1. How Should Clinicians Consider the Results of a Drug Clinical Trial? Module 4 Submodule 4.2

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.

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.

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

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. 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

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

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. 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. 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. 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. 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.

28. Possible Scenarios of Observed Treatment Differences for Adverse Outcomes (Harms) in Noninferiority Trials Piaggio, G. et al. JAMA 2006;295:1152-1160.