Randomized Controlled Trials in Long-Term Care Residents with Dementia: A Systematic Review

Randomized Controlled Trials in Long-Term Care Residents with Dementia: A Systematic Review Edward J. Mills, MSc, and Tiffany W. Chow, MD Objective: To evaluate the quality of reporting of randomized controlled trials for pharmacologic interventions in long-term care residents with dementia. Data sources: We performed electronic searches of AMED, CINAHL, E-PSYCHE, Cochrane Controlled Trials Register, and MEDLINE. We also searched the reference lists of included studies and bibliographies of relevant review articles.

two lacked informed consent. Eleven trials gave adequate description of withdrawals and 14 trials reported adverse events adequately. We found incomplete reporting of methods of randomization, allocation concealment, restriction, blinding, sample size estimation and intention-to-treat analysis. Sensitivity analysis indicated that reporting of allocation concealment was associated with increased quality of trial according to the quality scale (P ⫽ 0.007).

Data Abstraction: We abstracted data independently, in duplicate, using a data abstraction sheet and a quality checklist.

Conclusions: Clinicians and the public do not have high-quality information to guide pharmacologic decision making for long-term care residents with dementia. The reporting quality is highly variable in the trials reviewed, and concerns exist surrounding the conduct of several trials. (J Am Med Dir Assoc 2003; 4: 302–307)

Data Synthesis: Fifteen trials met inclusion criteria. Five trials lacked institutional ethical review, while

Keywords: Nursing home; long term care; dementia; systematic review.

Research should be generalizable. A special subgroup of patients with dementia deserves its own research effort. Until a cure is available, dementia will create a constant flow of older people to long-term care facilities. The subgroup of patients with dementia who reside in long-term care facilities differs from those studied in pivotal trials for U.S. Food and Drug Administration approval. Institutionalized patients have complicating medical or physical comorbidities,1–3 more advanced stages of dementia,4,5 or severe behavioral disturbances.6 – 8 Results of randomized controlled trials (RCTs) for participants at-large in the community cannot necessarily be applied to long-term care residents with polypharmacy and sequelae of late-stage or end-stage dementia. We conducted a systematic review to determine the reporting quality of RCTs

supporting pharmacological interventions in the treatment of patients in long-term care facilities with dementia.

Study Selection: All randomized controlled trials for pharmacologic interventions in patients with dementia residing in long-term care facilities.

The University of Oxford (E.J.M.) and the Rotman Research Institute, University of Toronto (T.W.C.). Address correspondence to: Tiffany Chow, MD, The Rotman Research Institute, 3560 Bathurst Street, 8th Floor, Posluns Bldg., Toronto, Ontario M6A 2E1. E-mail: [email protected]. This research was supported by a grant from Pfizer, Inc.

Copyright ©2003 American Medical Directors Association DOI: 10.1097/01.JAM.0000095257.68552.3D 302 Mills and Chow

METHODS Study Identification In consultation with an information specialist, we conducted a search of English and non-English language articles in the following databases: AMED (1985-May 2003), CINAHL (1982- May 2003), E-Psyche (1993-May 2003), Cochrane Controlled Trials Register (CENTRAL, May 2003) and MEDLINE (1966-May 2003). We supplemented this search by looking for unpublished trials on the National Research Register (UK) and Clinicaltrials.gov (US). We did not limit searches to English language or specific publication years. We used the MeSH terms: “Nursing homes” OR “Long term care,” and “Dementia.” Our search therefore included skilled nursing (SNF), assisted living (ALF), and residential care facilities (RCF). We searched the reference lists of included studies and the bibliographies of relevant review articles. Study Selection Two reviewers (E.M., T.C.), working independently and in duplicate, searched the databases, identified relevant abJAMDA – November/December 2003

Table 1.

The Jadad Scale*

(1) Is the study randomized? (2) Is the study double blinded? (3) Is there a description of withdrawals? (4) Is the randomization adequately described? (5) Is the blindness adequately described? *Each question demands a yes or no response. In total, five points can be awarded with higher scores indicating superior quality.

stracts, and decided on article eligibility after reading the full reports. To be included in the final review, a manuscript had to report the results of a randomized controlled trial of a pharmacological intervention in a long-term care facility of patients with dementia. We categorized trials as randomized, if they used the words “randomized,” “random,” or “randomly” in reference to participant allocation. We excluded nonrandomized trials, those that examined nursing home placement as an outcome, or that reanalyzed previously published RCTs. Data Extraction and Quality Assessment The same two reviewers extracted data independently and in duplicate and evaluated study quality. We resolved discrepancies by consensus. We appraised the articles using a 22-item structured data abstraction form. The questions pertained to the type of intervention used, the pharmacologic intervention, the sample size, whether ethical review was reported and how informed consent was obtained, and information about the reporting of withdrawals and adverse events. The complete questionnaire can be obtained from the authors. The 22-item data abstraction form also includes a comprehensive quality assessment of each report using two methods. First, we determined the reporting of randomization technique and allocation concealment. Allocation concealment refers to the author’s clarification of whether study personnel knew the randomization sequence assignment before interventions.9 Related measures of quality included reporting of who was blinded in the trial,10 a priori sample size estimation, and use of intention-to-treat analysis. In the second method, we assessed quality using the Jadad scale,11 which contains two questions each on randomization and blinding, and one question on reporting of dropouts and withdrawals (See Table 1). We completed all of these evaluations and resolved discrepancies by consensus. We performed a sensitivity analysis to determine if trials that reported unclear allocation concealment or funding source affected the higher quality Jadad score (⬎3/5) using logistic regression. We used ␬statistic to determine inter-rater reliability of search results. RESULTS Search Results Figure 1 details the yield of the searches and study selection. The ␬ statistic for inclusion of studies was 0.98 (95% CI, 0.94 –1). We retrieved a total of 27 articles for consideration. We excluded: four trials due to being outpatient trials;12–15 four studies as re-analyses of previously published trials;16 –20 ORIGINAL STUDIES

Fig. 1. Flow of studies considered for review.

one RCT of treatment regimen (including nursing, psychosocial and unspecified medical interventions);21 one nonrandomized parallel trial;22 and one study on long-term care residents without dementia.23 The 15 trials included (Table 2) an average of 122 participants (95% CI, 64 –180) or a median of 59 participants per study. Ten trials were from the United States, two from the Netherlands,24,25 one from Germany26 and one from Australia.27 All were in the English language, published between 1977 and February 2003. All 15 studies were conducted in skilled nursing facilities (SNF). The trials investigated 15 different pharmaceutical agents,4,5,24 –34 with 2 withdrawing, as opposed to adding, the study drug.35,36 Of the 15 trials, 10 reported approval from an institutional review board. Thirteen trials reported informed consent. Eleven adequately described trial withdrawals. Fourteen trials contained adequate descriptions of adverse events. Sources of funding varied: seven were funded by pharmaceutical companies, six by granting agencies, one did not report sources of funding, and one was funded by both a pharmaceutical company and a granting agency. Table 3 lists the reported methodological criteria. Regression analysis indicated that allocation concealment was associated with high quality score on the Jadad scale (P ⫽ 0.007), whereas funding source was not (P ⫽ 0.31). DISCUSSION The findings of this review should be of concern to clinicians. This study indicates that this literature1 is limited to 15 RCTs of only 15 pharmacological interventions;2 inconsistently report ethical review and methods of collecting informed consent;3 have limited safeguards against the intrusion of bias, such as randomization, concealed allocation of participants, and blinding; and4 display wide variation in methodMills and Chow 303

304 Mills and Chow

JAMDA – November/December 2003

1994

1997

1998 1999 2000 2000 2000 2000 2001 2001

2001 2002

2003

Thapa

Bridges-Partlet

Tariot Filip Magai Street Streim Van Dongen Jansen Portsteinsson

Tariot Wouters-Wesseling

Brodaty

Guardian

Guardian Guardian

NA NA Guardian Patient/guardian Patient/Guardian Patient/Guardian Patient/Guardian Patient/Guardian

Guardian

Patient

Patient/guardian Guardian

Informed Consent

Yes

Yes Yes

No Yes Yes Yes Yes Yes Yes Yes

Yes

Yes

No Yes

Description of Withdrawals

Yes

Yes No

Yes No No Yes Yes Yes Yes Yes

Yes

Yes

No Yes

Description of Adverse Events

Pharma

Granting body Pharma Granting body Pharma Granting body Pharma NA Pharma/granting body Pharma Pharma

Granting body

Granting body

Pharma Granting body

Source of Funding

No No No No No No No Yes No Yes No No Yes No Yes 4

Yes Yes Yes Yes Yes Yes No Yes No Yes Yes Yes Yes Yes Yes 13

No Yes No No No No Yes No No Yes Yes Yes Yes No No 6

No No Yes No Yes No No Yes Yes Yes No Yes Yes Yes Yes 9

No Yes Open Yes Yes No Yes No No No Yes Yes Yes No No 7

No No No Yes No No No No No Yes No Yes Yes No Yes 5

No No No No Yes No Yes No Yes Yes Yes Yes Yes No Yes 8

2 4 2 4 4 3 4 3 3 4 4 4 5 3 4 -

1977 1990 1994 1997 1998 1999 2000 2000 2000 2000 2001 2001 2001 2002 2003

Yes

Yes Yes

NA NA Yes Yes NA Yes NA Yes

Yes

Yes

NA Yes

Ethics Review

Gaitz Coccaro Thapa Bridges-Partlet Tariot Filip Magai Street Streim Van Dongen Jansen Portsteinsson Tariot Wouters-Wesseling Brodaty Total number of studies meeting each criterion

donepezil Nutritional supplement Risperidone

hydergine haloperidol/oxazepam/ diphenhydramine Withdrawal of antipsychotics Withdrawal of neuroleptics carbamazapine selegiline sertraline olanzapine nortryptyline Ginkgo biloba methylphenidate divalproex sodium

Intervention

Year of Randomization Placebo Allocation Restriction Complete Description A priori Sample Size Intention-to- Jadad Score Publication Described Controlled Concealment of Blinding Calculation Treat

345

208 42

51 173 31 206 69 214 5 56

36

271

54 59

n

Author

Reported Methodological Criteria

1977 1990

Gaitz Coccaro

Table 3.

Year of Publication

Study Characteristics

Author

Table 2.

ologies without evidence of widely accepted standard of research practice. This study had a number of limitations. Our focus was on the quality of reporting of published RCTs. Does the quality of reporting correlate with the quality of the trial? Despite the paucity of data addressing this important question, the available literature yields a correlation between how investigators conduct their trials and how they are subsequently reported.37,38 It is possible that the investigators conducted their trials appropriately but made incomplete reports. Another limitation may be inadvertent exclusion of RCTs from our review. It may be that RCTs exist in indexed journals, but with incorrectly applied MeSH headings or without our selected keywords in the abstracts.39,40 If this is the case, this has implications for clinicians who use databases to acquire patient-relevant evidence. A finding of considerable concern is the infrequent reporting of ethics review. Ethics review and informed consent are the backbone of clinical research.41,42 In total, five trials did not report institutional ethics review. A further two trials did not report receiving informed consent for participation in the trial. One trial obtained informed consent from patients with dementia and did not report assent from the patient’s legal representative. The absence of reporting does not conclusively indicate that ethics review or informed consent did not happen. However, reporting of these issues in this vulnerable (cognitively impaired, institutionalized) population is necessary to ensure the rights of the participants and the scientific rigor of the protocol.43 In 1996, the CONSORT statement (Consolidated Standards of Reporting Trials) was published as a source of recommendations for the conduct and reporting of RCTs.44 A total of 141 medical journals have now adopted the recommendations for reporting RCTs.45 The statement comprises a checklist and flow diagram template to help improve the quality of reports of RCTs. The evidence-based checklist includes items to be addressed in the report; the flow diagram provides readers with a clear picture of the progress of all participants in the trial, from the time they are randomized until the end of their involvement. The intent is to make the experimental process more clear, flawed or not, so that users of the data can more appropriately evaluate its validity for their purposes. This review indicates that there is a paucity of application of the CONSORT recommendations in the included studies, thus making critical appraisal and generalizability more difficult. We chose specific methodologic criteria based on CONSORT recommendations and previous studies that have indicated the potential for bias when these criteria are excluded. For example, we examined reports of the methods of randomization. Providing a description of randomization is an important guide with which the reader can assess the methods for generating the random allocation sequence and the likelihood of bias in group assignment. The term “random” has been used incorrectly in the past to describe trials in which non-random or quasi-random techniques have been used.9 Issues related to randomization, such as descriptions of restriction, clarify how authors allocated the sample groups to apORIGINAL STUDIES

propriate sizes. Studies of randomization procedures indicate that many studies have similar intervention group sizes, yet do not report restriction.46,47 The trials in this review showed inadequate utilization of restriction. A description of allocation concealment is important, as selection bias arises from a decision to accept or reject a participant from the trial with foreknowledge of allocation to treatment or control. Trials in which the allocation sequence had been inadequately or unclearly concealed exaggerate treatment effects.9 Our review found that reporting of allocation concealment was significantly associated with higher quality score on the Jadad scale (P ⫽ 0.007). The medical literature often misuses the terms “doubleblind” and “single-blind.” Blinding may refer to any of the trial participants, including the researchers or assessors. A more fruitful endeavor than using terms such as “doubleblind” specifies the blinding of groups in a trial.10 Our study found that blinding was inadequately described in seven studies. We additionally examined two statistical concepts related to all RCTs, a priori sample size calculations and intentionto-treat analysis. Inconclusive results can occur when investigators enroll fewer patients than needed to answer the research question. Given this threat to credibility, researchers should consider conducting sample size calculations to avoid the potential of type II errors.48 Only 5 of the 15 studies in our review performed a priori sample size calculations. Intention– to-treat analysis preserves the randomization sequence and considers drop outs and lost to follow-up participants.49,50 This is a necessary procedure in analyzing randomized controlled trials. In our study, seven studies did not report performing intention-to-treat analysis. Future RCTs in long-term care populations should include these features in their research design in order to assure meaningful results. Our study also identified that private pharmaceutical funding sponsored most trials. This issue has been shown to exaggerate treatment effects,51 however, we did not test for outcome effects. Our sensitivity analysis did not find that pharmaceutical funding affected quality score (P ⫽ 0.31). Clinicians using results of RCTs to inform best practice owe it to their patients to present the intervention’s benefits and risks. Unexplained loss to follow-up is a reality of conducting trials but is important to include in the report, in order that clinicians understand reasons for withdrawal from a study, such as adverse events, tolerability of the trial, or drug tolerability. Adverse event profiles help identify contraindications to prescribing the drug or specify the need for clinical monitoring. Of the quality indicators for RCTs, reporting of participant withdrawal and adverse events may rank as the most pertinent for clinician-readers. A clinician’s application of RCT results to patients can be complicated by apparent differences in patient populations beyond diagnosis. In our study, we identified the paucity of RCTs of treatments for long-term care residents. SNF residents are not necessarily more impaired than those at RCFs or ALFs, as the frequency of polypharmacy and multiple medical problems per individual are similar among residents at those types of facilities52. It may then be reasonable to suggest that Mills and Chow 305

conclusions of RCTs from one type of facility apply to residents at the others. For management of dementia, some studies have stratified the drug efficacy by severity of dementia. RCFs and ALFs vary in admission requirements52 and therefore the severity of dementia present. A clinician may do best to apply the conclusions of an RCT on this basis of dementia severity and not by the type of institutional facility. In conclusion, despite the broad use of pharmacological agents in this population, the number of investigations is limited in scope and methodological quality. Clinicians and the public do not have high-quality information to guide pharmacological decision-making in dementia within the long-term care setting. The reporting quality varied highly in the trials reviewed, and serious concerns exist surrounding the conduct of several trials. Additional research using high quality methodology is warranted to identify urgently needed pharmacological treatment for this vulnerable population. Given the administrative limitations of conducting large multicenter trials in long-term care facilities, clinicians should consider conducting n-of-1 trials with their patients,24 which would yield useful data collected in an evidence-based fashion. REFERENCES 1. Magaziner J, German P, Zimmerman SI, et al. The prevalence of dementia in a statewide sample of new nursing home admissions aged 65 and older: Diagnosis by expert panel. Epidemiology of Dementia in Nursing Homes Research Group, Gerontologist 2000;40:663– 672. 2. Smith GE, Kokmen E, O’Brien PC. Risk factors for nursing home placement in a population-based dementia cohort. J Am Geriatr Soc 2000;48:519–525. 3. Kopetz S, Steele CD, Brandt J, et al. Characteristics and outcomes of dementia residents in an assisted living facility. Int J Geriatr Psychiatry 2000;15:586 –593. 4. Tariot PN, Erb R, Podgorski CA, et al. Efficacy and tolerability of carbamazepine for agitation and aggression in dementia. Am J Psychiatry 1998;155:54 – 61. 5. Tariot PN, Cummings JL, Katz IR, 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. J Am Geriatr Soc 2001;49:1590 –1599. 6. Rovner BW, German PS, Broadhead J, et al. The prevalence and management of dementia and other psychiatric disorders in nursing homes. Int Psychogeriatr 1990;2:13–24. 7. Steele C, Rovner B, Chase GA, et al. Psychiatric symptoms and nursing home placement of patients with Alzheimer’s disease, Am J Psychiatry 1990;147:1049 –1051. 8. Brodaty H, Draper B, Saab D, et al. Psychosis, depression and behavioural disturbances in Sydney nursing home residents: prevalence and predictors. Int J Geriatr Psychiatry 2001;16:504 –512. 9. Schulz KF, Chalmers I, Hayes RJ, et al. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273:408 – 412. 10. Montori VM, Bhandari M, Devereaux PJ, et al. In the dark: The reporting of blinding status in randomized controlled trials, J Clin Epidemiol 2002;55:787–790. 11. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Control Clin Trials 1996;17:1–12. 12. Smith F, Talwalker S, Gracon S, et al. The use of survival analysis techniques in evaluating the effect of long-term tacrine (Cognex) treatment on nursing home placement and mortality in patients with Alzheimer’s disease. J Biopharm Stat 1996;6:395– 409. 306 Mills and Chow

13. Olin JT, Fox LS, Pawluczyk S, et al. A pilot randomized trial of carbamazepine for behavioral symptoms in treatment-resistant outpatients with Alzheimer disease. Am J Geriatr Psychiatry 2001;9:400 – 405. 14. Knopman D, Schneider L, Davis K, et al. Long-term tacrine (Cognex) treatment: Effects on nursing home placement and mortality. Tacrine Study Group. Neurology 1996;47:166 –177. 15. Blume J, Ruhlmann KU, de la Haye R, et al. Vascular-induced disorders of cerebral performance in the elderly. Long-term therapy with pentoxifylline and psychological mental training [in German]. Fortschr Med 1990;108:638 – 642. 16. Mintzer J, Faison W, Street JS, et al. Olanzapine in the treatment of anxiety symptoms due to Alzheimer’s disease: A post hoc analysis. Int J Geriatr Psychiatry 2001;16 (Suppl 1):S71–77. 17. Blume J, Ruhlmann KU, de la Haye R, et al. Vascular-induced organic mental disorders in the aged. Long-term therapy with pentoxifylline and psychological training [in German], Vasa Suppl 1991;33:162. 18. Tariot PN, Jakimovich LJ, Erb R, et al. Withdrawal from controlled carbamazepine therapy followed by further carbamazepine treatment in patients with dementia. J Clin Psychiatry 1999;60:684 – 689. 19. Kennedy JS, Zagar A, Bymaster F, et al. The central cholinergic system profile of olanzapine compared with placebo in Alzheimer’s disease. Int J Geriatr Psychiatry 2001;16 (Suppl 1):S24 –32. 20. Street JS, Clark WS, Kadam DL, et al. Long-term efficacy of olanzapine in the control of psychotic and behavioral symptoms in nursing home patients with Alzheimer’s dementia. Int J Geriatr Psychiatry 2001;16 (Suppl 1):S62–70. 21. Opie J, Doyle C, O’Connor DW. Challenging behaviours in nursing home residents with dementia: A randomized controlled trial of multidisciplinary interventions. Int J Geriatr Psychiatry 2002;17:6 –13. 22. Smith RC, Vroulis G, Johnson R, et al. Comparison of therapeutic response to long-term treatment with lecithin versus piracetam plus lecithin in patients with Alzheimer’s disease. Psychopharmacol Bull 1984;20:542–545. 23. Howe MN, Price IR. Effects of transdermal nicotine on learning, memory, verbal fluency, concentration, and general health in a healthy sample at risk for dementia. Int Psychogeriatr 2001;13:465– 475. 24. Jansen IH, Olde Rikkert MG, Hulsbos HA, Hoefnagels WH. Toward individualized evidence-based medicine: Five “N of 1” trials of methylphenidate in geriatric patients. J Am Geriatr Soc 2001;49:474 – 476. 25. Wouters-Wesseling W, Wouters AE, Kleijer CN, et al. Study of the effect of a liquid nutrition supplement on the nutritional status of psycho-geriatric nursing home patients. Eur J Clin Nutr 2002;56:245– 251. 26. van Dongen MC, van Rossum E, Kessels AG, et al. The efficacy of ginkgo for elderly people with dementia and age-associated memory impairment: New results of a randomized clinical trial. J Am Geriatr Soc 2000;48:1183–1194. 27. Brodaty H, Ames D, Snowdon J, et al. A randomized placebo-controlled trial of risperidone for the treatment of aggression, agitation, and psychosis of dementia. J Clin Psychiatry 2003;64:134 –143. 28. Gaitz CM, Varner RV, Overall JE. Pharmacotherapy for organic brain syndrome in late life. Evaluation of an ergot derivative vs placebo. Arch Gen Psychiatry 1977;34:839 – 845. 29. Coccaro EF, Kramer E, Zemishlany Z, et al. Pharmacologic treatment of noncognitive behavioral disturbances in elderly demented patients. Am J Psychiatry 1990;147:1640 –1645. 30. Filip V, Kolibas E. Selegiline in the treatment of Alzheimer’s disease: A long-term randomized placebo-controlled trial. Czech and Slovak Senile Dementia of Alzheimer Type Study Group. J Psychiatry Neurosci 1999; 24:234 –243. 31. Magai C, Kennedy G, Cohen CI, et al. A controlled clinical trial of sertraline in the treatment of depression in nursing home patients with late-stage Alzheimer’s disease. Am J Geriatr Psychiatry 2000;8:66 –74. 32. Street JS, Clark WS, Gannon KS, et al. Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: A double-blind, randomized, placebocontrolled trial. The HGEU Study Group, Arch Gen Psychiatry 2000;57:968 –976. JAMDA – November/December 2003

33. Streim JE, Oslin DW, Katz IR, et al. Drug treatment of depression in frail elderly nursing home residents, Am J Geriatr Psychiatry 2000;8: 150 –159. 34. Porsteinsson AP, Tariot PN, Erb R, et al. Placebo-controlled study of divalproex sodium for agitation in dementia, Am J Geriatr Psychiatry 2001;9:58 – 66. 35. Thapa PB, Meador KG, Gideon P, et al. Effects of antipsychotic withdrawal in elderly nursing home residents, J Am Geriatr Soc 1994;42:280–286. 36. Bridges-Parlet S, Knopman D, Steffes S. Withdrawal of neuroleptic medications from institutionalized dementia patients: results of a doubleblind, baseline-treatment-controlled pilot study, J Geriatr Psychiatry Neurol 1997;10:119 –126. 37. Liberati A, Himel HN, Chalmers TC. A quality assessment of randomized control trials of primary treatment of breast cancer, J Clin Oncol 1986;4:942–951. 38. Huwiler-Muntener K, Juni P, Junker C, et al. Quality of reporting of randomized trials as a measure of methodologic quality, Jama 2002;287: 2801–2804. 39. Wilczynski NL, Walker CJ, McKibbon KA, et al. Reasons for the loss of sensitivity and specificity of methodologic MeSH terms and textwords in MEDLINE, Proc Annu Symp Comput Appl Med Care 1995;436 – 440. 40. Wilczynski NL, Walker CJ, McKibbon KA, et al. Preliminary assessment of the effect of more informative (structured) abstracts on citation retrieval from MEDLINE, Medinfo 1995;8 Pt 2:1457–1461. 41. Ernst E. 50 years ago: The Nuremberg Doctors’ Tribunal. Part 4: Nazi medicine’s relevance today [in German]. Wien Med Wochenschr 1997; 147:70 –71.

ORIGINAL STUDIES

42. Ernst E, Weindling PJ. The Nuremberg Medical Trial: have we learned the lessons? J Lab Clin Med 1998;131:130 –135. 43. Murray GD. Promoting good research practice, Stat Methods Med Res 2000;9:17–24. 44. Altman DG. Better reporting of randomised controlled trials: The CONSORT statement. BMJ 1996;313(7057):570 –571. 45. CONSORT. CONSORT Statement, www.consort-statement.org 2003. (Accessed June 4, 2003). 46. Altman DG, Dore CJ. Randomisation and baseline comparisons in clinical trials. Lancet 1990;335(8682):149 –153. 47. Adetugbo K, Williams H. How well are randomized controlled trials reported in the dermatology literature. Arch Dermatol 2000;136:381– 385. 48. Freiman JA, Chalmers TC, Smith H, Jr., et al. The importance of beta, the type II error and sample size in the design and interpretation of the randomized control trial. Survey of 71 “negative” trials. N Engl J Med 1978;299:690 – 694. 49. Hollis S. A graphical sensitivity analysis for clinical trials with nonignorable missing binary outcome. Stat Med 2002;21:3823–3834. 50. Hollis S, Campbell F. What is meant by intention to treat analysis? Survey of published randomised controlled trials. BMJ 1999;319(7211): 670 – 674. 51. Lexchin J, Bero L, Djulbegovic B, et al. Pharmaceutical industry sponsorship and research outcome and quality: Systematic review. BMJ 2003; 326:1167–1170. 52. Zimmerman S, Gruber-Baldini AL, Sloane PD, et al. Assisted living and nursing homes: Apples and oranges? Gerontologist 32(Sp2):107–117, 2003.

Mills and Chow 307