Clinical Track, National Rx Drug Abuse Summit, April 2-4, 2013. Risk Reduction presentation by Dr. Melinda Campopiano, Dr. Jag Khalsa and Dr. Douglas Throckmorton.

1. 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

2. 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

3. 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.

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to 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

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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

13. • 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

14. 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 Primary Care
which intermittently places Interventions
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

15. 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 that
their 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.

16. 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

17. www.integration.samhsa.gov/
clinical-practice/sbirt

18. melinda.campopiano@samhsa.hhs.gov

19. Rx Drug Abuse to Injection Drug Use and Infections:
Risk Reduction and Treatment Management

20. National Institute on Drug Abuse DPMCDA

21. 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%

22. Illicit and Prescription Drug Abuse-MTF
2012

23. Deaths from Opioid Pain Relievers

24. Lifetime Prescription Opioid Misuse and Heroin Use
among Persons 12 and Older: 2011
Prescription Opioid Misuse Heroin Use
25
22.3 22.6
20
14.7
15
%
10 8.8
7.6
5
1.8 2.5 1.8 1.5
0.3
0
12 to 17 18 to 25 26 to 34 35 to 49 50 and older
Age
Source: SAMHSA, NSDUH, 2012
S. Lankenau, PhD

25. Lifetime Opioid Misuse among 18 to 25 Year Olds: 2003-10
codeine oxycodone hydrocodone heroin methadone
16
15.2
14.5 14.6 14.2
14
13.1
Young Adult Misusers (%)
12.4 12.3
12 11.5
11.6 11.4
10 10.8 10.8 10.8 10.8
10.1
8.9
8
6 5.6 5.4
5
5.1 5.1 5.2 5 4.7
4
1.8 2 2 2.4
1.6 1.6 1.7 1.8
2
1.5 1.6 1.5 1.4 1.7 1.8
1.2 1.4
0
2003 2004 2005 2006 2007 2008 2009 2010
Source: SAMSHA, NSDUH, 2004-2011
S. Lankenau, PhD

26. Rates of Opioid Overdose Deaths, Sales, and
Treatment Admissions: 1999-2010
Source: CDC, MMWR, 2011
S. Lankenau, PhD

27. Substance Abuse Co-morbidity
• CNS and Other Physiological
Systems
• Depression, Anxiety disorder,
Conduct disorder, PTSD,
Neuropathy
• Cardiovascular, Hepatic, Metabolic,
Drug-interactions
• Infections

28. Pharmacological Interventions
Medical detoxification and treatment
• Opiates (Methadone, LAAM,
buprenorphine)
• Nicotine (“patch”)
• Sedative/Hypnotics
• Alcohol
• Cocaine
• Hallucinogens and Club Drugs

29. 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

30. Epidemiology
• Infections:
• Approximately 3 billion worldwide
• TB, 2.3 billion
• HIV, 33 million
• Viral Hepatitis: B: 300 million, C: 170 million

31. 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

32. PIs
NRTIs
NNRTIs
Fusion
Integrase
inhibitors
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

33. 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)

34. 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

35. 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

36. Annual age-adjusted
mortality, 1999-2008, >22m
death records*
* From: K Ly et al, Ann Intern Med 2012; 156:271-8

37. Incidence of Acute Hepatitis C, by Age Group: 2000-09
Source: CDC, NNDSS, 2010 Lankenau, PhD
S.

38. 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

39. National Institute on Drug Abuse DPMCDA
Stages of Liver Damage

40. National Institute on Drug Abuse DPMCDA
Natural History of HCV Pathology
HCV

41. 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

42. 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)

43. 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.

44. 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, 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

45. Medical Consequences: Infections (contd.)
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.

46. 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.

47. 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

48. 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

49. National Institute on Drug Abuse Medical Consequence Branch
Contact

50. National Institute on Drug Abuse Medical Consequence Branch

51. Douglas C. Throckmorton MD
Deputy Director for Regulatory Programs
CDER, FDA
• April 2 – 4, 2013
• Omni Orlando Resort
• at ChampionsGate

52. Agenda
• Background: FDA efforts to improve
human abuse liability assessment and
regulation
• Abuse-Deterrent Opioids Draft
Guidance
52

53. 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
54
Source: CDC NCIPC November 2011

55. 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)
56

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
57

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
58

59. 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. 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 60
60
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
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
62
from multiple states 62

63. 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

64. 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

65. 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

66. 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

67. 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

68. 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

69. 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

70. 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

71. 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

72. 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

73. 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

74. 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

75. 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

76. 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

77. 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

78. 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