Analgesic clinical trials

and their 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

Outline

1.Limitations of existing pain treatments

2.Negative trials and some possible explanations

3.An evidence-based approach to analgesic clinical trial design

4.Study-level analyses

5.Subject-level analyses

6.Novel clinical trial designs

Limitations of existing pharmacologic treatments for pain

• A substantial percentage of patients either fail to obtain satisfactory relief or cannot tolerate the side effects of treatment.

• In patients who do improve, there is typically partial relief of pain, not complete relief.

• In patients whose pain is relieved, there are often limited improvements in functioning and sleep.

• Side effects of many pharmacologic treatments are a burden to patients.

Gabapentin enacarbil in painful DPNGabapentin extended-release in PHNLacosamide in painful DPN (2 trials)Lamotrigine in painful DPN (2 trials)Lamotrigine in mixed neuropathic pain conditionsLevetiracetam in PHNOxcarbazepine in painful DPN (2 trials)Oxcarbazepine in lumbosacral radiculopathyPregabalin in painful DPN (3 trials)Pregabalin in painful HIV neuropathyPregabalin in lumbosacral radiculopathyPropentofylline in PHNTopiramate in painful DPN (3 trials)

1see Finnerup NB, et al. Pain 2010;150:573-581.

20 recent negative neuropathic pain trials (and there are many others1)

And it would be very easy to do a

similar list for clinical trials of

chronic low back pain,

osteoarthritis, etc.

Unfortunately, we often do not know which of these results are true negativestrue negatives (i.e., examples of “drug failure”)

• some of these drugs may not be efficacious in the specific pain conditions in which they were studied

and which results are false negatives (i.e., examples of “study failure”)

• some of these may be failed studies of truly efficacious drugs

Trial results

Treatment

EfficaciousNot

efficacious

Positive True positive False positive

Negative False negative True negative

Gabapentin enacarbil in painful DPNGabapentin extended-release in PHNLacosamide in painful DPN (2 trials)Lamotrigine in painful DPN (2 trials)Lamotrigine in mixed neuropathic pain conditionsLevetiracetam in PHNOxcarbazepine in painful DPN (2 trials)Oxcarbazepine in lumbosacral radiculopathyPregabalin in painful DPN (3 trials)Pregabalin in painful HIV neuropathyPregabalin in lumbosacral radiculopathyPropentofylline in PHNTopiramate in painful DPN (3 trials)

1see Finnerup NB, et al. Pain 2010;150:573-581.

20 recent negative neuropathic pain trials (and there are many others1)

Why have so many recent analgesic trials been negative?

1. Preclinical animal models and methods are identifying some drugs that have limited or no efficacy.

2. Early proof-of-concept (i.e., Phase 2) trials are identifying some drugs or dosages that have limited or no efficacy.

3. Many of these recent results are actually false negatives.• ~ 50% of depression trials fail...

4. Placebo group patients improved “too much.”

5. The optimal pain conditions or pain patients were not studied.

6. Temporal changes in characteristics of patients enrolling in trials and in types of sites conducting trials.

An evidence-based

approach to analgesic

clinical trial design

1. Investigate relationships between the methodologic features of clinical trials and their “assay sensitivity” (i.e., their ability to distinguish efficacious treatments from placebo or less efficacious treatments)

• e.g., are certain patient, study design, or study site characteristics associated with greater assay sensitivity?

2. Determine whether assay sensitivity can be increased by modifying these patient or study features

• e.g., possibly by efforts to reduce placebo group improvement

Patient factors

•Minimum pain duration•Maximum pain duration •Baseline diary compliance•Minimum mean baseline pain intensity•Maximum mean baseline pain intensity•Baseline pain variability•Baseline pain consistency•History of treatment failure(s)•Sources of patient referrals•History of

psychopathology

Study design factors

•Research design(e.g., parallel group

vs. cross-over)•Number of treatment arms•Study duration•Study quality•Baseline period duration•Titration period presence and duration•Dosing strategy (e.g., flexible vs. fixed)•Permitted use of rescue and/or concomitant analgesics•Presence of active comparator •Outcome measures•Methods of data collection (e.g., paper vs. electronic)

Study site factors

•Sources of patient referrals•Number of sites•Site investigator and staff experience•Site investigator and staff training•Inclusion of patient training•Methods for accelerating enrollment•Geographic region

Study-level analyses

Some recent findings on placebo group responses in neuropathic pain trials

1. There is greater improvement in placebo groups of negative vs. positive neuropathic pain trials.

• Katz J, Finnerup NB, Dworkin RH. Clinical trial outcome in neuropathic pain: relationship to study characteristics. Neurology 2008;70:263-272.

2.There is greater placebo group improvement in longer vs. shorter painful DPN trials.• Quessy SN, Rowbotham MC. Placebo response in neuropathic pain trials. Pain 2008;138:479-483.

3. Placebo group improvement—but not active treatment group improvement—is significantly less in PHN compared with painful DPN trials.

• Dworkin RH, Turk DC, Peirce-Sandner S, et al. Placebo and treatment group responses in postherpetic neuralgia vs. painful diabetic peripheral neuropathy clinical trials in the REPORT database. Pain 2010;150:12-16.

Subject-level analyses

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

1. Minimum pain intensity

2. Maximum pain intensity

3. Variability

4. Consistency

5. Extreme ratings

6. Adherence

“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.

Novel clinical trial designs

Sequential Parallel Comparison Design (SPCD)Efficacy analysis is based on results of the 8 groups in green boxes

Randomize

ActiveTreatment

Responder

Active Treatment

Non- Responder

Placebo

Non- Responder

Randomize

Responder

Active Treatment

Active Treatment

Active Treatment Placebo

Treatment Phase 1

Treatment Phase 2

Results

Results

Res

Non- Res Res

Non- Res

Non- Res

Non- Res

Non- ResRes Res Res

• The first treatment phase compares the active treatment

with placebo, as in a conventional parallel-group design.

• In addition, the first treatment phase identifies a group of

placebo non-responders.

• The second treatment phase compares the active

treatment with placebo in the placebo non-responders

from the first phase.

• The active-treatment vs. placebo difference in the

second phase is expected to be at least as large as in the

first phase, and larger if placebo non-response in the

first phase predicts placebo non-response in the second

phase.

“There is little doubt that reducing the

attrition rate of drug candidates in

clinical development represents the

greatest challenge and opportunity for

pharmaceutical research and

development.”

Paul SM, et al. Nature Rev Drug Disc 2010;9:203-214.

There is little doubt that reducing the

attrition rate of analgesic treatments

in clinical development represents the

greatest challenge and opportunity for

the ACTION public-private

partnership.