1. The impact of (some) patient and site factors on assay sensitivity Robert H. Dworkin, PhD Professor of Anesthesiology, Neurology, Oncology, and Psychiatry Professor, Center for Human Experimental Therapeutics University of Rochester School of Medicine and Dentistry

2. Patient factorsConsiderations for improving assay sensitivity Pain duration: minimum Pain duration: maximum Baseline pain intensity: minimum Baseline pain intensity: maximum Baseline pain variability Baseline pain consistency Baseline diary compliance Prior treatment failure Psychopathology Subject training

3. Study design factorsConsiderations for improving assay sensitivity Research design Number of treatment groups Active comparator Initial dose titration period Flexible vs. fixed dosing Rescue medication Concomitant analgesics Baseline period duration Study duration

4. Study site factorsConsiderations for improving assay sensitivity Number of sites Staff training Staff-patient interactions Geographic location Patient referral sources Accelerated enrollment Protocol concealment Infrastructure

5. J Clin Psychopharmacol 2007;27:1-5

6. Effect size as a function of interview quality: HAM-D ratings in major depressive disorder RCTs mean difference vs pboSES p Study 1 1 all raters0.50.46*0.61 high quality6.81.330.02 Study 2 2 all raters2.14 0.20 high quality5.990.01 *standardized effect size of SSRIs from meta-analysis. 1 Kobak KA, et al. Interview quality and signal detection in clinical trials. Am J Psychiatry 2005;162:628. 2 Cogger KO. Rating rater improvement: a method for estimating increased effect size and reduction of clinical trial costs. J Clin Psychopharm 2007;27:418-420.

7. Select the number that best describes your neuropathic pain during the past 24 hours. (Circle one number only) 012345678910 No pain Worst possible pain Primary efficacy endpoint: daily pain diary

8. Patient factorsStudy design factorsStudy site factors Baseline pain intensity: minimum Baseline period duration Staff training Baseline pain intensity: maximum Staff patient interactions Baseline pain variability Protocol concealment Baseline pain consistency Baseline diary compliance Subject training

9. Can baseline pain diaries be used to identify patients who will provide increased assay sensitivity?

10. “Individuals with a greater pain variability index at baseline were more likely to be responders... to placebo... suggesting that a high pain variability may be a predictor of a placebo response.” Harris RE, et al. Arthritis Rheum 2005;52:3670-3674. “Because of the larger placebo response for pain-related endpoints … in the high variability patients, the apparent treatment effect size of MLN was smaller in patients with higher pain variability.” Palmer RH, et al. International Conference on Accelerating the Development of Enhanced Pain Treatments, Bermuda, March 2011. “In duloxetine studies for 3 chronic pain conditions (DPNP, CLBP, OA), patients with higher baseline pain variation had a smaller effect size and/or lower treatment response (relative to placebo) compared with patients with lower baseline pain variation. Zhang S, et al. International Conference on Accelerating the Development of Enhanced Pain Treatments, Bermuda, March 2011.

11. Selecting subjects based on characteristics of their baseline pain ratings that might reflect rating “diligence” or “competence” is likely to be less efficient than providing training before the baseline so that fewer subjects will be excluded because of their baseline ratings.

12. Patient selection Patient training

13. Patient training: 1.Educating the patient that it is very important that pain ratings be made in a conscientious and thoughtful manner because this is necessary for the study to succeed in determining whether or not the treatment is effective. 2.Identification of personal anchors and use of reminders for rating pain in a consistent manner throughout the study. 3.Educational scripts and interviews specifically designed to manage patient expectations.

14. “Though it is natural to hope for a positive outcome during the trial, we want you to be aware that there is a good likelihood that you are on placebo during this trial. Though you are likely to appreciate the care that you get from the study staff in this trial, it is very important that you don’t tell us that you are better if you’re really not, just because you are appreciative of the study staff, and you feel that you will be letting them down if you don’t improve. We need you to report your condition as accurately as you possibly can...” —D.L. Zimbroff, 2001

15. “Both investigators and patients were blinded to the following information: entry criteria for patients’ pain intensity, baseline pain intensity, definition of responder groups, visit at which randomization occurred, treatment during the withdrawal phase, efficacy failure criteria, and computation rules and time windows in the IVRS system used to calculate the baseline intensity and pain response.” Hewitt DJ, et al. Pain 2011;152:514-521.

16. Baseline score inflation in psychiatry “The HAM-D ratings completed by the on-site evaluator were significantly higher than the centralized raters’ scores at screening and baseline, but not at endpoint. At screening, 36% of patients who were judged to be eligible for the study by the on-site evaluator (ie, they scored at least 17 on the HAM-D, the study’s minimum severity criterion) were rated as study ineligible by a centralized rater…. …lower baseline scores are associated with greater change with placebo.”

17. Patient education: 1. Missing data diminishes the scientific value of the study and of the other subjects’ participation. 2. Emphasize importance of outcome assessments even if subject decides to discontinue study treatment and visits, although consent can, of course, be withdrawn at any time.

18. Internal validity vs. external validity (i.e., generalizability )