Randomised Controlled Trials in the Social Sciences Challenges
- Slides: 41
Randomised Controlled Trials in the Social Sciences: Challenges and Prospects Assessing Nonpharmacological treatments Challenges and reporting guidelines for Randomised Controlled Trials I. Boutron Dept of Epidemiology, Biostatistics and Clinical Research 12/1/2020 1
Overview • Specific methodological issues when assessing Nonpharmacological treatments • Quality tools • Reporting guidelines 2
Overview • Specific methodological issues when assessing Nonpharmacological treatments • Quality tools • Reporting guidelines 3
Different types of NPT Non-pharmacological treatments (NPT) take in many different treatments Therapist-dependent interventions - surgery Participative interventions - rehabilitation - technical operation (arthroscopy, …) - education Non implantable devices - orthopedic braces or orthosis - laser treatment
Assessing Nonpharmacological treatments • Randomized controlled trials (RCT) – Gold standard of therapeutic evaluation • The design, conduct and reporting of RCTs aim at providing valid results • Standard of the methodology of RCTs has been developed in the context of pharmacological treatments (PT) • Specific methodological issues when assessing NPTs – – Blinding Placebo Complexity of treatments Care providers’ influence 5
Are NPT trials specific? Quality of trials assessing PT and NPT of hip and knee osteoarthritis published in high impact factor journals (1992 -2002)* A 6 5 4 3 2 1 0 -1 B PT NPT 6 5 4 3 2 1 0 -1 A. PT (n=60) versus NPT (n=50) B. Comparison (1) 1 Jadad scale * Boutron, Tubach, Giraudeau, Ravaud Jama, 2003 2 Jadad scale 3 4 (2) (3) (4) Oral drug, intra-venous, intramuscular (n = 46) Intra-articular injection (n = 14) Surgery, arthroscopy, joint lavage (n = 23) Rehabilitation, acupuncture, education(n = 27) 6
Are NPT trials specific? The feasibility of blinding * Boutron I, Tubach F, Giraudeau B, Ravaud P, JCE, 2003 7
Are NPT trials specific? The success of blinding 8
Are NPT trials specific? Placebo PT Surgery Rehabilitation, education Placebo Matching placebo Simulated procedure Sham intervention Example Saline solution in identical syringes Sham arthroscopy* Sham education program with similar frequency and duration of sessions but with different content ** - Ethical issue False negative Issue * Moseley et al. , NEJM 2002 **Edworthy et al. J Rheumatol 1999 9
Are NPT trials specific? Placebo Paterson, C. et al. BMJ 2005 10
Are NPT trials specific? Placebo • Externally clearly different placebo – Physiotherapy for knee OA* • Placebo treatment consisted of sham ultrasonography – Assessment of lifestyle advice** • Placebo treatment consisted of a syrup placebo *Bennell, Ann Rheum Dis, 2005 **Spigt, JCE, 2005 11
Are NPT trials specific? The methods of blinding – Full blinding Study cohort: 145 non-pharmacological trials (2004)* • Full blinding attempted • externally identical placebo/control • Unblinded care providers not involved in the subsequent patient care • Example – Transplantation of embryonic dopamine neurons** • four twist-drill holes made through the frontal bone after local anesthesia • the dura mater was not penetrated * Boutron, Ravaud, Submitted ** Freed, NEJM, 2001 12
Are Non pharmacological trials specific? The methods of blinding – Partial blinding • Partial blinding attempted (blind trial hypothesis) – Externally clearly different placebo / control – Manipulation of information • Patients not informed of the existence of a placebo • Patients not aware of the nature of the placebo • Confidence in treatments sometimes tested 13
Are Non pharmacological trials specific? The methods of blinding – Partial blinding • Zelen design or modified zelen design – Usual care compared to a complex, physical therapy-based intervention for patello-femoral joint osteoarthritis of the knee • 1) Researchers invited patients to participate in a cohort. • 2) Randomization • 3) Patients randomized to the intervention arm informed that they would receive the experimental treatment and signed a second consent form Quilty, J Rheumatol. 2003 14
Are Non pharmacological trials specific? The methods of blinding – Outcome assessors • Blinding of outcome assessors – Centralized assessment (video, audiotape or photography ) – Outcome assessors blinded of study hypothesis • To assess the analgesic effect of breast feeding in term neonates compared to mothers’ arms, pacifiers, placebo (i. e. , sterile water) or glucose – Videotape of the children during the painful procedure – Two specially trained observers independently assessed the recordings using a specific scale. – Observers were blinded to the purpose of the study and had been told that they were assessing agreement of their scores in different situations – Patients reported outcomes • Blinding is impossible if patients cannot be blinded Carbajal R, Bmj. 2003 15
Are NPT trials specific? Complex intervention • Several components – Rehabilitation : exercises, drugs, education etc • Description of the intervention – Quantitative data • Number of sessions, timing of each session, duration of each session – Qualitative data • Content of each session, how it is delivered, supervision, content of information exchanged etc • Standardization procedure – Specific training – Quality control procedures • Potential gap between the intended intervention (as described in the protocol ) and the actual administered intervention • Barrier for systematic reviews 16
Are NPT trials specific? Influence of care providers • Systematic review of the surgical and medical volumeoutcome literature (Jan 1, 1980 - Dec 31, 2000)* – 71% of hospital volume-outcomes studies positive (88/124) – 70% of physician volume-outcomes studies positive (31/44) – No studies showed the opposite relationship – Relationship strongest for high risk/rare surgeries: • Pancreas/esophagus cancer, pediatric cardiac surgery • NNT at high v. low volume provider: 7 to 11 – Much more modest volume-outcome effect for common procedures (CABG, CEA, PTCA, breast/colon cancer) • NNT: 62 to 500 *Halm et al, Ann Intern Med 2002 17
Are NPT trials specific? • Specific issues in assessing NPT – Blinding – Placebo – Complexity of treatments – Healthcare providers’ influence • Need of specific standards 18
Overview • Specific methodological issues when assessing Nonpharmacological treatment • Quality tools • Reporting guidelines 19
Quality tools Why? • Assessing the quality of reports of trials is particularly important – clinicians’ critical appraisal of healthcare literature – systematic reviews • Accurate estimates of the treatment effect 20
Quality tools Why? • Several quality tools • Few quality tools were developped according to scientific standards – Jadad scale* – Delphi list** • Validated quality tools were mainly developped in the context of PT – Importance of blinding – No item related to care providers and the complexity of the intervention ** Jadad, Control Clin Trials, 1996 * Verhagen, JCE, 1998 21
Development of a specific checklist The example of CLEAR NPT • Quality: Internal validity • Delphi consensus method • Selection of items • From existing checklist or scales • From specific items • From the Collaborative Review Groups of the Cochrane Collaboration recommandations • Interviews of clinicians • Experts • Members of Collaborative Review Groups of the Cochrane Collaboration (n=41) • Clinicians involved in RCTs assessing NPTs (n=58) • Methodologists, epidemiologists (n=55) – 55 experts participated(36%) Boutron & Ravaud, JCE, 200522
Initial checklist 38 items Decision of the steering comittee Selection of items with a score of 8/9 for more than 40% of experts 1 st Round 54 experts/55 Checklist 21 items 2 nd Round 46 experts/55 Decision of the steering comittee Selection of items With a score of 9/9 for more than 40% of experts Checklist 11 items Decision of the steering comittee Sélection of all items Addition of 2 items for randomisation Addition of 1 item for the intention-to-treat analyses 3 rd Round 49 experts/55 Final Checklist 10 items 5 sub items 23
CLEAR NPT • Was the generation of allocation sequences adequate? • Was the treatment allocation concealed? • Were the main outcomes analyzed according to the intention-to-treat principle? • Were details of the intervention administered to each group made available? • Were care providers’ experience or skill in each arm appropriate? • Was participant (ie, patients) adherence assessed quantitatively? • Was the follow-up schedule the same in each group? 24
CLEAR NPT • Were participants adequately blinded? • Were care providers or persons caring for the participants adequately blinded? – If care providers and or participants were not adequately blinded • Were all other treatments and care (ie, co-interventions) the same in each randomized group? • Were withdrawals and lost to follow-up the same in each randomized group? • Were outcome assessors adequately blinded to assess the primary outcomes? – If outcome assessors were not adequately blinded, • Were specific methods used to avoid ascertainment bias (systematic differences in outcome assessment) 25
CLEAR NPT • Adequate assessment of trials quality • Improvement of critical appraisal of medical litterature • Improvement of the quality of systematic reviews 26
Overview • Specific methodological issues when assessing Nonpharmacological treatment • Quality tools • Reporting guidelines 27
Reporting guidelines Why? • Critical appraisal of the quality of clinical trials is possible only if the design, conduct, and analysis of RCTs are thoroughly and accurately described in published articles • Evidence of incomplete and inadequate reporting 28
Reporting guidelines 29
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Reporting guidelines 31
Reporting guidelines Dissemination • Publication – 11 journals – Over than 1000 citations • Editors endorsements including the ICMJE (International Committee for Medical Journal Editors) – instructions to authors – submission check-list • Website – www. consort-statement. org 32
Reporting guidelines Dissemination • Various extensions of the CONSORT Statement since the original version (parallel arm, superiority, efficacy) • • Cluster RCT Harm Herbal therapy Non inferiority trials • Several other extensions are in progress • 2 x 2 factorial design 33
Reporting guidelines for NPT trials Why? • 119 RCTs published in 1998 and 1999 in three major cardiothoracic journals (Annals of Thoracic Surgery, European Journal of Cardiothoracic Surgery, The Journal of Thoracic and Cardiovascular Surgery) • 70 % of RCTs fulfilled less than half of the CONSORT criteria Anyannu, Eur J of Cardio-thoracic Surgery, 2004 34
Reporting guidelines for NPT trials Why? Study of trials assessing PT and NPT of hip and knee osteoarthritis (1992 -2002) When blinding was judge possible, blinding was less often reported in NPT trials NPT PT Blinding of patients 46% 98% Blinding of healthcare providers 43% 83% Blinding of outcome assessors 72% 98% * Boutron & Ravaud, Jama, 2003 35
Reporting guidelines for NPT trials Why? Study of surgical papers (n = 158) published in 2004* • Reporting of details of the intended intervention – – Surgical procedure Pre-operative care Anesthesia Post-operative care 87 % 15 % 35 % 49 % • Surgeons – Selection criteria for surgeon – Number of interventions performed by surgeon – Number of surgeons involved * Jacquier I, Boutron I, Ravaud P, Ann. Surgery 40 % 11 % 33 % 36
Reporting guidelines for NPT trials Why? Study of rehabilitation papers (n = 171) published between 1997 -1998* • Timing of the intervention • Description of the intervention • Intervention’s adherence * Dijkers at al. Am J Phys Med Rehabil, 2002. 68 % 50 % 34% 37
Reporting guidelines Development of the extention of the CONSORT to NPT Steering committee – D. Moher – P. Ravaud – I. Boutron Selection of experts – Editors – Clinicians – Methodologists Two stages method – Preliminary survey – Consensus meeting 38
Preliminary survey • Objective – To identify items to be discussed based the experts’ opinion • Methods – All items of the CONSORT checklist – 7 specific questions on key issues were added – Items were selected for discussion if more than 1/3 of the experts answered that the item should be modified or another item should be added 39
Consensus meeting • 3 days – February 8 -10 th 2006, Paris • 30 experts • Agenda – Presentations – Discussions – Consensus • Manuscript in process 40
Conclusions • Specific issues in assessing NPT – – Placebo Blinding Complexity of the intervention Care providers’ influence • Specific guidelines – Specific quality tools • CLEAR NPT – Specific reporting guidelines • Development of an extension of the CONSORT for Non. Pharmacological treatment (CONSORT meeting, Paris, 2006) 41
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