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Published randomized controlled trials of drug therapy for dementia often lack complete data on harm

  • P.E. Lee
    Correspondence
    Corresponding author. Tel.: +604-806-8029; fax: +604-806-8390.
    Affiliations
    Division of Geriatric Medicine, University of British Columbia, St. Paul's Hospital, Providence Building, Ward 9B, 1081 Burrard Street, Vancouver, British Columbia, Canada
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  • H.D. Fischer
    Affiliations
    Institute for Clinical Evaluative Sciences (ICES), Toronto, Ontario, Canada
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  • P.A. Rochon
    Affiliations
    Institute for Clinical Evaluative Sciences (ICES), Toronto, Ontario, Canada

    Kunin-Lunenfeld Applied Research Unit, Baycrest, Toronto, Ontario, Canada

    Department of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada

    Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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  • S.S. Gill
    Affiliations
    Institute for Clinical Evaluative Sciences (ICES), Toronto, Ontario, Canada

    Department of Medicine, Queen's University, Kingston, Ontario, Canada
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  • N. Herrmann
    Affiliations
    Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
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  • C.M. Bell
    Affiliations
    Institute for Clinical Evaluative Sciences (ICES), Toronto, Ontario, Canada

    Department of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada

    Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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  • K. Sykora
    Affiliations
    Institute for Clinical Evaluative Sciences (ICES), Toronto, Ontario, Canada
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  • G.M. Anderson
    Affiliations
    Institute for Clinical Evaluative Sciences (ICES), Toronto, Ontario, Canada

    Department of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
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      Abstract

      Objective

      The objective of the study was to determine the extent to which published randomized controlled trials (RCTs) report data on harm.

      Study Design and Setting

      A systematic search strategy was used to identify RCTs published between 1996 and 2005 on the use of cholinesterase inhibitors or atypical antipsychotics in patients with dementia. A structured abstraction form was used to determine if data on mortality or serious adverse events were reported and if the articles followed Consolidated Standards of Reporting Trials format for reporting harm.

      Results

      Thirty-three RCTs were identified (27 on cholinesterase inhibitors and 6 on atypical antipsychotics). Nineteen trials (58%) had explicit data on mortality and only four (12%) reported regulatory-agency-defined serious adverse events. Most abstracts (31, 94%) stated that harm was studied but few studies (9, 27%) provided a clear definition of the measures of harm.

      Conclusions

      Although most published RCTs state that they examine harm, many failed to provide data on mortality and most lacked clear definitions or detailed analyses of harm. Better reporting of harm would provide timely and important information that could help physicians and the public to make more informed decisions.

      Keywords

      What is new?
      • Despite frequently stating that they examined harms, representative randomized clinical trials of medications to treat older adults with dementia often failed to report information on well-defined serious adverse events and deaths.
      • Closer attention to definitions of harm, analyses, and better reporting of serious adverse events would provide information that could help make informed decisions regarding harm-benefit tradeoffs.
      • Randomized clinical trials should state if they have collected data on serious adverse events using regulatory agency definitions, and they should make the data on serious adverse events readily available.

      1. Introduction

      “Primum non nocere” (Do no harm) is one of the basic tenets of medicine [
      • Smith C.M.
      Origin and uses of primum non nocere—above all, do no harm!.
      ]. To be properly aware of potential harm associated with a medical therapy, physicians often rely on the published literature, particularly randomized control trials (RCTs). If crucial harm data are missing, physicians may not have the information necessary to make an informed decision about prescribing a medication. The public and health care professionals should have access to the data that they need and authors and editors should make an effort to provide that information [
      • Ioannidis J.P.
      • Lau J.
      Completeness of safety reporting in randomized trials: an evaluation of 7 medical areas.
      ,
      • Ioannidis J.P.
      • Evans S.J.
      • Gotzsche P.C.
      • O'Neill R.T.
      • Altman D.G.
      • Schulz K.
      • et al.
      Better reporting of harms in randomized trials: an extension of the CONSORT statement.
      ].
      The published literature on RCTs of all prescription drugs is enormous and not amenable to a comprehensive systematic review. However, two representative classes of drugs are of specific interest to the elderly with dementia—cholinesterase inhibitors (ChEI) and atypical antipsychotics. The first published RCT examining the use of newer ChEI to treat memory loss in patients with dementia appeared in 1996 [
      • Rogers S.L.
      • Friedhoff L.T.
      The efficacy and safety of donepezil in patients with Alzheimer's disease: results of a US multicentre, randomized, double-blind, placebo-controlled trial. The Donepezil Study Group.
      ] and the first published RCT of atypical antipsychotics to manage psychological and behavioral problems in patients with dementia appeared in 1999 [
      • Katz I.R.
      • Jeste D.V.
      • Mintzer J.E.
      • Clyde C.
      • Napolitano J.
      • Brecher M.
      Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, double-blind trial. Risperidone Study Group.
      ,
      • De Deyn P.P.
      • Rabheru K.
      • Rasmussen A.
      • Bocksberger J.P.
      • Dautzenberg P.L.
      • Eriksson S.
      • et al.
      A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia.
      ]. Both drug classes were actively marketed and widely used prior to the safety warnings. For example, in Ontario by 2002, 2.6% of older adults in the community were prescribed an atypical antipsychotic and 1.9% were prescribed a ChEI [
      • Mamdani M.
      • Rapoport M.
      • Shulman K.I.
      • Herrmann N.
      • Rochon P.
      Mental health-related drug utilization among older adults.
      ]. Use of these drugs was even higher in the nursing home populations where 15% of residents were prescribed an atypical antipsychotic within one year of admission [
      • Bronskill S.E.
      • Anderson G.M.
      • Sykora K.
      • Wodchis W.P.
      • Gill S.
      • Shulman K.I.
      • et al.
      Neuroleptic drug therapy in older adults newly admitted to nursing homes: incidence, dose, and specialist contact.
      ].
      Both drug classes have been subject to regulatory agency warnings related to safety issues. In 2005, based on two previously unpublished RCTs [
      Johnson & Johnson Pharmaceutical Research & Development Synopsis.
      ,
      Johnson & Johnson Pharmaceutical Research & Development Synopsis.
      ], public warnings were issued by Health Canada [
      • Health Canada
      Public advisory—Health Canada endorsed important safety information on Reminyl (galantamine).
      ] and the United States Federal Drug Administration (FDA) [
      • United States Food and Drug Administration
      Reminyl (galantamine hydrobromide) prescribing information update re: patients with MCI.
      ] linking galantamine, a ChEI, to death in patients with mild cognitive impairment. In March 2006, the manufacturers of donepezil reported a potential increased risk of death in one trial assessing patients with vascular dementia on treatment [
      • Eisai Co
      LCCD. Eisai reports results from latest donepezil study in vascular dementia.
      ]. In 2005, Health Canada and the FDA issued public warnings based on data from RCT showing increased mortality in patients with dementia receiving atypical antipsychotics [
      • Health Canada
      Health Canada advises consumers about important safety information on atypical antipsychotic drugs and dementia.
      ,
      • United States FDA Public Health Advisory
      Deaths with antipsychotics in elderly patients with behavioral disturbances.
      ] and a subsequent meta-analysis of published and unpublished clinical trials showed an increased risk of death in older adults with dementia treated with atypical antipsychotics [
      • Schneider L.S.
      • Dagerman K.S.
      • Insel P.
      Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials.
      ].
      The problem of widespread use of drugs that are subsequently found to be harmful may be due in part to the difficulty of obtaining public access to the safety information that drug manufacturers must submit to regulators for prelicensure assessment. Information submitted to regulators prior to drug approval is deemed to be proprietary. A full discussion of the balance between intellectual property and public safety that must be struck by regulators is beyond the scope of this paper; however, another issue related to protecting the public is the failure of published RCTs to adequately report harm [
      • Ioannidis J.P.
      • Lau J.
      Completeness of safety reporting in randomized trials: an evaluation of 7 medical areas.
      ].
      The purpose of this paper is to systematically identify all published RCTs of ChEI and atypical antipsychotics in patients with dementia published prior to the safety warnings and to describe the content and format of harm reporting in these studies. By limiting the analysis to RCTs published before the regulatory agency safety warnings for these two drug classes, the study focus is on what information on harm was available in journals prior to the warnings not how the literature may have responded to regulatory concerns over harm. This will help increase our understanding of how well harm is reported in published RCTs and will provide a useful guide to authors and journals as they try to ensure that providers and patients have full information on the effects of drugs.

      2. Methods

      2.1 Literature search strategy

      Electronic searches of MEDLINE (1966 to May Week 4, 2005), EMBASE (1980–2005 Week 6) and the Cochrane Databases (inception to fourth quarter 2004) were performed. We didn't want to include studies that were released after the FDA/Health Canada safety warnings had already been made public. For our search, the keywords included: dementia; Alzheimer's disease (AD); dementia, vascular. For drug groups, we used the keywords cholinesterase inhibitors and antipsychotics. Cholinesterase inhibitors, donepezil, galantamine, and rivastigmine and their CAS registry numbers were identified. Trials assessing tacrine, another cholinesterase inhibitor, were not included. Although tacrine showed a modest degree of efficacy among a small proportion of patients with mild to moderate AD, it has important adverse effects, which limits its clinical usefulness [
      • Arrieta J.L.
      • Artalejo F.R.
      Methodology, results and quality of clinical trials of tacrine in the treatment of Alzheimer's disease: a systematic review of the literature.
      ]. For the atypical antipsychotics, we included aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone. Reference lists from the identified articles were manually searched and cross-referenced. Clinical experts were contacted to identify additional trials.

      2.2 Selection of eligible trials

      Published, RCTs with a placebo arm that assessed medication efficacy or tolerability for ChEI or atypical antipsychotics for symptomatic treatment of patients with AD or vascular dementia were included. Studies that evaluated a mixed population of patients with dementia were included if AD was the most common dementia in the trial. Open-label extensions of RCTs, post hoc analyses, subgroup analyses of previously published data, editorials, and commentaries were excluded.
      For ChEI, 54 abstracts identified through a search of MEDLINE were reviewed in detail. From these abstracts, 24 clinical trials were selected. The remaining abstracts did not meet our inclusion criteria (letters, review articles, nonrandomized clinical trials, or assessment of the use of ChEIs such as physostigmine, velnacrine, metrifonate, eptastigmine, or tacrine). Seventeen abstracts were identified through EMBASE and three of these trials met inclusion criteria and were included. An additional trial assessing donepezil was not accessible for detailed review [
      • Peng D.
      • Xu X.
      • Hou Q.
      The safety and efficacy of aricept in patients with Alzheimer disease.
      ]. In total, there were 27 randomized placebo controlled trials: 15 donepezil [
      • Rogers S.L.
      • Friedhoff L.T.
      The efficacy and safety of donepezil in patients with Alzheimer's disease: results of a US multicentre, randomized, double-blind, placebo-controlled trial. The Donepezil Study Group.
      ,
      • Holmes C.
      • Wilkinson D.
      • Dean C.
      • Vethanayagam S.
      • Olivieri S.
      • Langley A.
      • et al.
      The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease.
      ,
      • Seltzer B.
      • Zolnouni P.
      • Nunez M.
      • Goldman R.
      • Kumar D.
      • Ieni J.
      • et al.
      Efficacy of donepezil in early-stage Alzheimer disease: a randomized placebo-controlled trial.
      ,
      • Courtney C.
      • Farrell D.
      • Gray R.
      • Hills R.
      • Lynch L.
      • Sellwood E.
      • et al.
      Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial.
      ,
      • Black S.
      • Roman G.C.
      • Geldmacher D.S.
      • Salloway S.
      • Hecker J.
      • Burns A.
      • et al.
      Efficacy and tolerability of donepezil in vascular dementia: positive results of a 24-week, multicenter, international, randomized, placebo-controlled clinical trial.
      ,
      • Wilkinson D.
      • Doody R.
      • Helme R.
      • Taubman K.
      • Mintzer J.
      • Kertesz A.
      • et al.
      Donepezil in vascular dementia: a randomized, placebo-controlled study.
      ,
      • Feldman H.
      • Gauthier S.
      • Hecker J.
      • Vellas B.
      • Subbiah P.
      • Whalen E.
      • et al.
      A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer's disease.
      ,
      • Tariot P.N.
      • Cummings J.L.
      • Katz I.R.
      • Mintzer J.
      • Perdomo C.A.
      • Schwam E.M.
      • et al.
      A randomized, double-blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer's disease in the nursing home setting.
      ,
      • Winblad B.
      • Engedal K.
      • Soininen H.
      • Verhey F.
      • Waldemar G.
      • Wimo A.
      • et al.
      A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD.
      ,
      • Mohs R.C.
      • Doody R.S.
      • Morris J.C.
      • Ieni J.R.
      • Rogers S.L.
      • Perdomo C.A.
      • et al.
      A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients.
      ,
      • Greenberg S.M.
      • Tennis M.K.
      • Brown L.B.
      • Gomez-Isla T.
      • Hayden D.L.
      • Schoenfeld D.A.
      • et al.
      Donepezil therapy in clinical practice: a randomized crossover study.
      ,
      • Homma A.
      • Takeda M.
      • Imai Y.
      • Udaka F.
      • Hasegawa K.
      • Kameyama M.
      • et al.
      Clinical efficacy and safety of donepezil on cognitive and global function in patients with Alzheimer's disease. A 24-week, multicenter, double-blind, placebo-controlled study in Japan. E2020 Study Group.
      ,
      • Burns A.
      • Rossor M.
      • Hecker J.
      • Gauthier S.
      • Petit H.
      • Moller H.J.
      • et al.
      The effects of donepezil in Alzheimer's disease—results from a multinational trial.
      ,
      • Rogers S.L.
      • Doody R.S.
      • Mohs R.C.
      • Friedhoff L.T.
      Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group.
      ,
      • Rogers S.L.
      • Farlow M.R.
      • Doody R.S.
      • Mohs R.
      • Friedhoff L.T.
      A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Donepezil Study Group.
      ], 6 rivastigmine [
      • Karaman Y.
      • Erdogan F.
      • Koseoglu E.
      • Turan T.
      • Ersoy A.O.
      A 12-month study of the efficacy of rivastigmine in patients with advanced moderate Alzheimer's disease.
      ,
      • Rosler M.
      • Anand R.
      • Cicin-Sain A.
      • Gauthier S.
      • Agid Y.
      • Dal-Bianco P.
      • et al.
      Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial.
      ,
      • Forette F.
      • Anand R.
      • Gharabawi G.
      A phase II study in patients with Alzheimer's disease to assess the preliminary efficacy and maximum tolerated dose of rivastigmine (Exelon).
      ,
      • Agid Y.
      • Dubois B.
      • Anand R.
      • Gharabawi G.
      Efficacy and tolerability of rivastigmine in patients with dementia of the Alzheimer type.
      ,
      • Corey-Bloom J.
      • Anand R.
      • Veach J.
      A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer's disease.
      ,
      • Sramek J.J.
      • Anand R.
      • Wardle T.S.
      • Irwin P.
      • Hartman R.D.
      • Cutler N.R.
      Safety/tolerability trial of SDZ ENA 713 in patients with probable Alzheimer's disease.
      ] and 6 galantamine [
      • Rockwood K.
      • Mintzer J.
      • Truyen L.
      • Wessel T.
      • Wilkinson D.
      Effects of a flexible galantamine dose in Alzheimer's disease: a randomised, controlled trial.
      ,
      • Erkinjuntti T.
      • Kurz A.
      • Gauthier S.
      • Bullock R.
      • Lilienfeld S.
      • Damaraju C.V.
      Efficacy of galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomised trial.
      ,
      • Wilkinson D.
      • Murray J.
      Galantamine: a randomized, double-blind, dose comparison in patients with Alzheimer's disease.
      ,
      • Wilcock G.K.
      • Lilienfeld S.
      • Gaens E.
      Efficacy and safety of galantamine in patients with mild to moderate Alzheimer's disease: multicentre randomised controlled trial. Galantamine International-1 Study Group.
      ,
      • Raskind M.A.
      • Peskind E.R.
      • Wessel T.
      • Yuan W.
      Galantamine in AD: a 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group.
      ,
      • Tariot P.N.
      • Solomon P.R.
      • Morris J.C.
      • Kershaw P.
      • Lilienfeld S.
      • Ding C.
      A 5-month, randomized, placebo-controlled trial of galantamine in AD. The Galantamine USA-10 Study Group.
      ] trials.
      A Medline search provided 16 abstracts evaluating atypical antipsychotic therapy from which six randomized, placebo control clinical trials were identified: three risperidone [
      • Katz I.R.
      • Jeste D.V.
      • Mintzer J.E.
      • Clyde C.
      • Napolitano J.
      • Brecher M.
      Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, double-blind trial. Risperidone Study Group.
      ,
      • De Deyn P.P.
      • Rabheru K.
      • Rasmussen A.
      • Bocksberger J.P.
      • Dautzenberg P.L.
      • Eriksson S.
      • et al.
      A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia.
      ,
      • Brodaty H.
      • Ames D.
      • Snowdon J.
      • Woodward M.
      • Kirwan J.
      • Clarnette R.
      • et al.
      A randomized placebo-controlled trial of risperidone for the treatment of aggression, agitation, and psychosis of dementia.
      ], two olanzapine [
      • Street J.S.
      • Clark W.S.
      • Gannon K.S.
      • Cummings J.L.
      • Bymaster F.P.
      • Tamura R.N.
      • et al.
      Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial. The HGEU Study Group.
      ,
      • De Deyn P.P.
      • Carrasco M.M.
      • Deberdt W.
      • Jeandel C.
      • Hay D.P.
      • Feldman P.D.
      • et al.
      Olanzapine versus placebo in the treatment of psychosis with or without associated behavioral disturbances in patients with Alzheimer's disease.
      ], and one quetiapine [
      • Ballard C.
      • Margallo-Lana M.
      • Juszczak E.
      • Douglas S.
      • Swann A.
      • Thomas A.
      • et al.
      Quetiapine and rivastigmine and cognitive decline in Alzheimer's disease: randomised double blind placebo controlled trial.
      ] trial. No published clinical trials that fulfilled inclusion criteria assessed the use of clozapine, aripiprazole, or ziprasidone in older adults with dementia. A search of EMBASE did not identify any additional studies for review.

      2.3 Content of harm reporting: serious adverse events and death

      The International Conference on Harmonization (ICH) defines serious adverse events (SAE) as any untoward medical occurrence that at any dose: results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect [
      • Edwards I.R.
      • Biriell C.
      Harmonisation in pharmacovigilance.
      ]. This definition of SAE forms the basis of prelicensure safety reporting by drug manufacturers required by many national drug regulatory agencies [
      • Health Canada
      Guidance for clinical trial sponsors. Clinical trial applications.
      ,
      • United States Food and Drug Administration
      Title 21—food and drugs chapter I—Food and Drug Administration Department of Health and Human Services, subchapter D—drugs for human use. 21CFR310.305.
      ,
      • United States Food and Drug Administration
      Title 21—food and drugs chapter I—Food and Drug Administration Department of Health and Human Services, subchapter D—drugs for human use. 21CFR314.80.
      ].
      An abstraction form was developed to determine if information on SAE that was clearly based on the ICH definition was available in the paper and if there was clear and complete reporting on mortality in the paper.

      2.4 Harm reporting in relation to CONSORT recommendations

      The format of harm reporting was evaluated in relation to recommendations made by the Consolidated Standards of Reporting Trials (CONSORT) group on reporting harm in RCTs [
      • Ioannidis J.P.
      • Evans S.J.
      • Gotzsche P.C.
      • O'Neill R.T.
      • Altman D.G.
      • Schulz K.
      • et al.
      Better reporting of harms in randomized trials: an extension of the CONSORT statement.
      ]. CONSORT provided a checklist outlining the location in the paper (i.e., abstract and title, introduction, methods, results, and discussion) where specific topics (e.g., intent to address harm, definition of harm, analysis of harm data) related to harm should be reported. An abstraction form was developed to collect data from each paper on the extent to which the paper provided the information recommended by CONSORT. This abstraction form identified 10 specific topics on harm (one from the title or abstract, one from the introduction, three from the methods, four from the results, and one from the discussion) that should be included in published RCTs (Appendix). If the paper met any one of the criteria that CONSORT defined for a topic, then it was counted as fulfilled for that topic.

      2.5 Data abstraction process

      Each paper was independently reviewed using the standard data abstraction form by two study investigators (PEL and HF). They indicated on the form if there was explicit reporting of the number of death and if ICH-defined-SAE were reported. They also indicated on the form if the paper fulfilled the CONSORT harm reporting suggestions for each of the ten defined topic areas. If the two reviewers did not agree on the initial rating, they discussed the scoring and rescored the paper based on that discussion.

      3. Results

      3.1 Selection of eligible trials

      Thirty-three RCTs were identified: 27 assessed cholinesterase inhibitors and 6 assessed atypical antipsychotics (see Table 1). All trials were published from 1996 to 2005 prior to the release of regulatory agency safety warnings. The sample size of subjects ranged from 50 to 978 participants. The duration of the trials varied from 6 to 60 weeks. Twenty-nine (88%) of the studies indicated that they were supported by pharmaceutical manufacturers, three indicated that they were funded by nonindustry sources [
      • Courtney C.
      • Farrell D.
      • Gray R.
      • Hills R.
      • Lynch L.
      • Sellwood E.
      • et al.
      Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial.
      ,
      • Greenberg S.M.
      • Tennis M.K.
      • Brown L.B.
      • Gomez-Isla T.
      • Hayden D.L.
      • Schoenfeld D.A.
      • et al.
      Donepezil therapy in clinical practice: a randomized crossover study.
      ,
      • Ballard C.
      • Margallo-Lana M.
      • Juszczak E.
      • Douglas S.
      • Swann A.
      • Thomas A.
      • et al.
      Quetiapine and rivastigmine and cognitive decline in Alzheimer's disease: randomised double blind placebo controlled trial.
      ], and the source of funding could not be determined for one study [
      • Sramek J.J.
      • Anand R.
      • Wardle T.S.
      • Irwin P.
      • Hartman R.D.
      • Cutler N.R.
      Safety/tolerability trial of SDZ ENA 713 in patients with probable Alzheimer's disease.
      ].
      Table 1Reporting of ICH-defined serious adverse events (SAE), adverse events and deaths experienced by participants in clinical trials evaluating the use of cholinesterase inhibitors or atypical antipsychotics for the symptomatic treatment of patients with AD
      TrialTreatmentNumber of subjectsICH Defined SAE Reported (Y/N)Any AE Reported (Y/N)Deaths N (%)
      Holmes et al.
      • Holmes C.
      • Wilkinson D.
      • Dean C.
      • Vethanayagam S.
      • Olivieri S.
      • Langley A.
      • et al.
      The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease.
      Placebo55NoNoNot reported
      Donepezil (10 mg)41Not reported
      Seltzer et al.
      • Seltzer B.
      • Zolnouni P.
      • Nunez M.
      • Goldman R.
      • Kumar D.
      • Ieni J.
      • et al.
      Efficacy of donepezil in early-stage Alzheimer disease: a randomized placebo-controlled trial.
      Placebo57NoYesNot reported
      Donepezil (10 mg)96Not reported
      Courtney et al.
      • Courtney C.
      • Farrell D.
      • Gray R.
      • Hills R.
      • Lynch L.
      • Sellwood E.
      • et al.
      Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial.
      Placebo283NoYes50 (18)
      Donepezil (5 & 10 mg)28263 (22)
      Black S et al.
      • Black S.
      • Roman G.C.
      • Geldmacher D.S.
      • Salloway S.
      • Hecker J.
      • Burns A.
      • et al.
      Efficacy and tolerability of donepezil in vascular dementia: positive results of a 24-week, multicenter, international, randomized, placebo-controlled clinical trial.
      Placebo199NoYes7 (4)
      Donepezil (5mg)1982 (1)
      Donepezil (10 mg)2066 (3)
      Wilkinson et al.
      • Wilkinson D.
      • Doody R.
      • Helme R.
      • Taubman K.
      • Mintzer J.
      • Kertesz A.
      • et al.
      Donepezil in vascular dementia: a randomized, placebo-controlled study.
      Placebo193NoYes1 (1)
      Donepezil (5 mg)2083 (1)
      Donepezil (10 mg)2152 (1)
      Feldman et al.
      • Feldman H.
      • Gauthier S.
      • Hecker J.
      • Vellas B.
      • Subbiah P.
      • Whalen E.
      • et al.
      A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer's disease.
      Placebo146YesYes0 (0)
      Donepezil (10 mg)1441 (1)
      Tariot et al.
      • Tariot P.N.
      • Cummings J.L.
      • Katz I.R.
      • Mintzer J.
      • Perdomo C.A.
      • Schwam E.M.
      • et al.
      A randomized, double-blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer's disease in the nursing home setting.
      Placebo105YesYes7 (7)
      Donepezil (10 mg)1033 (3)
      Winblad et al.
      • Winblad B.
      • Engedal K.
      • Soininen H.
      • Verhey F.
      • Waldemar G.
      • Wimo A.
      • et al.
      A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD.
      Placebo144NoYes3 (2)
      Donepezil (10 mg)1424 (3)
      Mohs et al.
      • Mohs R.C.
      • Doody R.S.
      • Morris J.C.
      • Ieni J.R.
      • Rogers S.L.
      • Perdomo C.A.
      • et al.
      A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients.
      Placebo217NoYes4 (2)
      Donepezil (10 mg)2143 (1)
      Greenberg et al.
      • Greenberg S.M.
      • Tennis M.K.
      • Brown L.B.
      • Gomez-Isla T.
      • Hayden D.L.
      • Schoenfeld D.A.
      • et al.
      Donepezil therapy in clinical practice: a randomized crossover study.
      Placebo-donepezil30NoYesNot reported
      Donepezil-placebo30Not reported
      Homma et al.
      • Homma A.
      • Takeda M.
      • Imai Y.
      • Udaka F.
      • Hasegawa K.
      • Kameyama M.
      • et al.
      Clinical efficacy and safety of donepezil on cognitive and global function in patients with Alzheimer's disease. A 24-week, multicenter, double-blind, placebo-controlled study in Japan. E2020 Study Group.
      Placebo131NoNoNot reported
      Donepezil (5 mg)136Not reported
      Burns et al.
      • Burns A.
      • Rossor M.
      • Hecker J.
      • Gauthier S.
      • Petit H.
      • Moller H.J.
      • et al.
      The effects of donepezil in Alzheimer's disease—results from a multinational trial.
      Placebo274YesYes2 (1)
      Donepezil (5 mg)2711 (0)
      Donepezil(10 mg)2732 (1)
      Rogers et al.
      • Rogers S.L.
      • Farlow M.R.
      • Doody R.S.
      • Mohs R.
      • Friedhoff L.T.
      A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Donepezil Study Group.
      Placebo162NoYes1 (1)
      Donepezil (5 mg)1540 (0)
      Donepezil (10 mg)1571 (1)
      Rogers et al.
      • Rogers S.L.
      • Doody R.S.
      • Mohs R.C.
      • Friedhoff L.T.
      Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group.
      Placebo153NoYes1 (1)
      Donepezil (5 mg)157Not reported
      Donepezil (10 mg)158Not reported
      Rogers et al.
      • Rogers S.L.
      • Friedhoff L.T.
      The efficacy and safety of donepezil in patients with Alzheimer's disease: results of a US multicentre, randomized, double-blind, placebo-controlled trial. The Donepezil Study Group.
      Placebo40NoNoNot reported
      Donepezil (1 mg)42Not reported
      Donepezil (3 mg)40Not reported
      Donepezil (5 mg)39Not reported
      Karaman et al.
      • Karaman Y.
      • Erdogan F.
      • Koseoglu E.
      • Turan T.
      • Ersoy A.O.
      A 12-month study of the efficacy of rivastigmine in patients with advanced moderate Alzheimer's disease.
      Placebo20NoNoNot reported
      Rivastigmine (12 mg)24Not reported
      Rosler et al.
      • Rosler M.
      • Anand R.
      • Cicin-Sain A.
      • Gauthier S.
      • Agid Y.
      • Dal-Bianco P.
      • et al.
      Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial.
      Placebo239NoNo0 (0)
      Rivastigmine (1-4 mg)2420 (0)
      Rivastigmine (6-8 mg)2421 (0)
      Forette et al.
      • Forette F.
      • Anand R.
      • Gharabawi G.
      A phase II study in patients with Alzheimer's disease to assess the preliminary efficacy and maximum tolerated dose of rivastigmine (Exelon).
      Placebo24NoNoNot reported
      Rivastigmine BID (12 mg)45Not reported
      Rivastigmine TID (12 mg)45Not reported
      Agid et al.
      • Agid Y.
      • Dubois B.
      • Anand R.
      • Gharabawi G.
      Efficacy and tolerability of rivastigmine in patients with dementia of the Alzheimer type.
      Placebo133NoYesNot reported
      Rivastigmine (4 mg)136Not reported
      Rivastigmine (6 mg)133Not reported
      Corey-Bloom et al.
      • Corey-Bloom J.
      • Anand R.
      • Veach J.
      A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer's disease.
      Placebo235NoNo0 (0)
      Rivastigmine (1-4 mg)2330 (0)
      Rivastigmine (6-12 mg)2311 (0)
      Sramek et al.
      • Sramek J.J.
      • Anand R.
      • Wardle T.S.
      • Irwin P.
      • Hartman R.D.
      • Cutler N.R.
      Safety/tolerability trial of SDZ ENA 713 in patients with probable Alzheimer's disease.
      Placebo10NoNoNot reported
      Rivastigmine BID (12 mg)20Not reported
      Rivastigmine TID (12 mg)20Not reported
      Rockwood et al.
      • Rockwood K.
      • Mintzer J.
      • Truyen L.
      • Wessel T.
      • Wilkinson D.
      Effects of a flexible galantamine dose in Alzheimer's disease: a randomised, controlled trial.
      Placebo125NoYes2 (2)
      Galantamine (24-36 mg)2610 (0)
      Erkinjuntti et al.
      • Erkinjuntti T.
      • Kurz A.
      • Gauthier S.
      • Bullock R.
      • Lilienfeld S.
      • Damaraju C.V.
      Efficacy of galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomised trial.
      Placebo196NoNo7 (4)
      Galantamine (24mg)3969 (2)
      Wilkinson et al.
      • Wilkinson D.
      • Murray J.
      Galantamine: a randomized, double-blind, dose comparison in patients with Alzheimer's disease.
      Placebo87NoYesNot reported
      Galantamine (18mg)88Not reported
      Galantamine (24mg)56Not reported
      Galantamine (36mg)54Not reported
      Wilcock et al.
      • Wilcock G.K.
      • Lilienfeld S.
      • Gaens E.
      Efficacy and safety of galantamine in patients with mild to moderate Alzheimer's disease: multicentre randomised controlled trial. Galantamine International-1 Study Group.
      Placebo215NoNoNot reported
      Galantamine (24mg)220Not reported
      Galantamine (32mg)218Not reported
      Raskind et al.
      • Raskind M.A.
      • Peskind E.R.
      • Wessel T.
      • Yuan W.
      Galantamine in AD: a 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group.
      Placebo213NoNo1 (1)
      Galantamine (24mg)2121 (1)
      Galantamine (32mg)2111 (1)
      Tariot et al.
      • Tariot P.N.
      • Solomon P.R.
      • Morris J.C.
      • Kershaw P.
      • Lilienfeld S.
      • Ding C.
      A 5-month, randomized, placebo-controlled trial of galantamine in AD. The Galantamine USA-10 Study Group.
      Placebo286NoYes4 (1)
      Galantamine (8mg)1401 (1)
      Galantamine (16mg)2793 (1)
      Galantamine (24mg)2733 (1)
      Brodaty et al.
      • Brodaty H.
      • Ames D.
      • Snowdon J.
      • Woodward M.
      • Kirwan J.
      • Clarnette R.
      • et al.
      A randomized placebo-controlled trial of risperidone for the treatment of aggression, agitation, and psychosis of dementia.
      Placebo170YesYes4 (2)
      Risperidone (2mg)1676 (4)
      De Deyn et al.
      • De Deyn P.P.
      • Rabheru K.
      • Rasmussen A.
      • Bocksberger J.P.
      • Dautzenberg P.L.
      • Eriksson S.
      • et al.
      A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia.
      Placebo114NoNoNot reported
      Risperidone (2mg)115Not reported
      Haloperidol115Not reported
      Katz et al.
      • Katz I.R.
      • Jeste D.V.
      • Mintzer J.E.
      • Clyde C.
      • Napolitano J.
      • Brecher M.
      Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, double-blind trial. Risperidone Study Group.
      Placebo163NoYes5 (3)
      Risperidone (0.5mg)1496 (4)
      Risperidone (1 mg)14813 (9)
      Risperidone (2 mg)1656 (4)
      De Deyn et al.
      • De Deyn P.P.
      • Carrasco M.M.
      • Deberdt W.
      • Jeandel C.
      • Hay D.P.
      • Feldman P.D.
      • et al.
      Olanzapine versus placebo in the treatment of psychosis with or without associated behavioral disturbances in patients with Alzheimer's disease.
      Placebo129NoNo2 (2)
      Olanzapine (1mg)1294 (3)
      Olanzapine (2.5mg)1343 (2)
      Olanzapine (5mg)1255 (4)
      Olanzapine (7.5mg)1323 (2)
      Street et al.
      • Street J.S.
      • Clark W.S.
      • Gannon K.S.
      • Cummings J.L.
      • Bymaster F.P.
      • Tamura R.N.
      • et al.
      Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial. The HGEU Study Group.
      Placebo47NoNoNot reported
      Olanzapine (5mg)56Not reported
      Olanzapine (10mg)50Not reported
      Olanzapine (15mg)53Not reported
      Ballard et al.
      • Ballard C.
      • Margallo-Lana M.
      • Juszczak E.
      • Douglas S.
      • Swann A.
      • Thomas A.
      • et al.
      Quetiapine and rivastigmine and cognitive decline in Alzheimer's disease: randomised double blind placebo controlled trial.
      Placebo31NoNo0 (0)
      Rivastigmine310 (0)
      Quetiapine311 (3)

      3.2 Reporting of mortality and ICH-defined SAE

      Nineteen trials (58%) explicitly reported on mortality in each arm of the trial. The fourteen trials without explicit data on deaths contained a total of 3,120 patients or about one-quarter of the total patient population. Only 4 of the 33 trials (three assessing ChEI [
      • Feldman H.
      • Gauthier S.
      • Hecker J.
      • Vellas B.
      • Subbiah P.
      • Whalen E.
      • et al.
      A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer's disease.
      ,
      • Tariot P.N.
      • Cummings J.L.
      • Katz I.R.
      • Mintzer J.
      • Perdomo C.A.
      • Schwam E.M.
      • et al.
      A randomized, double-blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer's disease in the nursing home setting.
      ,
      • Burns A.
      • Rossor M.
      • Hecker J.
      • Gauthier S.
      • Petit H.
      • Moller H.J.
      • et al.
      The effects of donepezil in Alzheimer's disease—results from a multinational trial.
      ] and one assessing atypical antipsychotics [
      • Brodaty H.
      • Ames D.
      • Snowdon J.
      • Woodward M.
      • Kirwan J.
      • Clarnette R.
      • et al.
      A randomized placebo-controlled trial of risperidone for the treatment of aggression, agitation, and psychosis of dementia.
      ]) even roughly followed ICH guidelines for the definition of reported SAEs. These four trials included a total of only 1,653 patients or about 12% of the total of 13,311 patients in 33 studies.

      3.3 Harm reporting in relation to CONSORT recommendations

      Table 2 provides a summary of the data on the location of information on harm and harm topics covered in the 33 studies. The vast majority of papers—94% (31/33)—indicated in the title or abstract that the study specifically looked at harm by referring to the safety or tolerability of the study medication, although a smaller proportion 76% (25/33) explicitly mentioned the intention to assess harm in the introduction. Most studies—85% (28/33)—had some description of the collection of data on harm but only nine (27%) defined specific harm with attention to grading, expected vs. unexpected events with reference to standardized and validated definitions or clear description of new definitions. As noted above, these nine trials included four that used a version of the ICH definition of SAE. One-third of the trials did not have a clear description of the methods used to analyze the harm data. All the trials provided information on withdrawals and contained information that could be used to provide denominators for rates calculation. Information about the absolute risk of some measure of harm could be found in 29 (88%) of the trials, although subgroup analyses or exploratory analyses for harm were performed in only five (15%) of the trials. In 30 trials (91%), there was some exploration of harm as part of their discussion; however, it was often limited to one or two sentences.
      Table 2Format of harm reporting in relation to CONSORT recommendations for 33 RCT of drug treatments for older patients with dementia
      Location and topic of harm reportingNumber and (%) of trials fulfilling recommendation
      Title or Abstract—indication that harm examined31 (94)
      Introduction—statement that measuring harm is part of study25 (76)
      Methods—specific harm and adverse events well defined9 (27)
      Methods—description of harm collection28 (85)
      Methods—plan for analysis of harm22 (67)
      Results—data on withdrawals from study33 (100)
      Results—data on denominators for calculating harm rates33 (100)
      Results—data on absolute rates of harm or adverse events per arm and by type of harm29 (88)
      Results—subgroup or exploratory analysis for harm5 (15)
      Discussion—balanced discussion of harm including study limitations30 (91)

      4. Discussion

      4.1 Reporting of deaths and SAE

      Our analysis shows that in about 40% of the studies, there was no explicit data on deaths. In some of the publications, it might be possible for the reader to calculate or infer death rates. However, clear information on mortality should be a minimum requirement for any published trial and readers should not be required to infer or estimate mortality rates. In the event that there are no deaths encountered during the course of the trial, this should be clearly stated.
      Our analysis suggests that reporting of SAE in published RCTs is inadequate. Only four trials used clear ICH definitions of SAE that are routinely required by regulators. This meant that for almost 90% of study participants there was no clear definition of SAE provided. This lack of a clear and consistent definition of SAE makes it difficult if not impossible for readers to compare and aggregate data on harm across studies. Pharmaceutical companies sponsored the vast majority of trials (88%). These companies are familiar with the standard definitions of SAE used by regulators and should be able to collect data on these events. Reporting of SAE is particularly important in situations where the benefits of therapy are not substantial and the population receiving the drugs is at high risk for adverse events—clearly the case in the use of cholinesterase inhibitors and atypical antipsychotics in elderly patients with dementia [
      • Lanctot K.L.
      • Herrmann N.
      • Yau K.K.
      • Khan L.R.
      • Liu B.A.
      • LouLou M.M.
      • et al.
      Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis.
      ,
      • Lee P.E.
      • Gill S.S.
      • Freedman M.
      • Bronskill S.E.
      • Hillmer M.P.
      • Rochon P.A.
      Atypical antipsychotic drugs in the treatment of behavioural and psychological symptoms of dementia: systematic review.
      ].
      The regulatory warnings about deaths and the use of atypical antipsychotics were issued six years after the initial trials were published. The signal for the potential increased risk of death only became apparent after unpublished and published RCTs data were analyzed. Our analysis shows that there was no mortality data on about one-quarter of the patients in published RCTs of atypical antipsychotics. More complete data on mortality could have helped to lead to the earlier identification of concerns. Recent studies [
      • Gill S.S.
      • Bronskill S.E.
      • Normand S.-L.T.
      • Bronskill S.E.
      • Hillmer M.P.
      • Rochon P.A.
      Antipsychotic drug use and mortality in older adults with dementia.
      ] show that atypical antipsychotic drugs increase mortality soon after exposure suggesting that even short-term RCT could have provided important information on mortality.
      Some authors have suggested that thinking about efficacy and harm as separate outcomes should cease, and using total SAE rates may be a better way to evaluate clinical trials [
      • Wright J.M.
      • Puil L.
      • Bassett C.L.
      Analysis of serious adverse events. Lipid-lowering therapy revisited.
      ]. This approach has drawn some criticism from others who suggest that readers of published trials are interested in all adverse events, not just those defined as serious [
      • Miller D.B.
      • Humphries K.H.
      A new way to evaluate randomized controlled trials? New approach does more harm than good.
      ]. We suggest that it is important that all trials report any effects of medications accurately with equal emphasis and detail on harm and benefits, so that others can weigh risks and benefits as they choose.
      In many cases, individual RCTs may not be large enough to detect statistically significant effects on mortality or SAE. However, this does not mean that data from individual trials is not useful. The ultimate detection of significant adverse effects may require meta-analysis of information from several RCTs and this type of analysis is only possible if individual trials consistently report mortality and commonly defined SAE data. Although reports of SAE submitted to regulators may be proprietary, if the RCT collects SAE data and if the results of that RCT are submitted for publication in a journal then it would not be unreasonable to expect the SAE data to be made available for publication.

      4.2 Reporting in relation to CONSORT recommendations

      The analysis shows that the vast majority of published RCTs indicate they plan to address the issue of harm. Perhaps as a result of well-established criteria for judging the validity of RCTs, all the studies reviewed provided detailed information on withdrawals and provided clear data on denominators for the calculation of rates of adverse events. However, basic methodological criteria related to the accurate assessment of harm including clear definitions of the harm outcomes, details of the analysis plan and exploratory or subgroup analyses were often not met.

      5. Limitations

      This article does not intend to evaluate the efficacy or safety of ChEI or atypical antipsychotic medication use in older adults with dementia as that has been addressed in other studies [
      • Lanctot K.L.
      • Herrmann N.
      • Yau K.K.
      • Khan L.R.
      • Liu B.A.
      • LouLou M.M.
      • et al.
      Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis.
      ,
      • Sink K.M.
      • Holden K.F.
      • Yaffe K.
      Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence.
      ]. The goal was to examine published RCTs of these two medications to draw some conclusions about harm reporting in general.
      The selection of only two drug classes may not provide a true representation of all public reporting of harm in RCTs; however, these two drug classes were selected for several reasons including that the trials were published recently, the drugs have been used widely, and that the tradeoff between risks and benefits is particularly important in the elderly population. These two classes of drugs have recently been identified as having important safety concerns. Although not representative, our study provides an important framework.
      Our adaptation of the CONSORT recommendations for harm reporting has not been validated. We used the CONSORT recommendations as a generally accepted standard that could be used to systematically describe harm reporting. There may be features of harm reporting that are not covered by our abstraction tool or by the CONSORT criteria and some CONSORT criteria such as subgroup analysis may not be applicable in all circumstances.

      6. Conclusions

      Although regulatory agencies have clear legislative responsibility and actions that they can take to protect the public from harm due to drug therapy, the publication of information on harm in journals can both inform the public and spur regulators to act. Improving methods for defining, analyzing, and reporting harm is a responsibility of both authors and editors. There is recognition that harm reporting should be part of RCT publications but there does not seem to be a standard approach to including them in the methods and results sections of publications. The CONSORT criteria are a set of guidelines that are meant to guide the appropriate reporting of harm in published trials. These recommendations might well serve as a standard for journals editors to apply to all RCTs.
      Most published RCTs of the drugs we reviewed lacked data on well-defined SAE and many lacked explicit data on deaths. Although most studies indicated that they would provide information on harm, most lacked clear definitions of harm and did not define or conduct adequate analysis of harm. At a minimum, editors of journals should ask that all RCTs provide information on mortality and that if they have collected data on SAE using regulatory agency definitions, which is the case in many trials, that they should also report the SAE data. Editors and reviewers should have the option of suggesting that this information is not relevant and need not be included in the final publication but authors should not have the option of failing to submit the information in the first place.
      Better reporting of death and SAE in published RCTs and closer attention to the definition and analyses of adverse events would provide timely and important information that could help physicians and the public to make informed decisions regarding harm benefit tradeoffs.

      Acknowledgment

      This work was supported by a CIHR Chronic Disease New Emerging Team grant (NET-54010). The NET program receives joint sponsorship from the Canadian Diabetes Association, the Kidney Foundation of Canada, the Heart and Stroke Foundation of Canada, and the CIHR Institutes of Nutrition, Metabolism & Diabetes and Circulatory & Respiratory Health.

      Appendix

      Tabled 1Abstraction form—reporting harms in randomized, controlled trials—an extension of the consort statement
      Ioannidis JPA, Evans SJW, Gotzsche PC, O'Neill RT, Altman DG, Schulz K, et al. Better reporting of harms in randomized trials: an extention of the CONSORT statement. Ann Intern Med 2004;141:781–788.
      Source of Information and specific question to be answeredY/NIf yes, page #If yes, then what terms and/or outcomes were included?
      Title and abstract
      Is there anything in the title or abstract that indicates that the study specifically looked at harm?
      • □Presents data on harm in abstract
      • □Uses term, harm
      • □Uses term, safety
      • □Uses term, tolerability
      • □Other (specify)
      Introduction
       Background
      Is there a statement in the introduction that addresses measuring harm as part of the study?
      Methods
       Outcomes
      Were specific harms or adverse events defined (with attention, when relevant, to grading, expected vs. unexpected events, reference to standardized and validated definitions, and description of new definitions)?
      • □Death
      • □Life threatening
      • □Hospitalization/prolong
      • □Disability/Incapacity
      • □Medically important event
        Ioannidis JPA, Evans SJW, Gotzsche PC, O'Neill RT, Altman DG, Schulz K, et al. Better reporting of harms in randomized trials: an extention of the CONSORT statement. Ann Intern Med 2004;141:781–788.
      • □Other (specify)
      Was there a clear description of how harms related data were collected (mode of data collection, timing, attribution methods, intensity of ascertainment, and harms-related monitoring and stopping rules, if pertinent)?
       Statistical methods
      Was plan for presenting and analyzing information on harms (including coding, handling of recurrent events, specification of timing issues, handling of continuous measures, and any statistical analyses) described?
      Results
       Participant flow
      Was there a description for each arm of the participant withdrawals that were due to harms and their experiences with the allocated treatment?
       Numbers analyzed
      Was there information provided on denominators that could be used to calculate rates of harm?
      Outcomes and estimation, ancillary analyses, adverse events
      Was information presented on the absolute risk of harm per arm and per adverse event type, grade, and seriousness, and were appropriate metrics for recurrent events, continuous variables, and scale variables, presented whenever pertinent?
      Was there any description of any subgroup analyses or exploratory analyses for harms?
      Discussion
      Interpretation, generalizability, overall evidence
      Was there a balanced discussion of benefits and harms with emphasis on study limitations, generalizability, and other sources of information on harms?
      a Ioannidis JPA, Evans SJW, Gotzsche PC, O'Neill RT, Altman DG, Schulz K, et al. Better reporting of harms in randomized trials: an extention of the CONSORT statement. Ann Intern Med 2004;141:781–788.

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