ER/LA Opioid Analgesics REMS Advisory Committee Briefing Book V2.0 30MAR2016 DRUG ...

538 Pages·2016·7.8 MB·English

ER/LA Opioid Analgesics REMS
Advisory Committee
Briefing Book
V2.0 30MAR2016
DRUG SAFETY AND RISK MANAGEMENT ADVISORY COMMITTEE
ANESTHETIC AND ANALGESIC DRUG PRODUCTS ADVISORY COMMITTEE
BRIEFING BOOK
FOR
THE EXTENDED-RELEASE AND LONG-ACTING (ER/LA) OPIOID ANALGESIC
RISK EVALUATION AND MITIGATION STRATEGY (REMS)
Actavis, Inc.
Aurolife Pharma, LLC
Aveva Drug Delivery System, Inc. (a subsidiary of Apotex)
Core Pharma (affiliated with Impax)*
Depomed, Inc.
Endo Pharmaceuticals Inc.
Impax Laboratories, Inc.
Janssen Pharmaceuticals, Inc.
Mallinckrodt Pharmaceuticals
Mylan Technologies, Inc.
Nesher Pharmaceuticals LLC
Novel Laboratories, Inc.
Noven Pharmaceuticals, Inc.
Par Pharmaceutical, Inc. (affiliated with Endo)*
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.
Vintage Pharmaceuticals LLC (affiliated with Endo)*
VistaPharm, Inc.
*Denotes company that is part of this REMS through affiliation with an RPC Participant Company
on this list
ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC
RELEASE
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ER/LA Opioid Analgesics REMS
Advisory Committee
Briefing Book
V2.0 30MAR2016

TABLE OF CONTENTS
TABLE OF CONTENTS .................................................................................................................2
LIST OF TABLES ...........................................................................................................................6
LIST OF FIGURES .......................................................................................................................10
LIST OF APPENDICES ................................................................................................................11
LIST OF ABBREVIATIONS ........................................................................................................12
1. EXECUTIVE SUMMARY ....................................................................................................13
2. BACKGROUND ....................................................................................................................27
2.1. Blueprint Elements ..............................................................................................27
2.2. Medication Guide ................................................................................................27
2.3. Elements to Assure Safe Use ...............................................................................28
2.4. Timetable for Submission of Assessments ..........................................................29
2.5. Current State of Opioid Abuse in the US ............................................................30
3. REMS ASSESSMENT ...........................................................................................................31
4. 36-MONTH FDA ASSESSMENT RESULTS ......................................................................32
4.1. Prescribers Who Have Successfully Completed Training ...................................32
4.1.1. Characteristics of ER/LA Opioid Analgesic Prescribers Completing
Training ...................................................................................................34
4.1.2. ER/LA Opioid Analgesic Prescribers Completing Non-RPC-
Supported REMS-Compliant Training ....................................................36
4.1.3. Challenges of ER/LA Opioid Analgesics REMS CE ..............................37
4.2. Independent Audit of Continuing Education Activities ......................................40
4.3. Patient Survey ......................................................................................................41
4.3.1. Methods ...................................................................................................42
4.3.2. Statistical Methods ..................................................................................43
4.3.3. Survey Administration .............................................................................43
4.3.4. Survey Results .........................................................................................46
4.3.4.1. Evaluation of Changes in Access based on Patient Survey
Results ............................................................................................49
4.3.5. Limitations of the Patient Survey ............................................................50
4.4. Prescriber Surveys ...............................................................................................50
4.4.1. Analysis of Prescriber Surveys ................................................................51
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Briefing Book
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4.4.2. Prescriber Survey .....................................................................................51
4.4.2.1. Methods..........................................................................................52
4.4.2.2. Statistical Methods .........................................................................53
4.4.2.3. Prescriber Survey Administration ..................................................53
4.4.2.4. Prescriber Survey Results ..............................................................53
4.4.2.5. Limitations of Prescriber Survey ...................................................61
4.4.3. Long-term Evaluation ..............................................................................61
4.4.3.1. Methods..........................................................................................62
4.4.3.2. Statistical Methods .........................................................................62
4.4.3.3. Long-term Evaluation Survey Administration...............................63
4.4.3.4. Long-term Evaluation Survey Results ...........................................63
4.4.3.5. Limitations of Long-term Evaluation Survey ................................64
4.5. Evaluation of Drug Utilization Patterns, Prescribing Behaviors, and Changes
to ER/LA Opioid Access .....................................................................................64
4.5.1. Drug Utilization Patterns .........................................................................65
4.5.1.1. Methods..........................................................................................66
4.5.1.2. Statistical Methods .........................................................................66
4.5.1.3. Results ............................................................................................67
4.5.2. Evaluation of Changes in Prescribing Behaviors ....................................69
4.5.2.1. Statistical Methods .........................................................................70
4.5.2.2. Results ............................................................................................70
4.5.3. Monitoring Patterns of Prescribing to Identify Changes in Access to
ER/LA Opioid Analgesics .......................................................................72
4.5.3.1. Statistical Methods .........................................................................72
4.5.3.2. Results ............................................................................................72
4.6. Surveillance Monitoring ......................................................................................73
4.6.1. Surveillance of Emergency Department Visits and Hospitalizations
for Opioid Overdose and Poisoning Events ............................................74
4.6.1.1. Methods..........................................................................................75
4.6.1.2. Statistical Methods .........................................................................76
4.6.1.3. Results for Commercially-Insured Patients ...................................76
4.6.1.4. Results for Medicaid Patients ........................................................78
4.6.1.5. Medicaid Patient Demographic and Clinical Characteristics ........78
4.6.1.6. Summary of Results .......................................................................78
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Briefing Book
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4.6.1.7. Limitations .....................................................................................78
4.6.2. Poison Center Programs ..........................................................................79
4.6.2.1. Methods..........................................................................................80
4.6.2.2. Statistical Methods .........................................................................80
4.6.2.3. Results ............................................................................................81
4.6.2.4. Abuse Exposure Results ................................................................83
4.6.2.5. Misuse Results ...............................................................................84
4.6.2.6. Major Medical Outcome, Hospitalization, or Death Results .........84
4.6.2.7. Death Results .................................................................................85
4.6.2.8. Under 20 Years Treated/Evaluated and Released Results .............86
4.6.2.9. Adult Treated/Evaluated and Released Results .............................87
4.6.2.10. Pediatric Unintentional Exposure Results .....................................88
4.6.2.11. Child and Adolescent Unintentional Exposure Results .................89
4.6.2.12. Adult Unintentional Exposure Results...........................................90
4.6.2.13. Unintentional Therapeutic Error Results .......................................91
4.6.2.14. Pediatric Unintentional General Exposure Results ........................92
4.6.2.15. Pediatric Unintentional General Exposures Major Medical
Outcome, Hospitalization, or Death Results ..................................93
4.6.2.16. Pediatric Unintentional General Exposures Treated/Evaluated
and Released Results......................................................................94
4.6.2.17. Adolescent Intentional Abuse Results ...........................................95
4.6.2.18. Poison Center Program Summary ..................................................96
4.6.2.19. Poison Center Program Results without Abuse Deterrent
Formulations ..................................................................................97
4.6.3. Rates of People in Substance Abuse Treatment Programs Abusing
ER/LA Opioid Analgesics .......................................................................97
4.6.3.1. NAVIPPRO® Drug Treatment Center Study .................................98
4.6.3.2. RADARS® Drug Treatment Center Study ...................................100
4.6.3.3. RADARS® Treatment Center Abuse Results ..............................101
4.6.4. RADARS® Treatment Center Abuse Summary ....................................102
4.6.5. College Survey Program ........................................................................102
4.6.5.1. College Survey Results ................................................................102
4.6.5.2. College Survey Program Abuse Summary ..................................103
4.6.6. Mortality Rates Resulting From Drug Poisoning ..................................103
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Briefing Book
V2.0 30MAR2016

4.6.6.1. Death Rates for Prescription Opioids with an ER/LA
Formulation Excluding Hydrocodone..........................................104
4.6.6.2. Death Rates for All Prescription Opioids excluding
Hydrocodone ................................................................................105
4.6.6.3. Mortality Rates Conclusion .........................................................106
5. FUNCTIONAL COMPONENTS .........................................................................................107
5.1. REMS Call Center .............................................................................................107
5.2. Dear DEA-Registered Prescriber Letter ............................................................107
5.3. Patient Counseling Document ...........................................................................110
6. PROPOSED REMS RECOMMENDATIONS ....................................................................111
7. CONCLUSION.....................................................................................................................115

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Advisory Committee
Briefing Book
V2.0 30MAR2016

LIST OF TABLES
TABLE 1: ER/LA OPIOID ANALGESICS REMS LESSONS LEARNED ..................................... 24
TABLE 2: FDA-REQUIRED REMS ASSESSMENTS .................................................................... 31
TABLE 3: ASSESSMENT SOURCE FOR EACH REMS-RELATED RISK .................................. 31
TABLE 4: PRESCRIBERS COMPLETING AN ACCREDITED REMS COMPLIANT CE
ACTIVITY........................................................................................................................ 33
TABLE 5: COMPARISON OF PATIENT SURVEY RESPONDENTS TO THE SAMPLING
FRAME ............................................................................................................................. 44
TABLE 6: COMPARISON OF RESPONDENTS TO ALL ER/LA OPIOID USERS IN THE
HIRD SINCE 2012 ........................................................................................................... 45
TABLE 7: MEDICATION GUIDE AND PATIENT COUNSELING DOCUMENT
RECEIPT AND UNDERSTANDING ............................................................................. 47
TABLE 8: PRESCRIBER SURVEY: COLLECTED PRESCRIBER CHARACTERISTICS .......... 53
TABLE 9: DESCRIPTION OF ELIGIBLE PRESCRIBERS AND ALL SURVEY
RESPONDENTS INVITED FROM IMS DATA FOR THE PRESCRIBER
FOLLOW-UP SURVEY .................................................................................................. 54
TABLE 10: PRESCRIBER SURVEY: COMPARISON OF HCPS INVITED FROM THE IMS
DATA AND HCPS RECRUITED BY CE PROVIDERS -
COMPLETED SURVEYS ............................................................................................... 58
TABLE 11: PRESCRIBER AWARENESS AND READING OF REMS MATERIALS ................... 60
TABLE 12: CHANGES IN PRESCRIBER BEHAVIOR FOLLOWING PARTICIPATION IN
REMS-COMPLIANT CE ................................................................................................. 64
TABLE 13: COMPARISON OF THE AVERAGE 3-MONTH PRESCRIPTION ACROSS
PRE-IMPLEMENTATION, IMPLEMENTATION, AND ACTIVE PERIOD ............... 68
TABLE 14: COMPARISON OF THE AVERAGE MONTHLY PROPORTION OF OPIOID
NON-TOLERANT PATIENTS PRESCRIBED PRODUCTS INDICATED FOR
OPIOID TOLERANT PATIENTS ONLY ACROSS PRE-IMPLEMENTATION
AND ACTIVE PERIOD ................................................................................................... 71
TABLE 15: DATA SOURCES USED FOR SAFETY SURVEILLANCE ......................................... 74
TABLE 16: INCIDENCE OF OPIOID OVERDOSE OR POISONING, BY TYPE OF EVENT
AND REMS PERIOD PER 10,000 PERSON-YEARS.................................................... 77
TABLE 17: SUMMARY OF OUTCOMES FROM ANALYSES OF RADARS® POISON
CENTER DATA ............................................................................................................... 82
TABLE 18: MEAN INTENTIONAL ABUSE RATE PER 100,000 POPULATION FOR
ER/LA REMS OPIOIDS AND COMPARATORS, 2010 - 2014 .................................... 83
TABLE 19: MEAN INTENTIONAL ABUSE RATE PER 1,000 PRESCRIPTIONS
DISPENSED FOR ER/LA REMS OPIOIDS AND COMPARATORS, 2010 -
2014 .................................................................................................................................. 83
TABLE 20: MEAN MISUSE RATE PER 100,000 POPULATION FOR ER/LA REMS
OPIOIDS AND COMPARATORS, 2010 - 2014 ............................................................. 84
TABLE 21: MEAN MISUSE RATE PER 1,000 PRESCRIPTIONS DISPENSED FOR ER/LA
REMS OPIOIDS AND COMPARATORS, 2010 - 2014 ................................................. 84
TABLE 22: MEAN MAJOR MEDICAL OUTCOME, HOSPITALIZATION, OR DEATH
RATE PER 100,000 POPULATION FOR ER/LA REMS OPIOIDS AND
COMPARATORS, 2010 - 2014 ....................................................................................... 85
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ER/LA Opioid Analgesics REMS
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Briefing Book
V2.0 30MAR2016

TABLE 23: MEAN MAJOR MEDICAL OUTCOME, HOSPITALIZATION, OR DEATH
RATE PER 1,000 PRESCRIPTIONS DISPENSED FOR ER/LA REMS OPIOIDS
AND COMPARATORS, 2010 - 2014 .............................................................................. 85
TABLE 24: MEAN DEATH RATE PER 100,000 POPULATION FOR ER/LA REMS
OPIOIDS AND COMPARATORS, 2010 - 2014 ............................................................. 86
TABLE 25: MEAN DEATH RATE PER 1,000 PRESCRIPTIONS DISPENSED FOR ER/LA
REMS OPIOIDS AND COMPARATORS, 2010 - 2014 ................................................. 86
TABLE 26: MEAN RATE PER 100,000 POPULATION OF TREATED/EVALUATED AND
RELEASED FOR PATIENTS UNDER 20 YEARS FOR ER/LA REMS OPIOIDS
AND COMPARATORS, 2010 - 2014 .............................................................................. 87
TABLE 27: MEAN RATE PER 1,000 PRESCRIPTIONS DISPENSED OF
TREATED/EVALUATED AND RELEASED FOR PATIENTS UNDER 20
YEARS FOR ER/LA REMS OPIOIDS AND COMPARATORS, 2010 - 2014 .............. 87
TABLE 28: MEAN RATE PER 100,000 POPULATION OF ADULT
TREATED/EVALUATED AND RELEASED FOR ER/LA REMS OPIOIDS
AND COMPARATORS, 2010 - 2014 .............................................................................. 88
TABLE 29: MEAN RATE PER 1,000 PRESCRIPTIONS DISPENSED OF ADULT
TREATED/EVALUATED AND RELEASED FOR ER/LA REMS OPIOIDS
AND COMPARATORS, 2010 - 2014 .............................................................................. 88
TABLE 30: MEAN PEDIATRIC UNINTENTIONAL EXPOSURE RATE PER 100,000
POPULATION FOR ER/LA REMS OPIOIDS AND COMPARATORS, 2010 -
2014 .................................................................................................................................. 89
TABLE 31: MEAN PEDIATRIC UNINTENTIONAL EXPOSURE RATE PER 1,000
PRESCRIPTIONS DISPENSED FOR ER/LA REMS OPIOIDS AND
COMPARATORS, 2010 - 2014 ....................................................................................... 89
TABLE 32: MEAN CHILD AND ADOLESCENT UNINTENTIONAL EXPOSURE RATE
PER 100,000 POPULATION FOR ER/LA REMS OPIOIDS AND
COMPARATORS, 2010 - 2014 ....................................................................................... 90
TABLE 33: MEAN CHILD AND ADOLESCENT UNINTENTIONAL EXPOSURE RATE
PER 1,000 PRESCRIPTIONS DISPENSED FOR ER/LA REMS OPIOIDS AND
COMPARATORS, 2010 - 2014 ....................................................................................... 90
TABLE 34: MEAN ADULT UNINTENTIONAL EXPOSURE RATE PER 100,000
POPULATION FOR ER/LA REMS OPIOIDS AND COMPARATORS, 2010 -
2014 .................................................................................................................................. 91
TABLE 35: MEAN ADULT UNINTENTIONAL EXPOSURE RATE PER 1,000
PRESCRIPTIONS DISPENSED FOR ER/LA REMS OPIOIDS AND
COMPARATORS, 2010 - 2014 ....................................................................................... 91
TABLE 36: MEAN UNINTENTIONAL THERAPEUTIC ERROR RATE PER 100,000
POPULATION FOR ER/LA REMS OPIOIDS AND COMPARATORS, 2010 -
2014 .................................................................................................................................. 92
TABLE 37: MEAN UNINTENTIONAL THERAPEUTIC ERROR RATE PER 1,000
PRESCRIPTIONS DISPENSED FOR ER/LA REMS OPIOIDS AND
COMPARATORS, 2010 - 2014 ....................................................................................... 92
TABLE 38: MEAN PEDIATRIC UNINTENTIONAL GENERAL EXPOSURE RATE PER
100,000 POPULATION FOR ER/LA REMS OPIOIDS AND COMPARATORS,
2010 - 2014 ....................................................................................................................... 93
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ER/LA Opioid Analgesics REMS
Advisory Committee
Briefing Book
V2.0 30MAR2016

TABLE 39: MEAN PEDIATRIC UNINTENTIONAL GENERAL EXPOSURE RATE PER
1,000 PRESCRIPTIONS DISPENSED FOR ER/LA REMS OPIOIDS AND
COMPARATORS, 2010 - 2014 ....................................................................................... 93
TABLE 40: MEAN PEDIATRIC UNINTENTIONAL GENERAL EXPOSURE MAJOR
MEDICAL OUTCOME, HOSPITALIZATION, OR DEATH RATE PER 100,000
POPULATION FOR ER/LA REMS OPIOIDS AND COMPARATORS, 2010 -
2014 .................................................................................................................................. 94
TABLE 41: MEAN PEDIATRIC UNINTENTIONAL GENERAL EXPOSURE MAJOR
MEDICAL OUTCOME, HOSPITALIZATION, OR DEATH RATE PER 1,000
PRESCRIPTIONS DISPENSED FOR ER/LA REMS OPIOIDS AND
COMPARATORS, 2010 - 2014 ....................................................................................... 94
TABLE 42: MEAN RATE PER 100,000 POPULATION OF UNINTENTIONAL GENERAL
EXPOSURE TREATED/EVALUATED AND RELEASED FOR PEDIATRIC
PATIENTS FOR ER/LA REMS OPIOIDS AND COMPARATORS, 2010 - 2014 ........ 95
TABLE 43: MEAN RATE PER 1,000 PRESCRIPTIONS DISPENSED OF
UNINTENTIONAL GENERAL EXPOSURE TREATED/EVALUATED AND
RELEASED FOR PEDIATRIC PATIENTS FOR ER/LA REMS OPIOIDS AND
COMPARATORS, 2010 - 2014 ....................................................................................... 95
TABLE 44: MEAN ADOLESCENT INTENTIONAL ABUSE EXPOSURE RATE PER
100,000 POPULATION FOR ER/LA REMS OPIOIDS AND COMPARATORS,
2010 - 2014 ....................................................................................................................... 96
TABLE 45: MEAN ADOLESCENT INTENTIONAL ABUSE EXPOSURE RATE PER 1,000
PRESCRIPTIONS DISPENSED FOR ER/LA REMS OPIOIDS AND
COMPARATORS, 2010 - 2014 ....................................................................................... 96
TABLE 46: MEAN PAST 30 DAY MENTION RATES PER 100,000 POPULATION FOR
ER/LA REMS OPIOIDS AND COMPARATORS, 2010 - 2014 .................................. 101
TABLE 47: MEAN PAST 30 DAY MENTION RATES PER 1,000 PRESCRIPTIONS
DISPENSED FOR ER/LA REMS OPIOIDS AND COMPARATORS, 2010 -
2014 ................................................................................................................................ 101
TABLE 48: MEAN PAST 90 DAY MENTION RATES PER 100,000 POPULATION FOR
ER/LA REMS OPIOIDS AND COMPARATORS, 2010 - 2014 .................................. 103
TABLE 49: MEAN PAST 90 DAY MENTION RATES PER 1,000 PRESCRIPTIONS FOR
ER/LA REMS OPIOIDS AND COMPARATORS, 2010 - 2014 .................................. 103
TABLE 50: MEAN POPULATION-ADJUSTED DEATH RATES FOR PRESCRIPTION
OPIOIDS WITH AN ER/LA FORMULATION AND COMPARATORS, 2005 -
2013 ................................................................................................................................ 104
TABLE 51: MEAN PRESCRIPTION-ADJUSTED DEATH RATES FOR PRESCRIPTION
OPIOIDS WITH AN ER/LA FORMULATION EXCLUDING HYDROCODONE
AND COMPARATORS, 2005 - 2013 ............................................................................ 105
TABLE 52: MEAN POPULATION-ADJUSTED DEATH RATES FOR ALL
PRESCRIPTION OPIOIDS EXCLUDING HYDROCODONE AND
COMPARATORS, 2005 - 2013 ..................................................................................... 105
TABLE 53: MEAN PRESCRIPTION-ADJUSTED DISPENSED DEATH RATES FOR ALL
PRESCRIPTION OPIOIDS EXCLUDING HYDROCODONE AND
COMPARATORS, 2005 - 2013 ..................................................................................... 106
TABLE 54: DISTRIBUTION OF DEAR DEA-REGISTERED PRESCRIBER LETTERS ............. 108
TABLE 55: LEARNED SOCIETIES AND PROFESSIONAL ASSOCIATIONS RECEIVING
REMS LETTER* ............................................................................................................ 109
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Advisory Committee
Briefing Book
V2.0 30MAR2016

TABLE 56: PATIENT COUNSELING DOCUMENT ACCESS VIA WEBSITE ........................... 110
TABLE 57: PATIENT COUNSELING DOCUMENT PAD FULFILLMENT................................. 110
TABLE 58: ER/LA OPIOID ANALGESICS REMS LESSONS LEARNED ................................... 111

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Briefing Book
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LIST OF FIGURES
FIGURE 1: CUMULATIVE NUMBERS OF ACCREDITED REMS-COMPLIANT CE
ACTIVITY COMPLETERS OVER TIME ...................................................................... 15
FIGURE 2: POISON CENTER PROGRAM SUMMARY ................................................................. 22
FIGURE 3: ACCREDITED REMS-COMPLIANT PARTICIPANTS, COMPLETERS AND
ER/LA PRESCRIBERS (FEBRUARY 28, 2013-FEBRUARY 29, 2016) ...................... 34
FIGURE 4: RPC-SUPPORTED, ACCREDITED REMS-COMPLIANT ER/LA OPIOID
ANALGESIC PRESCRIBERS COMPLETING TRAINING BY PROFESSION
(FEBRUARY 28, 2013- FEBRUARY 28, 2015) ............................................................. 35
FIGURE 5: ER/LA OPIOID ANALGESIC PRESCRIBERS COMPLETING RPC-
SUPPORTED, ACCREDITED REMS-COMPLIANT TRAINING BY
PRACTICE TYPE (FEBRUARY 28, 2013- FEBRUARY 28, 2015) .............................. 36
FIGURE 6: FDA BLUEPRINT MESSAGES COVERED IN A NON-RPC-SUPPORTED CE
ACTIVITY ADMINISTERED BY NIDA ....................................................................... 37
FIGURE 7: DISTRIBUTION OF PATIENT KAS SCORES .............................................................. 47
FIGURE 8: PRESCRIBER SURVEY AND LONG-TERM EVALUATIONS SURVEY
TIMEFRAMES ................................................................................................................. 51
FIGURE 9: OPIOID ICD-9 VALIDATION SCHEME ....................................................................... 75

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