CO-1
REMS Program Companies
AADPAC & DSRMAC May 3 - 4, 2016 CO-2
Introduction and REMS Design
Paul Coplan, ScD, MBA RPC Metrics Subteam Chair Purdue Pharma L.P. CO-3
RPC Is Consortium of 24 Companies
Noven Pharmaceuticals, Inc. Actavis, Inc. Pernix Therapeutics Apotex Inc. Perrigo Company plc Aurolife Pharma, LLC
Depomed, Inc. Pfizer, Inc.
Endo Pharmaceuticals Inc. Purdue Pharma L.P.
Impax Laboratories, Inc. Ranbaxy Pharmaceuticals, Inc.
Inspirion Delivery Technologies Rhodes Pharmaceuticals L.P.
Janssen Pharmaceuticals, Inc. Roxane Laboratories, Inc.
Mallinckrodt Pharmaceuticals Sandoz, Inc.
Mylan Technologies, Inc. The PharmaNetwork LLC
Nesher Pharmaceuticals LLC Upsher-Smith Laboratories, Inc.
Novel Laboratories, Inc. VistaPharm, Inc. CO-4
Development of REMS Framework
RPC initial framework FDA joint advisory committee (July 2010) FDA task force CO-5
Agenda
REMS Design & Paul Coplan, ScD, MBA RPC Metrics Subteam Chair Implementation Purdue Pharma LP Continuing Education Marsha Stanton, PhD, RN RPC Continuing Education Subteam Chair Activities: Design and Results Pernix Therapeutics Charles Argoff, MD Public Health Impact Professor of Neurology Albany Medical College and Albany Medical Center REMS Assessments: M. Soledad Cepeda, MD, PhD RPC Metrics Subteam Member Design and Results Janssen Pharmaceuticals, Inc. Richard Dart, MD, PhD Surveillance Database Results Rocky Mountain Poison & Drug Center, Denver Health Professor of Emergency Medicine, University of Colorado Laura Wallace, MPH Lessons Learned RPC Metrics Subteam Member Purdue Pharma LP
Conclusion Paul Coplan, ScD, MBA CO-6
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, United BioSource Corporation FISPE CO-7 Opioid Abuse Includes Multiple Abuse Categories
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 CO-8
Opioid Analgesic Prescriptions CO-9 Drug Overdose Deaths Involving Opioids By Type of Opioid
Deaths per 100,000 population
Year
Source: Rudd MMWR 2016, National Vital Statistics System. CO-10 Goal of REMS for Extended Release/ Long Acting Opioid Analgesics
“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 CO-11 RPC Committed to Fulfilling Goal of REMS
Educate prescribers to select and manage patients Educate patients to understand and prevent risks Did not include specific actions targeted at abusers CO-12 ER/LA Opioid REMS is Novel in Scope and Tools
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 CO-13
Components of the REMS
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 CO-14
1-Page Medication Guide
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 CO-15
1-Page Patient Counseling Document CO-16
Dear Prescriber Letters
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 CO-17
CE Activities to Train Prescribers
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 CO-18
CE Completers versus Target
Other Years ER/LA Opioid Completers of REMS Performance Prescriber REMS- Date Active Target Completers compliant CE March 2013 0 Start
March 2015 2 80,000 37,512 44,619
March 2016* 3 160,000 66,219 91,274
March 2017 4 192,000 - -
*Unaudited data provided by CE provider organizations for RPC-funded courses CO-19 REMS Call Center to Answer Questions
RPC maintains toll-free call center . Provides REMS information and answer queries . 1.800.503.0784 CO-20 Website Contains Comprehensive Information on REMS
http://www.er-la-opioidrems.com/IwgUI/rems/home.action CO-21
Timing of REMS Implementation
Pre-REMS Period Implementation REMS Active Period
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 Aproval
MARCH 2013 1st CE course available CO-22
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 CO-23
Key Limitations of Assessments
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 CO-24
REMS Continuing Education Progress and Results
Marsha Stanton, PhD, RN RPC Continuing Education Subteam Chair Pernix Therapeutics CO-25
REMS Components Accomplishments/Key Findings Evidence-based Improvements Number of trained • Make Blueprint more concise • Increasing numbers per year prescribers • Increase to healthcare team • Remediation of those that Audit of CE • 100% alignment with Blueprint did not meet financial trainings disclosure requirements • Patient: High awareness of Medication Guide • Prescribers: Low awareness of REMS communications materials • Launch of awareness • Prescribers: Training associated REMS campaign with higher knowledge scores assessments • More representative survey • Prescribers: Product-specific populations knowledge is limited • Opioid prescriptions decreasing • Improvements in inappropriate prescribing Surveillance • Significant decreases in some, but • Expanded access to Medicaid data monitoring not all, safety outcomes • Use of National Death Index CO-26 REMS is Focused on Accredited Education
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 CO-27
Overview of CE Training
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 CO-28 REMS CE Includes 6 Content Sections of FDA Blueprint
1. Assessing patients for treatment 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 CO-29
CE Trainings Audited
Assessment REMS communication activities Number of trained* prescribers
Audit of CE trainings Patient survey
Prescriber survey Long-term evaluation of trained* prescribers Evaluation of drug utilization patterns Evaluation of changes in prescribing behavior Surveillance monitoring Monitoring patterns of prescribing to identify changes in access CO-30
CE Audit Results
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
*36-Month Assessment Report CO-31
Process for CE Development
CE providers submit grant proposals to RPC RPC provides grants CE providers determine course content . Medication manufacturers cannot participate in content development CO-32 Overview of REMS-Compliant CE Providers*
151 proposals submitted 31 CE proposals approved 839 total CE activities have been conducted
*As of 2/29/16 CO-33
FDA Prescriber Completer Goals
Prescribers with ≥ 1 ER/LA Opioid Rx in Previous Year (N=320,000) Complete REMS-Compliant CE Completers Goals Goals Set by FDA Set by FDA Goal Date % n
March 2015 25% 80,000
March 2016 50% 160,000
March 2017 60% 192,000 CO-34 Numbers of Completers of REMS- Compliant CE Increasing by Year
200,000
157,493 150,000
Cumulative 100,000 Completers 82,131 (N) 66,219
50,000 37,512
0 Feb 2015 Feb 2016
ER/LA opioid prescribers counted HCP completers towards FDA completer goals (inclusive) CO-35
Prescriber Completers by Specialty
0.002% No response Non-pain 19.7% Specialist
Pain 12.8% Specialist Primary Care 67.4%
**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 CO-36 REMS-compliant CE Offered Nation-Wide
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) CO-37
Future Evaluation Deadlines
CE activities approved through 2018 CE providers submit proposals each year . Provided to FDA on an ongoing basis CO-38 Difficulties Achieving Completer Targets
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 CO-39
RPC Not Only Source of Education
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 CO-40
Evolution of RPC-Supported Activities
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 CO-41
Conclusion
Development of many systems/processes Open communications among stakeholders Diverse and comprehensive CE courses provided Significant number of the target prescriber population educated CO-42
Perspective of a Pain Medicine Physician and Educator
Charles Argoff, MD Professor of Neurology, Albany Medical College Director, Comprehensive Pain Center, Albany Medical Center CO-43
Clinical Perspectives
ER/LA opioid CE program has been successful . Targets audiences that need information . HCPs are changing clinical behavior and prescribing habits CO-44 Education Is Cornerstone of Changing Behavior
Photographs provided with permission from American College of Physicians / Pri-Med CO-45 Pain Management Involves Many Treatment Modalities
Pharmaco- therapy Physical Medicine and Interventional Approaches Rehabilitation Multimodal Therapeutic Strategies for Pain and Associated Disability Complementary Psychological and Alternative Support Medicine Lifestyle Change
Fine PG, et al., 2005. CO-46
A Physician Perspective: Benefits
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 CO-47 Initial Study Linking Training with Prescriber Behavior and Outcomes
Design Retrospective observational study
Data Source Electronic Health Records (EHR): (Pri-Med) All HCPs who use EHR, stratified by whether or Population not they took REMS-compliant CE Patients of these HCPs Changes before / after training implementation in: 1. Prescribing patterns for all, ER/LA and IR opioids Outcomes 2. Patient outcomes, including abuse/dependence and overdose based on ICD codes in EHR
Time Period Jun 2013 – Jan 2016
Study neither reviewed by FDA nor provided in RPC Briefing Document CO-48
Changes in Prescribing After Training
Opioid Trained HCPs1 Control HCPs prescriptions (N=441) (N=4,669)
ER/LA 10% decrease 4% increase
IR 3% increase 3% increase
1) HCPs who took REMS-compliant CE Study neither reviewed by FDA nor provided in RPC Briefing Document CO-49 Improvements in Outcomes Among Patients of Trained Prescribers
Patients of Patients of Outcomes1 Trained HCPs2 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 Study neither reviewed by FDA nor provided in RPC Briefing Document CO-50
Study Conclusion
Prescribing-behavior and patient-outcome data suggest positive impact of REMS Evidence of effect within trained group compared to control group
Study not provided in RPC Briefing Document CO-51 EHR Data Supported by Other Published Studies CO-52
Overall Conclusion
REMS education making impact Appropriate use of ER/LA opioids can be facilitated by greater prescriber knowledge CO-53
REMS Assessment Metrics: Education Contributed to Improvements
M. Soledad Cepeda, MD, PhD RPC Metrics Subteam Member Janssen Research & Development CO-54
Overview of Assessments
Assessment REMS communication activities
Number of trained* prescribers
Audit of CE trainings
Patient survey
Prescriber survey
Long-term evaluation of trained* prescribers
Evaluation of drug utilization patterns
Evaluation of changes in prescribing behavior
Surveillance monitoring
* Trained = completed REMS-compliant training CO-55
REMS Components Accomplishments/Key Findings Evidence-based Improvements Number of trained • Make Blueprint more concise • Increasing numbers per year prescribers • Increase to healthcare team • Remediation of those that did Audit of CE • 100% alignment with Blueprint not meet financial disclosure trainings requirements • Patient: High awareness of Medication Guide • Prescribers: Low awareness of REMS communications materials • Launch of awareness REMS • Prescribers: Training associated campaign assessments with higher knowledge scores • More representative survey • Prescribers: Product-specific populations knowledge is limited • Opioid prescriptions decreasing • Improvements in inappropriate prescribing Surveillance • Significant decreases in some, but • Expanded access to Medicaid data monitoring not all, safety outcomes • Use of National Death Index CO-56
Patient Survey
20 minute 80 survey items . 22 knowledge questions Administered by HealthCore Commercially insured patients Completed either by phone or online CO-57
Patient Knowledge Studied
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? CO-58 ER/LA Opioid Patient Survey Population
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
*HealthCore Integrated Research Database (HIRD) CO-59 Patient Survey Responders Compared to Commercially Insured ER/LA Opioid Users
Responders more often . Female . Younger Geographically similar 94% white 23% lower than high school degree
*HIRD database CO-60
Knowledge Assessed in Two Ways
Overall score Number of questions answered correctly by ≥ 80% of responders CO-61
Mean Score Was 86%
110 101 100 90 80 70 Number 70 62 of 60 Patients 50 44 41 40 34 30 26 18 20 10 10 4.5<5 <53 <52 0 0 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 73% met or exceeded FDA target
FDA Recommended Target ≥ 80% Correct CO-62 Patients Demonstrated High Understanding of Risks
% Patients Who Responded Correctly Risk (N=423) Do not give ER/LA opioid analgesics to other people who 98% have the same condition as you Selling or giving away ER/LA opioid analgesics is against 98% the law Seek emergency medical help for side effects such as trouble breathing, shortness of breath, fast heartbeat, 97% chest pain, or swelling of their face, tongue, or throat after taking or using ER/LA opioid analgesics Talk to a healthcare provider about taking or using more ER/LA opioid analgesics if the current dose doesn't 96% control the pain It is not okay to drink alcohol while taking or using ER/LA 93% opioid CO-63 Five Questions Answered Correctly by <80% of Responders
% Correct Areas of Low Knowledge (N=423) Do not use a hot tub or sauna while using ER/LA opioid analgesics 77% if pain persists (patch only)
ER/LA opioid analgesic pills should not be split or crushed 76% (oral formulations)
Do not store ER/LA opioid analgesics in a medicine cabinet with 71% other medications in the household.
Inform healthcare provider of any fever (patch only) 70%
Read the attached Medication Guide every time an ER/LA opioid 55% prescription is filled
Includes all questions with response rates <80% CO-64
Medication Guide Widely Read
98% reported reading guide at least once . Average knowledge score = 86% correct 2% reported not reading . Average knowledge score = 72% correct CO-65 Less than Half of Patients Received Patient Counseling Document
43% reported receiving Patient Counseling Document from provider 26% reported providers referenced Patient Counseling Document CO-66 Patients Generally Satisfied with Access to ER/LA Opioids
71% of patients able to obtain prescription when needed for pain 78% of patients satisfied with access CO-67 REMS Includes Prescriber Assessments
Assessment Metrics REMS communication activities Number of trained* prescribers Audit of CE trainings
Patient survey Prescriber Knowledge, Awareness Prescriber survey of REMS Materials Long-term evaluation of trained* Knowledge Retention prescribers Evaluation of drug utilization patterns Evaluation of changes in prescribing behavior Surveillance monitoring
* Trained = completed REMS-compliant training CO-68
Prescriber Survey Design
~25 minutes 124 survey items . 68 knowledge questions Prescribers with training . REMS-compliant CE providers Prescribers without training . National prescription database (IMS) 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
IMS Recruited Prescribers Reported NOT Reported Recruited Completing a Completing a by REMS-compliant REMS-compliant CE Providers CE Activity CE Activity (N=301) (N=179) (N=132) REMS Material % % %
Medication Guide 67.4 40.2 71.2
Patient Counseling 53.5 22.3 48.5 Document ER/LA Opioid 49.5 11.7 55.3 Analgesics Website Dear DEA-Registered 44.5 16.8 47.7 Prescriber Letter CO-72 Trained Prescribers Used Patient Counseling Document More
Prescribers Recruited Through IMS Data Reported NOT Reported Prescribers Completing a Completing a Recruited by REMS-compliant REMS-compliant CE Providers CE Activity CE Activity (N=301) (N=179) (N=132) Prescriber Behavior % % % Use the Patient Counseling Document 70% 50% 68% with patients Use of Structured Interview Tools or 69% 53% 76% Screening Tools Completion of Patient- 77% 70% 84% Prescriber Agreement
Perform Urine Drug 70% 64% 80% Tests CO-73 Prescriber Survey Assessed Understanding of Blueprint Knowledge Areas
Prescribers Reported NOT Completing a REMS- Completing a REMS- compliant CE Activity compliant CE Activity (N=433)* (N=179) Difference Mean score Mean score Est. 95% CI Assess patients 91.9 87.7 -4.2 (-6.6, -1.8) Initiate, modify, 80.2 74.6 -5.6 (-7.3, -3.8) discontinue dose 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 87.8 78.9 -8.8 (-11.1, -6.6) information Specific drug 60.7 50.9 -9.8 (-14.0, -5.5) information 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
Long-Term Evaluation Survey
To determine knowledge retention and practice changes 6-12 months following completion of REMS- compliant training CO-75
Long-Term Evaluation Survey Design
~30 minute survey 102 survey items . 65 knowledge questions including case scenarios Prescribers identified through RPC supported CE providers CO-76 Long-Term Evaluation Survey of REMS Prescribers
Recruitment target = 600 responders . 328 completed survey . Feb to April 2015 CO-77 Prescribers who Completed Long- Term Evaluation Survey
56% male 66% MDs or DOs 60% in practice >15 years 46% prescribed ER/LA opioids >10 times in last month CO-78 Long-Term Evaluation Survey: Topline Results
FDA Blueprint Message Mean score 1. Assessment 83.4 2. Initiation, modification, or 67.8 discontinuation of therapy 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 Insights from Long-Term Evaluation Survey
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% CO-80 Utilization Patterns Beginning to Change
Assessment REMS communication activities Number of trained* prescribers Audit of CE trainings Patient survey Prescriber survey
Long-term evaluation of trained* prescribers
Evaluation of drug utilization patterns
Evaluation of changes in prescribing behavior
Surveillance monitoring CO-81 Opioid Prescription Volume Decreasing Compared with Pre-REMS
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 CO-82
Prescribing Behavior Studied
Assessment REMS communication activities Number of trained* prescribers Audit of CE trainings Patient survey Prescriber survey
Long-term evaluation of trained* prescribers
Evaluation of drug utilization patterns
Evaluation of changes in prescribing behavior
Surveillance monitoring CO-83 Decreases in Prescriptions for Specialties with Less Compelling Reasons to Prescribe
ER/LA Opioids Type of Prescriber % Prescriptions Dentist -49 Emergency Medicine Physician -26 Surgeon -21 Neurologist -18 Other Prescriber Specialty -16 Pediatrician -16 Decrease Primary Care Physician -14 Rheumatologist -14 Oncologists -12 Hospice/Palliative Physician -6 Physician/Rehabilitation -2 Pain Physician 0.4 No significant change Anesthesiologist +3 Physician Assistant +31 Increase 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 -3.7% and ER/LA opioids
Opioid-naïve patients starting on extended- -8.8% release hydromorphone
Opioid-naive patients starting on fentanyl -1.7% patches
Opioid-naïve patients starting on high-dose -2.9% extended-release morphine CO-86 Surveillance Monitoring to Determine Impact on Outcomes
Assessment REMS communication activities Number of trained* prescribers Audit of CE trainings Patient survey Prescriber survey
Long-term evaluation of trained* prescribers
Evaluation of drug utilization patterns
Evaluation of changes in prescribing behavior
Surveillance monitoring CO-87 Emergency Department Visits and Hospitalization Due to Opioid Overdose
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 CO-88 Changes in Baseline Characteristics After the REMS
Commercially insured* Medicaid Pre-REMS Active Period Pre-REMS Active Period
(N=80,209) (N=43,730) (N=3,488) (N=3,625) Characteristics % % % % 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 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 85 87 245 262 10,000 person- (77 – 94) (75 – 100) (183 – 321) (203 – 323) years (95% CI) CO-90 Adjusted Risk Ratio (RR) for Opioid Overdose after REMS
Unadjusted RR Adjusted RR After vs Before REMS After vs Before REMS (95% CI) (95% CI)
Commercially 1.0 0.8 insured (0.9 – 1.2 ) (0.7 – 1.0)
1.1 0.8 Medicaid (0.8 – 1.5) (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 Only • Increase Medicaid and Medicare Patient survey commercially representation insured sample • Include caregivers • Closer communications and IT support between survey vendor and CE providers Prescriber & • Sample size • Already recruited 2/3 of sample Long-term • Knowledge size in 3 weeks for the Long- prescriber surveys term survey • Communication of results to CE providers • Expanded access to 2 additional ED & • Commercially states of Medicaid data hospitalizations due insured patients • Using National Death Index data to overdose • No death data since it now has post-REMS data CO-93
Conclusions
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 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 Components Accomplishments/Key Findings Evidence-based Improvements Number of trained • Make Blueprint more concise • Increasing numbers per year prescribers • Increase to healthcare team • Remediation of those that did Audit of CE • 100% alignment with Blueprint not meet financial disclosure trainings requirements • Patient: High awareness of Medication Guide • Prescribers: Low awareness of REMS communications materials • Launch of awareness • Prescribers: Training associated REMS campaign with higher knowledge scores assessments • More representative survey • Prescribers: Product-specific populations knowledge is limited • Opioid prescriptions decreasing • Improvements in inappropriate prescribing Surveillance • Significant decreases in some, • Expanded access to Medicaid data monitoring but not all, safety outcomes • Use of National Death Index CO-96
Overview of Surveillance Results
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 CO-97
Data Sources Used for Surveillance
Assessment Component Data Source HIRD Emergency Department Visits & Hospitalizations Medicaid Data
Intentional Exposures Among Adolescents & Adults RADARS® System
Unintentional Exposures Among Infants and Children
® Substance Abuse NAVIPPRO Treatment Programs
Washington State Medical Mortality Rates Examiner Database
Table 15. Page 74, Sponsor Briefing Book CO-98
Orientation to RADARS System
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 CO-99 RADARS Examines Prescription Drug Abuse from Multiple Perspectives
Criminal Justice: Poison Center Data Drug Diversion
Substance Abuse College Student Treatment Programs Survey
Illicit Market Price Web Monitoring CO-100
RADARS System Limitations
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 CO-101 Methods to Address Limitations of RADARS Programs
Analyze trends and patterns of independent RADARS programs and other data sources Compare and contrast independent trends Sensitivity analyses conducted CO-102 Poison Center Program (2003 - Present)
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
2014 coverage CO-103 Poison Centers and Intentional Abuse Cases
Poison centers in operation for 20-50 years Each case managed by a specially trained nurse or
Incoming Call pharmacist Every Rx opioid or stimulant Initial Triage case submitted to RADARS Care Advice Standardized medical Disposition record with mandatory data
Reporting & QA/QC fields and definitions CO-104
Definition of Intentional Abuse
“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. CO-105 Rate of ER/LA Opioid Intentional Abuse Reported to Poison Centers Decreased
% Change ER/LA IR Prescription Assessment1 Opioids Opioids Stimulants Population -44%* -31% -13% Adjusted (-51%, -37%) (-36%, -25%) (-19%, -7%) (95% CI) Prescription -44%* -25% -26% Adjusted (-50%, -38%) (-30%, -19%) (-33%, -19%) (95% CI) Dosing Unit -37%* -25% -26% Adjusted (-43%, -31%) (-31%, -18%) (-31%, -20%) (95% CI)
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
*Image from FDA Briefing document Page 190 FDA BB 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
ER/LA Opioids -100 -50 0 50 100 150 200 Improved following REMS Worsened following REMS CO-109
Relation Between RADARS System and other Data Sources Strong Correlation of Prescription Opioid CO-110 Abuse: Poison Centers and Drug Abuse Warning Network (DAWN)
Rate of Opioid Abuse
160 DAWN 3.5
140 2.8 120 RADARS DAWN RADARS oxycodone oxycodone Poison Center 100 abuse drug-related 2.1 population ED visits R=0.95 80 per population 100,000 per 60 1.4 100,000 40 0.7 20
0 0 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014
See also Davis J, Pharmacoepidemiol Drug Safety (Epub 2013) CO-111 Strong Correlation of Deaths: Poison Centers and National Mortality Data (NVSS)
National and Semisynthetic (2005 to 2015)
6.5 6.5 0.8 RADARS 1 5.5 5.5 Poison Center 0.7 0.6 4.5 4.5 RADARS NVSS 0.5 Poison Center deaths3.5 3.5 deaths per 0.4 per 100,0002.5 2.5 NVSS 1,000,000 population 0.3 population 1.5 1.5 R=0.67 0.2 0.5 0.5 0.1
-0.5 -0.5 0
2007 2010 2013 2003 2004 2005 2006 2008 2009 2011 2012 2014 2015
Year CO-112 Strong Correlation of Heroin Mortality: Poison Centers and National Mortality Data (NVSS)
Heroin Deaths, 2005 to 2015
5.0 0.25 4.5 R=0.90 4.0 0.20 3.5 RADARS NVSS 3.0 0.15 deaths per RADARS Poison Center 100,000 2.5 Poison Center deaths per population 2.0 0.10 1,000,000 1.5 population 1.0 0.05 0.5 NVSS
0.0 0.00
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 Year Strong Correlation of Prescription Opioid AbuseCO -113 Reported to RADARS Treatment Centers and Treatment Episode Dataset (TEDS)
Individuals Entering Treatment for Prescription Opioids (2005 to 2015)
30 700.7
25 TEDS 600.6 RADARS SAMHSA Treatment 500.5 20 TEDS Center rate per rate per RADARS 400.4 15 100,000 100,000 300.3 population population 10 R=0.94 200.2
5 100.1
0 0 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 While Total Opioid Deaths Rose Through 2014, CO-114 Natural & Semisynthetic Opioids Plateaued in 2011
2.5
2.5
2.0 1.2
2 1.1 NVSS Total Relative Relative 1.5 Opioid 1 change1.5 Deaths change in rate in rate NVSS Natural & 0.9 since 2011 since 2003 1.0 Semisynthetic 1 0.8
0.7 0.5 0.5 0.6
0 0 0.5 2003 2004 20052005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
NVSS=National Vital Statistics System Year CO-115 Deaths from Natural & Semisynthetic Category Plateaued in 2012
2.5 Relative change in NVSS Relative change rates since 2003 in rate since 2011 1.4
2 -1.2NVSS Total Opioid Deaths - NVSS – Nat & Semisynth 1 Relative 1.5 - NSDUH Nonmedical use change -0.8RADARS Poison Deaths - WA Medical Examiner 1 0.6 - RADARS Poison Ctr Abuse -0.4RADARS Treatment Ctrs 0.5 0.2
0 0 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 Year CO-116 Deaths from Natural & Semisynthetic Category Plateaued in 2012
2.5 Relative change in NVSS Relative change rates since 2003 in rate since 2011 1.4
2 -1.2NVSS Total Opioid Deaths - NVSS – Nat & Semisynth 1 Relative 1.5 - NSDUH Nonmedical use change -0.8RADARS Poison Deaths - WA Medical Examiner 1 0.6 ER/LA REMS - RADARS Poison Ctr Abuse Florida -0.4RADARS Treatment Ctrs 0.5 Abuse Deterrent Form Take Back Programs 0.2 Prescription Monitoring Plans 0 0 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 Year CO-117 Surveillance Detected Decreases in Abuse and Misuse for ER/LA Opioids
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 CO-118
Lessons Learned from the REMS and Recommended Improvements
Laura Wallace, MPH RPC Metrics Sub team member Purdue Pharma L.P. CO-119
REMS is Novel Program
CE courses Scope . Consortium of 24 companies . 19 CE providers . 839 accredited education programs . Range of assessments and data sources CO-120 Learnings from the REMS: Collaboration and Project Management
>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. CO-121 Learnings from the REMS: Communication Activities
Systematic review of activities Many under-performed Lower awareness of REMS CO-122 Learnings From the REMS: Assessments
Assessments Survey Surveillance Studies
Patient survey Drug utilization patterns
Prescriber survey Changes in prescribing behavior
Surveillance monitoring Prescriber long-term evaluation (including ED visits and hospitalization) CO-123
ER/LA Opioids Only Part of the Issue
ER/LA opioids = 10% of opioid prescribing IR opioids = 90% of opioid prescribing CO-124
Goals of RPC’s Recommendations
To ensure balance between . Reducing abuse, misuse, and addiction . Avoiding undue burden to healthcare system . Allow access to appropriate patients CO-125 RPC Recommendation #1: Enhance Communication
Improve REMS CE website Planned launch of awareness campaign CO-126 RPC Recommendation #2: Expand to Extended Healthcare Team
Current REMS: focus on recent ER/LA opioid prescribers Clinicians report education of all team members is critical for implementation of REMS learning CO-127 Expand REMS to Extended Healthcare Team - Implementation
Pharmacy, nurse, other professional societies critical partners Availability of accredited CE to new healthcare providers & those in underserved communities CO-128 RPC Recommendation #3: Revise the FDA Blueprint
Prescriber education to reflect evolving stakeholder input and feedback Needs of adult learners CO-129 RPC Recommendations: Revise the Blueprint
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 CO-130 RPC Recommendation #4: If Training is Required, Tie to DEA Registration
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 CO-131 RPC Recommendation #5: Harmonize Federal Course Content
Overall Analysis of NIDA Course to FDA Blueprint
Partial 8% Yes 31%
No 61%
N=76 CO-132 Improve REMS in Evidence-Driven Ways
Based on lessons learned Improve provider knowledge and further reduce misuse and abuse CO-133
Conclusions
Paul Coplan, ScD, MBA RPC Metrics Subteam Chair Purdue Pharma L.P. CO-134 Summary: Communication and Education Components
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 CO-135 Summary: Results of Surveillance Assessments
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) CO-136
Summary: Prescribing Changes
Prescribing metrics . Some decrease in inappropriate prescribing CO-137
Lessons Learned
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 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
Phases of ER/LA Opioid REMS
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 CO-140
RPC Acknowledgements
CE Subteam Metrics Subteam RPC Members and External Collaborators . Brian Kilmartin (Teva) . Greg Wedin (Upsher- . Actavis – Tara Brolly . Ekaterina Walker Smith) . Endo – Mark Collins & Tina (Purdue) . Kal Elhoregy (Endo) Latch . Lisa Zimmerman (Pernix) . Karla Werre . HealthCore . Mark Tyrrell (Impax) (Mallinckrodt) . Linda Kitlinski . Marsha Stanton (Pernix) . Laura Wallace . inVentiv Health Consulting . Michelle Zachman (Purdue) . IMS Health (Upsher-Smith) . Linda Noa . Ogilvy CommonHealth . Nathan Kopper (Mallinckrodt) Worldwide (Mallinckrodt) . Mark Tyrrell (Impax) . Pfizer – Robert Kristofco, Ken . Terry Lumati (Depomed) . Nathan Kopper Petronis, Sharon Reid & Gary (Mallinckrodt) Wilson . Paul Coplan (Purdue) . Polaris . Soledad Cepeda . Purdue – Jaren Howard, Robert (Janssen) Josephson & Nelson Sessler . RADARS System . RPC Supported CE Providers . United BioSource Corporation CO-141
REMS - Overall Conclusions
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 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