The impact of (some) patient and site factors on assay sensitivity Robert H. Dworkin, PhD Professor of Anesthesiology, Neurology, Oncology, and Psychiatry.

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

Patient factors Considerations 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

Study design factors Considerations 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

Study site factors Considerations for improving assay sensitivity

Number of sites

Staff training

Staff-patient interactions

Geographic location

Patient referral sources

Accelerated enrollment

Protocol concealment

Infrastructure

J Clin Psychopharmacol 2007;27:1-5

Effect size as a function of interview quality:HAM-D ratings in major depressive disorder RCTs

mean difference vs pbo SES p

Study 11

all raters 0.5 0.46* 0.61high quality 6.8 1.33 0.02

Study 22

all raters 2.14 0.20high quality 5.99 0.01

*standardized effect size of SSRIs from meta-analysis.

1Kobak KA, et al. Interview quality and signal detection in clinical trials. Am J Psychiatry 2005;162:628.

2Cogger KO. Rating rater improvement: a method for estimating increased effect size and reduction of clinical trial costs. J Clin Psychopharm 2007;27:418-420.

Select the number that best describes your neuropathic pain during the past 24 hours. (Circle one number only)

0 1 2 3 4 5 6 7 8 9 10

Nopain

Worst possible pain

Primary efficacy endpoint:

daily pain diary

Patient factors Study design factors Study 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

Can baseline pain diaries be used to

identify patients who will provide

increased assay sensitivity?

“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.

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.

Patient selection

Patient training

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.

“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

“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.

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.”

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.

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