risk reduction final-rev
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Risk Reduction
Dr. Melinda Campopiano, MD Medical Officer, Substance Abuse and Mental Health
Services Administration (SAMSHA)
Dr. Jag Khalsa Chief, Medical Consequences Branch, DPMC, National
Institute on Drug Abuse
Dr. Douglas Throckmorton, MD Deputy Director for Regulatory Programs in the Center for
Drug Evaluation and Research, FDA
Learning Objectives
1. Describe SBIRT and define its use to clinicians.
2. Investigate the use of abuse deterrent formulations.
3. State evidence of the emerging epidemic of Hepatitis C infection in youth transitioning from prescription drug abuse to injection drug use.
4. Outline solutions to reduce risk of Hepatitis by prescribers
Disclosure Statement
• Melinda Campopiano has no financial relationships with proprietary entities that produce health care goods and services.
• Jag Khalsa has no financial relationships with proprietary entities that produce health care goods and services.
• Douglas Throckmorton has no financial relationships with proprietary entities that produce health care goods and services.
SBIRT: Screening, Brief Intervention and Referral to Treatment
Melinda Campopiano von Klimo, MD Division of Pharmacologic Therapies Center for Substance Abuse Treatment
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SBIRT
• “Comprehensive, integrated, public health approach
to the screening and identification of risky alcohol and
drug use, and the timely delivery of brief interventions
aimed at reducing risk.”
• Provides the basis for the 2009 VA/DOD clinical
practice guidelines.
• Validated by the USPSTF (Grade: B
Recommendation).
• Adopted by TJC as an ORYX measure.
Goals of SBIRT
To provide empirically-based and clinically useful practices to prevent alcohol and drug use disorders and intervene when evidence suggests at-risk or harmful
consumption patterns and consequences of use.
Iden%fying pa$ents whose substance use is at hazardous or harmful levels.
Exploring the nega$ve consequences of substance use with pa$ents for the purpose of mo$va$ng posi$ve behavior change.
Ac%vely Assis%ng pa$ents with appropriate treatment and linkages to recovery support for pa$ents who require more extensive treatment and access to specialty care.
Screening
Detects health problems related to hazardous and harmful substance use at an early stage before acute or chronic disease result.
Uncovers substance use patterns that increase future disease risk and can complicate the course and management of health problems.
Prompts assessment of persons who screen positive for at-risk substance use.
Provides the opportunity to reinforce positive behavior by persons who screen negative.
Brief Intervention
Brief dialogues between the medical provider and the patient that assist patients in realizing how their substance use may be putting them at risk for negative health and social consequences and attempts to motivate patients to adopt healthier behaviors.
Successful application of appropriate treatment and transitions to and from treatment and between levels of care are supported by active development of a working relationship with your community substance abuse treatment providers.
SBIRT is Effective
Solberg et al., 2008
• SBIRT is a clinically effective and cost-efficient approach to the diagnosis and management of substance use disorders.
• SBIRT is effective for patients in a variety of health care settings including emergency departments, clinics and private office settings.
• SBIRT has been widely studied and has been found to be highly effective in reducing substance use, especially alcohol use.
• SBIRT reduces the harms related to alcohol use such as accidents, injuries, depression and mortality.
• SBIRT appears to be effective in reducing the harmful consequences of other substance use disorders.
• Small to moderate reductions in alcohol consumption that are sustained over 6 to12 month periods or longer.
• Led to reduced hospital admissions, traumas and injuries up to 3 years post intervention.
Gentilello, 1999; Solberg, Maciosek, & Edwards, 2008
Patterns of Prescription Drug Misuse
Dependent – High risk use associated with psychological and physiological dependence
Harmful and Hazardous Use – A pattern or quantity of drug misuse which intermittently places an individual at risk for harm
Low Risk Prescription drug use– A pattern of prescription drug use which does not exceed recommended levels; high risk behaviors are avoided
Primary Care Interventions
Screening Incorporated into general
medical care
Done with a validated screening instrument
Brief Intervention Hazardous/harmful use: Motivational discussion focused on raising the
individuals awareness of their substance use and its
consequences .
Brief Treatment Moderate to high risk use:
Brief treatment is more comprehensive than a brief
intervention and may require a certified provider.
Referral to Treatment Alcohol or drug abuse/
dependence: Patient is referred to treatment. This is
a proactive process that facilitates patient access to
care...
Screening, Brief Intervention, and Referral to Treatment (SBIRT)
SBIRT and Prescription Medication Safety
• Risk stratify patients prior to opioid prescribing
• Provide safe opioid use education • Identify need for Substance Use
Disorder treatment • Targeted risk reduction for overdose
prevention
www.integration.samhsa.gov/clinical-practice/sbirt
melinda.campopiano@samhsa.hhs.gov
Rx Drug Abuse to Injection Drug Use and Infections: Risk Reduction and Treatment Management
National Institute on Drug Abuse DPMCDA
Epidemiology
• Substance Abuse: • 200-500 m, 110 m life-time users, 19 m current • Cost to the US society: • $561 billion/year • Illicit drugs, $181b, tobacco, $195b, alcohol, $185b • (Diabetes, $160b, Cancer, $210b)
• Rx Drug Abuse • Among 18-25 yr olds-12.7% (NSDUH 2012) • Non-medical past year use of Pain relievers:
9.8%
Illicit and Prescription Drug Abuse-MTF 2012
Deaths from Opioid Pain Relievers
8.8
22.3 22.6
14.7
7.6
0.3 1.8 2.5 1.8 1.5
0
5
10
15
20
25
12 to 17 18 to 25 26 to 34 35 to 49 50 and older
Prescription Opioid Misuse Heroin Use
Age
Lifetime Prescription Opioid Misuse and Heroin Use among Persons 12 and Older: 2011
%
Source: SAMHSA, NSDUH, 2012 S. Lankenau, PhD
14.5 14.6 15.2
14.2 13.1
12.4 12.3
11.4
8.9 10.1
10.8 10.8 10.8 10.8 11.6
11.5
5 5.6
5.1
5.4
5.1 5.2 5 4.7
1.6 1.6 1.5 1.6 1.5 1.4 1.7 1.8 1.2 1.4
1.7 1.8 1.8 2 2 2.4
0
2
4
6
8
10
12
14
16
2003 2004 2005 2006 2007 2008 2009 2010
codeine oxycodone hydrocodone heroin methadone
Lifetime Opioid Misuse among 18 to 25 Year Olds: 2003-10 Yo
ung
Adu
lt M
isus
ers
(%)
Source: SAMSHA, NSDUH, 2004-2011 S. Lankenau, PhD
Rates of Opioid Overdose Deaths, Sales, and Treatment Admissions: 1999-2010
Source: CDC, MMWR, 2011 S. Lankenau, PhD
Substance Abuse Co-morbidity
• CNS and Other Physiological Systems
• Depression, Anxiety disorder, Conduct disorder, PTSD, Neuropathy
• Cardiovascular, Hepatic, Metabolic, Drug-interactions
• Infections
Pharmacological Interventions
Medical detoxification and treatment
• Opiates (Methadone, LAAM, buprenorphine)
• Nicotine (“patch”) • Sedative/Hypnotics • Alcohol • Cocaine • Hallucinogens and Club Drugs
Interventions
SETTINGS • Outpatient Drug Rehab and Drug
Treatment Centers
• Inpatient Short-term Drug Rehab and Drug Treatment Centers
• Inpatient Long-Term Drug Rehab and Drug Treatment Centers (Residential)
• (Provide care 24 hr/d [TCs]
• Integrated Treatment Centers
Epidemiology
• Infections:
• Approximately 3 billion worldwide
• TB, 2.3 billion • HIV, 33 million • Viral Hepatitis: B: 300 million, C: 170 million
National Institute on Drug Abuse DPMCDA
Treatment of HIV
HIV
Treatment saves lives Extends life for 15 years (UK study)
Guidelines: CD4 counts, <350 Anti-retroviral medications: 24 in 5 classes
PIs NRTIs NNRTIs Fusion inhibitors
Integrase Inhibitors
Amprenavir Abacavir, Apricitabine Delavirdine Enfiurvir5de,T20 Raltegravir
Atazanavir Didanosine (ddI) Efavirenz Maraviroc Daranuvir Emtricitabine, Entecavir Nevirapine
Fosamprenavir Lamivudine Etravirine Indinavir Stavudine Rilpivirine Lopinavir Tinofovir, Adefovir (NtRTIs) Nelfinavir Zalcitabine Ritonavir Zidovudine (AZT) Saquinavir Tipranavir
PIs=Protease inhibitor s; NRTIs=Nucleoside or nucleotide reverse transcriptase inhibitors; NNRTIs=Non-Nucleoside reverse transcriptase inhibitors ; IIs=Integrase inhibitors
National Institute on Drug Abuse DPMCDA
Viral Hepatitis C Infection
A type of liver inflammation caused by the hepatitis C virus (HCV), which can progress to a chronic liver disease in up to 85% of those
infected (CCSA, 2005; CDC, 2006).
• Enters the body when blood from an infected person comes in contact with blood of a non-infected person (Basrur, 2006)
• Uses liver cells to multiply; the body’s immune system in turn attacks the infected cells, causing them to become inflamed, damaged and even destroyed (Winston & Winston, 2005)
• Constantly changes once inside the body. This makes it difficult for the body’s immune system to clear the virus (CLF, 1999)
National Institute on Drug Abuse DPMCDA
Viral Hepatitis C
• Is 10-15 times more infectious through blood than the HIV (Health Canada, 2002)
• Is tough and can live up to 4 days outside of the human body (CDC, 2006)
• Up to 6 different versions (genotypes) and several subtypes (CLF, 1999)
• Does not have a vaccine to prevent infection (CDC, 2006)
• Can be successfully treated in 40-80% of people, depending on the virus genotype
• IDU: A MAJOR ROLE IN ACQUISITION AND TRANSMISSION OF HCV AND HIV
• 20-40% HCV infection in IDUs; up to 90+% in HIV-infected IDUs
National Institute on Drug Abuse DPMCDA
Treatment of HIV
HIV
Treatment saves lives Extends life for 15 years (UK study)
Guidelines: CD4 counts, <350 Anti-retroviral medications: 24 in 5 classes
Annual age-adjusted mortality, 1999-2008, >22m
death records*
* From: K Ly et al, Ann Intern Med 2012; 156:271-8
Incidence of Acute Hepatitis C, by Age Group: 2000-09
Source: CDC, NNDSS, 2010 S. Lankenau, PhD
Rates of Newly Reported Cases of Hepatitis C among Persons Aged 15--24 years and Other Age Groups, Massachusetts: 2002--09
Source: CDC, MMWR, 2011 S. Lankenau, PhD
National Institute on Drug Abuse DPMCDA
Stages of Liver Damage
National Institute on Drug Abuse DPMCDA
Natural History of HCV Pathology HCV
National Institute on Drug Abuse DPMCDA
Treatment of Infected Drug Abusers
HCV
Highest prevalence (50-90%) Highest incidence (10-40%/year)
~ 1 million IDUs with HCV in the US
Barriers to Care: poverty, homelessness, drug abuse, mental health, negative health experiences Lack of available services; health, social support etc.; lack of comp primary care Physician concerns: poor adherence, neuropsych side effects; re-infection Few people who inject drugs are in care; even fewer receive treatment
Edlin
National Institute on Drug Abuse DPMCDA
Treatment of Infected Drug Abusers
HCV
TREATMENT MODELS Collaborative: Community-based Needle exchange prog and tertiary
Multidisciplinary: Primary care, mental health care, substance abuse tx and intensive care tx.
Integrated: Staff cross institutional boundaries, tertiary care provided in community-based settings
Intensive case management: Effective Edlin (an example of 69% SVR, 6% drop-out)
National Institute on Drug Abuse DPMCDA
Treatment of Infected Drug Abusers HCV
TREATMENT: Pharmacologic treatment:
Ribavirin (Ribapak, Rebeton [Schering])
peg-Interferon alfa 2b (Pegintron, Merck)
Telaprevir (Incivek, Vertex)
Bociprevir (Victrelis-Meck)
Combinations
Universal preventive vaccine (horizon)
Caution: Severe ADRs with the first two.
Staph aureus, Pseudomonas, Streptococcal strains A, B, & viridans Endocarditis (infection of the heart valves):
Tx: Penicillin/streptomycin, gentamycin, naficillin etc., cephalosporins-ciprofloxacin, rifampin
Streptococcal infections, E.coli, Klebsille, Clostridia, fungal pathogens e.g., Candida species Skin and soft tissue infections:
Tx: antifungal and antibiotics Pseudomonas aeruginosa, and fungal infections Bone joint infections-osteomyelitis:
Tx: antibiotics
Medical Consequences (Infections)
Viral Hepatitis-B, C, D, from parenteral drug use Hepatitis/hepatic fibrosis, liver cancer:
Tx: vaccines for A and B; interferons, ribavirin, boceprevir, telaprevir
HTLV-I and II: Human T-cell Leukemia/lymphoma virus: types I and II more severe consequences if co-infected with HIV-1: Cancers, immune dysfunction, neurological disorders:
Tx: ARTs, interferons
Cytomegalovirus (CMV), Epstein Barr virus (EBV) Pathogens found when immune system is severely impaired (e.g., with HIV): Neurological, ocular and GI disorders; Tx: acyclovir, foscarnet, gancyclovir.
Medical Consequences: Infections (contd.)
Human immunodeficiency Virus (HIV): AIDS:
Tx: ARVs (PIs, NRTIs, NNRTIs, Fusion, and CCR5 blocker (Selzentry)
HIV: Pneumocystis carinii pneumonia: affects the respiratory tract-immunodeficiency, AIDS-defining condition:
Tx: Dapsone, pentamidine, atovaquone
Mycobacterium tuberculosis: Tuberculosis (TB) of the lung, and other organs:
Tx: isoniazid+pyridoxine; isoniazid+rifampin, pyrazinamide, ethambutal, streptomycin, Cipro.
Medical Consequences: Infections (contd.)
Toxoplasmosis gondii: protozoal parasite leading to toxoplasmic encephalitis with clear neurologic signs:
Tx: TMP-SMX (Bactrim); dapsone+pyrimethamine+folic acid
Fungal infections: Candida, Histoplasmosis, cryptococcoses, coccidiomycosis Vaginitis, meningitis:
Tx: fluconazole, ketoconazole, itraconazole.
Opportunistic Viral Infections: Herpes simplex virus (HSV) Vaginitis and other mucocutaneous tract infections:
Tx: acyclovir
Medical Consequences: Infections (contd.)
Risk Reduction
• Screening/Testing • Counseling/Messaging/
Education • Referral • Intervention/Prevention/
Treatment • Reduce IDU/Safer Injecting/
Sexual Transmission • Reduce Alcohol use • Medical Care/Tx as Prevention • Follow-up
National Institute on Drug Abuse Medical Consequence Branch
Contact
National Institute on Drug Abuse Medical Consequence Branch
• April 2 – 4, 2013 • Omni Orlando Resort • at ChampionsGate
Douglas C. Throckmorton MD Deputy Director for Regulatory Programs
CDER, FDA
Agenda
• Background: FDA efforts to improve human abuse liability assessment and regulation
• Abuse-Deterrent Opioids Draft Guidance
52
Overall Message
• Incentivizing the development and use of abuse-deterrent formulations is one important piece of ongoing FDA work on opioids abuse
• FDA is committed to providing guidance and to taking a flexible approach in this area of emerging science focused on public health
• Rigorous scientific data are needed to demonstrate a new formulation is abuse-deterrent
53
54
A Major Public Health Issue
Source: CDC NCIPC November 2011
Part of Larger FDA Efforts to Confront Prescription Drug Abuse and Misuse
• Improving the use of opioids through careful and appropriate regulations
• Improving the use of opioid through education of prescribers and patients
• Improving the use of opioids through partnership and collaboration
• Improving the use of opioids through improved science and labeling
55
56
Improving the Use of Opioids Through
Education • Opioid Risk Evaluation and
Mitigation Strategy (REMS)
57
ER/LA Opioid REMS
Go to FDA.GOV and type opioid REMS in search box
or http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm163647.htm
58
Opioids: FDA Risk Evaluation and Mitigation Strategy (REMS)
• Focus is long-acting and extended-release opioids (ER/LA opioids) • Disproportionate share of misuse and abuse
• Manufacturers required to make educational materials available for prescribers and patients based on FDA-approved materials • CE for prescribers to encourage participation
58
ER/LA REMS: Recent Actions
• Continuing Education materials now available • https://search.er-la-opioidrems.com/Guest/
GuestPageExternal.aspx
• FDA ‘Letter’ to prescribers highlighting availability of REMS educational materials • Take advantage of the CE materials now available at
low (or no) cost • Know and apply the information in the latest approved
labels • Educate patients on opioids use, risks and proper
storage/disposal 59
60 60
Improving Opioids Use Through Partnership: FDA Safe Use Initiative
• Medicines are essential for the treatment of an important human condition (pain)
• Pain has both medical and social aspects to its treatment • No single entity or institution ‘owns’ the problem
• Multiple tx modalities exist, including several classes of drugs (Rx and OTC): opiates, NSAIDs, APAP…. • The available drugs all have ‘challenges’
• Complex social, regulatory and legal issues
61
Improving Opioids Use Through Partnership
• FDA need to work in partnership with other parts of the healthcare system to promote the best uses of drugs • FDA Safe Use Initiative—Focus on
Collaboration
61
62
Safe Use Activities on Opioids
• Physician Patient Agreement (PPA) development • Partnership with multiple groups to craft and test a
model PPA to be used when valuable • FDA convened pain management specialists,
GPs, pharmacists, dentists and nurse practitioners to work on potential models for public use
• PDMPs and Data-sharing • Collaborating with Brandeis University to pilot and test
a surveillance tool using integrated PDMP data from multiple states 62
Improving the Use of Opioids Through Regulatory Guidance and Improved Labeling
• Improving the science of abuse assessment before a drug is on the market, so that appropriate controls are put in place to reduce the likelihood that a drug will be abused after marketing
• Protecting public health through accurate labeling of drugs that can be abused
• Recognizing the development of successful abuse-deterrent formulations through labeling to encourage their use
63
Abuse-Deterrent Opioids Guidance
• Opioids specially formulated to reduce abuse are one potentially important step toward creating safer opioids
• Guidance on their development was promised as part of ONDCP Rx Drug Abuse Plan (2011)
• Guidance mandated under FDASIA* • Goal date January 9, 2013
64 * Food and Drug Administration Safety and Innovation Act
Background: Types of Abuse-deterrent Technologies
• Physical/Chemical • OxyContin • Opana ER • Palladone (now withdrawn)
• Agonist/Antagonist • Suboxone (contains naloxone)
• Aversion • E.g., soap added to burn nose if insufflated
• Delivery systems • Depot formulations, implants
• Pro-drugs 65
Background: Examples of Reformulated Opioids: Limited Experience
• (oxycodone ER) • Original formulation approved 1995 • Reformulated OxyContin approved 2010
• (oxymorphone ER) • Original formulation approved 2006 • Reformulated Opana approved 2011
• (oxycodone IR) • (hydromorphone IR in OROS) • (buprenorphine/naloxone) • (morphine/naltrexone)
66
Background: Opioids with ‘Abuse-Deterrent’ Claim in Labeling
• None to date • Science of abuse deterrence is new
• Technologies and how to assess them are rapidly evolving
• Conclusions need to be based on rigorous assessment of best available science
67
Background: Developing Guidance on Abuse-Deterrent Formulations
• Broad interest in issue…. • Discussed at Public Advisory
Committees • Topic at several meetings: 2008 to 2010 • Tone generally conservative about data
needed to conclude a new formulation is abuse-deterrent
68
Abuse-Deterrent Opioids Draft Guidance: Highlights
• Pre-Market Assessment of Abuse-Deterrent Features • Manufacturing: e.g., crushing, extraction • Pharmacokinetics (PK) • Clinical Abuse Potential Studies • Statistical analysis
• Post-Market Assessment of Impact on Abuse • Labeling Claims for Abuse-Deterrent Formulations
• Tier 1: Physical/chemical Barriers to Abuse • Tier 2: PK Data • Tier 3: Demonstration of Reduced Abuse Potential • Tier 4: Demonstration of Reduced Abuse (Postmarket)
• Areas of Additional Research Needs 69
Abuse-Deterrent Opioids Draft Guidance: Highlights
• Overall Purpose • Reflect state of the science of abuse
deterrence (relatively new), and need to take flexible while still rigorous, scientific approach in evaluation and labeling of drugs as data accumulates
70
Abuse-Deterrent Opioids Draft Guidance: Highlights
• Goals: Two over-arching goals: • Encourage the development of successful
abuse-deterrent formulations of opioids • Assure appropriate development and
availability of generic drugs, reflecting their importance in US healthcare
• Accomplishing this: encouraging the use of successful abuse-deterrent formulations through accurate labeling
71
Abuse-Deterrent Opioids Draft Guidance: Highlights
• Goals (cont) • Outline the studies to be conducted for
assessing potential abuse-deterrent formulations (4 categories)
• Give advice on conduct of studies • Assessment of new formulations • Assessment of clinical impact of new
formulations • Post-marketing evaluation of
new formulations 72
Abuse-Deterrent Opioids Draft Guidance: Highlights
• Goals (cont): Evaluation and Labeling • Outline how FDA will evaluate studies
• Focus will be on rigor and consistency of studies and analyses
• Outline potential claims in labeling of abuse-deterrence based on data to encourage use of successful formulations
• Four ‘tiers’ of labeling explicitly laid out in Guidance depending on the types and quality of data available
73
Labeling Claims for Abuse-Deterrent Formulations
• Grouped according to source and type of data • Tier 1: Physical/Chemical Barriers to Abuse
• Examples: data on crushing and extraction • Tier 2: PK Data
• Clinical serum concentrations (e.g., Tmax, Cmax) • Tier 3: Demonstration of Reduced Abuse
Potential • Clinical Abuse Potential Studies
• Tier 4: Demonstration of Reduced Abuse • Postmarketing data on use and misuse of marketed
product • Differs according to technology
used to create formulation 74
Abuse-Deterrent Opioids Draft Guidance: Highlights
• Goals (cont): Improving the science by identifying areas where work is needed: • Characterizing the quantitative link between:
• Changes in the pharmacokinetics of opioids in different formulations
• Results of clinical studies using those same formulations
• Differences in abuse in the community • Characterizing the best methods to analyze clinical
data on abuse • Characterizing the best methods to analyze
the impact of formulations on rates of abuse in the community 75
Issues
• Does not address how FDA will approach generics evaluation, approval, and withdrawal
• Does not set ‘bright line’ standard of what constitutes meaningful ‘abuse deterrence’ • Will need more experience before we can set such a
standard • Few examples of well-characterized formulations to date
• Need more data on the link between non-clinical and pre-market studies and post-market impact on abuse, overdose, and death
76
Next Steps
• Currently collecting comments to a public Docket on the Draft Guidance
• Meeting to discuss Draft Guidance planned for September 30 and October 1, 2013
77
Conclusions
• Draft Guidance is one part of the work FDA is doing to improve the use of opioids and reduce their abuse
• Draft Guidance provides a roadmap to flexible assessment of abuse-deterrent technologies based on available science
• Draft Guidance offers meaningful incentives for companies to develop new technologies
• Draft Guidance identifies areas of needed scientific work
• External discussion and comment key to help inform necessary science and changes to the Guidance
78
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