NDA 020732/S-023
`NDA 020733/S-027
`NDA 022410/S-039
`
`Indivior Inc.
`10710 Midlothian Turnpike
`Suite 125
`North Chesterfield, VA 23235
`
`Attention
`
`Rachel Capone
`Manager, Regulatory Affairs
`
`Dear Ms. Capone:
`
`SUPPLEMENT APPROVAL
`
`Please refer to your supplemental new drug applications (sNDAs) dated and received
`June 18, 2019, and your amendments, submitted under section 505(b) of the Federal
`Food, Drug, and Cosmetic Act (FDCA) for SUBUTEX (buprenorphine) sublingual tablets
`(NDA 020732/S-023), SUBOXONE (buprenorphine and naloxone) sublingual tablets
`(NDA 020733/S-027), and SUBOXONE (buprenorphine and naloxone) sublingual film
`(NDA 022410/S-039).
`
`These Prior Approval sNDAs proposed modifications to the approved risk evaluation
`and mitigation strategy (REMS) for SUBUTEX sublingual tablets, SUBOXONE
`sublingual tablets, and SUBOXONE sublingual film.
`
`We have completed our review of these supplemental applications, as amended and
`they are approved effective on the date of this letter.
`
`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
`
`The REMS for SUBOXONE (buprenorphine and naloxone) sublingual film was originally
`approved on August 30, 2010. The REMS for SUBUTEX (buprenorphine) sublingual
`tablets and the REMS for SUBOXONE (buprenorphine and naloxone) sublingual tablets
`were originally approved on December 22, 2011. The most recent modification was
`approved on October 26, 2018. The REMS consists of a Medication Guide, elements to
`assure safe use, an implementation system, and a timetable for submission of
`assessments of the REMS. Your proposed modification to the REMS consists of
`modifying the REMS Document to the new format in accordance with the October 2017
`Draft Guidance: Format and Content of a REMS Document Guidance for Industry.
`In addition to the modification described above, changes to the supporting document
`and assessment plan were also included in the submission.
`
`Reference ID: 4569246
`
`

`

`NDA 020732/S-023
`NDA 020733/S-027
`NDA 022410/S-039
`Page 2
`
`Your proposed modified REMS, submitted on June 18, 2019, amended and appended
`to this letter, is approved.
`
`The timetable for submission of assessments of the REMS remains the same as that
`approved on August 31, 2012.
`
`The revised REMS assessment plan must include, but is not limited to, the following:
`1. An evaluation of patients’ understanding of the serious risks of SUBOXONE
`sublingual film.
`2. A report on periodic assessments of the distribution and dispensing of the
`
`
`Medication Guide in accordance with 21 CFR 208.24.
`
`3. A report on failures to adhere to distribution and dispensing requirements for the
`Medication Guide, and corrective actions taken to address noncompliance.
`4. A survey of prescribers’ understanding of the serious risks of SUBOXONE
`
`sublingual film and the:
`
`a) need for appropriate patient monitoring
`b) need for patient adherence to conditions of safe use
`c) need to check that patients are using the drug appropriately and making
`adequate progress towards treatment goals
`d) need to make sure prescriptions are provided in amounts commensurate
`with patient stability
`e) importance of psychosocial support services
`f) The results of the prescriber survey will be stratified by stage of treatment
`(i.e., those initiating treatment [month 1] vs. established patients [month
`2+]). The stratification will be applied to the analysis of the 12 possible
`steps prescribers use to reduce inappropriate use or diversion in their
`practices.
`g) Specific measures that will be taken to increase awareness if surveys of
`prescribers indicate that prescriber awareness is not adequate
`5. A survey of pharmacists’ understanding of the serious risks of SUBOXONE
`sublingual film and the need for patient adherence to conditions of safe use.
`6. An analysis to evaluate SUBOXONE sublingual film utilization patterns including
`frequency of office visits, amount dispensed in prescriptions to new patients and
`other indicators of adherence to practices important to safe use. The analysis of
`utilization patterns (frequency of office visits per patient, amount of medication
`dispensed in prescriptions, etc.) will be stratified by stage of treatment (i.e., new
`[month 1] vs. established patients [month 2+]).
`7. An analysis and summary of surveillance and monitoring activities for abuse,
`misuse, overdose and addiction and any intervention taken resulting from signals
`of abuse, misuse, overdose and addiction. Surveillance data are to be drawn
`from multiple sources and are to place a special focus on pediatric exposures.
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4569246
`
`

`

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`NDA 020733/S-027
`NDA 022410/S-039
`Page 3
`
`The SUBOXONE/SUBUTEX REMS will undergo periodic review to evaluate the
`effectiveness of the strategies and tools in accomplishing the goals and objectives of
`the REMS. Appropriate revisions to the REMS will be proposed based on the
`evaluations. Based on the monitoring and evaluation of these elements to assure safe
`use, Indivior will take reasonable steps to improve implementation of these elements,
`
`such as suggesting changes to the prescriber or pharmacist brochures or mailing an
`additional letter to healthcare providers (HCPs) based on which specific risks messages
`seem to have low understanding.
`
`Medication Guide Distribution Audits
`Indivior will periodically assess the distribution and dispensing of the SUBOXONE
`sublingual film, Authorized Generic of SUBOXONE sublingual film, SUBOXONE
`sublingual tablet, and SUBUTEX sublingual tablet Medication Guide in accordance with
`21 CFR 208.24. Periodic audits of the packaging facility will be conducted to monitor
`compliance with inclusion of the Medication Guide within the product packaging. The
`Knowledge, Attitudes, and Behavior (KAB) surveys described in Section 4.2.12 below
`will also assess this by querying patients about whether they received a Medication
`Guide when their prescription for SUBOXONE Sublingual film and Authorized Generic
`of SUBOXONE sublingual film was dispensed. Failures to adhere to Medication Guide
`distribution and dispensing requirements will be identified and appropriate actions will
`be implemented to address non-compliance. This information will be provided in the
`regular assessment reports for the REMS.
`
`Surveillance and Epidemiology
`Epidemiology and surveillance data reporting reflects emails Indivior received from the
`FDA on 14 JAN 2019, 19 MAR 2019, 24 SEP 2019, and 22 NOV 2019, and referenced
`in the REMS Assessment Acknowledgement Letter received on 02 AUG 2019.
`
`Data Sources
`As part of the REMS program, Indivior will conduct analysis and summary of
`surveillance/epidemiologic data on abuse, misuse, overdose (mortality), and addiction.
`
`These data sources include:
`
`x Researched Abused, Diversion and Addiction-Related Surveillance (RADARS®)
`System:
`o Poison Control Centers
`o Treatment Centers - Survey of Key Informants’ Patients (SKIP)/Opioid
`Treatment Program (OTP)
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4569246
`
`

`

`NDA 020732/S-023
`NDA 020733/S-027
`NDA 022410/S-039
`Page 4
`
`o Drug Diversion
`x National Forensic Laboratory Information System (NFLIS)
`x National Survey of Drug Use (NSDUH)
`x National Survey of Substance Abuse Treatment Services (N-SSATS)
`x Treatment Episodes Dataset (TEDS)
`x Medical Examiners Data
`x Assessment of Adherence in Medical Records/Administrative Claims - Feasibility
`Assessment
`x Literature Review
`
` Researched Abuse, Diversion and Addiction Related Surveillance (RADARS®) System
`
`The RADARS System provides post-marketing surveillance of prescription medication
`abuse, misuse, and diversion to pharmaceutical companies, regulatory agencies, and
`policy making organizations. The RADARS System is comprised of multiple
`independent surveillance programs which gather data from several unique populations
`along the spectrum of the drug abuse pathway.i
`
`RADARS System Poison Center
`The RADARS System Poison Center Program obtains data from participating poison
`centers, which manage exposure calls from individuals within the general population
`and from HCPs who are seeking advice regarding potential toxic exposures, including
`exposures to prescription opioids.ii Poison Center Program data collected through the
`RADARS System provide an estimate of change in intentional abuse, misuse, and
`deaths associated with these drugs. The Poison Center Program collects data from 50
`of the 55 regional US poison centers in 48 states.
`
`Objective
`
`x To examine trends in buprenorphine and other opioid exposures reported to US
`Poison Centers.
`
`Outcomes
`
`Intentional abuse exposures
`x
`Intentional misuse exposures
`x
`x Pediatric (ages 0-5 years) unintentional general exposures
`x Major medical outcome, hospitalization, or death
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4569246
`
`

`

`NDA 020732/S-023
`NDA 020733/S-027
`NDA 022410/S-039
`Page 5
`
`Measures
`
`x Rate per population
`x Utilization based rate (e.g., dosing unit dispensed)
`x Proportion of SUBOXONE intentional cases (i.e., intentional abuse, intentional
`misuse, suspected suicide, intentional unknown) that also involved
`benzodiazepines
`x Number of unspecified abuse cases for buprenorphine
`
`
`Buprenorphine Categorizations
`
`x Any buprenorphine (Active Pharmaceutical Ingredient [API])
`
`x All single ingredient tablets
`
`x All combination tablets
`
`x All combination film products
`
`x SUBOXONE sublingual film
`
`x Authorized Generic of SUBOXONE sublingual film
`
`x Suboxone sublingual tablets
`
`x Subutex sublingual tablets
`
`Note: It is not possible to differentiate Authorized Generic of SUBOXONE sublingual
`film in all RADARS Systems; this category will be included when feasible.
`
`Comparators (API)
`x Hydrocodone
`
`x Methadone
`
`x Oxycodone
`
`
`Analysis
`
`x Quarterly and annual population rates and utilization-based rates will be
`calculated. Results will be presented graphically with modeled trend lines and
`95% confidence intervals going back to 2011; tabular data for case counts and
`rates will also be provided. No formal statistical comparisons will be conducted.
`For all tables and figures, the total number of individuals for each data point will
`be included where applicable. Additionally, case narratives will be provided for all
`fatal exposure cases involving SUBOXONE in the RADARS Poison Center
`Program. As appropriate, for utilization-based analyses of methadone, provide a
`sensitivity analysis that accounts for methadone’s unique distribution mechanism.
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4569246
`
`

`

`NDA 020732/S-023
`NDA 020733/S-027
`NDA 022410/S-039
`Page 6
`
`RADARS System Treatment Center Programs
`The Treatment Center Programs Combined includes data from two distinct RADARS
`System programs: The Opioid Treatment Program and the Survey of Key Informants’
`Patients Program (OTP/SKIP).iii,iv
`
`The Opioid Treatment Program gathers data from 71 participating medication-assisted
`treatment programs (public and private) in 33 states yielding approximately 7,000
`survey respondents annually. Patients enrolling at these treatment centers are asked to
`voluntarily complete an anonymous questionnaire with items about primary drug of
`abuse, sources of drug acquisition, use in the month prior to treatment, and routes of
`abuse.
`
`The Survey of Key Informants’ Patients Program gathers data from a key informant
`network of 154 treatment programs yielding approximately 3,000 survey respondents
`annually from 47 states. The patients who seek treatment at primarily private substance
`abuse treatment programs are recruited by key informants to voluntarily complete an
`anonymous questionnaire with items about primary drug of abuse, sources of drug
`acquisition, use in the month prior to treatment, and routes of abuse.
`
`These two programs use the same core data collection form, enabling data to be
`combined, and complement each other by providing information from patients entering
`both private and public opioid use disorder treatment programs.
`
`
`Objective
`x To examine trends in the abuse of buprenorphine vs. comparators and to
`
`characterize the route of abuse profile for SUBOXONE among individuals
`
`entering substance abuse treatment centers.
`
`Outcome
`x Past month abuse
`Measures
`x Rate per population
`x Utilization based rate (e.g., dosing unit dispensed)
`x Route of abuse profiles for SUBOXONE sublingual film and comparators
`(proportion of abusers who report abusing it via injection, insufflation, or other
`
`routes)
`o The number and percent of respondents who report multiple routes of abuse
`(i.e., respondents with multiple responses regarding routes of abuse)
`
`x Proportion of SUBOXONE abusers who report that buprenorphine is their
`primary drug of abuse
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4569246
`
`

`

`NDA 020732/S-023
`NDA 020733/S-027
`NDA 022410/S-039
`Page 7
`
`Buprenorphine Categorizations
`x Any buprenorphine (API)
`x All single ingredient tablets
`x All combination tablets
`x All combination film products
`
`x SUBOXONE sublingual film
`
`x Authorized Generic of SUBOXONE sublingual film
`
`x SUBOXONE sublingual tablets
`
`x SUBUTEX sublingual tablets
`
`Comparators (API)
`x Hydrocodone
`
`x Methadone
`
`x Oxycodone
`
`Analysis
`x Quarterly and annual population rates and utilization-based rates (i.e., rate per
`
`dosing units dispensed) will be calculated for buprenorphine and comparators as
`well as for buprenorphine product categories. Results will be presented
`
`graphically with modeled trend lines and 95% confidence intervals going back to
`2011; tabular data for case counts and rates will also be provided. For all tables
`and figures, the total number of individuals for each data point will be included
`where applicable. No formal statistical comparisons will be conducted. As
`appropriate, for utilization-based analyses of methadone, provide a sensitivity
`analysis that accounts for methadone’s unique distribution mechanism.
`
`RADARS System Drug Diversion
`The Drug Diversion Program provides surveillance data on the diversion of prescription
`drugs by conducting a quarterly survey of drug diversion investigators.v Drug diversion
`investigators include municipal police departments, multi-jurisdictional drug task forces,
`county sheriffs’ departments, pharmaceutical boards and departments of health. Drug
`diversion investigators submit data on the number of documented drug diversion cases
`within their jurisdiction for specific prescription drugs of interest.
`
`Objective
`x To examine trends in the diversion of buprenorphine vs. comparators.
`Outcome
`x Diversion cases
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4569246
`
`

`

`NDA 020732/S-023
`NDA 020733/S-027
`NDA 022410/S-039
`Page 8
`
`Measures
`x Rate per population
`x Utilization based rate (e.g., dosing unit dispensed)
`Buprenorphine Categorizations
`x Any buprenorphine (API)
`
`x All single ingredient tablets
`
`x All combination tablets
`
`x All combination film products
`
`x Suboxone sublingual film
`
`x Authorized Generic of SUBOXONE sublingual film
`
`x SUBOXONE sublingual tablets
`
`x SUBUTEX sublingual tablets
`
`Comparators (API)
`x Hydrocodone
`
`x Methadone
`
`x Oxycodone
`
`Analysis
`x Background information, including the agency type, the jurisdiction, the number
`of quarters providing completed surveys, and the population within the
`jurisdiction will be provided. Information on the number of investigators working
`on drug diversion cases and the number of new cases of prescription drug
`diversion will also be included to provide information on drug activity.
`x Quarterly and annual population rates and utilization-based rates will be
`calculated. Results will be presented graphically with modeled trend lines and
`95% confidence intervals going back to 2011; tabular data for case counts and
`rates will be provided in an appendix. No formal statistical comparisons will be
`
`conducted.
`x For all tables and figures, the total number for each data point will be included
`
`where applicable. As appropriate, for utilization-based analyses of methadone,
`provide a sensitivity analysis that accounts for methadone’s unique distribution
`mechanism.
`
`Internet Monitoring of Media Reports
`A third party is utilized to monitor any news media reports related to the abuse, misuse
`and diversion of buprenorphine.
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4569246
`
`

`

`NDA 020732/S-023
`NDA 020733/S-027
`NDA 022410/S-039
`Page 9
`
`National Forensic Laboratory Information System (NFLIS)
`The National Forensic Laboratory Information System (NFLIS) is a program of the DEA,
`Diversion Control Division, which systematically collects drug identification results and
`associated information from drug cases submitted to and analyzed by Federal, State,
`and local forensic laboratories. These laboratories analyze controlled and noncontrolled
`substances secured in law enforcement operations across the country. As of 2017, the
`participation rate (defined as percentage of national drug caseload represented by
`laboratories who have joined NFLIS) was 98%, with 50 state and 101 local/municipal
`lab systems, representing 277 individual labs.vi Federal data from the DEA and US
`Customs and Border Protection (CBP) laboratories is also included.
`
`NFLIS results are made available through mid-year and annual reports. These reports
`provide information on the total number of buprenorphine drug reports and cases
`analyzed as well as regional results. The NFLIS reports do not include information on
`specific products but do include information at the API level. The statistical methodology
`is provided as an Appendix to each report.
`
`Objective
`x To describe the drug seizure counts and utilization-adjusted rates for
`
`buprenorphine and comparators.
`
`Outcomes
`x Drug reports (drug-level data)
`x Drug cases (case-level data, which typically describes all drugs identified within a
`drug-related incident)
`Note: per NFLIS report, a small proportion of laboratories may assign a single
`case number to all drug submissions related to an entire investigation.
`
`Measure
`x Utilization-based rate (e.g., dosing units dispensed)
`Buprenorphine Categorization
`x Buprenorphine (API)
`Comparators (API)
`x Hydrocodone
`x Methadone
`x Oxycodone
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4569246
`
`

`

`NDA 020732/S-023
`NDA 020733/S-027
`NDA 022410/S-039
`Page 10
`
`Analysis
`x All drug reports and drug case data are obtained from published Annual Reports,
`including the most recent annual report available before the end of the applicable
`
`SUBOXONE/SUBUTEX REMS Assessment Report reporting period, and a
`
`minimum of 5 years historical data. References to any tables used will be
`
`included. Utilization data are obtained from a separate data source that provides
`estimates of national drug utilization. Utilization based rates are calculated by
`dividing the number of cases by the total dosing units dispensed in that year.
`Methodology and definitions of terms will be provided. For all tables and figures,
`the total number for each data point will be included where applicable. As
`appropriate, for utilization-based analyses of methadone, provide a sensitivity
`analysis that accounts for methadone’s unique distribution mechanism.
`
`National Survey on Drug Use and Health (NSDUH)
`The NSDUH produces prevalence estimates for indicators of substance use and mental
`health among people aged 12 years old or older in the civilian, noninstitutionalized
`
`population of the US (https://www.datafiles.samhsa.gov/study-series/national-survey-
`drug-use-and-health-nsduh-nid13517). Results can be weighted to provide a nationally
`representative estimate.
`
`Assessment of the use and misuse of buprenorphine was added to the 2015 NSDUH.
`Use of prescription drugs is defined as (a) the use of one's own prescription medication
`as directed by a doctor. Misuse of prescription drugs is defined as use in any way not
`directed by a doctor, including use without a prescription of one's own medication; use
`in greater amounts, more often, or longer than told to take a drug; or use in any other
`way not directed by a doctor.
`
`Consistent with NSDUH methodology, respondents will be classified as having a past-
`year Opioid Use Disorder if they had either a heroin use disorder (i.e., dependence or
`abuse) or pain reliever use disorder related to their misuse of prescription pain relievers
`in the past year, or if they had both disorders.
`
`The reason for misuse is based on answers to questions about respondents’ reasons
`for misusing pain relievers for their last misuse. Respondents can report more than one
`reason, and if they report more than one reason, they are also asked to report the main
`
`reasons. The reasons for misuse include to relieve pain, to relax, to experiment, to get
`
`high, for sleep, for emotions, for other drug effect, because hooked, or for some other
`reason. Reasons for misuse for a specific product are only asked if that product was the
`last prescription pain reliever that was misused. Therefore, only a subset of those who
`report misuse of a specific product will provide information on reasons for misuse of that
`product.
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4569246
`
`

`

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`NDA 022410/S-039
`Page 11
`
`Objective
`x To describe buprenorphine, use and misuse in a nationally representative
`sample of individuals 12 and older, as well as reason for misuse. Results will be
`stratified by Opioid Use Disorder.
`Outcomes
`x Use
`
`x Misuse
`
`x Reasons for buprenorphine misuse
`
`Measures
`x Prevalence of use and misuse
`Buprenorphine Categorization
`x Buprenorphine (API)
`
`x Suboxone
`
`x Buprenorphine (generic)
`
`x Buprenorphine plus naloxone (generic) (select years only)
`
`Comparators (API)
`x Hydrocodone
`
`x Methadone
`
`x Oxycodone
`
`x Oxymorphone
`
`x Fentanyl
`
`x Morphine
`
`x Tramadol
`
`Analysis
`x NSDUH data will be obtained from published annual reports and public use
`datasets available on or before the end of the applicable SUBOXONE/SUBUTEX
`REMS Assessment Report reporting period. References to any tables used will
`
`be included. The prevalence of use and misuse of buprenorphine (API) and
`comparators will be obtained from published annual reports and/or public use
`data files. Prevalence rates for buprenorphine misuse will be stratified by Opioid
`Use Disorder using public use data files. The reason for misuse of specific
`buprenorphine products (e.g., SUBOXONE) will be obtained from public use data
`files and will be presented overall and stratified by presence of Opioid Use
`Disorder. For all tables and figures, the total number of individuals for each data
`point will be included where applicable.
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4569246
`
`

`

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`Page 12
`
`National Survey of Substance Abuse Treatment Services (N-SSATS)
`The N-SSATS is an annual census of facilities providing substance abuse treatment.vii
`Conducted by the Substance Abuse and Mental Health Services Administration
`(SAMHSA), the N-SSATS is designed to collect data on the location, characteristics and
`use of alcohol and drug abuse treatment facilities and services throughout the 50 states,
`the District of Columbia, and other US jurisdictions. Facilities include both private (for-
`profit and non-profit) as well as government facilities, and cover inpatient, residential
`(non-hospital), and outpatient treatment. Data are provided as part of the annual
`reports.
`
`The N-SSATS does not collect data on misuse of buprenorphine but collects treatment
`
`facilities information and the number of clients treated with buprenorphine as
`medication-assisted therapy.
`
`Objective
`x To describe medication-assisted therapy with buprenorphine at national
`
`treatment facilities.
`
`Outcomes
`x Facilities providing buprenorphine
`
`x Clients receiving buprenorphine
`
`Measures
`x Proportion of facilities providing any buprenorphine
`
`x Number of clients receiving buprenorphine
`
`o Overall
`o By program type
`– Opioid Treatment Program (OTP)
`– Non-OTP facilities
`
`Buprenorphine Categorization
`x Buprenorphine (API, for Medication Assisted Therapy)
`Analysis
`x All treatment admission data are from published Annual Reports, including the
`most recent annual report available before the end of the applicable
`SUBOXONE/SUBUTEX REMS Assessment Report reporting period and a
`minimum of 5 years historical data. Buprenorphine utilization data, which will be
`provided as context for any changes to the trends in facilities providing clients
`receiving buprenorphine treatment over time, are obtained from a separate data
`source that provides estimates of national drug utilization. References to any
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4569246
`
`

`

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`Page 13
`
`tables used will be included. For all tables and figures, the total number for each
`
`data point will be included where applicable.
`
`Literature Surveillance
`A summary and comment/critique of the past 5 years of published observational studies
`on buprenorphine prescribing practices, misuse, abuse and unintentional overdose will
`be provided. Investigations of vulnerable populations or those of special interest such as
`adolescents, pregnancy/fetal exposure, incarcerated or parolee/probationers will be
`highlighted. Unless accompanied by a review or analysis that can be generalized to a
`wider audience, editorials, case reports, and case series will not be the focus of this
`critique.
`
`Assessment of Adherence in Medical Records/Administrative Claims - Feasibility
`Assessment
`The feasibility of medical records (administrative claims data and electronic medical
`records) to evaluate adherence to (and best practices for) the Appropriate Use Checklist
`will be explored and summarized as new information is available.
`
`
`Mortality Data
`The Centers for Disease Control and Prevention (CDC) Drug-Involved Mortality (DIM)
`data will be utilized to provide national-level information on buprenorphine involved fatal
`overdoses. The study period for mortality analyses will be 2010 through the most recent
`data available. Typically, data are available 7-9 quarters following the end of a calendar
`year. Drug term assignment is done by manual adjudication of death certificates by
`experts at the CDC; all mentions are checked against the term list. One consistent
`definition and set of ICD-10 codes is utilized to designate an opioid-related death;
`currently there is limited access to literal text on the death certificate. These data
`contain all deaths regardless of state of residence and state of occurrence, and both
`can be reported. To access these data, a proposal will be developed and submitted to
`the CDC Research Data Center for approval. After approval, analyses are done on site
`at a CDC Research Data Center.
`
`Decedent counts and population- and drug utilization-adjusted rates (both yearly and
`quarterly) will be presented. Drug utilization-adjusted rates will be calculated for the
`period July 2010 through the most recent DIM data available. Results will provide
`national estimates of mortality. Age-specific mortality counts and rates will also be
`provided; due to disclosure protections, some age-specific data might be suppressed
`and/or data could be aggregated temporally or geographically for reporting. A sensitivity
`analysis based on the quality of data reported by states will also be included. Where
`possible, annual state-level rates and decedent counts will be provided; due to
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4569246
`
`

`

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`NDA 020733/S-027
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`disclosure protections, some states might be suppressed and/or data could be
`aggregated temporally or geographically for reporting. All results will be presented at the
`API level only for buprenorphine and comparators (oxycodone, hydrocodone,
`
`methadone).
`
`Concomitant substance analysis for buprenorphine involved deaths will be provided for
`3 classes: benzodiazepines, opioids, and alcohol.
`
`Treatment Episode Dataset (TEDS)
`TEDS is a compilation of client-level data routinely collected by the individual state
`administrative data systems to monitor their substance abuse treatment systems.viii
`Generally, facilities that are required to report to the state substance abuse agency
`(SSA) are those that receive public funds and/or are licensed or certified by the SSA to
`provide substance abuse treatment (or are administratively tracked for other reasons).
`TEDS is an admission-based system and TEDS admissions do not represent
`individuals. Thus, an individual admitted to treatment twice within a calendar year would
`be counted as two admissions. TEDS does not include all admissions to substance
`abuse treatment. It includes admissions at facilities that are licensed or certified by a
`
`state substance abuse agency to provide substance abuse treatment (or are
`administratively tracked for other reasons). In general, facilities reporting TEDS data are
`those that receive state alcohol and/or drug agency funds (including federal block grant
`funds) for the provision of alcohol and/or drug treatment services.
`
`TEDS collects data on primary, secondary, and tertiary substance problems.
`
`Prescription opioids comprise the category: Other opiates and synthetics— and includes
`buprenorphine, codeine, hydrocodone, hydromorphone, meperidine, morphine, opium,
`oxycodone, pentazocine, propoxyphene, tramadol and any other drug with morphine-
`
`like effects. Substance problems are further defined in the item detailed drug code,
`which includes specific opioids such as hydrocodone, oxycodone and buprenorphine.
`Only about half of the states collect information on detailed drug code and while
`selected information is available in national reports, it is not available in TEDS publicly-
`available data sets.
`
`Objective
`x To describe counts and percentages of admissions including buprenorphine as
`the primary, secondary, or tertiary drug of abuse.
`Buprenorphine Categorization
`x Buprenorphine (API)
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4569246
`
`

`

`NDA 020732/S-023
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`NDA 022410/S-039
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`Comparators (as captured in TEDS Annual Reports)
`x Any opiates
`x Oxycodone (Oxycontin, Percocet)
`x Hydrocodone (Vicodin)
`x Hydromorphone (Dilaudid)
`
`x Non-prescription methadone
`
`x Other opiates or synthetics
`
`x Heroin
`
`x Alcohol and Other illicit drugs
`
`o Alcohol
`o Marijuana/hashish
`o Cocaine
`– Crack
`– Other Cocaine
`o Stimulants
`– Methamphetamines/speed
`o Tranquilizers
`– Alprazolam (Xanax)
`– Other benzodiazepines
`o Sedatives
`Analysis
`x All treatment admission data will be obtained from published Annual Reports.
`Data for all years in which they are available will be provided as well as for other
`drugs of abuse for context including alcohol and illicit drugs. References to any
`
`tables used will be included. For all tables and figures, the total number of
`admissions for each data point will be included where applicable. Possible
`explanations for the notable increase in abuse reports for buprenorphine
`between 2014 and 2016 will be provided.
`
`Abuse and Misuse of Buprenorphine by Adolescents and Young Adults
`NSDUH data will be utilized to characterize abuse and misuse in adolescent (12- 17
`years of age) and young adult (18 to 25 years of age) populations using the same
`methodology described previously (Section 4.2.5).
`
`Additional data sources that characterize abuse and misuse in adolescent and young
`adult populations will be explored and included if available.
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4569246
`
`

`

`NDA 020732/S-023
`NDA 020733/S-027
`NDA 022410/S-039
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`
`National Survey on Drug Use and Health (NSDUH)
`Objective
`x To describe buprenorphine, use and misuse among adolescents (12-17 years of
`age) and you