Design and Reporting Modifications in Industry-Sponsored Comparative Psychopharmacology Trials

1. Design and Reporting Modifications in Industry-Sponsored Comparative • Psychopharmacology Trials • DANIEL J. SAFER, M.D.1 • J nerve mental dis 2002

2. BMJ 2006;333;782-; originally published online 6 Oct 2006; Anders W Jørgensen, Jørgen Hilden and Peter C Gøtzsche review meta-analyses of the same drugs: systematic supported meta-analyses and other Cochrane reviews compared with industry

3. Are you at risk? falling victim to misleading presentations as a result of conflict of interest of investigators Not at all A little Moderate risk High risk

4. Spinning • get in groups of 2 to 5 • write down 3 ways in which papers can mislead • 3 minutes

5. Spinning • get in groups of 2 to 5 • write down three ways to avoid being mislead • 3 minutes

6. Conclusions and Funding, Als-Nielsen, JAMA 2003 • 25 Cochrane reviews, 370 RCTs • random selection of 167 of 1081 (issue 2, 2001) • excluded • 101 < 5 studies • 6 no concealment variability • 2 no binary outcome • 16 non-pharmacological • abstracted • sources of funding • effect on primary outcome • adverse effects • methodological quality (concealment, blinding)

7. Scale Used to Grade Conclusions in Trials 6 Points Experimental intervention highly preferred and should now be considered the standard intervention in all patients, or similar 5 Points Experimental intervention preferred to control, but further trials still indicated, experimental may be more costly, or similar 4 Points Experimental and control intervention about equal, but the experimental cheaper, easier to administer, or similar minor advantage 3 Points Experimental and control intervention about equal, but the control may be cheaper, easier to administer, or similar minor advantage 2 Points Control intervention preferred to experimental intervention, but experimental intervention might be promising under some circumstances, or similar 1 Point Control intervention highly preferred and should now be considered the standard intervention in all patients, or similar

8. Relation Between Funding Source and Conclusions in 370 Randomized Drug Trials Abbreviation: IQR, interquartile range. *Conclusions in trials were assessed by a 1-6 point scale. If the conclusions recommended the experimental drug as the treatment of choice without disclaimers, 6 points was assigned, and if not, 1-5 points was assigned. +p<.001, using Kruskal-Wallis test (medians) or X2 test (proportions)

9. Als-Nielson, JAMA, 2003 • bigger effect size, more likely stronger recommendation • blinding, more likely stronger recommendation • after adjustment, industry funding, odds ratio 5.3 (95% CI 2.0 to 14.4)

11. 1 Read methods and resultsbypass the discussion

12. ACP Journal Club? • secondary journal since 1991 • provides structured summaries • articles important to internists • high methodologic quality • therapy, randomization • diagnosis, blind comparison to a gold standard • may provide more information than original article • concealment of randomization • who is blind • patients, caregivers, outcome data collectors, adjudictors of outcome, data analysts • loss to follow-up

13. PROGRESS, Lancet 2001

14. PROGRESS, Lancet 2001

15. Methods

16. Results

18. Interpretation

19. perindopril R NO placebo Ask MD if patient will give two drugs perindopril + indapamide YES R R placebo

20. PROGRESS Trial – ACP JC

21. PROGRESS

22. PROGRESS

23. ACP Journal Club

24. 2 Read the abstract reported in evidence-based secondary publications (ACPJC)

25. Use of placebo when active comparator optimal Do you manage patients with type II diabetes? Is there any agent you would routinely suggest for patients with diabetic nephropathy? Angiotensin receptor blockers for diabetic nephropathy vs. ACE inhibitors Parving H-H et al. N Engl J Med 2001;345(12):870-878 Brenner BM N Engl J Med 2001;345(12):861-869 Lewis EJ et al. N Engl J Med 2001;345(12):851-60. Hostetter TH. N Engl J Med 2001;345(12):910-912

26. Incomparable comparators • 8 RCTS of 2nd generation neuroleptics vs. 20 mg/d haloperidol • fewer extrapyramidal symptoms • standard dose haloperidol < 12 mg • RCT paroxetine qd vs. amitriptyline bid • less daytime somnolence • standard amitriptyline qhs Safer J Nerv Ment Dis 2002;190(9):583-92. Geddes J et al BMJ 2000;321(7273):1371-6. Christiansen PE, et al. Acta Psychiatr Scand 1996;93(3):158-63

27. Neurology 2006;66;1294-1295 • Jacqueline A. French and Richard J. Kryscio • trials • Active control trials for epilepsy : Avoiding bias in head-to-head

28. Use of appropriate active comparator instead of placebo For profitagency Nonprofitagency 136 trials of new treatments for multiple myeloma 40% 79% Mann H et al. James Lind Library, 2003

29. Goetschze in methods pharmaceutical other than reporting bias (though has reporting bias implications as well)

30. 3 Beware faulty comparators

31. Irbesartan vs amlodipine in diabetic nephropathy • in comparison to amlodipine, irbesartan reduced the combined endpoint of all cause mortality, progression to end stage renal disease, and doubling of serum creatinine (RRR 20%, 95% CI 7.5% to 32%) • did irbesartan reduce all-cause mortality?

32. Risk reduction with irbesartan (vs. amlodipine) Doubling of creatinine concentration RRR 33% (16-47%) End-stage renal disease RRR 23% (-0.5-41%) All-cause mortality RRR -3% (-35-22%) Composite endpoint RRR 20% (7.5-32%) -40 -24 -8 8 24 40 56 RRR (95% CI) RCT 1715 DM 2 nephropathy, HTN irbesartan vs amlodipine NEJM 2001; 345: 851

33. What has gone wrong? • widely varying importance • biggest effect on least important • most important no effect • criteria for use of composite • similar patient-importance • similar effect

34. UKPDS Diabetes-related endpoints Sudden death Death from hypoglycemia Death from hyperglycemia Fatal MI Nonfatal MI Angina Heart failure Stroke Renal failure Amputation Vitreous hemorrhage Retinal photocoagulation Blindness in one eye Cataract extraction After 10 years of treatment with diet + SU or insulin: 35.3% with diet: 38.5% RD: 3.2% NNT for 10 years: 31 SIMILAR PATIENT IMPORTANCE? SIMILAR TREATMENT EFFECT? 2.7% 1 in 35 reviews note thisdominance

35. 4 Beware composite endpoints

36. 5,269 patients with abnormal glucose tolerance test randomized to lifestyle advice, or advice + rosiglitazone followed for 3 to 5 years

41. What is the authors’ message? • rosiglitazone to prevent diabetes: • strong indication (for all) • weak indication (for some) • not indicated

42. Doctor, what do I gain by taking rosiglitazone? • Doc: less chance of diabetes • Pt: what happens if I get diabetes • Doc: you have to take a drug • Pt: the same drug I’m taking to prevent diabetes? • Doc: I could give you a drug with less problems • Pt: I’ll take a drug every day for 3 years to lower my risk of taking the same or a less toxic drug from 25 to 10%???

46. What is your view? • rosiglitazone to prevent diabetes: • strong indication (for all) • weak indication (for some) • not indicated • what has gone wrong here?

47. Other problematic surrogates • tests of cognitive function instead of function and behavior in Alzheimer’s • bone density instead of fractures in osteoporosis • oxygenation instead of mortality in ARDS • asymptomatic DVT instead of symptomatic thromboembolism • pulmonary function instead of exacerbations and qol in respiratory disease • lipids instead of CV events in atherosclerosis

48. Another surrogate • patients with CV disease • higher HDL associated with lower CV risk • strongly agree • agree • disagree • raising HDL should decrease CV risk • strongly agree • agree • disagree

50. 5 Beware substitute endpoints