role of stakeholders in the issue - including pharma and fda

8/18/2019 Role of Stakeholders in the Issue - Including Pharma and FDA

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G. Caleb Alexander, MD, MS [email protected]

April 14, 2016

Role of Stakeholders in the Opioid Epidemic:Including Pharma and the FDA


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• Disclosures

• Consultant: IMS Health, PainNavigator, Delta Faucet

• Chair, Food and Drug Administration, Peripheral andCentral 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


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What I say is my own $0.02 –

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

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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 worldthrough a four-part mission of training, research, clinicalcare and public service

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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®)

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UndertreatmentOf Pain

Externalities

Diversion

Stakeholders

Complex Problem

Addiction


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UndertreatmentOf Pain

Externalities

Diversion

Stakeholders

Complex Problem

Addiction


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STOP


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Stakeholders Key issues

Health insurers

Coverage and reimbursement; costs of care; quality

Prescribers

Prescriber autonomy; tension between regulatory orenforcement oversight and ability for professional self-policing

Pharmacies Pharmacist autonomy; pressure to identify and intervene uponrogue prescribers or dispensaries

Wholesalers

Important role in supply chain; subject to fines and other legalaction for support of “pill-mills”

Consumer groups Access to therapies; historical under treatment of pain

Manufacturers Marketing and promotion of therapies; effort to identify safertherapies 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 publichealth goals while not interfering with “practice of medicine”

The Blind Man and the Elephant?


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Manufacturers

• Abuse vs. addiction

• Abuse deterrent formulations

• Marketing and promotion

XR


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Similarities Between Illicit & Prescription Drugs

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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 forResponsible Opioid Prescribing)

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Types of Abuse Deterrence

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Slide from A. Kolodny. 2013.


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Settlements for allegations of unlawful

promotion

• Merck and Co. (2007)

–

$4.85 billion in blanket settlement on claims of patients who suffered heartattacks and strokes caused by painkiller, Vioxx (no admission of fault)

•

GlaxoSmithKline (2007) –

$64M class-action settlement on claims that GSK misled consumers aboutsafety 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 admissionof fault)

• Bristol-Myers Squib (2008)

–

$515M across 20 states after charges of Medicaid fraud and charges thatpushed 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)


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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 company’s approval)

–

Insomnia, fibromyalgia

–

Claimed it was safe in children and elderly, despite warning on thelabel that safety was not established in these populations

• DOJ investigated Orphan Medical and Caronia for violatingthe Food Drug and Cosmetic Act

–

Manufacturer pleaded guilty, Caronia did not – Caronia was convicted

• Probation, community service, $25 fine


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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 satisfyrigorous conditions to justify it (heightened scrutiny)

–

Court found that restricting off-label promotion in this case doesnot directly advance government’s interest in reducing unsafe use

because it ‘paternalistically blocks the free flow of information’that could improve a physician’s prescribing decisions

–

It is the physician’s role to determine which information is

useful, not the government’s


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United States v Caronia – Consequences

• Relaxing restrictions on off-label marketing have

generated many concerns – Physician’s and consumer’s must wade through marketing

claims on their own

– Reduces incentives for manufacturers to conduct well-

controlled 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


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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

01 Qato DM, Alexander GC. JAMA. 2011.


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Opioid Labeling

• Controlled Substance Act – Schedule II – written prescription, no refills, month supply

– Schedule III – written or oral prescription, refills limited to 6months, less control of wholesale distribution

• Hydrocodone listed as Schedule III, recommended up-scheduling

by DEA in 2003, ultimately recommended for up-scheduling byFDA 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 DEA’s initial request?

’


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

Effect of US Drug Enforcement Administration’s Rescheduling of HydrocodoneCombination Analgesic Products on Opioid Analgesic Prescribing


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Regulatory: Prescriber Education

• FDA mandated a Risk Evaluation and MitigationStrategy (REMS) for extended-release opioids.

!

manufacturers [to] set up training programs and makeavailable education materials on the safe use of theseproducts 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 thesepatients, 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!


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Regulatory: Patient Education

•

Medication Guides for long-acting opioids should begiven to every patient who receives a prescription.

• FDA partners with outside organizations to helpeducate patients about the best uses of opioids.!

including DrugFree.org (formerly the Partnership forDrug Free America) and is a member of the NationalCouncil on Patient Information and Education.

• FDA maintains a website to educate patients on theappropriate disposal of opioids once they’re no longerneeded.

Segal J. 2013.


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Regulatory: Patient Education

•

Medication Guides for long-acting opioids should begiven to every patient who receives a prescription.

• FDA partners with outside organizations to helpeducate patients about the best uses of opioids.!

including DrugFree.org (formerly the Partnership forDrug Free America) and is a member of the NationalCouncil on Patient Information and Education.

• FDA maintains a website to educate patients on theappropriate disposal of opioids once they’re no longerneeded.

Segal J. 2013.


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

Risk Evaluation and


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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: populationsize, seriousness of disease, expected benefit and duration of treatment,seriousness of known or potential adverse events, product novelty

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


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Abuse Deterrent Formulations

•

Abuse-deterrent formulations target the known orexpected routes of abuse, such as crushing in order tosnort or dissolving in order to inject, for the specificopioid drug substance in that formulation.

•

FDA considers the development of abuse-deterrentformulations to be a public health priority and isencouraging their development.

Segal J. 2013.


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1@ NEJM. February 2016.


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• Informing Evidence with Action

–

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

•

Intervening Comprehensively – All along supply chain; clinic, community

and addiction treatment settings; primary,secondary and tertiary prevention; creatingsynergies across different interventions

•

Promoting appropriate & safe opioid use – Reducing overuse; focus on safe use,

storage and disposal; optimizing use inaccordance with best practices


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


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role of stakeholders in the issue - including pharma and fda

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