Risk reduction final-rev

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

[email protected]

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


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


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)


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


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


Stages of Liver Damage


Natural History of HCV Pathology HCV


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


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)


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.


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


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


•  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


•  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


•  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


•  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


•  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

Documents

Risk reduction final-rev