Evaluating Abuse, Misuse, Diversion, Overdose, Addiction, and Death in the

Patient Population

ISCTM February 18, 2014

Beatrice Setnik, Ph.D.

INC Research, Raleigh, NC

Overview

• Prevalence of Rx drug misuse, abuse and diversion amongst patients is not well characterized

• Initiatives taken to gather more data:

– Post marketing requirement for long-acting opioids issued Sept. 2014 stipulating: • Assessment of RX opioid abuse, misuse, addiction, overdose and

death

• Development /validation of tools/ instruments to measure outcomes of interest

Definitions

Smith SM et al., Classification and definition of misuse, abuse, and related events in clinical trials: ACTTION systematic review and recommendations. Pain. 2013 Nov;154(11):2287-96

Katz NP, Adams EH, Chilcoat H, Colucci RD, Comer SD, Goliber P, et al. Challenges in the development of prescription opioid abuse-deterrent formulations. Clin J Pain 2007 Oct;23(8):648-60.

• Misuse, abuse, and diversion are behavioral events whereas death, overdose, addiction are tangible, diagnostic events

• Challenging to create one tool that fits all

• Instruments that assess overdose, addiction: – e.g. Overdose Baseline Questionnaire; Refill Questionnaire – e.g. Diagnostic and Statistical Manual, Addiction Severity Index,

Alcohol and Drug Diagnostic Instrument

• Current instruments are insufficient to measure misuse, abuse, and diversion in pain patients – Abuse Potential Measures e.g. Drug Effects Questionnaire, ARCI*

• Not validated in pain patient populations • Content validity not established in pain patients

– e.g. Drug Liking due to euphoria or pain relief? • Do not address actual abuse, misuse and diversion

A Measurement Dilemma

*Addiction Research Center Inventory (ARCI)

• Current instruments are insufficient to measure misuse, abuse, and diversion in pain patients – Abuse/Misuse Assessments e.g. SOAPP-R, ORT, DAST, COMM*

• Current instruments are in-clinic assessments used to assess risk or presence of aberrant behaviors

• Lack distinction between abuse and misuse • Diversion typically not addressed • Tampering/alternate routes of administration not addressed • Specific drug products abused/misused are not identified • Do not quantify number of attempts at misuse, abuse and diversion

– Adverse events • Aberrant behaviors/events of euphoria often under-reported; patients not

likely to admit behaviors, ‘good effects’ may not always be considered AEs • Investigators/clinic staff may not always be trained to identify aberrant

behaviors • No systematic method to obtain information when aberrant events occurs • Adverse events of interest are not direct signals of abuse/misuse; may be

indicators of abuse/misuse of another substance *Screener and Opioid Assessment for Patients with Pain- Revised (SOAPP-R); Opioid Risk Tool (ORT); Drug Abuse Screening Test (DAST); Current Opioid Misuse Measure (COMM)

A Measurement Dilemma

Self-Reported Misuse, Abuse & Diversion Questionnaire (SR-MAD)

• Self-report, confidential, online questionnaire

collected via a third party – Assesses past behavior and does NOT predict future behavior

– Intended to be used in a pain patient population

– Baseline (as part of a clinical trial, registry or survey) and Post baseline (with investigational drug) assessment

– Probes past (lifetime and/or past 30 days) behaviors related to Rx opioid misuse, abuse and diversion

– Determines frequency of tampering and use by various (unintended) routes of administration (i.e. snorting, injection)

– Rx opioid specific

– Segregates behaviors according to misuse, abuse, and diversion

– Output to include the severity of Rx opioid MAD (algorithm under early stage of development)

Development Path – SR-MAD

• Instrument drafted (comprehension tested in non-pain patients)

• Early version paper/pencil included in a large patient study as an exploratory assessment; assessed lifetime behaviors

• Advisory board held with experts to obtain feedback

• Two of three rounds of cognitive debrief interviews in pain patients completed; last round ongoing: – Instrument adapted to online version following first round

– Past 30 day version and investigational drug version created prior to third round

• Validation study further planned

Setnik et al., Content validation of the prescription opioid misuse, abuse, and diversion instrument in the chronic pain patient population. Poster. College on Problems of Drug Dependence Annual Meeting. June 2013.

SR-MAD: Exploratory Phase IV Study Results

• Early lifetime paper/pencil version of SR-MAD administered at baseline in a clinical trial – Phase IV, multicenter, primary care based, open-label study to assess

the success of converting opioid experienced patients with chronic moderate to severe pain to extended release morphine.

– Patients were opioid experienced (taking daily opioid for ≥ days), chronic moderate to severe patients (≥ 3 months) (N=684, safety population) and had no history of opioid and/or alcohol abuse

Setnik et al., A primary care-based open-label study assessing the success of converting opioid-experienced patients with chronic pain to EMBEDA using a standardized conversion guide and identifying behaviors related to prescription opioid misuse, abuse, and diversion. (abstract) American Pain Society Annual Scientific Meeting. May 8-11, 2013.

SR-MAD: Exploratory Phase IV Study Results

• A total of 587 (85.4%) subjects returned the questionnaire. Of these: • The majority of patients (60%) reported taking more prescription

opioid medication than prescribed (≥1 time/lifetime) • 11% of patients reported having chewed or crushed their opioid • 2% of patients reported having tried to snort, smoke, or inject their

opioid pills • The most common reason was ‘to treat my pain better’ suggesting

misuse; a small number (1-4 patients) per question indicated ‘to feel pleasant or high’ suggesting abuse

• 8% of patients reported obtaining an opioid from more than 1 doctor at the same time

• 7% of patients reported giving away their opioid medication • 9% of patients obtained a prescription opioid medication from

someone who was not a doctor • 17% of patients suspected that someone else may have taken their

medication without asking them.

Assessing Adverse Events

• AEs broadly reviewed by CDER/CSS; refined to a screening list of 213 abuse-related AEs for assessing abuse potential of drugs – Goal: To improve consistency, sensitivity, and specificity in the

identification, reporting and interpretation of abuse related events during development and post-marketing of CNS-active drugs

• List included AEs related to psychoactive effects; therapeutic indications and excluded risk/comorbid factors, non-specific signs and symptoms; complications & consequences; withdrawal signs & symptoms

• Considerations to new coding version; improvement of sensitivity and specificity

Love L.A. and Sun S. Proposed Query to Capture Abuse-Related Adverse Events. (abstract) College on Problems of Drug Dependence – 75th Annual Meeting, San Diego, CA, June 2013.

Proposed Query to Capture Abuse-Related AEs

• Methodology for collecting abuse-related AEs requires standardization; differentiation from misuse important

– Standardized clinical probes/training for eliciting AEs

– Collection of consistent and meaningful details for case narratives

– Sample classification of abuse-related AE types (chronological) 1. ‘psychoactive effects’ (e.g. elevated mood, feeling drunk)

2. ‘behavior ’ (e.g. drug abuse, drug diversion)

3. ‘physical signs of abuse’ (e.g. needle marks, drug screen positive)

4. ‘outcomes’ (e.g. accidental death, accidental overdose)

– Clinical probes will vary according to type of AE (e.g. ‘outcomes’ event will require different information compared to ‘pyschoactive effect’ event)

Assessing Adverse Events

Interpreting Adverse Events

• Clinical probes (standardized questionnaires/ checklists) need to collect information consistently across studies to include (not limited to): – Collection at all time-points (AEs are not coded in real time hence probes

cannot be triggered in real time)

– Summarize all aberrant events observed in individual patient over time

– Intentionality

– Types of drugs involved; investigational vs. concomitant vs. contraband

– Causality: drug-related; co-morbidity; other drug?

– Duration of event

– Medical history

– Motive (behavioral)- related to abuse or misuse?

– Triggering additional data collection e.g. UDT

– Defining threshold of what is clinically relevant

• Other signals of interest include aberrant pill counts, concomitant medications, frequent requests for refills, pharmacy /doctor shopping

Summary

• Aberrant behaviors occur in the patient population and are important to measure

• Currently there are no validated tools that quantify behaviors related to abuse, misuse, and diversion

• New instruments (e.g. SR-MAD) are required to assess these behaviors in patients

• Adverse events require a structured approach to obtain meaningful information regarding abuse potential evaluation