Role of Stakeholders in the Opioid Epidemic:

Including Pharma and the FDA

G. Caleb Alexander, MD, MS
galexand@jhsph.edu
April 14, 2016

Disclosures and Funding

Disclosures
Consultant: IMS Health, PainNavigator, Delta Faucet
Chair, Food and Drug Administration, Peripheral and
Central Nervous System (PCNS) Advisory Committee
Funding
AHRQ and NHLBI
Centers for Disease Control and Prevention
U.S. Food and Drug Administration
Arnold Foundation, Robert Wood Johnson Foundation
PhRMA

What I say is my own $0.02

at the present time and sometimes you get what you pay for

Johns Hopkins
Center for Drug Safety & Effectiveness
The Center will improve the safe and effective use of
medicines in the United States and around the world
through a four-part mission of training, research, clinical
care and public service

Outline

Background
Manufacturers
Food and Drug Administra:on
The Way Forward

What is the top selling drug in the U.S.?

A.Aripiprazole (Abilify)
B.Sildafenil (Viagra)
C.Hydrocodone/APAP (Vicodin)
D.Atorvastatin (Lipitor)
E.Esomeprazole (Nexium)
F.Etanercept (Enbrel)
6

hBps://www.youtube.com/watch?v=dnEERbXe5ZU

Complex Problem
Stakeholders
Diversion
Externalities
Addiction

Undertreatment
Of Pain

Complex Problem
Stakeholders
Diversion
Externalities
Addiction

Undertreatment
Of Pain

STOP

Suppose your favorite sports team just

won the big game
Why did they win?
BeBer athletes?
BeBer strategy?
More prac:ce?

Now, suppose your team just lost

Why did they lose?

Bad weather?
Poor calls?
Too many injuries?

Where you stand depends

upon where you sit

The Blind Man and the Elephant?

17

Stakeholders

Key issues

Health insurers

Coverage and reimbursement; costs of care; quality

Prescribers

Prescriber autonomy; tension between regulatory or

enforcement oversight and ability for professional self-policing

Pharmacies

Pharmacist autonomy; pressure to identify and intervene upon

rogue prescribers or dispensaries

Wholesalers

Important role in supply chain; subject to fines and other legal

action for support of pill-mills

Consumer groups

Access to therapies; historical under treatment of pain

Manufacturers

Marketing and promotion of therapies; effort to identify safer

therapies less prone to abuse or diversion; market incentives

Public health agencies

Availability of treatment services; costs for the safety net

Regulatory authorities

Market access; drug labeling; drug promotion; attaining public

health goals while not interfering with practice of medicine

Outline

Background
Manufacturers
Food and Drug Administra:on
The Way Forward

Manufacturers
Abuse vs. addiction
Abuse deterrent formulations
Marketing and promotion

19

Similarities Between Illicit & Prescription Drugs

Dr. Nora D. Volkow, Director, (NIDA) Na:onal Ins:tute of Health.

Compare and contrast

HTML: FDA Science Board 2016 Meeting
https://collaboration.fda.gov/p68dsl6oy5c/?
launcher=false&fcsContent=true&pbMode=normal
Time: 2:30-5:00 PM Session
Speaker #14: 1:05:38 (Richard Fanelli, Head of Regulatory
Affairs, Purdue Pharma)
Speaker #15: 1:09:18 (Andrew Kolodny, Physicians for
Responsible Opioid Prescribing)

21

22

Types of Abuse Deterrence

Type of Abuse
Deterrence
Physical Barrier

Chemical Barrier

Deni3on

Prevents physical tampering such as chewing, cu_ng, OxyCon:n OP, Opana

crushing, grinding, or gra:ng
ER, ReXista, DEXERx
(COL-003), TQ-1015,
Exalgo, Ultram ER
Resists extrac:on with common solvents such as
Acurox, OxyCon:n OP,
water or alcohol
ReXista, DEXERx, Egalet
Morphine, Ultram ER

Agonist/Antagonist Antagonist is released upon manipula:on, which

Combina3on
reduces or defeats euphoric feeling
Aversion

Example(s)

Talwin NX, Suboxone,

Embeda, Oxytrex,
OxyNal
OXECTA, Acurox

Produces unpleasant and irrita:ng eects if drug is

tampered or dosage is altered
Alternate Route of Method of drug administra:on, such as intramuscular Probuphine
Delivery/
injec:on or subcutaneous implant, disfavors abuse
Administra3on
Prodrug
Biologically inac:ve un:l metabolized into an ac:ve
NRP-290
form, usually in the gastrointes:nal tract

Loureno, et al Expert Opin Drug Deliv. 2013;10:229-40.

Ques:on: Do abuse-deterrent
formula:ons (ADFs) have a lower,
higher, or the same addic:ve
poten:al as their non-ADF
formula:on?

Percent of Respondents

60%
50%
40%
30%
20%
10%
0%

Lower

Same

Higher

Addic3ve Poten3al of ADFs Compared

to Non-ADF Formula3ons

24

Slide from A. Kolodny. 2013.

Settlements for allegations of unlawful

promotion
Merck and Co. (2007)
$4.85 billion in blanket settlement on claims of patients who suffered heart
attacks and strokes caused by painkiller, Vioxx (no admission of fault)

GlaxoSmithKline (2007)
$64M class-action settlement on claims that GSK misled consumers about
safety of Paxil (antidepressant) in pediatric patients (no admission of fault)

Eli Lilly (2007)

$500M settlement that played down risks of diabetes from Zyprexa and
promoted off-label use for schizophrenia and bipolar disorder (no admission
of fault)

Bristol-Myers Squib (2008)

$515M across 20 states after charges of Medicaid fraud and charges that
pushed unapproved use of Abilify in the treatment of children (found at fault)

Pfizer (2008)
$894M settlement on claims of unlawful marketing of painkillers Bextra and
Celebrex (no admission of fault)

United States v Caronia - Background

In 2005, Alfred Caronia was a drug rep for Orphan Medical
Zyrem (CNS depressant sodium oxybate)
Approved by FDA to treat narcolepsy

Caronia promoted it to physicians for unapproved indications

(with companys approval)
Insomnia, fibromyalgia
Claimed it was safe in children and elderly, despite warning on the
label that safety was not established in these populations

DOJ investigated Orphan Medical and Caronia for violating

the Food Drug and Cosmetic Act
Manufacturer pleaded guilty, Caronia did not
Caronia was convicted
Probation, community service, $25 fine

United States v Caronia Appeal

Caronia appealed, arguing that he had been prosecuted for
his speech (First Amendment)
Government argued that his speech was evidence of his
intent to misbrand the drug (speech not prosecuted)
Conviction was overturned by the Circuit Court
Court found that the prosecution has criminalized speech
Such restrictions on speech require the government to satisfy
rigorous conditions to justify it (heightened scrutiny)
Court found that restricting off-label promotion in this case does
not directly advance governments interest in reducing unsafe use
because it paternalistically blocks the free flow of information
that could improve a physicians prescribing decisions
It is the physicians role to determine which information is
useful, not the governments

United States v Caronia Consequences

Relaxing restrictions on off-label marketing have
generated many concerns
Physicians and consumers must wade through marketing
claims on their own
Reduces incentives for manufacturers to conduct wellcontrolled trials of potential off-label use
Could lead to proliferation of poorly documented claims
about efficacy and safety of (often high cost) products
Leads to poor prescribing and escalating costs

31

32

Outline

Background
Manufacturers
Food and Drug Administra:on
The Way Forward

Regulatory Interventions
Up-scheduling hydrocodone
Labeling revisions
Prescriber and patient education
Risk Evaluation and Mitigation Strategies (REMS)
Abuse deterrent formulations
Treatments for opioid overdose and dependency
Improved packaging and storage strategies to prevent abuse

34

Qato DM, Alexander GC. JAMA. 2011.

Opioid Labeling
Controlled Substance Act

Schedule II written prescription, no refills, month supply

Schedule III written or oral prescription, refills limited to 6
months, less control of wholesale distribution
Hydrocodone listed as Schedule III, recommended up-scheduling
by DEA in 2003, ultimately recommended for up-scheduling by
FDA October 2013
Decision fraught with controversy
FDA Advisory Committee 19/10
What data would you need in order to weigh in?
What would convince you?
What would you be concerned about?
Why did it take the FDA 10 years to act on the DEAs initial request?

Effect of US Drug Enforcement Administrations Rescheduling of Hydrocodone

Combination Analgesic Products on Opioid Analgesic Prescribing"

36

JAMA Intern Med. 2016;176:399-402.

37

38

4/13/1
6

39

Regulatory: Prescriber Education

FDA mandated a Risk Evaluation and Mitigation
Strategy (REMS) for extended-release opioids.
manufacturers [to] set up training programs and make
available education materials on the safe use of these
products for all U.S. licensed opioid prescribers
Content for the training will .include:
Information on weighing the risks and benefits of opioid therapy,
choosing patients appropriately, managing and monitoring these
patients, and counseling them on the safe use of these drugs, how
to recognize potential and actual misuse, abuse, and addiction.

While prescribers are not required to take this training,

FDA will encourage them to do so

Regulatory: Patient Education

Medication Guides for long-acting opioids should be
given to every patient who receives a prescription.
FDA partners with outside organizations to help
educate patients about the best uses of opioids.
including DrugFree.org (formerly the Partnership for
Drug Free America) and is a member of the National
Council on Patient Information and Education.
FDA maintains a website to educate patients on the
appropriate disposal of opioids once theyre no longer
needed.

Segal J. 2013.

Regulatory: Patient Education

Medication Guides for long-acting opioids should be
given to every patient who receives a prescription.
FDA partners with outside organizations to help
educate patients about the best uses of opioids.
including DrugFree.org (formerly the Partnership for
Drug Free America) and is a member of the National
Council on Patient Information and Education.
FDA maintains a website to educate patients on the
appropriate disposal of opioids once theyre no longer
needed.

Segal J. 2013.

43

Dusetzina SB, et al. Med Care. 2012;50:466-478.

Risk Evaluation and

Mitigation Strategies
Authorized by FDAAA of 2007
Focus is to ensure that benefits of drug
or biologic outweigh its risk
Components of REMS may include:

Medication Guide
Communication Plan
Elements to Assure Safe Use (ETASU)
Implementation System

REMS developed by sponsors, reviewed/approved by FDA

Factors influencing determination of need for REMS include: population
size, seriousness of disease, expected benefit and duration of treatment,
seriousness of known or potential adverse events, product novelty

44

Qato QM, Alexander GC. JAMA. 2011;306:1595-96

Abuse Deterrent Formulations

Abuse-deterrent formulations target the known or
expected routes of abuse, such as crushing in order to
snort or dissolving in order to inject, for the specific
opioid drug substance in that formulation.
FDA considers the development of abuse-deterrent
formulations to be a public health priority and is
encouraging their development.

Segal J. 2013.

46

NEJM. February 2016.

Outline

Background
Manufacturers
Food and Drug Administra:on
The Way Forward

 Informing Evidence with Action

Scaling up evidence-based interventions;
rapidly implementing and evaluating
promising policies and programs

Intervening Comprehensively
All along supply chain; clinic, community
and addiction treatment settings; primary,
secondary and tertiary prevention; creating
synergies across different interventions

Promoting appropriate & safe opioid use

Reducing overuse; focus on safe use,
storage and disposal; optimizing use in
accordance with best practices
48

49

CDC MMWR. May 14, 1999/Vol. 48/No. 18.

52