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How Should Clinicians Consider the Results of a Drug Clinical Trial? Module 4 Submodule 4.2
Objective <ul><li>To enhance prescribers’ ability to: </li></ul><ul><ul><li>Critically evaluate clinical trial design and ...
CONSORT Statement Checklist <ul><li>Title & Abstract </li></ul><ul><li>Introduction & Background  </li></ul><ul><li>Method...
Selection of Unbiased Information <ul><li>Check the title of the papers </li></ul><ul><ul><li>Are they interesting? </li><...
Example <ul><li>Piperacillin/tazobactam vs imipenem/cilastatin in the treatment of  nosocomial pneumonia- -a double blind ...
Why is the Author’s Disclosure Important? “ Analysis of randomized clinical trials published in the literature, either med...
Abstract <ul><li>Was the research question of interest to you?  </li></ul><ul><li>Were the clinically relevant outcomes in...
Abstract (Example) <ul><li>A Randomized, Double Blind, Placebo Controlled Trial of a Topical Cream Containing Glucosamine ...
Introduction/Background <ul><ul><li>The disease/condition being evaluated </li></ul></ul><ul><ul><li>The type of patients ...
Don’t Skip the Methods and Results Sections McAlister. J Gen Intern Med 1999;14:236-242, Putnam W, CMAJ 2002;166:1525-1530...
Guidelines to Distinguish Useful vs. Useless Results <ul><li>Use of randomization to assign patients to treatment </li></u...
Why is it Important to Review the Quality of RCT? McAlister. J Gen Intern Med 1999;14:236-242, Putnam W, CMAJ 2002;166:152...
Validity of Clinical Trials <ul><li>Comparator </li></ul>Comparability of Effects Comparability of Treatment Groups at Bas...
Comparator or Control Treatment <ul><li>Placebo </li></ul><ul><ul><li>Does the treatment work in a group of patients? </li...
Randomization Diabetologia (2004) 47:1175–1187 Women’s Health Initiative Hormone Trial Subjects and Methods The randomizat...
Intervention & Blinding Blinding   “ Participants, clinic staff, investigators and outcomes adjudicators were blinded to t...
Other Factors To Be Considered When Evaluating the Validity of a Trial <ul><li>Contamination </li></ul><ul><li>Cross over ...
And…… <ul><li>Adherence to treatment </li></ul><ul><li>Follow-up </li></ul><ul><li>Drop-out </li></ul><ul><li>Patients inc...
<ul><li>Null hypothesis  (H o ) –  </li></ul><ul><ul><li>The statement of “no difference” where the researcher hopes to di...
http://www.consort-statement.org/Statement/figure1.htm Results. Diagram Flow of Participants   The CONSORT diagram showing...
Results <ul><li>Participant flow </li></ul><ul><li>Dates of recruitment </li></ul><ul><li>Baseline data </li></ul><ul><li>...
Brandes, J. L. et al. JAMA 2007;297:1443-1454. Results Presented clearly, objectively and in sufficient detail, numbers ad...
Estimates of Treatment Effect ARR: Absolute risk reduction, RD: risk difference, RRR: relative risk reduction, CER: contro...
Precision of Estimates of Treatment Effect: Confidence Intervals Effect sizes (95% confidence intervals) in pain relief be...
Superiority Trial JAMA . 2001;285(15):1987-91.  Ann Intern Med , 2001;134:663-94,  JAMA . 2006;295(10):1152-60, Control Cl...
Randomized Clinical Trial Antimicrob Agents Chemother. 2002 Jun;46(6):1746-54. Objective : To compare the efficacy, safety...
Equivalence and NonInferiority Trials <ul><li>Equivalence Trials </li></ul><ul><ul><li>The new drug is ‘ just as good as ’...
Possible Scenarios of Observed Treatment Differences for Adverse Outcomes (Harms) in Noninferiority Trials Piaggio, G. et ...
Systematic Reviews User’s Guides to the Medical Literature. Manual for Evidence Based Clinical Practice. Chicago, AMA Pres...
Discussion/Comments <ul><li>Interpretation </li></ul><ul><li>Generalizability </li></ul><ul><li>Overall evidence </li></ul...
Lessons Learned <ul><li>In this module, you learned:  </li></ul><ul><ul><li>That randomization, blinding and choice of con...
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Module 4 Submodule 4. 2 Final June 2007

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  • This is the Submodule 4.1 related to the critical appraisal of the published results of a drug clinical trial.
  • Transcript of "Module 4 Submodule 4. 2 Final June 2007"

    1. 1. How Should Clinicians Consider the Results of a Drug Clinical Trial? Module 4 Submodule 4.2
    2. 2. Objective <ul><li>To enhance prescribers’ ability to: </li></ul><ul><ul><li>Critically evaluate clinical trial design and results </li></ul></ul><ul><ul><li>Determine whether or not the results are sufficiently compelling to change current clinical practice </li></ul></ul>
    3. 3. CONSORT Statement Checklist <ul><li>Title & Abstract </li></ul><ul><li>Introduction & Background </li></ul><ul><li>Methods </li></ul><ul><ul><li>Participants, interventions, measurements, outcomes, sample size, randomization, blinding, statistical methods </li></ul></ul><ul><li>Results </li></ul><ul><ul><li>Participant flow, recruitment, baseline data, # participants analyzed, outcomes & estimation, ancillary analysis, adverse events </li></ul></ul><ul><li>Discussion & Comments </li></ul><ul><ul><li>Interpretation, generalizability & overall evidence </li></ul></ul>Ann Intern Med, 2001;134 (8):657-662. www.annals.org
    4. 4. Selection of Unbiased Information <ul><li>Check the title of the papers </li></ul><ul><ul><li>Are they interesting? </li></ul></ul><ul><ul><li>Are they useful? </li></ul></ul><ul><ul><li>Are they relevant to your practice? </li></ul></ul><ul><li>Review the sponsor and authors for any financial relationship with the manufacturer. </li></ul><ul><ul><li>Was the study sponsored by a manufacturer? </li></ul></ul><ul><ul><li>Were the authors independent from the sponsor to: design, organize, analyze, select the results and discuss findings? </li></ul></ul><ul><ul><li>Did the manufacturer review and edit the manuscript? </li></ul></ul><ul><ul><li>Did the manufacturer require written approval of the manuscript before submission for publication? </li></ul></ul><ul><ul><li>Is there a potential for conflict of interest of investigators? </li></ul></ul>Yes Go to the next paper No
    5. 5. Example <ul><li>Piperacillin/tazobactam vs imipenem/cilastatin in the treatment of nosocomial pneumonia- -a double blind prospective multicentre study. Schmitt DV, et al. Infection. 2006 Jun;34(3):127-34. </li></ul><ul><li>Effectiveness of discontinuing antibiotic treatment after three days versus eight days in mild to moderate-severe community acquired pneumonia: randomised, double blind study. el Moussaoui R, et al BMJ. 2006 Jun 10;332(7554):1355. </li></ul><ul><li>Novel, single-dose microsphere formulation of azithromycin versus 7-day levofloxacin therapy for treatment of mild to moderate community-acquired Pneumonia in adults. D'Ignazio J, et al. Antimicrob Agents Chemother. 2005 Oct;49(10):4035-41. </li></ul><ul><li>Combination therapy versus monotherapy: a randomised pilot study on the evolution of inflammatory parameters after ventilator associated pneumonia . Damas P, et al. Crit Care. 2006;10(2):R52. </li></ul><ul><li>Single-dose azithromycin microspheres vs clarithromycin extended release for the treatment of mild-to-moderate community-acquired pneumonia in adults. Drehobl MA, et al. Chest. 2005 Oct;128(4):2230-7. </li></ul><ul><li>Community-Acquired Pneumonia Recovery in the Elderly Study Group. Community-Acquired Pneumonia Recovery in the Elderly (CAPRIE): efficacy and safety of moxifloxacin therapy versus that of levofloxacin therapy. Anzueto A, Net al. Clin Infect Dis. 2006 Jan 1;42(1):73-81. </li></ul><ul><li>Check the title of the papers </li></ul><ul><ul><li>Are they interesting? </li></ul></ul><ul><ul><li>Are they useful? </li></ul></ul><ul><ul><li>Are they relevant? </li></ul></ul>
    6. 6. Why is the Author’s Disclosure Important? “ Analysis of randomized clinical trials published in the literature, either medical or surgical specialties, has shown that industry-funded trials are more likely to be associated with statistically significant pro-industry findings ” (JAMA 2003;290:921-8) BMJ 2002;325:249-53, BMC Health Serv Res 2002;2:18-24, JAMA 2003;289:454-465, JAMA 1999;282:1474-5.
    7. 7. Abstract <ul><li>Was the research question of interest to you? </li></ul><ul><li>Were the clinically relevant outcomes included? </li></ul><ul><li>Were the treatment and outcome adequately measured? </li></ul><ul><li>Were the study patients similar to your own? </li></ul><ul><li>Is the treatment accessible, acceptable and affordable? </li></ul>
    8. 8. Abstract (Example) <ul><li>A Randomized, Double Blind, Placebo Controlled Trial of a Topical Cream Containing Glucosamine Sulfate, Chondroitin Sulfate, and Camphor for Osteoarthritis of the Knee. Cohen M, Wolfe R, Mai T, Lewis D. </li></ul><ul><li>Objective. To assess the ability of a topical preparation of glucosamine sulfate and chondroitin sulfate to reduce pain related to osteoarthritis (OA) of the knee. </li></ul><ul><li>Methods. Sixty-three patients were randomized to receive either a topical glucosamine and chondroitin preparation or placebo to be used as required over an 8 week period. Efficacy was assessed using a visual analog scale (VAS) for pain as well as the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and the SF-36 questionnaire. </li></ul><ul><li>Results. VAS scores indicated a greater mean reduction in pain for the glucosamine/chondroitin preparation group (mean change -3.4 cm, SD 2.6 cm) compared to the placebo group (mean change -1.6 cm, SD 2.7 cm) after 8 weeks. After 4 weeks the difference between active and placebo groups in their mean reduction from baseline was 1.2 (95% CI 0.1 to 2.4, p = 0.03) and after 8 weeks was 1.8 (95% CI for difference between groups, 0.6 to 2.9 cm; p = 0.002). </li></ul><ul><li>Conclusion. Topical application of glucosamine and chondroitin sulfate is effective in relieving the pain from OA of the knee and improvement is evident within 4 weeks. </li></ul>J Rheumatol. 2003 Mar;30(3):523-8.
    9. 9. Introduction/Background <ul><ul><li>The disease/condition being evaluated </li></ul></ul><ul><ul><li>The type of patients who are normally affected by the condition </li></ul></ul><ul><ul><li>What is the scientific rationale for conducting the current study. </li></ul></ul><ul><ul><li>How the condition is diagnosed (e.g., lab values, screening methods) </li></ul></ul><ul><ul><li>How the disease is normally treated (non-pharmacological & pharmacological) </li></ul></ul><ul><ul><li>What is considered a treatment failure </li></ul></ul>
    10. 10. Don’t Skip the Methods and Results Sections McAlister. J Gen Intern Med 1999;14:236-242, Putnam W, CMAJ 2002;166:1525-1530, Young JM, J Eval Clin Pract 2001;7:201-210, Anne Le Henanft, JAMA 2006;295:1147-1151 Percentage of respondents expressing confidence in basic evidence-based medicine (EBM) skills. *p < 0.01 for comparison between EBM users and nonusers.
    11. 11. Guidelines to Distinguish Useful vs. Useless Results <ul><li>Use of randomization to assign patients to treatment </li></ul><ul><li>Report of all clinically relevant outcomes </li></ul><ul><li>Study patients similar to your own? </li></ul><ul><li>Consideration of both clinical and statistical significance? </li></ul><ul><li>Therapeutic maneuver feasible in your practice </li></ul><ul><li>Inclusion of all patients in the analysis and justification the authors’ conclusion </li></ul>
    12. 12. Why is it Important to Review the Quality of RCT? McAlister. J Gen Intern Med 1999;14:236-242, Putnam W, CMAJ 2002;166:1525-1530, Young JM, J Eval Clin Pract 2001;7:201-210, Anne Le Henanft, JAMA 2006;295:1147-1151 24 Statistical test considering the non-inferiority or equivalence margin 72 Use of intention to treat analysis 78 Sample size calculated % All Reports Characteristics of the Trial
    13. 13. Validity of Clinical Trials <ul><li>Comparator </li></ul>Comparability of Effects Comparability of Treatment Groups at Baseline Comparability of Information <ul><li>Randomization </li></ul><ul><li>Blinding </li></ul>Miettinen OS. Theoretical Epidemiology: Principles of occurrence research in Medicine, 1985:25-35.
    14. 14. Comparator or Control Treatment <ul><li>Placebo </li></ul><ul><ul><li>Does the treatment work in a group of patients? </li></ul></ul><ul><li>Active </li></ul><ul><ul><li>Is the treatment superior to another active treatment? </li></ul></ul>NEJM 1994;331:394-398, JAMA 2006;295:1704-1706, Lancet 2005;366:895-906. <ul><li>Example: </li></ul><ul><li>ASCOT Study </li></ul><ul><li>Multicenter, randomised, controlled trial </li></ul><ul><li>Combination of amlodipine + perindopril (intervention) was compared with atenolol + bendroflumethiazide (control) </li></ul><ul><li>Effect on non-fatal myocardial infarction and fatal CHD </li></ul>
    15. 15. Randomization Diabetologia (2004) 47:1175–1187 Women’s Health Initiative Hormone Trial Subjects and Methods The randomization procedure was developed at the WHI Clinical Coordinating Center and implemented locally through a distributed study database, using a “ randomized permuted block algorithm, stratified by clinical centre site and age .” Table 1 Baseline characteristics of non-diabetic women randomized to oestrogen plus progesterone or placebo in the Women’s Health Initiative 6.2 474 6.6 531    Current user 19.9 1515 19.9 1596    Past user 73.9 5635 73.4 5883    Never used 0.56 Hormone use 1.3 99 1.4 112    Unknown 2.0 155 2.1 171    Asian/Pacific Islander 0.4 27 0.3 22    American Indian 5.0 385 5.4 429    Hispanic 6.5 493 6.0 480    Black 84.8 6468 84.9 6800    White 0.64 Race/ethnicity 21.5 1641 21.1 1691    70–79 45.1 3440 45.1 3617    60–69 33.4 2546 33.8 2706    50–59 0.35 63.3 (7.1) 7627 63.2 (7.1) 8014 Age at screening, years Mean (SD) or % n Mean (SD) or % n p value a Placebo, ( n =7627) Oestrogen + Progestin, ( n =8014) Characteristic
    16. 16. Intervention & Blinding Blinding “ Participants, clinic staff, investigators and outcomes adjudicators were blinded to treatment assignment. When required for safety or symptom management, an unblinding officer provided the clinic gynecologists with the treatment assignment. Neither the clinic gynecologists nor any of the staff or investigators involved with the clinical care of the participants were involved in assessing the study outcomes.” Diabetologia (2004) 47:1175–1187 Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women’s Health Initiative Hormone Trial
    17. 17. Other Factors To Be Considered When Evaluating the Validity of a Trial <ul><li>Contamination </li></ul><ul><li>Cross over </li></ul><ul><li>Co-intervention </li></ul><ul><li>Timing and duration of intervention </li></ul><ul><li>Locale of treatment </li></ul>
    18. 18. And…… <ul><li>Adherence to treatment </li></ul><ul><li>Follow-up </li></ul><ul><li>Drop-out </li></ul><ul><li>Patients included in the analysis </li></ul><ul><li>Ethical considerations </li></ul>
    19. 19. <ul><li>Null hypothesis (H o ) – </li></ul><ul><ul><li>The statement of “no difference” where the researcher hopes to disprove with the study results. </li></ul></ul><ul><ul><li>The goal of a study is to ‘reject’ the null hypothesis. </li></ul></ul>Hypothesis Testing P value: Probability of obtaining a result at least as extreme as the observed result when the null hypothesis is true
    20. 20. http://www.consort-statement.org/Statement/figure1.htm Results. Diagram Flow of Participants The CONSORT diagram showing the flow of participants through each stage of a randomized trial
    21. 21. Results <ul><li>Participant flow </li></ul><ul><li>Dates of recruitment </li></ul><ul><li>Baseline data </li></ul><ul><li>Numbers analyzed </li></ul><ul><li>Outcomes and estimation </li></ul><ul><li>Ancillary analysis </li></ul><ul><li>Adverse events </li></ul>CNS Drugs. 2005;19(2):125-36. Flow Diagram of the Study Population PP: Per Protocol, ITT: Intention to Treat
    22. 22. Brandes, J. L. et al. JAMA 2007;297:1443-1454. Results Presented clearly, objectively and in sufficient detail, numbers add up properly, analysis appropriate for the nature of data, interpreted correctly, relevant variables included in the analysis
    23. 23. Estimates of Treatment Effect ARR: Absolute risk reduction, RD: risk difference, RRR: relative risk reduction, CER: control event rate, EER: experimental event rate Example Calculation Estimate 1/ARR or 1/RD CER-EER/ CER CER-EER trial trial 1) 20 2) 2,000 NNT 1) (8%-3%)/8%= 0.63% 2) (0.08%-0.03%)/0.08%= 0.63% RRR 1) 8%-3%= 5% 2) 0.08%-0.03%= 0.05% ARR (RD)
    24. 24. Precision of Estimates of Treatment Effect: Confidence Intervals Effect sizes (95% confidence intervals) in pain relief between topical therapies or nonsteroidal antiinflammatory drugs (NSAID) and placebo or vehicle. Symbols represent the point estimate. J Rheumatol. 2006 Sep;33(9):1841-4.
    25. 25. Superiority Trial JAMA . 2001;285(15):1987-91. Ann Intern Med , 2001;134:663-94, JAMA . 2006;295(10):1152-60, Control Clin Trials 2002;23:570-583. Lancet 2005;365:573-578. Lancet, 1999;354:716-722. NEJM, 2004;350:2050-2059. Clin Therapeutics. 1996;18(5):797-810. The new drug is more efficacious ‘better than’ the control in terms of efficacy or safety by a predefined margin (known as delta, ∆). Example: Valsartan 20 mg once daily (n=140) Valsartan 80 mg once daily (n=150) Valsartan 160 mg once daily (n=148) Valsartan 320 mg once daily (n=150) Intervention Valsartan is more efficacious than placebo in reducing high blood pressure Alternative hypothesis Superiority Type of study Compared to placebo, the reductions of diastolic blood pressure from baseline were 3.37, 5.20, 5.32 and 6.48 mm Hg for valsartan 20, 80, 160 and 320 mg, respectively, at 8 weeks. Treatment effect Placebo once daily (n=148) Control There is no difference between valsartan and placebo for reductions in DBP Null hypothesis
    26. 26. Randomized Clinical Trial Antimicrob Agents Chemother. 2002 Jun;46(6):1746-54. Objective : To compare the efficacy, safety, and tolerability of moxifloxacin (400 mg IV follow by 400 mg oral moxifloxacin) versus co-amoxiclav (1.2 g IV in a infusion three times a day followed by 625 mg oral co-amoxiclav three times a day), with or without clarithromycin (500 mg) twice daily (i.v. or orally), for 7 to 14 days in adult patients with community-acquired pneumonia requiring initial parenteral therapy. Results : Although the trial was designed, on the basis of predefined outcomes, to demonstrate the equivalence of the two regimens, the results showed statistically significant higher clinical success rates (for moxifloxacin, 93.4%, and for comparator regimen, 85.4%; difference [Delta], 8.05%; 95% confidence interval [CI], 2.91 to 13.19%; P = 0.004) and bacteriological success rates (for moxifloxacin, 93.7%, and for comparator regimen, 81.7%; Delta, 12.06%; 95% CI, 1.21 to 22.91%) for patients treated with moxifloxacin…. Thus, it is concluded that monotherapy with moxifloxacin is superior to that with a standard combination regimen of a beta-lactam and a beta-lactamase inhibitor, co-amoxiclav, with or without a macrolide, clarithromycin, in the treatment of patients with community-acquired pneumonia admitted to a hospital.
    27. 27. Equivalence and NonInferiority Trials <ul><li>Equivalence Trials </li></ul><ul><ul><li>The new drug is ‘ just as good as ’ the control </li></ul></ul>Antimicrobial agents and Chemotherapy, 2005; 49(10):4035–4041, Pediatrics, 2004; 114(1): e96-e101. JAMA . 2001;285(15):1987-91. Ann Intern Med , 2001;134:663-94, JAMA . 2006;295(10):1152-60, Control Clin Trials 2002;23:570-583. Lancet 2005;365:573-578. Lancet, 1999;354:716-722. NEJM, 2004;350:2050-2059. For example a randomized, double-blind, noninferiority study was designed to demonstrate that a single 2.0-g oral dose of a novel microsphere formulation of azithromycin was at least as effective as 7 days of levofloxacin, 500 mg/day, in the treatment of adult patients with mild to moderate community-acquired pneumonia. <ul><li>Noninferiority Trials </li></ul><ul><ul><li>The new drug is ‘ not worse than ’ the control </li></ul></ul>These trials are conducted for drugs that might have better safety profile and more tolerability, are easier to administer, and have lower cost . For example, a trial was designed to determine whether azithromycin was as effective as erythromycin estolate in the treatment of pertussis, using bacterial eradication from the nasopharynx as the primary outcome measure.
    28. 28. Possible Scenarios of Observed Treatment Differences for Adverse Outcomes (Harms) in Noninferiority Trials Piaggio, G. et al. JAMA 2006;295:1152-1160.
    29. 29. Systematic Reviews User’s Guides to the Medical Literature. Manual for Evidence Based Clinical Practice. Chicago, AMA Press, 2002. Evidence-Based Medicine, Elsevier, 2005. <ul><li>What data were analyzed (individual or aggregate)? </li></ul><ul><li>Did authors assess validity of individual studies? </li></ul><ul><li>What sources of information were searched to gather the studies? </li></ul><ul><li>What type of studies were included? </li></ul>
    30. 30. Discussion/Comments <ul><li>Interpretation </li></ul><ul><li>Generalizability </li></ul><ul><li>Overall evidence </li></ul><ul><li>Impact on your practice </li></ul>
    31. 31. Lessons Learned <ul><li>In this module, you learned: </li></ul><ul><ul><li>That randomization, blinding and choice of control treatment are key features to establish the validity of a randomized clinical trial. </li></ul></ul><ul><ul><li>Other characteristics of clinical trials that are important to determine their validity, such as: contamination, co-intervention, timing of intervention, site of treatment, adherence to treatment, sample size, follow-up, data analysis, ethical considerations and generalizability of results. </li></ul></ul>
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