Publication Bias in Antipsychotic Trials: An Analysis of Efficacy Comparing the Published Literature to the US Food and Drug Administration Database

English version České info

Background:
Publication bias compromises the validity of evidence-based medicine, yet a growing body of research shows that this problem is widespread. Efficacy data from drug regulatory agencies, e.g., the US Food and Drug Administration (FDA), can serve as a benchmark or control against which data in journal articles can be checked. Thus one may determine whether publication bias is present and quantify the extent to which it inflates apparent drug efficacy.

Methods and Findings:
FDA Drug Approval Packages for eight second-generation antipsychotics—aripiprazole, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, risperidone long-acting injection (risperidone LAI), and ziprasidone—were used to identify a cohort of 24 FDA-registered premarketing trials. The results of these trials according to the FDA were compared with the results conveyed in corresponding journal articles. The relationship between study outcome and publication status was examined, and effect sizes derived from the two data sources were compared. Among the 24 FDA-registered trials, four (17%) were unpublished. Of these, three failed to show that the study drug had a statistical advantage over placebo, and one showed the study drug was statistically inferior to the active comparator. Among the 20 published trials, the five that were not positive, according to the FDA, showed some evidence of outcome reporting bias. However, the association between trial outcome and publication status did not reach statistical significance. Further, the apparent increase in the effect size point estimate due to publication bias was modest (8%) and not statistically significant. On the other hand, the effect size for unpublished trials (0.23, 95% confidence interval 0.07 to 0.39) was less than half that for the published trials (0.47, 95% confidence interval 0.40 to 0.54), a difference that was significant.

Conclusions:
The magnitude of publication bias found for antipsychotics was less than that found previously for antidepressants, possibly because antipsychotics demonstrate superiority to placebo more consistently. Without increased access to regulatory agency data, publication bias will continue to blur distinctions between effective and ineffective drugs.

: Please see later in the article for the Editors' Summary

Vyšlo v časopise: Publication Bias in Antipsychotic Trials: An Analysis of Efficacy Comparing the Published Literature to the US Food and Drug Administration Database. PLoS Med 9(3): e32767. doi:10.1371/journal.pmed.1001189
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pmed.1001189

Souhrn

Zdroje

1. DwanKAltmanDGArnaizJABloomJChanAW 2008 Systematic review of the empirical evidence of study publication bias and outcome reporting bias. PLoS ONE 3 e3081 doi:10.1371/journal.pone.0003081

2. HopewellSLoudonKClarkeMJOxmanADDickersinK 2009 Publication bias in clinical trials due to statistical significance or direction of trial results. Cochrane Database Syst Rev 2009 MR000006

3. McGauranNWieselerBKreisJSchülerY-BKölschH 2010 Reporting bias in medical research—a narrative review. Trials 11 37

4. SterneJAGavaghanDEggerM 2000 Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol 53 1119 1129

5. TurnerEH 2004 A taxpayer-funded clinical trials registry and results database. PLoS Med 1 e60 doi:10.1371/journal.pmed.0010060

6. RisingKBacchettiPBeroL 2008 Reporting bias in drug trials submitted to the Food and Drug Administration: review of publication and presentation. PLoS Med 5 e217 doi:10.1371/journal.pmed.0050217

7. LeeKBacchettiPSimI 2008 Publication of clinical trials supporting successful new drug applications: a literature analysis. PLoS Med 5 e191 doi:10.1371/journal.pmed.0050191

8. TurnerEHMatthewsAMLinardatosETellRARosenthalR 2008 Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 358 252 260

9. GoldnerEMHsuLWaraichPSomersJM 2002 Prevalence and incidence studies of schizophrenic disorders: a systematic review of the literature. Can J Psychiatry 47 833 843

10. UstünTBRehmJChatterjiSSaxenaSTrotterR 1999 Multiple-informant ranking of the disabling effects of different health conditions in 14 countries. WHO/NIH Joint Project CAR Study Group. Lancet 354 111 115

11. US Food and Drug Administration 2012 Drugs@FDA: FDA approved drug products [database]. Available: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed 12 February 2012

12. US Department of Justice 1996 The Freedom of Information Act 5 U.S.C. § 552, as amended by Public Law No. 104-231, 110 Stat. 3048. FOIA Update, Vol. XVII, No. 4 Washington (District of Columbia) US Department of Justice Available: http://www.justice.gov/oip/foia_updates/Vol_XVII_4/page2.htm. Accessed 3 February 2012

13. SchererRWLangenbergPvon ElmE 2007 Full publication of results initially presented in abstracts. Cochrane Database Syst Rev 2007 MR000005

14. Council of Biology 1969 Proposed definition of a primary publication. CBE Newsletter November 1968 1 2

15. WoernerMGMannuzzaSKaneJM 1988 Anchoring the BPRS: an aid to improved reliability. Psychopharmacol Bull 24 112 117

16. KaySROplerLALindenmayerJP 1989 The Positive and Negative Syndrome Scale (PANSS): rationale and standardisation. Br J Psychiatry Suppl 59 67

17. AbrahaIMontedoriA 2010 Modified intention to treat reporting in randomised controlled trials: systematic review. BMJ 340 c2697

18. MallinckrodtCHClarkSWSCarrollRJMolenberghG 2003 Assessing response profiles from incomplete longitudinal clinical trial data under regulatory considerations. J Biopharm Stat 13 179 190

19. WoolleySBCardoniAAGoetheJW 2009 Last-observation-carried-forward imputation method in clinical efficacy trials: review of 352 antidepressant studies. Pharmacotherapy 29 1408 1416

20. StataCorp 2009 Stata statistical software: release 11 [computer program] College Station (Texas) StataCorp

21. HedgesLV 1982 Estimation of effect size from a series of independent experiments. Psychol Bull 92 490 499

22. RosenthalR 1991 Meta-analytic procedures for social research Newbury Park (California) Sage

23. HedgesLVOlkinI 1985 Statistical methods for meta-analysis New York Academic Press

24. SuttonAJAbramsKRJonesDRSheldonTASongF 2000 Fixed effects methods for combining study estimates. Methods for meta-analysis in medical research Chichester John Wiley & Sons 57 72

25. HigginsJGreenS 2011 Cochrane handbook for systematic reviews of interventions, version 5.1.0. Section 16.15.14. The Cochrane Collaboration

26. DerSimonianRLairdN 1986 Meta-analysis in clinical trials. Control Clin Trials 7 177 188

27. SterneJACBradburnMJEggerM 2001 Meta–analysis in Stata. EggerMSmithGDAltmanD Systematic reviews in health care: meta-analysis in context, 2nd edition 347 369

28. HigginsJPThompsonSG 2002 Quantifying heterogeneity in a meta-analysis. Stat Med 21 1539 1558

29. IoannidisJPPatsopoulosNAEvangelouE 2007 Uncertainty in heterogeneity estimates in meta-analyses. BMJ 335 914 916

30. OrsiniNHigginsJBottaiMBuchanI 2005 Heterogi: Stata module to quantify heterogeneity in a meta-analysis, revised 2006-01-25 [computer program]. Statistical Software Components S449201 Boston Boston College Department of Economics Available: http://EconPapers.repec.org/RePEc:boc:bocode:s449201. Accessed 12 February 2012

31. PotkinSGLitmanRETorresRWolfgangCD 2008 Efficacy of iloperidone in the treatment of schizophrenia: initial phase 3 studies. J Clin Psychopharmacol 28 S4 S11

32. HigginsJPTThompsonSGDeeksJJAltmanDG 2003 Measuring inconsistency in meta-analyses. BMJ 327 557 560

33. CitromeL 2010 Iloperidone redux: a dissection of the Drug Approval Package for this newly commercialised second-generation antipsychotic. Int J Clin Pract 64 707 718

34. CutlerAJKalaliAHWeidenPJHamiltonJWolfgangCD 2008 Four-week, double-blind, placebo- and ziprasidone-controlled trial of iloperidone in patients with acute exacerbations of schizophrenia. J Clin Psychopharmacol 28 S20 S28

35. BorisonRLArvanitisLAMillerBG 1996 ICI 204,636, an atypical antipsychotic: efficacy and safety in a multicenter, placebo-controlled trial in patients with schizophrenia. U.S. SEROQUEL Study Group. J Clin Psychopharmacol 16 158 169

36. KeckPBuffensteinAFergusonJFeighnerJJaffeW 1998 Ziprasidone 40 and 120 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 4-week placebo-controlled trial. Psychopharmacology (Berl) 140 173 184

37. BorisonRLPathirajaAPDiamondBIMeibachRC 1992 Risperidone: clinical safety and efficacy in schizophrenia. Psychopharmacol Bull 28 213 218

38. de OliveiraIRMiranda-ScippaAMde SenaEPPereiraELRibeiroMG 1996 Risperidone versus haloperidol in the treatment of schizophrenia: a meta-analysis comparing their efficacy and safety. J Clin Pharm Ther 21 349 358

39. DickersinKRennieD 2003 Registering clinical trials. JAMA 290 516 523

40. ChouinardGJonesBRemingtonGBloomDAddingtonD 1993 A Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol 13 25 40

41. MarderSRMeibachRC 1994 Risperidone in the treatment of schizophrenia. Am J Psychiatry 151 825 835

42. MarderSRDavisJMChouinardG 1997 The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials. J Clin Psychiatry 58 538 546

43. MakhinsonM 2010 Biases in medication prescribing: the case of second-generation antipsychotics. J Psychiatr Pract 16 15 21

44. HeresSDavisJMainoKJetzingerEKisslingW 2006 Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine: an exploratory analysis of head-to-head comparison studies of second-generation antipsychotics. Am J Psychiatry 163 185 194

45. LeuchtSArbterDEngelRRKisslingWDavisJM 2009 How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Mol Psychiatry 14 429 447

46. MelanderHAhlqvist-RastadJMeijerGBeermannB 2003 Evidence b(i)ased medicine—selective reporting from studies sponsored by pharmaceutical industry: review of studies in new drug applications. BMJ 326 1171 1173

47. WoodsSWStolarMSernyakMJCharneyDS 2001 Consistency of atypical antipsychotic superiority to placebo in recent clinical trials. Biol Psychiatry 49 64 70

48. KirschIDeaconBJHuedo-MedinaTBScoboriaAMooreTJ 2008 Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med 5 e45 doi:10.1371/journal.pmed.0050045

49. FournierJCDeRubeisRJHollonSDDimidjianSAmsterdamJD 2010 Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA 303 47 53

50. TurnerEHRosenthalR 2008 Efficacy of antidepressants. BMJ 336 516 517

51. CohenJ 1988 Statistical power analysis for the behavioral sciences New York Lawrence Erlbaum Associates

52. KraemerHCKupferDJ 2006 Size of treatment effects and their importance to clinical research and practice. Biol Psychiatry 59 990 996

53. MöllerH-J 2008 Do effectiveness (“real world”) studies on antipsychotics tell us the real truth? Eur Arch Psychiatry Clin Neurosci 258 257 270

54. Villalta-GilVVilaplanaMOchoaSHaroJMDolzM 2006 Neurocognitive performance and negative symptoms: are they equal in explaining disability in schizophrenia outpatients? Schizophr Res 87 246 253

55. O'ConnorAB 2009 The need for improved access to FDA reviews. JAMA 302 191 193

56. AsamoahAKSharfsteinJM 2010 Transparency at the Food and Drug Administration. N Engl J Med 362 2341 2343

57. SmallJGHirschSRArvanitisLAMillerBGLinkCG 1997 Quetiapine in patients with schizophrenia. A high- and low-dose double-blind comparison with placebo. Seroquel Study Group. Arch Gen Psychiatry 54 549 557

58. ArvanitisLAMillerBG 1997 Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group. Biol Psychiatry 42 233 246

59. KaneJMCarsonWHSahaARMcQuadeRDIngenitoGG 2002 Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 63 763 771

60. PotkinSGSahaARKujawaMJCarsonWHAliM 2003 Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs placebo in patients with schizophrenia and schizoaffective disorder. Arch Gen Psychiatry 60 681 690

61. McEvoyJPDanielDGCarsonWHMcQuadeRDMarcusRN 2007 A randomized, double-blind, placebo-controlled, study of the efficacy and safety of aripiprazole 10, 15 or 20 mg/day for the treatment of patients with acute exacerbations of schizophrenia. J Psychiatr Res 41 895 905

62. KaneJCanasFKramerMFordLGassmann-MayerC 2007 Treatment of schizophrenia with paliperidone extended-release tablets: a 6-week placebo-controlled trial. Schizophr Res 90 147 161

63. MarderSRKramerMFordLEerdekensELimP 2007 Efficacy and safety of paliperidone extended-release tablets: results of a 6-week, randomized, placebo-controlled study. Biol Psychiatry 62 1363 1370

64. DavidsonMEmsleyRKramerMFordLGuohuaP 2007 Efficacy, safety and early response of paliperidone extended-release tablets (paliperidone ER): results of a 6-week, randomized, placebo-controlled study. Schizophr Res 93 117 130

65. KaneJMEerdekensMLindenmayerJ-PKeithSJLesemM 2003 Long-acting injectable risperidone: efficacy and safety of the first long-acting atypical antipsychotic. Am J Psychiatry 160 1125 1132

66. BeasleyCMTollefsonGTranPSatterleeWSangerT 1996 Olanzapine versus placebo and haloperidol: acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology 14 111 123

67. BeasleyCMSangerTSatterleeWTollefsonGTranP 1996 Olanzapine versus placebo: results of a double-blind, fixed-dose olanzapine trial. Psychopharmacology (Berl) 124 159 167

68. DanielDGZimbroffDLPotkinSGReevesKRHarriganEP 1999 Ziprasidone 80 mg/day and 160 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 6-week placebo-controlled trial. Ziprasidone Study Group. Neuropsychopharmacology 20 491 505