rems program companies - food and drug · pdf fileco-3 rpc is consortium of 24 companies...

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REMS Program Companies

AADPAC & DSRMAC

May 3 - 4, 2016

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Introduction and REMS Design

Paul Coplan, ScD, MBA

RPC Metrics Subteam Chair

Purdue Pharma L.P.

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RPC Is Consortium of 24 Companies

Actavis, Inc.

Apotex Inc.

Aurolife Pharma, LLC

Depomed, Inc.

Endo Pharmaceuticals Inc.

Impax Laboratories, Inc.

Inspirion Delivery Technologies

Janssen Pharmaceuticals, Inc.

Mallinckrodt Pharmaceuticals

Mylan Technologies, Inc.

Nesher Pharmaceuticals LLC

Novel Laboratories, Inc.

Noven Pharmaceuticals, Inc.

Pernix Therapeutics

Perrigo Company plc

Pfizer, Inc.

Purdue Pharma L.P.

Ranbaxy Pharmaceuticals, Inc.

Rhodes Pharmaceuticals L.P.

Roxane Laboratories, Inc.

Sandoz, Inc.

The PharmaNetwork LLC

Upsher-Smith Laboratories, Inc.

VistaPharm, Inc.

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RPC initial framework

FDA joint advisory committee (July 2010)

FDA task force

Development of REMS Framework

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REMS Design &

Implementation

Paul Coplan, ScD, MBARPC Metrics Subteam Chair

Purdue Pharma LP

Continuing Education

Activities: Design and Results

Marsha Stanton, PhD, RNRPC Continuing Education Subteam Chair

Pernix Therapeutics

Public Health ImpactCharles Argoff, MDProfessor of Neurology

Albany Medical College and Albany Medical Center

REMS Assessments:

Design and Results

M. Soledad Cepeda, MD, PhDRPC Metrics Subteam Member

Janssen Pharmaceuticals, Inc.

Surveillance Database ResultsRichard Dart, MD, PhDRocky Mountain Poison & Drug Center, Denver Health

Professor of Emergency Medicine, University of Colorado

Lessons LearnedLaura Wallace, MPHRPC Metrics Subteam Member

Purdue Pharma LP

Conclusion Paul Coplan, ScD, MBA

Agenda

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Additional Experts

Daniel P. Alford, MD Boston University School of Medicine

Daina Esposito, MPH HealthCore, Inc.

Syd Philips, MPH IMS Health

Valerie Smothers, MA MedBiquitous

Annette Stemhagen, DrPH,

FISPEUnited BioSource Corporation

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Abuse/addiction of prescription opioids

Immediate release (IR) opioids

Extended-release/long-acting (ER/LA)

opioids

Abuse/addiction of illegal drugs

Heroin

Illicitly produced fentanyl

Opioid Abuse Includes Multiple Abuse Categories

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Opioid Analgesic Prescriptions

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Drug Overdose Deaths Involving Opioids By Type of Opioid

Source: Rudd MMWR 2016, National Vital Statistics System.

Deaths

per

100,000

population

Year

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“The goal of this REMS is to reduce serious

adverse outcomes resulting from inappropriate

prescribing, misuse, and abuse of extended-

release or long-acting opioid analgesics while

maintaining patient access to pain medications.

Adverse outcomes of concern include addiction,

unintentional overdose, and death.”

-FDA, ER/LA REMS, July 2012

Goal of REMS for Extended Release/ Long Acting Opioid Analgesics

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Educate prescribers to select and manage

patients

Educate patients to understand and prevent

risks

Did not include specific actions targeted at

abusers

RPC Committed to Fulfilling Goal of REMS

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ER/LA REMS first to require

Collaboration by many companies

Accredited CE as primary tool

Complexities

Rules governing industry support of CE

FDA’s rules for REMS implementation

Processes for decision-making

Contracting by many companies

ER/LA Opioid REMS is Novel in Scope and Tools

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Communication components

Dear Prescriber Letter

Call center

Website

Education and training

Patient education

Medication Guide (pharmacists)

Patient Counseling Document (prescribers)

Continuing education for prescribers

Assessment studies of the REMS

Components of the REMS

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Tool for patient education

Proper storage and taking ER/LA opioids

Preventing abuse, addiction and overdose

Distributed by pharmacists to patients when

opioids dispensed and part of product labelling

Tailored for methadone, patch or oral

formulation

1-Page Medication Guide

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1-Page Patient Counseling Document

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Target is 1.3 million prescribers registered to

prescribe Schedule 2 and 3 narcotics, state

licensing boards, and professional societies

Letter sent twice

Letter now sent annually to new prescribers

Dear Prescriber Letters

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Train prescribers using CE activities

FDA Blueprint for Prescriber Education

CE providers develop course content

REMS allows for CE courses not funded by

RPC to count toward goals as long as content

in FDA Blueprint is covered

CE Activities to Train Prescribers

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Date

Years

REMS

Active

Performance

Target

March 2013 0 Start

March 2015 2 80,000

March 2016* 3 160,000

March 2017 4 192,000

CE Completers versus Target

*Unaudited data provided by CE provider organizations for RPC-funded courses

Other

Completers of

REMS-

compliant CE

44,619

91,274

-

ER/LA Opioid

Prescriber

Completers

37,512

66,219

-

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RPC maintains toll-free call center

Provides REMS information and answer

queries

1.800.503.0784

REMS Call Center to Answer Questions

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Website Contains Comprehensive Information on REMS

http://www.er-la-opioidrems.com/IwgUI/rems/home.action

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Timing of REMS Implementation

Pre-REMS Period

REMS Aproval

2010 2011 2012 2013 2014 2015

Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4

JULY 2012

REMS Active Period Implementation

MARCH 2013

1st CE course

available

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REMS Assessments

Assessment

Dear Prescriber Letters sent to prescribers

Number of trained* prescribers

Audit of CE trainings

Prescriber survey

Long-term evaluation of trained* prescribers

Patient survey

Surveillance monitoring for abuse, misuse, overdose & death

Evaluation of drug utilization patterns

Evaluation of changes in prescribing behavior

Changes in patient access to opioids assessed by prescribing patterns

* Prescribers who completed REMS-compliant CE course

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Assessing behaviors in prescribers who

completed REMS training was limited by firewalls

preventing industry influence in CE

Survey samples not fully generalizable to the

population of ER/LA opioid patients and

prescribers

The REMS was part of a multi-faceted program to

prevent opioid abuse and its individual

contribution is difficult to assess

Key Limitations of Assessments

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REMS Continuing Education Progress and Results

Marsha Stanton, PhD, RN

RPC Continuing Education Subteam Chair

Pernix Therapeutics

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REMS

Components Accomplishments/Key Findings Evidence-based Improvements

Number of trained

prescribers• Increasing numbers per year

• Make Blueprint more concise

• Increase to healthcare team

Audit of CE

trainings • 100% alignment with Blueprint

• Remediation of those that

did not meet financial

disclosure requirements

REMS

assessments

• Patient: High awareness of

Medication Guide

• Prescribers: Low awareness of

REMS communications materials

• Prescribers: Training associated

with higher knowledge scores

• Prescribers: Product-specific

knowledge is limited

• Opioid prescriptions decreasing

• Improvements in inappropriate

prescribing

• Launch of awareness

campaign

• More representative survey

populations

Surveillance

monitoring

• Significant decreases in some, but

not all, safety outcomes

• Expanded access to Medicaid

data

• Use of National Death Index

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1st time integral component to a REMS

1st used to address major public health issue

Offers in-depth learning

Fulfills general CE requirement of various

state licensure boards

REMS is Focused on Accredited Education

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FDA Blueprint is roadmap

CME and CE

Providers use Blueprint to create activities

Print, live lecture, interactive discussions,

internet

> 3 hours

Pre-test and periodic evaluations throughout

the educational activities

Overview of CE Training

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1. Assessing patients for treatment

REMS CE Includes 6 Content Sections of FDA Blueprint

2. Initiating therapy, modifying dosing, and

discontinuing use

3. Managing therapy

4. Counseling patients and caregivers on safe use

5. General drug information

6. Specific drug information

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CE Trainings Audited

Assessment

REMS communication activities



Patient survey

Prescriber survey




Surveillance monitoring

Monitoring patterns of prescribing to identify changes in access

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29* audits performed (Mar 2014 – Feb 2015)

100% met all requirements for content,

accuracy, and assessment

9 audits had non-content-related observations

Failure to prominently display financial

disclosure

All remediated

CE Audit Results

*36-Month Assessment Report

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CE providers submit grant proposals to RPC

RPC provides grants

CE providers determine course content

Medication manufacturers cannot

participate in content development

Process for CE Development

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151 proposals submitted

31 CE proposals approved

839 total CE activities have been conducted

Overview of REMS-Compliant CE Providers*

*As of 2/29/16

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FDA Prescriber Completer Goals

Goal Date

Prescribers with ≥ 1 ER/LA Opioid Rx in Previous Year

(N=320,000)

Complete REMS-Compliant CE

Goals Set by FDA

Completers Goals

Set by FDA

% n

March 2015 25% 80,000

March 2016 50% 160,000

March 2017 60% 192,000

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Numbers of Completers of REMS-Compliant CE Increasing by Year

Cumulative

Completers

(N)

37,512

66,219

82,131

157,493

0

50,000

100,000

150,000

200,000

Feb 2015 Feb 2016

ER/LA opioid prescribers counted

towards FDA completer goalsHCP completers

(inclusive)

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Prescriber Completers by Specialty

67.4%

12.8%

19.7%

Primary Care

Pain

Specialist

Non-pain

Specialist

**Specialty reporting is not required of CE providers. N=20,704 ER/LA opioid analgesic prescribers of 37,512 total who

received training (2/28/13 – 2/28/15) from 36-month Assessment Report

0.002%

No response

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National conferences

Primary and specialty organizations

Local/Regional conferences

State Medical Societies / Federation of State

Medical Boards

Medical schools

Health systems (e.g. Kaiser Permanente)

REMS-compliant CE Offered Nation-Wide

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CE activities approved through 2018

CE providers submit proposals each year

Provided to FDA on an ongoing basis

Future Evaluation Deadlines

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Limited ability to promote programs

Blueprint results in lengthy courses not tailored

to individual learner needs

Only ER/LA opioid prescribers “count” toward

REMS goals

Difficulties Achieving Completer Targets

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Federal agencies including

Medscape/NIDA (115,000 completers)

Academic institutions

Prescriber Clinical Support System for Opioid

therapies (PCSSO)-SAMHSA

Non RPC-supported CE providers

Professional organizations

State medical associations

Other health systems

RPC Not Only Source of Education

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Explore adaptive approaches

Increased online activities

Web casts

i-books

Blended learning (i.e. combining digital and

face to face formats)

Case-based studies to enhance participation

Evolution of RPC-Supported Activities

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Development of many systems/processes

Open communications among stakeholders

Diverse and comprehensive CE courses

provided

Significant number of the target prescriber

population educated

Conclusion

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Perspective of a Pain Medicine Physician and Educator

Charles Argoff, MD

Professor of Neurology, Albany Medical

College

Director, Comprehensive Pain Center,

Albany Medical Center

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ER/LA opioid CE program has been

successful

Targets audiences that need information

HCPs are changing clinical behavior and

prescribing habits

Clinical Perspectives

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Education Is Cornerstone of Changing Behavior

Photographs provided with permission from American College of Physicians / Pri-Med

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Fine PG, et al., 2005.

Multimodal TherapeuticStrategies

for Pain and Associated Disability

Pharmaco-

therapy

Interventional

Approaches

Psychological

Support

Lifestyle

Change

Complementary

and Alternative

Medicine

Physical

Medicine and

Rehabilitation

Pain Management Involves Many Treatment Modalities

CO-46

Positive outcomes from REMS-compliant CE

include

Changes in practice

Increased urine drug testing and patient

counseling

Improved awareness of potential for misuse

and abuse

Reduction in number of opioid scripts

A Physician Perspective: Benefits

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Initial Study Linking Training with Prescriber Behavior and Outcomes

Design Retrospective observational study

Data Source Electronic Health Records (EHR): (Pri-Med)

Population

All HCPs who use EHR, stratified by whether or

not they took REMS-compliant CE

Patients of these HCPs

Study neither reviewed by FDA nor provided in RPC Briefing Document

Outcomes

Changes before / after training implementation in:

1. Prescribing patterns for all, ER/LA and IR opioids

2. Patient outcomes, including abuse/dependence

and overdose based on ICD codes in EHR

Time Period Jun 2013 – Jan 2016

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Changes in Prescribing After Training

Opioid

prescriptions

Trained HCPs1

(N=441)

Control HCPs

(N=4,669)

ER/LA 10% decrease 4% increase

IR 3% increase 3% increase

1) HCPs who took REMS-compliant CE


CO-49

Improvements in Outcomes Among Patients of Trained Prescribers

Outcomes1

Patients of

Trained HCPs2

Patients of

Control HCPs

Abuse / dependence 50% decrease 29% increase

Overdose 53% decrease 17% increase

1) Assessed based on ICD-9 and ICD-10

2) HCPs who took REMS-compliant CE


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Prescribing-behavior and patient-outcome

data suggest positive impact of REMS

Evidence of effect within trained group

compared to control group

Study Conclusion

Study not provided in RPC Briefing Document

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EHR Data Supported by Other Published Studies

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REMS education making impact

Appropriate use of ER/LA opioids can be

facilitated by greater prescriber knowledge

Overall Conclusion

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REMS Assessment Metrics: Education Contributed to Improvements

M. Soledad Cepeda, MD, PhD

RPC Metrics Subteam Member

Janssen Research & Development

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Overview of Assessments

Assessment




Patient survey

Prescriber survey





* Trained = completed REMS-compliant training

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REMS


Number of trained




Audit of CE


• Remediation of those that did

not meet financial disclosure

requirements

REMS

assessments


Medication Guide


REMS communications

materials







prescribing


campaign


populations

Surveillance

monitoring

• Significant decreases in some, but

not all, safety outcomes

• Expanded access to Medicaid

data


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20 minute

80 survey items

22 knowledge questions

Administered by HealthCore

Commercially insured patients

Completed either by phone or online

Patient Survey

CO-57

Does the patient understand the risks

associated with ER/LA opioids?

Did the patient receive and understand the

Medication Guide?

Was the Patient Counseling Document used

during the office visit?

Is the patient satisfied with access to ER/LA

opioids?

Patient Knowledge Studied

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Inclusion criteria

Commercially insured patients*

≥ 1 ER/LA opioid Rx over the past year

Target sample size: 400 patients

423 patients completed survey

2,441 were randomly selected

ER/LA Opioid Patient Survey Population

*HealthCore Integrated Research Database (HIRD)

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Patient Survey Responders Compared to Commercially Insured ER/LA Opioid Users

*HIRD database

Responders more often

Female

Younger

Geographically similar

94% white

23% lower than high school degree

CO-60

Overall score

Number of questions answered correctly by

≥ 80% of responders

Knowledge Assessed in Two Ways

CO-61

Mean Score Was 86%

73% met or exceeded

FDA target

Number

of

Patients

3 2 04.5

1018

26

44

62

101

41

70

34

0

10

20

30

40

50

60

70

80

90

100

110

<5 <5<5

40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89 90-94 95-99 100

Score

FDA Recommended Target ≥ 80% Correct

CO-62

Patients Demonstrated High Understanding of Risks

Risk

% Patients Who

Responded

Correctly

(N=423)

Do not give ER/LA opioid analgesics to other people who

have the same condition as you98%

Selling or giving away ER/LA opioid analgesics is against

the law98%

Seek emergency medical help for side effects such as

trouble breathing, shortness of breath, fast heartbeat,

chest pain, or swelling of their face, tongue, or throat after

taking or using ER/LA opioid analgesics

97%

Talk to a healthcare provider about taking or using more

ER/LA opioid analgesics if the current dose doesn't

control the pain

96%

It is not okay to drink alcohol while taking or using ER/LA

opioid93%

CO-63

Five Questions Answered Correctly by <80% of Responders

Areas of Low Knowledge

%

Correct

(N=423)

Do not use a hot tub or sauna while using ER/LA opioid analgesics

if pain persists (patch only)77%

ER/LA opioid analgesic pills should not be split or crushed

(oral formulations)76%

Do not store ER/LA opioid analgesics in a medicine cabinet with

other medications in the household.71%

Inform healthcare provider of any fever (patch only) 70%

Read the attached Medication Guide every time an ER/LA opioid

prescription is filled55%

Includes all questions with response rates <80%

CO-64

98% reported reading guide at least once

Average knowledge score = 86% correct

2% reported not reading

Average knowledge score = 72% correct

Medication Guide Widely Read

CO-65

43% reported

receiving Patient

Counseling

Document from

provider

26% reported

providers referenced

Patient Counseling

Document

Less than Half of Patients Received Patient Counseling Document

CO-66

71% of patients able to obtain prescription

when needed for pain

78% of patients satisfied with access

Patients Generally Satisfied with Access to ER/LA Opioids

CO-67

REMS Includes Prescriber Assessments

* Trained = completed REMS-compliant training

Assessment Metrics




Patient survey

Prescriber survey Prescriber Knowledge, Awareness

of REMS Materials

Long-term evaluation of trained*

prescribersKnowledge Retention


Evaluation of changes in prescribing

behavior


CO-68

~25 minutes

124 survey items

68 knowledge questions

Prescribers with training

REMS-compliant CE providers

Prescribers without training

National prescription database (IMS)

Prescriber Survey Design

CO-69

Prescriber Survey Population

Inclusion criterion

≥ 1 ER/LA opioid Rx over the past year

Target sample size: 600 prescribers

Feb to April 2015

612 prescribers completed survey

301 with training1

311 without training2

1. Completed REMS-compliant CE program; 2. IMS database; 54% reported participation in REMS-compliant CE

CO-70

Prescriber Survey: Baseline Characteristics of Responders With and Without Training

Prescribers split based on self-reported

training

Trained responders

Similar gender

More likely to be physicians

Have pain management training

Fewer years in practice

CO-71

Limited Awareness of REMS Materials by Prescribers

REMS Material

Prescribers

Recruited

by

CE Providers

(N=301)

IMS Recruited

Reported NOT

Completing a

REMS-compliant

CE Activity

(N=179)

Reported

Completing a

REMS-compliant

CE Activity

(N=132)

% % %

Medication Guide 67.4 40.2 71.2

Patient Counseling

Document53.5 22.3 48.5

ER/LA Opioid

Analgesics Website49.5 11.7 55.3

Dear DEA-Registered

Prescriber Letter44.5 16.8 47.7

CO-72

Prescriber Behavior

Prescribers

Recruited by

CE Providers

(N=301)

Prescribers Recruited Through

IMS Data

Reported NOT

Completing a

REMS-compliant

CE Activity

(N=179)

Reported

Completing a

REMS-compliant

CE Activity

(N=132)

% % %

Use the Patient

Counseling Document

with patients

70% 50% 68%

Use of Structured

Interview Tools or

Screening Tools

69% 53% 76%

Completion of Patient-

Prescriber Agreement77% 70% 84%

Perform Urine Drug

Tests70% 64% 80%

Trained Prescribers Used Patient Counseling Document More

CO-73

Prescriber Survey Assessed Understanding of Blueprint Knowledge Areas

Prescribers

Completing a REMS-

compliant CE Activity

(N=433)*

Reported NOT

Completing a REMS-

compliant CE Activity

(N=179) Difference

Mean score Mean score Est. 95% CI

Assess patients 91.9 87.7 -4.2 (-6.6, -1.8)

Initiate, modify,

discontinue dose80.2 74.6 -5.6 (-7.3, -3.8)

Manage therapy 86.1 84.3 -1.8 (-3.4, -0.3)

Counseling 92.2 89.2 -3.1 (-4.5, -1.6)

General drug

information87.8 78.9 -8.8 (-11.1, -6.6)

Specific drug

information60.7 50.9 -9.8 (-14.0, -5.5)

Overall Score 84.7 79.7 -5.0 (-6.2, -3.7)

*Combines prescribers recruited by CE providers and prescribers recruited through IMS who reported completing a REMS-

compliant CE activity

CO-74

To determine knowledge retention and

practice changes

6-12 months following completion of REMS-

compliant training

Long-Term Evaluation Survey

CO-75

~30 minute survey

102 survey items

65 knowledge questions including case

scenarios

Prescribers identified through RPC supported

CE providers

Long-Term Evaluation Survey Design

CO-76

Recruitment target = 600 responders

328 completed survey

Feb to April 2015

Long-Term Evaluation Survey of REMS Prescribers

CO-77

56% male

66% MDs or DOs

60% in practice >15 years

46% prescribed ER/LA opioids >10 times in

last month

Prescribers who Completed Long-Term Evaluation Survey

CO-78

Long-Term Evaluation Survey: Topline Results

FDA Blueprint Message Mean score

1. Assessment 83.4

2. Initiation, modification, or

discontinuation of therapy67.8

3. Management of ongoing therapy 90.6

4. Patient counseling 93.4

5. General drug information 83.6

6. Product-specific drug information 57.0

Overall score 82.8

CO-79

Mean knowledge score 82.8% correct

~70% of questions were answered correctly by

at least 80% of participants

No questions on product-specific information

had a correct response rate above 80%

Insights from Long-Term Evaluation Survey

CO-80

Utilization Patterns Beginning to Change

Assessment




Patient survey

Prescriber survey





CO-81

4.3% decrease in ER/LA prescription volume

95% CI 2.4 to 6.1

20.7% decrease in ER/LA prescription volume

in patients between 19 - 40 years of age

7.6% decrease in IR prescription volume

Opioid Prescription Volume Decreasing Compared with Pre-REMS

CO-82

Prescribing Behavior Studied

Assessment




Patient survey

Prescriber survey





CO-83

Decreases in Prescriptions for Specialties with Less Compelling Reasons to Prescribe

Type of Prescriber %

ER/LA Opioids

Prescriptions

Dentist -49

Decrease

Emergency Medicine Physician -26

Surgeon -21

Neurologist -18

Other Prescriber Specialty -16

Pediatrician -16

Primary Care Physician -14

Rheumatologist -14

Oncologists -12

Hospice/Palliative Physician -6

Physician/Rehabilitation -2

Pain Physician 0.4 No significant change

Anesthesiologist +3

IncreasePhysician Assistant +31

Nurse Practitioners +34

CO-84

Volume of Prescriptions Increasing Among Physician Assistants and Nurse Practitioners

Physician Assistants % Change

COX-2 Inhibitors 23%

Benzodiazepines 18%

Cholesterol Lowering Drugs 28%

Ulcer Medications 31%

Anti-Convulsants 40%

Anti-Depressants 27%

Nurse Practitioners % Change

COX-2 Inhibitors 22%

Benzodiazepines 22%

Cholesterol Lowering Drugs 30%

Ulcer Medications 34%

Anti-Convulsants 38%

Anti-Depressants 28%

CO-85

Some Improvement in Inappropriate Prescribing

Areas of Problematic Prescribing Decrease

Concomitant prescribing of benzodiazepines

and ER/LA opioids-3.7%

Opioid-naïve patients starting on extended-

release hydromorphone-8.8%

Opioid-naive patients starting on fentanyl

patches-1.7%

Opioid-naïve patients starting on high-dose

extended-release morphine-2.9%

CO-86

Surveillance Monitoring to Determine Impact on Outcomes

Assessment




Patient survey

Prescriber survey





CO-87

Retrospective cohort study of commercially

insured patients

Medicaid data from one state

Patients who received ≥ 1 ER/LA opioid

Before REMS through August 2014

Opioid overdose defined using diagnosis

claims for poisoning/overdose by opioids

Emergency Department Visits and Hospitalization Due to Opioid Overdose

CO-88

Characteristics

Commercially insured* Medicaid

Pre-REMS

(N=80,209)

Active Period

(N=43,730)

Pre-REMS

(N=3,488)

Active Period

(N=3,625)

% % % %

Alcoholism 5.0 6.2 14.7 19.3

Anxiety disorder 29.7 39.5 47.6 60.4

Bipolar disorder 4.6 5.6 19.7 24.7

Depressive disorder 28.2 35.8 45.8 56.0

History of suicide attempt 0.8 1.1 4.5 5.0

Post-traumatic stress disorder 1.8 2.7 6.2 9.9

Sleep disorder 30.3 37.8 38.5 50.7

Opioid type dependence 5.8 10.6 28.4 35.4

Other drug dependence 6.5 9.9 33.2 37.9

History of overdose/poisoning 0.9 1.3 2.3 3.6

History of benzodiazepine use 46.9 51.6 55.5 57.6

Changes in Baseline Characteristics After the REMS

CO-89

Emergency Department Visits and Hospitalizations for Opioid Overdose

Commercially Insured Medicaid

Pre-REMS After REMS Pre-REMS After REMS

Duration (months) 24 14 24 14

Number of Patients 80,209 43,730 3,488 3,625

Number of Events 391 194 52 67

Person – Time 46,199 22,354 2,126 2,559

Unadjusted

incidence rate per

10,000 person-

years (95% CI)

85(77 – 94)

87(75 – 100)

245(183 – 321)

262(203 – 323)

CO-90

Adjusted Risk Ratio (RR) for Opioid Overdose after REMS

Unadjusted RR

After vs Before REMS

(95% CI)

Adjusted RR

After vs Before REMS

(95% CI)

Commercially

insured

1.0

(0.9 – 1.2 )

0.8

(0.7 – 1.0)

Medicaid1.1

(0.8 – 1.5)

0.8

(0.6 – 1.2)

CO-91

Sensitivity Analysis Suggests Abuse Deterrent Formulations not Source of Overdose Decrease

Analysis excluded abuse deterrent

formulations

RR = 0.8

95% CI 0.7 – 1.0

CO-92

Addressing Assessment Limitations

REMS Component Limitations Evidence-based solution

Patient survey

Only

commercially

insured sample

• Increase Medicaid and Medicare

representation

• Include caregivers

Prescriber &

Long-term

prescriber surveys

• Sample size

• Knowledge

• Closer communications and IT

support between survey vendor

and CE providers

• Already recruited 2/3 of sample

size in 3 weeks for the Long-

term survey

• Communication of results to CE

providers

ED &

hospitalizations due

to overdose

• Commercially

insured patients

• No death data

• Expanded access to 2 additional

states of Medicaid data

• Using National Death Index data

since it now has post-REMS data

CO-93

Data show

Good reach of Medication Guide

Limited awareness of REMS materials

Knowledge of product-specific information

is limited

Decreases in inappropriate prescribing

Numerical reductions in ED visits and

hospitalizations due to opioid overdose

Conclusions

CO-94

Surveillance Data of the Public Health Impact

Richard C. Dart, MD, PhD

RADARS® System

Rocky Mountain Poison & Drug Center

University of Colorado

CO-95

REMS


Number of trained




Audit of CE


• Remediation of those that did

not meet financial disclosure

requirements

REMS

assessments


Medication Guide


REMS communications materials







prescribing


campaign


populations

Surveillance

monitoring

• Significant decreases in some,

but not all, safety outcomes

• Expanded access to

Medicaid data


CO-96

Significant decreases in some, but not all, safety outcomes

Began prior to implementation of REMS and were not

limited to ER/LA products covered by REMS

ER/LA decline > IR decline in most outcomes

Multi-faceted approach

Role of individual interventions can’t be determined

Survey methodology limitations

ER/LA product account for about 10-25% of total opioid

prescribed in United States

Longer monitoring and refinement of analyses are needed

to assess effect of ER/LA REMS program

Overview of Surveillance Results

CO-97

Assessment Component Data Source

Emergency Department

Visits & Hospitalizations

HIRD

Medicaid Data

Intentional Exposures Among

Adolescents & Adults RADARS® System

NAVIPPRO®

Unintentional Exposures Among

Infants and Children

Substance Abuse

Treatment Programs

Mortality RatesWashington State Medical

Examiner Database

Data Sources Used for Surveillance

Table 15. Page 74, Sponsor Briefing Book

CO-98

Independent entity under Denver Health and

Hospital Authority

Financed by subscriptions

Subscribers do not participate in developing

system, in data collection and do not have access

to raw data

Data sets provided to FDA as requested

Orientation to RADARS System

CO-99

RADARS Examines Prescription Drug Abuse from Multiple Perspectives

Substance Abuse

Treatment Programs

College Student

Survey

Illicit Market Price Web Monitoring

Poison Center DataCriminal Justice:

Drug Diversion

http://www.topsecretwriters.com/2011/06/pharmaceutical-companies-are-turning-americans-into-drug-addicts/

http://www.topsecretwriters.com/2011/06/pharmaceutical-companies-are-turning-americans-into-drug-addicts/

CO-100

Individual programs do not include every

geographic region

Spontaneous reporting susceptible to bias

Self-reporting involves recall bias

Cannot make direct causal links between

outcomes and drugs

RADARS System Limitations

CO-101

Analyze trends and patterns of independent

RADARS programs and other data sources

Compare and contrast independent trends

Sensitivity analyses conducted

Methods to Address Limitations of RADARS Programs

CO-102

Population

Children, adolescents, adults, elderly

Poison centers in 46 states, D.C., territories

85%-93% of US population

Definition/Type of Cases

Spontaneous reports of

acute events associated

with ≥ 1 Rx drug of interest

565,284 opioid exposures

Poison Center Program(2003 - Present)

2014 coverage

CO-103

Poison centers in operation

for 20-50 years

Each case managed by a

specially trained nurse or

pharmacist

Every Rx opioid or stimulant

case submitted to RADARS

Standardized medical

record with mandatory data

fields and definitions

Poison Centers and Intentional Abuse Cases

Incoming Call

Initial Triage

Care Advice

Disposition

Reporting & QA/QC

CO-104

“An exposure resulting from the intentional

improper or incorrect use of a substance

where the person was likely attempting to gain

a high, euphoric effect, or some other

psychotropic effect.”

National Poison Data System. Coding Users’ Manual©,

Version 3.1, 2014.

Definition of Intentional Abuse

CO-105

Rate of ER/LA Opioid Intentional Abuse Reported to Poison Centers Decreased

% Change

Assessment1

ER/LA

Opioids

IR

Opioids

Prescription

Stimulants

Population

Adjusted

(95% CI)

-44%*

(-51%, -37%)

-31%

(-36%, -25%)

-13%

(-19%, -7%)

Prescription

Adjusted

(95% CI)

-44%*

(-50%, -38%)

-25%

(-30%, -19%)

-26%

(-33%, -19%)

Dosing Unit

Adjusted

(95% CI)

-37%*

(-43%, -31%)

-25%

(-31%, -18%)

-26%

(-31%, -20%)

1) Change from 3Q 2010 to 4Q 2014

* p<0.001 compared to prescription IR opioids and stimulants

CO-106

Poison Center Intentional Abuse Decreased for all ER/LA REMS Products

Page 190 FDA BB*Image from FDA Briefing document

CO-107

Treatment Centers Abuse Decreased for Most ER/LA REMS Products

*Image from FDA Briefing document

CO-108

Multiple Programs Indicate Improvement in ER/LA Opioids

Poison Center-Adolescent Abuse

Poison Center-Misuse

Poison Center-Adult Unintentional Exposures

Poison Center-Child and Adolescent

Unintentional Exposures

Poison Center-Major Medical Outcome

Hospitalization or Death

Poison Center-Death

Washington Medical Examiner Deaths

NAVIPPRO ASI-MV

College Survey – Nonmedical use

-100 -50 0 50 100 150 200

Worsened following REMS

ER/LA Opioids

Improved following REMS

CO-109

Relation Between RADARS System and other Data Sources

CO-110

0

0.7

1.4

2.1

2.8

3.5

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

Strong Correlation of Prescription OpioidAbuse: Poison Centers and Drug Abuse Warning Network (DAWN)

Rate of Opioid Abuse

See also Davis J, Pharmacoepidemiol Drug Safety (Epub 2013)

0

20

40

60

80

100

120

140

160

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

RADARS

Poison Center

DAWN

R=0.95

RADARS

oxycodone

abuse

population

per

100,000

DAWN

oxycodone

drug-related

ED visits

population

per

100,000

CO-111

Strong Correlation of Deaths: Poison Centers and National Mortality Data (NVSS)

NVSS

R=0.67

RADARS

Poison Center1

National and Semisynthetic (2005 to 2015)

RADARS

Poison Center

deaths

per

1,000,000

population

R=0.67

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

-0.5

0.5

1.5

2.5

3.5

4.5

5.5

6.5

200

3

200

4

200

5

200

6

20

07

200

8

200

9

20

10

201

1

201

2

20

13

201

4

201

5

Year

-0.5

6.5

5.5

4.5

3.5

2.5

1.5

0.5

NVSS

deaths

per

100,000

population

CO-112

Strong Correlation of Heroin Mortality: Poison Centers and National Mortality Data (NVSS)

0.00

0.05

0.10

0.15

0.20

0.25

0.00.51.01.52.02.53.03.54.04.55.0

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

Year

Heroin Deaths, 2005 to 2015

NVSS

RADARS

Poison Center

R=0.90

NVSS

deaths per

100,000

population

RADARS

Poison Center

deaths per

1,000,000

population

CO-113

0

10

20

30

40

50

60

70

0

5

10

15

20

25

30

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

Strong Correlation of Prescription Opioid Abuse Reported to RADARS Treatment Centers and Treatment Episode Dataset (TEDS)

RADARS

Treatment

Center

rate per

100,000

population

RADARS

TEDS

R=0.94

Individuals Entering Treatment for Prescription Opioids

(2005 to 2015)

SAMHSA

TEDS

rate per

100,000

population

0.7

0.6

0.5

0.4

0.3

0.2

0.1

CO-114While Total Opioid Deaths Rose Through 2014, Natural & Semisynthetic Opioids Plateaued in 2011

YearNVSS=National Vital Statistics System

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

0

0.5

1

1.5

2

2.5

2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

2.5

2.0

1.5

1.0

0.5

0

2005

NVSS Total

Opioid

Deaths

NVSS Natural &

Semisynthetic

Relative

change

in rate

since 2011

Relative

change

in rate

since 2003

CO-115

0

0.2

0.4

0.6

0.8

1

1.2

1.4

0

0.5

1

1.5

2

2.5

2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

Deaths from Natural & Semisynthetic Category Plateaued in 2012

- NVSS Total Opioid Deaths

- NVSS – Nat & Semisynth

- NSDUH Nonmedical use

- WA Medical Examiner

- RADARS Treatment Ctrs

Relative change in NVSS

rates since 2003

- RADARS Poison Deaths

- RADARS Poison Ctr Abuse

Year

Relative

change

Relative change

in rate since 2011

CO-116

Deaths from Natural & Semisynthetic Category Plateaued in 2012

0

0.2

0.4

0.6

0.8

1

1.2

1.4

0

0.5

1

1.5

2

2.5

2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

- NVSS Total Opioid Deaths

- NVSS – Nat & Semisynth

- NSDUH Nonmedical use

- WA Medical Examiner

- RADARS Treatment Ctrs

- RADARS Poison Deaths

- RADARS Poison Ctr Abuse

Relative

change

Relative change in NVSS

rates since 2003

Year

Prescription Monitoring Plans

Take Back Programs

Abuse Deterrent Form

ER/LA REMS

Florida

Relative change

in rate since 2011

CO-117

Generally consistent trends across multiple

independent sources

Abuse decreases for ER/LA greater than IR

opioids in several, but not all outcomes

NVSS deaths plateau between 2011 and 2014

for Natural & Semisynthetic opioids

Decrease in Poison Center mortality

Multi-faceted contributions to these trends

Not possible to determine role of individual

interventions

Surveillance Detected Decreases in Abuse and Misuse for ER/LA Opioids

CO-118

Lessons Learned from the REMS and Recommended Improvements

Laura Wallace, MPH

RPC Metrics Sub team member

Purdue Pharma L.P.

CO-119

CE courses

Scope

Consortium of 24 companies

19 CE providers

839 accredited education programs

Range of assessments and data sources

REMS is Novel Program

CO-120

>800 REMS-compliant CE courses

Consistent messaging

Positive ratings by completers

Resulting in generally good knowledge of

safe opioid prescribing

Due to collaboration of RPC, FDA, CE

community, data providers, etc.

Learnings from the REMS: Collaboration and Project Management

CO-121

Systematic review of activities

Many under-performed

Lower awareness of REMS

Learnings from the REMS: Communication Activities

CO-122

Learnings From the REMS: Assessments

Assessments

Survey Surveillance Studies

Patient survey Drug utilization patterns

Prescriber survey Changes in prescribing behavior

Prescriber long-term evaluation


(including ED visits and

hospitalization)

CO-123

ER/LA opioids = 10% of opioid prescribing

IR opioids = 90% of opioid prescribing

ER/LA Opioids Only Part of the Issue

CO-124

To ensure balance between

Reducing abuse, misuse, and addiction

Avoiding undue burden to healthcare

system

Allow access to appropriate patients

Goals of RPC’s Recommendations

CO-125

Improve REMS CE website

Planned launch of awareness campaign

RPC Recommendation #1: Enhance Communication

CO-126

Current REMS: focus on recent ER/LA opioid

prescribers

Clinicians report education of all team

members is critical for implementation of

REMS learning

RPC Recommendation #2: Expand to Extended Healthcare Team

CO-127

Pharmacy, nurse, other professional societies

critical partners

Availability of accredited CE to new healthcare

providers & those in underserved communities

Expand REMS to Extended Healthcare Team - Implementation

CO-128

Prescriber education to reflect evolving

stakeholder input and feedback

Needs of adult learners

RPC Recommendation #3: Revise the FDA Blueprint

CO-129

Include tools to manage risks (such as

co-prescribing of naloxone)

Condense content

Utilize case studies

Use adaptive approaches or a demonstration

of knowledge/competence

Emphasize general principles of safe ER/LA

opioid prescribing

Address other topics in pain management

Establish standard assessment across CE

RPC Recommendations: Revise the Blueprint

CO-130

If training is made mandatory, consider

tying Schedule 2 and 3 narcotic DEA

registration to either completion of

prescription opioid education or other

attestation of knowledge, such as board

certification in pain medicine

Ensure all prescribers have appropriate

training in use of ER/LA opioids

No undue burden on prescribers or

pharmacists

RPC Recommendation #4: If Training is Required, Tie to DEA Registration

CO-131

RPC Recommendation #5: Harmonize Federal Course Content

Yes31%

No61%

Partial8%

Overall Analysis of NIDA Course to FDA Blueprint

N=76

CO-132

Based on lessons learned

Improve provider knowledge and further

reduce misuse and abuse

Improve REMS in Evidence-Driven Ways

CO-133

Conclusions

Paul Coplan, ScD, MBA

RPC Metrics Subteam Chair

Purdue Pharma L.P.

CO-134

Communication components

3 million copies of the Dear Prescriber Letter sent

In prescriber survey, 33% of prescribers reported

reading it

CE Training

839 CE courses conducted

438,000 participants, 157,493 completers, 66,219

ER/LA prescriber completers

Survey Results

Knowledge score: Patients = 86%, Prescribers = 83%

questions correct

Summary: Communication and Education Components

CO-135

Abuse

44% abuse decrease in RADARS Poison Center Program

21% abuse decrease in ASI-MV System

46% abuse decrease RADARS Drug Treatment Center Program

Misuse

23% decrease in patient misuse in RADARS Poison Center

Program

Overdose

Numerical decrease in overdose ER visits

Death

39% decrease in fatalities involving opioid analgesics

(Washington state)

Summary: Results of Surveillance Assessments

CO-136

Prescribing metrics

Some decrease in inappropriate

prescribing

Summary: Prescribing Changes

CO-137

Dear Prescriber Letter, key tool to inform

prescribers about REMS, not sufficient

Need for aligning competing CE courses on

opioids

Consistent post-training measures for CE

courses

Concise Medication Guide can have good

reach

Lessons Learned

CO-138

Other Company Initiatives to Reduce Opioid Abuse and Misuse

Post-marketing studies of ER/LA opioids to assess

Long-term efficacy of opioids

Addiction, abuse, overdose, death in people with pain

Measure incidence

Identify risk factors

Develop validated measures

Unused medication take-back programs

Abuse-deterrent formulations

New molecular entities to treat pain

CO-139

First phase: Development and Implementation

DSaRM and AADP joint meeting July 2010

2011 White House Prescription Drug Abuse

Prevention Plan

Results from first 3-4 years after approval

Second phase: Evaluation and Revision

Califf/Woodcock 2016 NEJM opioid article

CDC Guidelines for Opioid Treatment

National Pain Strategy

DSaRM and AADP joint meeting May 2016

Phases of ER/LA Opioid REMS

CO-140

RPC Acknowledgements

CE Subteam

Brian Kilmartin (Teva)

Ekaterina Walker

(Purdue)

Lisa Zimmerman (Pernix)

Mark Tyrrell (Impax)

Marsha Stanton (Pernix)

Michelle Zachman

(Upsher-Smith)

Nathan Kopper

(Mallinckrodt)

Terry Lumati (Depomed)

Metrics Subteam

Greg Wedin (Upsher-

Smith)

Kal Elhoregy (Endo)

Karla Werre

(Mallinckrodt)

Laura Wallace

(Purdue)

Linda Noa

(Mallinckrodt)

Mark Tyrrell (Impax)

Nathan Kopper

(Mallinckrodt)

Paul Coplan (Purdue)

Soledad Cepeda

(Janssen)

RPC Members and External Collaborators

Actavis – Tara Brolly

Endo – Mark Collins & Tina

Latch

HealthCore

Linda Kitlinski

inVentiv Health Consulting

IMS Health

Ogilvy CommonHealth

Worldwide

Pfizer – Robert Kristofco, Ken

Petronis, Sharon Reid & Gary

Wilson

Polaris

Purdue – Jaren Howard, Robert

Josephson & Nelson Sessler

RADARS System

RPC Supported CE Providers

United BioSource Corporation

CO-141

Novel approach that includes CE activities

Contributed to increased awareness and

knowledge among patients and prescribers

Contributed to decreases in serious risks of

ER/LA opioids

Identified areas for improvement

REMS - Overall Conclusions

CO-142

RPC (REMS)

AADPAC & DSRMAC

May 3 - 4, 2016

CO-143

CO-144

CO-145

CO-146

CO-147

CO-148

CO-149

CO-150

CO-151

CO-152

CO-153

CO-154

CO-155

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