Guidelines: problems aplenty

Abstract

This critique is about the problems and adverse treatment consequences associated with medical treatment guidelines. It explicates the many ways in which they are misused, misleading, invalid, and a negative influence on clinical practice and health policy. The epistemological and methodological mistakes and mis-attributions associated with randomised controlled trials, and the resultant meta-analyses that are the major influence on guidelines, are discussed. The influences on the probity of the scientific process, and the biases that are an inevitable concomitant of the profit-driven pharmaceutical industries are enumerated, especially because doctors are naïve about fraud, and other adverse influences like advertising and gifts. The corrupted nature of the whole science publishing enterprise is a further powerful negative influence on the declining quality of the massively increased number of papers in journals which are often ‘pay-to-publish’ with lower standards of peer-review, or sometimes frankly incompetent, or faked, peer-review. The major publishing houses are now making profits exceeding those of large pharmaceutical houses. The net result of all these influences indicates that both RCT and M-A should be regarded with a great deal of caution and should not be considered, as they currently are, as an inherently superior form of evidence. Medical science and medical scientific publishing are in a state of crisis.

Introduction

Doctors who aspire to keep up to date with medical science and practice have been cast adrift in a sea of mis-information epitomised by the now all-pervasive and all-influencing guidelines. They fuck you up, the bloody guidelines. They weren’t designed to, but they do. They’re filled with faults, then add egregious extras, just for you. A parody: my apologies to Philip Larkin Guidelines are the ‘final common pathway’ communicating data, that are generated by randomised controlled trials (RCTs), to practicing doctors. This commentary assembles the evidence that most RCTs, and therefore guidelines, are seriously flawed, and are often a negative influence on good clinical practice [1, 2]. First and foremost, this is because so many RCTs are based on corrupted data and corrupted methodology, which emanates from the systematic errors, manipulations, and distortions of clinical trial processes (mostly by ‘big pharma’): and distortions of the resulting ‘evidence’. As Orwell said, ‘
In a time of universal deceit, telling the truth is a revolutionary act
’. A great majority of all trials published are paid for by ‘big pharma’ [3], so that distorts the greater part of all published, and unpublished, medical science. The Lancet editor, Richard Horton, expressed this scathingly: ‘
much published drug-trial research is McScience
’; it is advertising, not science. He is among an increasing number of journal editors and prominent researchers who have commented in relation to this, along with other ex-editors of leading medical journals [4-10]. Horton has reviewed Kassirer’s (ex-NEJM editor) just-published book [11] and comments that ‘
The best editors get fired
’ [because making money and publishing good science are antithetical enterprises]. All these editors came to the realisation that they were being duped, manipulated, and blackmailed into publishing misleading science, through the prestigious publications they were in charge of. These publications had been turned into cash-cows and, [Horton] ‘
little more than information-laundering operations for industry
’, and [Smith] ‘extensions of the marketing-arm of pharmaceutical companies’ [7, 12].

References

1. Feinstein, A.R. and R.I. Horwitz, Problems in the “evidence” of “evidence-based medicine”. The American journal of medicine, 1997. 103(6): p. 529-535.

2. Sniderman, A.D., et al., The necessity for clinical reasoning in the era of evidence-based medicine. Mayo Clin Proc, 2013. 88(10): p. 1108-14.

3. Lundh, A., et al., Industry sponsorship and research outcome. Cochrane Database Syst Rev, 2017. 2: p. MR000033.

4. Angell, M., The truth about drug companies: How they deceive us and what to do about it. New York: Random House, 2005: p. 336.

5. Angell, M., Drug Companies & Doctors: A Story of Corruption. New York Review of Books, 2009. 56: p. http://www.metododibella.org/cms-web/upl/doc/Documenti-inseriti-dal-2-11-2007/Truth%20About%20The%20Drug%20Companies.pdf.

6. Smith, R., Travelling but never arriving: reflections of a retiring editor. British Medical Journal, 2004. 329(7460): p. 242-244.

7. Smith, R.L., Medical Journals Are an Extension of the Marketing Arm of Pharmaceutical Companies. Public Library of Science: Medicine, 2005. 2: p. e138.

8. Horton, R., The Dawn of McScience. New York Review of Books, 2004. 51: p. 7-9.

9. Kassirer, J.P., On the take: How medicine’s complicity with big business can endanger your health. 2004: Oxford University Press.

10. Kassirer, J.P., Commercialism and medicine: an overview. Camb Q Healthc Ethics, 2007. 16(4): p. 377-86; discussion 439-42.

11. Horton, R., The best editors get fired. Lancet, 2017. 390.

12. Horton, R., Memorandum by Richard Horton (PI 108). The pharmaceutical industry and medical journals. UK Parliament: Select Committee on Health. Minutes of Evidence, 2004: p. https://publications.parliament.uk/pa/cm200405/cmselect/cmhealth/42/4121604.htm.

13. Kassirer, J.P., Joint ownership: the shared responsibilities of journal editors and publishers. Md Med, 2007. 8(1): p. 10-2.

14. Lexchin, J. and D.W. Light, Commercial influence and the content of medical journals. BMJ, 2006. 332(7555): p. 1444-7.

15. Ioannidis, J.P., The Mass Production of Redundant, Misleading, and Conflicted Systematic Reviews and Meta-analyses. Milbank Q, 2016. 94(3): p. 485-514.

16. Woolf, S.H., et al., Clinical guidelines: potential benefits, limitations, and harms of clinical guidelines. BMJ, 1999. 318(7182): p. 527-30.

17. Sackett, D.L., et al., Evidence based medicine: what it is and what it isn’t. BMJ, 1996. 312(7023): p. 71-2.

18. Greenhalgh, T., et al., Six ‘biases’ against patients and carers in evidence-based medicine. BMC medicine, 2015. 13: p. 200.

19. Fava, G.A., Meta-analyses and conflict of interest. CNS Drugs, 2012. 26(2): p. 93-6.

20. Moncrieff, J. and P. Thomas, The pharmaceutical industry and disease mongering. Psychiatry should not accept so much commercial sponsorship. British Medical Journal, 2002. 325(7357): p. 216; author reply 216.

21. Moynihan, R., I. Heath, and D. Henry, Selling sickness: the pharmaceutical industry and disease mongering. British Medical Journal, 2002. 324(7342): p. 886-91.

22. Wolinsky, H., Disease mongering and drug marketing. Does the pharmaceutical industry manufacture diseases as well as drugs? EMBO Rep, 2005. 6(7): p. 612-4.

23. Gillman, P.K., Disease mongering: one of the hidden consequences. Public Library of Science: Medicine, 2006. 3(7): p. e316. DOI: 10.1371/journal.pmed.0030316.

24. Heath, I., Combating Disease Mongering: Daunting but Nonetheless Essential. Public Library of Science: Medicine, 2006. 3(4): p. e146.

25. Kumar, C.J., et al., Awareness and Attitudes about Disease Mongering among Medical and Pharmaceutical Students. Public Library of Science: Medicine, 2006. 3(4): p. e213.

26. Moynihan, R. and D. Henry, The Fight against Disease Mongering: Generating Knowledge for Action. Public Library of Science: Medicine, 2006. 3(4): p. e191 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16597180.

27. Edgar, A., The dominance of big pharma: power. Med Health Care Philos, 2013. 16(2): p. 295-304.

28. Greenhalgh, T., Intuition and evidence–uneasy bedfellows? Br J Gen Pract, 2002. 52(478): p. 395-400.

29. Schunemann, H.J., et al., A guide to guidelines for professional societies and other developers of recommendations: introduction to integrating and coordinating efforts in COPD guideline development. An official ATS/ERS workshop report. Proc Am Thorac Soc, 2012. 9(5): p. 215-8.

30. Mercuri, M., et al., When guidelines don’t guide: the effect of patient context on management decisions based on clinical practice guidelines. Acad Med, 2015. 90(2): p. 191-6.

31. do Prado-Lima, P.A.S., The surprising blindness in modern psychiatry: do guidelines really guide? CNS Spectr, 2017. 22(4): p. 312-314.

32. Cabarkapa, S., et al., Prostate cancer screening with prostate-specific antigen: A guide to the guidelines. Prostate Int, 2016. 4(4): p. 125-129.

33. Waters, D.D. and S.M. Boekholdt, An Evidence-Based Guide to Cholesterol-Lowering Guidelines. Can J Cardiol, 2017. 33(3): p. 343-349.

34. Chuang, Y.C., et al., Effects of long-term antiepileptic drug monotherapy on vascular risk factors and atherosclerosis. Epilepsia, 2012. 53(1): p. 120-8.

35. Lenzer, J., Why we can’t trust clinical guidelines. Bmj, 2013. 346(58): p. f3830.

36. Goodman, N.W., Who will challenge evidence-based medicine? Journal of the Royal College of Physicians of London, 1999. 33(3): p. 249-51.

37. Goodman, N.W., Criticizing evidence-based medicine. Thyroid, 2000. 10(2): p. 157-160.

38. Ioannidis, J.P., Hijacked evidence-based medicine: stay the course and throw the pirates overboard. Journal of clinical epidemiology, 2016. 73: p. 82-86.

39. Fava, G.A., Evidence-based medicine was bound to fail: a report to Alvan Feinstein. Journal of Clinical Epidemiology, 2017. 84: p. 3-7.

40. Pedros, C., et al., Prevalence, risk factors and main features of adverse drug reactions leading to hospital admission. Eur J Clin Pharmacol, 2014. 70(3): p. 361-7.

41. Robb, G., et al., Medication-related patient harm in New Zealand hospitals. N Z Med J, 2017. 130(1460): p. 21-32.

42. Parameswaran Nair, N., et al., Adverse Drug Reaction-Related Hospitalizations in Elderly Australians: A Prospective Cross-Sectional Study in Two Tasmanian Hospitals. Drug Saf, 2017. 40(7): p. 597-606.

43. Boileau, I., et al., Influence of a low dose of amphetamine on vesicular monoamine transporter binding: a PET (+)[11C]DTBZ study in humans. Synapse, 2010. 64(6): p. 417-20.

44. Benard-Laribiere, A., et al., Incidence of hospital admissions due to adverse drug reactions in France: the EMIR study. Fundam Clin Pharmacol, 2015. 29(1): p. 106-11.

45. Cosgrove, L., et al., Conflict of Interest Policies and Industry Relationships of Guideline Development Group Members: A Cross-Sectional Study of Clinical Practice Guidelines for Depression. Account Res, 2017. 24(2): p. 99-115.

46. Bastian, H., Nondisclosure of Financial Interest in Clinical Practice Guideline Development: An Intractable Problem? PLoS Med, 2016. 13(5): p. e1002030.

47. Campsall, P., et al., Financial Relationships between Organizations That Produce Clinical Practice Guidelines and the Biomedical Industry: A Cross-Sectional Study. PLoS Med, 2016. 13(5): p. e1002029.

48. Blumsohn, A., Authorship, ghost-science, access to data, and control of the pharmaceutical scientific literature: who stands behind the word? AAAS Professional Ethics Report, 2006. 19: p. 1-4.

49. Leucht, S., W. Kissling, and J.M. Davis, Second-generation antipsychotics for schizophrenia: can we resolve the conflict? Psychol Med, 2009. 39(10): p. 1591-602.

50. Huston, P. and D. Moher, Redundancy, disaggregation, and the integrity of medical research. Lancet, 1996. 347(9007): p. 1024-6.

51. Spielmans, G.I. and I. Kirsch, Drug approval and drug effectiveness. Annu Rev Clin Psychol, 2014. 10: p. 741-66.

52. Worrall, J., Causality in medicine: getting back to the Hill top. Prev Med, 2011. 53(4-5): p. 235-8.

53. Parker, G., Evaluating treatments for the mood disorders: time for the evidence to get real. Australian and New Zealand Journal of Psychiatry, 2004. 38(6): p. 408-14.

54. Mulder, R., et al., The limitations of using randomised controlled trials as a basis for developing treatment guidelines. Evid Based Ment Health, 2017.

55. Bothwell, L.E., et al., Assessing the Gold Standard–Lessons from the History of RCTs. N Engl J Med, 2016. 374(22): p. 2175-81.

56. Naudet, F., et al., Has evidence-based medicine left quackery behind? Intern Emerg Med, 2015. 10(5): p. 631-4.

57. Naudet, F., et al., Understanding the Antidepressant Debate in the Treatment of Major Depressive Disorder. Therapie, 2015. 70(4): p. 321-7.

58. Shorter, E., A brief history of placebos and clinical trials in psychiatry. Can J Psychiatry, 2011. 56(4): p. 193-7.

59. Thompson, R.P., Causality, mathematical models and statistical association: dismantling evidence-based medicine. J Eval Clin Pract, 2010. 16(2): p. 267-75.

60. Hill, A.B., The Environment and Disease: Association or Causation? Proc R Soc Med, 1965. 58: p. 295-300.

61. Nutt, D.J. and P. Blier, Neuroscience-based Nomenclature (NbN) for Journal of Psychopharmacology. J Psychopharmacol, 2016. 30(5): p. 413-5.

62. Worley, L., Neuroscience-based nomenclature (NbN). Lancet Psychiatry, 2017. 4(4): p. 272-273.

63. Gorwood, P., et al., Editorial: Neuroscience-based Nomenclature (NbN) replaces the current label of psychotropic medications in European Psychiatry. Eur Psychiatry, 2017. 40: p. 123.

64. Blier, P., M.A. Oquendo, and D.J. Kupfer, Progress on the Neuroscience-Based Nomenclature (NbN) for Psychotropic Medications. Neuropsychopharmacology, 2017. 42(10): p. 1927-1928.

65. Moncrieff, J., Antidepressants: misnamed and misrepresented. World Psychiatry, 2015. 14(3): p. 302-3.

66. Johnstone, E.C., et al., Neurotic illness and its response to anxiolytic and antidepressant treatment. Psychol Med, 1980. 10(2): p. 321-8.

67. Le Noury, J., et al., Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence. Bmj, 2015. 351: p. h4320.

68. Sharma, T., et al., Suicidality and aggression during antidepressant treatment: systematic review and meta-analyses based on clinical study reports. BMJ, 2016. 352: p. i65.

69. Moncrieff, J., Misrepresenting harms in antidepressant trials. BMJ, 2016. 352: p. i217.

70. Dubicka, B., et al., Paper on suicidality and aggression during antidepressant treatment was flawed and the press release was misleading. BMJ, 2016. 352: p. i911.

71. Gotzsche, P.C., Author’s reply to Dubicka and colleagues and Stone. BMJ, 2016. 352: p. i915.

72. Healy, D., Clinical trials and legal jeopardy. Bulletin of medical ethics, 1999(153): p. 13-18.

73. Jureidini, J.N., J.D. Amsterdam, and L.B. McHenry, The citalopram CIT-MD-18 pediatric depression trial: Deconstruction of medical ghostwriting, data mischaracterisation and academic malfeasance. Int J Risk Saf Med, 2016. 28(1): p. 33-43.

74. Kirsch, I., et al., Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med, 2008. 5(2): p. e45.

75. Kirsch, I. and T.J. Moore, The Emperor’s New Drugs: An Analysis of Antidepressant Medication Data Submitted to the U.S. Food and Drug Administration. Prevention & Treatment, 2002. 5.

76. Locher, C., et al., Efficacy and Safety of Selective Serotonin Reuptake Inhibitors, Serotonin-Norepinephrine Reuptake Inhibitors, and Placebo for Common Psychiatric Disorders Among Children and Adolescents: A Systematic Review and Meta-analysis. JAMA psychiatry, 2017.

77. Allison, D.B., et al., Reproducibility: A tragedy of errors. Nature, 2016. 530(7588): p. 27-9.

78. Fountoulakis, K.N., R.S. McIntyre, and A.F. Carvalho, From Randomized Controlled Trials of Antidepressant Drugs to the Meta-Analytic Synthesis of Evidence: Methodological Aspects Lead to Discrepant Findings. Curr Neuropharmacol, 2015. 13(5): p. 605-15.

79. Fountoulakis, K.N., M.T. Samara, and M. Siamouli, Burning issues in the meta-analysis of pharmaceutical trials for depression. J Psychopharmacol, 2014. 28(2): p. 106-17.

80. Tendal, B., et al., Multiplicity of data in trial reports and the reliability of meta-analyses: empirical study. BMJ, 2011. 343: p. d4829.

81. Siontis, K.C., E. Evangelou, and J.P. Ioannidis, Magnitude of effects in clinical trials published in high-impact general medical journals. Int J Epidemiol, 2011. 40(5): p. 1280-91.

82. Mansournia, M.A. and D.G. Altman, Invited commentary: methodological issues in the design and analysis of randomised trials. Br J Sports Med, 2017.

83. Altman, D. and J.M. Bland, Confidence intervals illuminate absence of evidence. British Medical Journal, 2004. 328(7446): p. 1016-7.

84. Greenland, S., et al., Statistical tests, P values, confidence intervals, and power: a guide to misinterpretations. Eur J Epidemiol, 2016. 31(4): p. 337-50.

85. Wasserstein, R.L. and N.A. Lazar, The ASA’s Statement on p-Values: Context, Process, and Purpose. The American Statistician, 2016. 70(2): p. 129-133.

86. Feinstein, A.R., Meta-analysis: statistical alchemy for the 21st century. J Clin Epidemiol, 1995. 48(1): p. 71-9.

87. Fuller, J., Rhetoric and argumentation: how clinical practice guidelines think. J Eval Clin Pract, 2013. 19(3): p. 433-41.

88. Fuller, J., Rationality and the generalization of randomized controlled trial evidence. J Eval Clin Pract, 2013. 19(4): p. 644-7.

89. White, J., Fraud fighter: ‘Faked research is endemic in China’ New Scientist, 2012(2891): p. http://www.newscientist.com/article/mg21628910.300-fraud-fighter-faked-research-is-endemic-in-china.html.

90. Gotzsche, P.C., et al., Ghost Authorship in Industry-Initiated Randomised Trials. PLoS Med, 2007. 4(1): p. e19.

91. Sismondo, S., Ghost management: how much of the medical literature is shaped behind the scenes by the pharmaceutical industry? PLoS Med, 2007. 4(9): p. e286.

92. Wislar, J.S., et al., Honorary and ghost authorship in high impact biomedical journals: a cross sectional survey. BMJ, 2011. 343: p. d6128.

93. Lexchin, J., Those Who Have the Gold Make the Evidence: How the Pharmaceutical Industry Biases the Outcomes of Clinical Trials of Medications. Sci Eng Ethics, 2011.

94. Ross, J.S., et al., Guest authorship and ghostwriting in publications related to rofecoxib: a case study of industry documents from rofecoxib litigation. JAMA, 2008. 299(15): p. 1800-12.

95. Barbour, V., How ghost-writing threatens the credibility of medical knowledge and medical journals. Haematologica, 2010. 95(1): p. 1-2.

96. Moynihan, R., Key opinion leaders: independent experts or drug representatives in disguise? BMJ, 2008. 336(7658): p. 1402-3.

97. Dechartres, A., et al., Evolution of poor reporting and inadequate methods over time in 20 920 randomised controlled trials included in Cochrane reviews: research on research study. BMJ, 2017. 357: p. j2490.

98. Ioannidis, J., Lies, Damned Lies, and Medical Science. Atlantic, 2010. November 17th.

99. Dechartres, A., et al., Association between analytic strategy and estimates of treatment outcomes in meta-analyses. Jama, 2014. 312(6): p. 623-630.

100. Steel, N., et al., A review of clinical practice guidelines found that they were often based on evidence of uncertain relevance to primary care patients. J Clin Epidemiol, 2014. 67(11): p. 1251-7.

101. Every‐Palmer, S. and J. Howick, How evidence‐based medicine is failing due to biased trials and selective publication. Journal of evaluation in clinical practice, 2014. 20(6): p. 908-914.

102. Popper, K., The Demarcation between Science and Metaphysics. Conjectures and Refutations: The Growth of Scientific Knowledge (1963), 1963. Ch 11.

103. Joiner, K. and R. Lusch, Evolving to a new service-dominant logic for health care. Innovation and Entrepreneurship in Health, 2016.

104. Hoffmann, T.C., V.M. Montori, and C. Del Mar, The connection between evidence-based medicine and shared decision making. Jama, 2014. 312(13): p. 1295-1296.

105. Tiihonen, J., et al., Pharmacological treatments and risk of readmission to hospital for unipolar depression in Finland: a nationwide cohort study. Lancet Psychiatry, 2017. 4(7): p. 547-553.

106. Jones, H., J. Geddes, and A. Cipriani, Lithium and Suicide Prevention, in The Science and Practice of Lithium Therapy, G. Malhi, J.M. Masson, and F. Bellivier, Editors. 2017, Springer. p. 223-240.

107. Wingard, L., et al., Reducing the rehospitalization risk after a manic episode: A population based cohort study of lithium, valproate, olanzapine, quetiapine and aripiprazole in monotherapy and combinations. J Affect Disord, 2017. 217: p. 16-23.

108. Baldessarini, R.J. and L. Tondo, International suicide rates versus adequate treatments. The British Journal of Psychiatry, 2017. 210(4): p. 298-299.

109. Shah, A., et al., Suicide rates in five-year age-bands after the age of 60 years: the international landscape. Aging Ment Health, 2016. 20(2): p. 131-8.

110. Curtin, S.C., M. Warner, and H. Hedegaard, Increase in Suicide in the United States, 1999-2014. NCHS Data Brief, 2016(241): p. 1-8.

111. Viola, S. and J. Moncrieff, Claims for sickness and disability benefits owing to mental disorders in the UK: trends from 1995 to 2014. BJPsych Open, 2016. 2(1): p. 18-24.

112. Tiihonen, J., et al., 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet, 2009. 374(9690): p. 620-7.

113. Brown, J., et al., Mental health as a reason for claiming incapacity benefit—a comparison of national and local trends. Journal of public health, 2008. 31(1): p. 74-80.

114. Whitaker, R. and L. Cosegrove, Psychiatry under the influence. 2015: Macmillan.

115. Gotzsche, P.C., A.H. Young, and J. Crace, Does long term use of psychiatric drugs cause more harm than good? BMJ, 2015. 350: p. h2435.

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