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, MDDeputy Director for Regulatory Programs in the Center for Drug Evaluation and Research, FDA
Learning Objectives1. 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.
The linked image cannot be displayed. The ﬁle may have been moved, renamed, or deleted. Verify that the link pointsto the correct ﬁle and location. SBIRT: Screening, Brief Intervention and Referral to Treatment Melinda Campopiano von Klimo, MD Division of Pharmacologic Therapies Center for Substance Abuse Treatment
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 SBIRTTo provide empirically-based and clinically useful practices to prevent alcohol and drug use disorders and intervene when evidence suggests at-risk or harmfulconsumption 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.
ScreeningDetects health problems related to hazardousand harmful substance use at an early stagebefore acute or chronic disease result.Uncovers substance use patterns that increasefuture disease risk and can complicate thecourse and management of health problems.Prompts assessment of persons who screenpositive for at-risk substance use.Provides the opportunity to reinforce positivebehavior by persons who screen negative.
Brief InterventionBrief dialogues between the medical provider andthe patient that assist patients in realizing howtheir substance use may be putting them at riskfor negative health and social consequences andattempts to motivate patients to adopt healthierbehaviors.
Successful application of appropriate treatment andtransitions to and from treatment and between levelsof care are supported by active development of aworking relationship with your community substanceabuse treatment providers.
SBIRT is Effective• 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. Solberg et al., 2008
• 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 MisuseDependent – High risk use associated withpsychological and physiologicaldependenceHarmful and Hazardous Use – Apattern or quantity of drug misuse Primary Carewhich intermittently places Interventionsan individual at risk for harmLow Risk Prescription drug use– A pattern ofprescription drug use which does not exceedrecommended levels; high risk behaviors areavoided
Screening, Brief Intervention, and Referral to Treatment (SBIRT) Screening Incorporated into general medical care Done with a validated screening instrument Brief Intervention Referral to Treatment Hazardous/harmful use: Alcohol or drug abuse/ Motivational discussion Brief Treatment dependence: Patient focused on raising the is referred to treatment. This is individuals awareness of Moderate to high risk use: a proactive process thattheir substance use and its Brief treatment is more facilitates patient access to consequences . comprehensive than a brief care... intervention and may require a certified provider.
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
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%
Pharmacological InterventionsMedical detoxification and treatment • Opiates (Methadone, LAAM, buprenorphine) • Nicotine (“patch”) • Sedative/Hypnotics • Alcohol • Cocaine • Hallucinogens and Club Drugs
InterventionsSETTINGS • 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
National Institute on Drug Abuse DPMCDA Viral Hepatitis C InfectionA 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-adjustedmortality, 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: 2000-09Source: CDC, NNDSS, 2010 Lankenau, PhD S.
Rates of Newly Reported Cases of Hepatitis C among PersonsAged 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.
Medical Consequences (Infections)Staph aureus, Pseudomonas, Streptococcal strains A, B, &viridans Endocarditis (infection of the heart valves): Tx: Penicillin/streptomycin, gentamycin, naficillin etc., cephalosporins-ciprofloxacin, rifampinStreptococcal infections, E.coli, Klebsille, Clostridia,fungal pathogens e.g., Candida speciesSkin and soft tissue infections: Tx: antifungal and antibioticsPseudomonas aeruginosa, and fungal infectionsBone joint infections-osteomyelitis: Tx: antibiotics
Medical Consequences: Infections (contd.)Viral Hepatitis-B, C, D, from parenteral drug useHepatitis/hepatic fibrosis, liver cancer: Tx: vaccines for A and B; interferons, ribavirin, boceprevir, telaprevirHTLV-I and II: Human T-cell Leukemia/lymphoma virus: types I andIImore severe consequences if co-infected with HIV-1: Cancers,immune dysfunction, neurological disorders: Tx: ARTs, interferonsCytomegalovirus (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, atovaquoneMycobacterium 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 parasiteleading to toxoplasmic encephalitis with clear neurologicsigns: Tx: TMP-SMX (Bactrim); dapsone+pyrimethamine+folic acidFungal infections: Candida, Histoplasmosis,cryptococcoses, coccidiomycosisVaginitis, meningitis: Tx: fluconazole, ketoconazole, itraconazole.Opportunistic Viral Infections: Herpes simplex virus(HSV)Vaginitis and other mucocutaneous tract infections: Tx: acyclovir
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
Douglas C. Throckmorton MD Deputy Director for Regulatory Programs CDER, FDA• April 2 – 4, 2013• Omni Orlando Resort• at ChampionsGate
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
A Major Public Health Issue 54Source: 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
Improving the Use of Opioids Through Education• Opioid Risk Evaluation and Mitigation Strategy (REMS) 56
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 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
Improving Opioids Use ThroughPartnership: 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 60 60 issues
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 61
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 62 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* Food and Drug Administration Safety and Innovation Act 64
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