that, in research on human beings, full information about funding, sponsors, institutional affiliations, and other potential conflicts of interest and incentives for participants must be disclosed (information available at www.wma.net/e/policy/17-c_e.html accessed on Dec 20, 2000). *Benjamin Djulbegovic, Charles L Bennett, Jared R Adams, G H Lyman *Divisions of Blood and Bone Marrow Transplantation, H Lee Moffitt Cancer Center and Research Institute, South Florida University, Tampa, FL33612, USA; Division of Haematology and Oncology, Northwestern University Medical School, Chicago, IL; and Division of Haematology and Oncology, Albany Medical College, Albany, NY 1 2
Horton R. The less acceptable face of bias. Lancet 2000; 356: 959–60. Angell M. Is academic medicine for sale? N Engl J Med 2000; 342: 1516–18.
Myopia and its mechanisms Sir—The report by David Goss (Oct 28, p 1456)1 presents a good review of the symptoms and some immediate antecedents of the two principal human refractive errors of myopia and hypermetropia. A word or two can, however, be added on potential causative mechanisms. For myopia, an elongated or ellipsoidal eye remains an embryonic characteristic up to the 215 mm stage, v as described by O Les er2 and confirmed by E Blechschmidt.3 Only at this stage does the eye appear as a
globe. Despite this original tubularity, most people, including Asian babies who grow up as myopes, are born hypermetropic. The initial hypermetropia is probably due to the lens increasing its transverse diameter but not its thickness at, and for some time after, birth. Since hypermetropia is commonly overcome by the accommodation of the lens (at times leading to strabismus), the development of accommodation may be viewed as an evolutionary result of the initial hypermetropia: neonates do not seem to accommodate since they have no need for this faculty in the earliest months. In normal emmetropic eyes, therefore, lenticular changes finely balance potential remnants of the earlier tubularity, with anomalies resulting when this tenuous equilibrium is disturbed. Goss reports that minus or concave correcting lenses generally promote myopia, whereas plus or convex lenses accentuate hypermetropia. On a developmental basis, this effect seems to apply only to normally sized eyes, the anterior segments of which have anomalies. The acquisition of myopia seems to coincide only with the duration of the function of accommodation (ie, to end with the onset of presbyopia)4 no matter whether a corrective lens is worn afterwards. The eyes do not seem to have lost the ability to elongate after presbyopia has set in, since Horner’s syndrome, when the pupil is partly or wholly occluded, can be accompanied by this refractive anomaly even in later years.5 Finally, many have considered the practicality of emmetropic children wearing reading glasses so that the need for accommodation and the degree of acquired myopia can be kept to a minimum. Considerations of vanity make this solution unfeasible. As for parental exhortation, also recommended by Goss, heeding is, these days, hardly fashionable. R A Weale Age Concern Institute of Gerontology, Waterloo Bridge Wing, Franklin-Wilkins Building, London SE1 8WA, UK 1 2
3
4 5
Goss DA. Nearwork and myopia. Lancet 2000; 356: 1456–57. v Leser O. Développement de la forme de l’oeil humain. Arch Ophthalmol 1925; 42: 81–109. Bleschschmidt E. The stages of human development before birth. Basel: S Karger, 1961: 149. Kent PR. Acquired myopia of maturity. Am J Optometry 1963; 40: 247–56. O’Leary DJ, Millodot M. Eyelid closure causes myopia in humans. Experientia 1979; 35: 1478–79.
THE LANCET • Vol 356 • December 23/30, 2000
For personal use only. Not to be reproduced without permission of The Lancet.