16-10-17 Advocacy for pain prevention and treatment in children - - PDF document

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16-10-17 Advocacy for pain prevention and treatment in children - - PDF document

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16-10-17 Advocacy for pain prevention and treatment in children Gary A. Walco, PhD Professor of Anesthesiology& Pain Medicine Adjunct Professor of Pediatrics and Psychiatry University of Washington School of Medicine Director of Pain

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Gary A. Walco, PhD Professor of Anesthesiology& Pain Medicine Adjunct Professor of Pediatrics and Psychiatry University of Washington School of Medicine Director of Pain Medicine Seattle Children’s Hospital

Advocacy for pain prevention and treatment in children

October 21, 2016 University of British Columbia, Department of Pediatrics

Disclosures

  • Special Government Employee, United States Food

and Drug Administration, Anesthetic and Analgesic Drugs Products Advisory Committee

  • Chair, Pediatric Research Network for Pain (PRN-

Pain), Co-Chair Pediatric Pain Research Consortium and member of executive committee, Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION)

  • Consultation to Pfizer Pharmaceuticals
  • Contributor to UpToDate

“A small body of determined spirits fired by an unquenchable faith in their mission can alter the course of history.” “We must become the change we want to see.” Mohandas Gandhi

Some inspiration

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A field is born…

1977: Jo Eland: children get far less analgesia (almost none) for the same operative procedures than do adult counterparts 1985: Jill Lawson: neonatal surgery without anesthesia 1985: Neil Schechter: Pediatric Clinics of NA paper on reasons for undertreatment of pain in children and possible remedies 1987: First International Symposium on Pediatric Pain (Donald Tyler and Elliot Krane, Seattle) 1987: Sunny Anand: better survival rates in premature neonates with post-operative pain management 1988: IASP SIG on Pain in Childhood (including committee on advocacy)

Education is not sufficient

  • Multiple studies show physicians do not

follow evidence-based guidelines

  • Fear that evidence-based practice will

suppress the “art” of medicine

  • Scientific evidence
  • Clinical judgment
  • Unacceptable practice deviations?
  • Didactic education is not sufficient
  • Practice-based with rehearsal is better

Kenny NP. Can Med Assoc J 1997;157:33-36

An ethical issue

Walco GA, Cassidy RC, Schechter NL. N Engl J Med 1994; 331:541-544

The fundamental principle of responsible medical care is not “do not hurt” but “do no harm.” Since pain seems harmful to patients, and care givers are categorically committed to preventing harm to their patients, not using all the available means of relieving pain must be justified. All health professionals should provide care that reflects the technological growth of the

  • field. The assessment and treatment of pain

in children are important parts of pediatric practice, and failure to provide adequate control of pain amounts to substandard and unethical medical practice.

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A policy approach

The Assessment and Management of Acute Pain in Infants, Children, and Adolescents PEDIATRICS Vol. 108 No. 3 September 2001 Prevention and Management of Pain in the Neonate: An Update PEDIATRICS Vol. 118 No. 5 November 2006

What about the consumer?

2004 Celeste Johnston McGill University Lonnie Zeltzer UCLA 2005

  • G. Allen Finley

Dalhousie University Gary Walco University of Washington 2006 Steven Weisman Medical College of Wisconsin 2007 Elizabeth Ely CHOP Jennie Tsao UCLA 2008 Bonnie Stevens University of Toronto Anna Taddio University of Toronto William Zempsky University of Connecticut 2010 Elliot Krane Stanford University 2011 Denise Harrison University of Ottawa Jennifer Stinson University of Toronto 2012 Christine Chambers Dalhousie University Renee Manworren Connecticut Children’s Lisa Peters Seattle Children’s 2014 Marsha Campbell-Yeo Dalhousie University Deirdre Logan Harvard University

Some fruits of the labor

  • S. 174/H.R. 963—Children’s

Compassionate Care Act of 2005/2007

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Chronic pain and healthcare reform Leading to this very important publication

March, 2016

Weighing in on the issues…

y

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Sponsors:

  • World Health Organization (Geneva, Switzerland)
  • Bill and Melinda Gates Foundation (Seattle, USA)
  • European Centre for Disease Prevention and Control (Stockholm, Sweden)
  • European Commission, Research Directorate General (Brussels, Belgium)
  • University Children’s Hospital Basel (Switzerland)
  • Adverse events case definitions
  • Pain
  • In response to immunization
  • Associated with immunization process

Needle pain Needle pain

Anna Taddio, BScPhm, PhD University of Toronto Jane Gidudu, MD, MPH CDC William Zempsky, MD University of Connecticut

Major initiative on needle pain

http://phm.utoronto.ca/helpinkids/index.html

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Neil Schechter, MD Harvard University

  • G. Allen Finley, MD

Dalhousie University

International efforts Rockefeller Institute, Bellagio Bellagio Declaration

“Pain is a universal experience among children in healthcare

  • facilities. There is now overwhelming evidence that pain has

both short term and long term negative consequences for the physical and emotional health of the child. The uniform application of available knowledge will significantly reduce the burden of pain and its consequences on children and their families. We believe that all health care facilities should commit to the developmentally appropriate prevention, assessment, and management of pain in children and adolescents aged 0 to 18 years.”

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ChildKind International

  • Policy
  • There is a facility-wide, evidence-informed, written policy on

pain assessment, prevention, and management.

  • Education
  • There are comprehensive and on-going education and

awareness programs for all staff, students/trainees, patients, and caregivers.

  • Assessment
  • All children have pain assessed using an evidence-informed,

developmentally appropriate process, and recorded in the patient record.

ChildKind International

  • Protocols
  • There are specific, evidence-informed protocols for pain

prevention and management,

  • Self‐Monitoring/Quality Improvement
  • There is a regular institutional self-monitoring program of the

above criteria. This program should review protocols, policies, and patient outcomes, with feedback to staff, within the framework of a continuous quality improvement.

ChildKind International: Progress to date

  • Five hospitals have been site visited and certified
  • Boston Children’s Hospital
  • Connecticut Children’s Hospital (Hartford)
  • Seattle Children’s Hospital
  • Hospital for Sick Children (Toronto)
  • Minnesota Children’s (Minneapolis)
  • Other centers now being considered
  • http://childkindinternational.org/
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Pediatric drug development: Choices for pediatricians

Do not treat children with potentially beneficial medications because they are not approved for use in children Treat with medications based on adult studies with limited data or anecdote (off label use)

Drug labeling for children

  • What percent of the medications used in pediatrics

are labeled for indications in children?

Off label, 80% Label, 20% Off label, 50% Label, 50%

United States Europ e

Limited or no data on….

  • Safety
  • Pharmacokinetics (PK)
  • Pharmacodynamics (PD)
  • Serious adverse events (SAE)
  • Efficacy
  • Long-term use
  • Long-term sequelae
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United States Food and Drug Administration

  • 1994: survey data to establish sufficiency for pediatric use and labeling
  • 1997: FDAMA (FDA Modernization Act): pediatric studies lead to patent extension
  • 1998: Pediatric Rule (challenged in 2000, enjoined by the Court in 2002)
  • 2002: Best Pharmaceuticals for Children Act (BPCA)
  • 2003: Pediatric Research Equity Act (PREA) replaced Pediatric Rule
  • 2007: FDAAA (FDA Amendments Act): reauthorization of BPCA and PREA
  • 2012: FDASIA (FDA Safety and Innovation Act)
  • Makes BPCA and PREA permanent
  • Pediatric development plans submitted earlier during drug development

BPCA and PREA

PREA

  • Drugs and biologics
  • Mandatory studies
  • Requires studies only on

indications under review

  • Orphan indications

exempt from study

  • Pediatric studies must be

labeled BPCA

  • Drugs and biologics
  • Voluntary studies
  • Studies relate to entire

moiety and may expand indications

  • Studies may be

requested for orphan indications

  • Pediatric studies must be

labeled

Analgesics with pediatric indications (US)

Acetaminophen, Aspirin, NSAIDs

  • APAP (>2 y)
  • ASA
  • Ibuprofen (> 6 m)

JIA indication (not pain per se)

  • Celecoxib
  • Diflunisal
  • EtodolacXL
  • Indomethcin
  • Ketorolac
  • Mefenamic acid
  • Meloxicam
  • Naproxen
  • Oxaprozin
  • Tolmetin
  • [Rofecoxib was on the list]

Opioids

  • Fentanyl transdermal (>2 y)
  • Buprenorphine injection
  • Fentanyl citrate injection
  • Meperidine

Combination Products

  • Codeine/APAP (> 3 y)
  • Hydrocodone/APAP (>2 y)
  • Pentazocine/APAP
  • Dihydrocodeine/ASA/Caffeine
  • Codeine/ASA/Butalbital/Caffeine
  • Oxycodone/Ibuprofen
  • Pentazocine/Naloxone
  • Carisoprodol/ASA/Codeine
  • Butalbital/APAP
  • Butalbital/APAP/Caffeine

Note: for the 0 to 6 month age group, there are 0

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Pediatric Research Network for Pain (PRN-Pain) Participating sites

— Children’s Health (Dallas, TX) — Children’s Healthcare Atlanta (Atlanta, GA) — CH Boston (Boston, MA) — CH Cincinnati (Cincinnati, OH) — CH Connecticut (Hartford, CT) — CH Colorado (Denver, CO) — CH Los Angeles (Los Angeles, CA) — CH Minnesota (Minneapolis, MN) — CH Philadelphia (Philadelphia, PA) — CH Wisconsin (Milwaukee, WI) — Children’s National MC (Washington, DC) — Duke Children’s (Durham, NC) — Johns Hopkins (Baltimore, MD) — Kosair CH (Louisville, KY) — Lurie CH (Chicago, IL) — Mayo Clinic (Rochester, MN) — Mercy CH (Kansas City, MO) — Phoenix CH (Phoenix, AZ) — Riley CH (Indianapolis, IN) — St. Jude (Memphis, TN) — Seattle CH (Seattle, WA) — Shriners Hospital (Portland, OR) — Stanford Children’s Health (Palo Alto, CA) — Texas CH (Houston, TX) — UCLA—Mattel CH (Los Angeles, CA) — Alberta CH (Calgary, AB) — British Columbia CH (Vancouver, BC) — IWK Grace (Halifax, NS) — Sick Kids (Toronto, ON) — Stollery CH (Edmonton, AB)

Initial investigators meeting

  • Name
  • Mission statement, vision, guiding principles
  • Governance (structure, leadership)
  • Membership criteria and responsibilities
  • Individuals
  • Institutions
  • Infrastructure
  • Charitable Arm
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Executive council

Gary A. Walco, PhD University of Washington Jeffrey L. Galinkin, MD University of Colorado Steven J. Weisman, MD Medical College of Wisconsin Elliot J. Krane, MD Stanford University Anna Taddio, BScPhm, PhD University of Toronto

Conundrum Another conundrum

  • Janet Woodcock, M.D., Director, Center for Drug

Evaluation and Research, stresses need for FDA to support collaborative research networks

  • FDA lawyers say PRN-Pain, as defined, cannot be

supported by FDA (no special relationship)

  • Consider entering a public-private partnership (PPP)
  • FDA already has a PPP on analgesics, the Analgesic,

Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION)

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Pediatric Pain Research Consortium

Pediatric Pain Research Consortium (PPRC)

Conundrum solved? ACTTION PPRC

  • Clinical Trials for Analgesic Medications for Acute

Pain in Infants, Children, and Adolescents (Washington, DC, January 23-24, 2013)

  • Day 1: To develop consensus and then generate a

manuscript on specific pain models and methodologies for analgesic trials for acute pain in infants, children, and adolescents

  • Day 2: Design a specific clinical trial for acute pain

to be conducted throughout the institutions that comprise the PPRC

PPRC consensus meeting, January, 2013

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Where do we go from here?

  • Raise funds and then conduct demonstration project on

acute pain through ACTTION PPRC

  • Hold a second meeting of PPRC focused on trial

designs for chronic pain in children and adolescents

  • Pediatric pain registry
  • Develop PRN-Pain to conduct trials with sponsors
  • Find a way to get Gary paid for his efforts

The (extricable?) link between opioids and chronic pain

  • August, 2015: US FDA approves OxyContin for use in

11 to 16 year olds

  • Public outcry (e.g., Congresspersons, addiction

groups)

  • Speculation and opinion versus data
  • The challenge when politics meets science…

Opioids, chronic pain, and pediatrics

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September 15-16, 2016

Joint Meeting of the Anesthetic and Analgesic Drug Products Advisory Committee, the Drug Safety and Risk Management Advisory Committee, and the Pediatric Advisory Committee Meeting

“The purpose of this public advisory committee meeting is to discuss the appropriate development plans for establishing the safety and efficacy of prescription opioid analgesics for pediatric patients, including obtaining pharmacokinetic data and the use of extrapolation.”

FDA advisory meeting: FDA presentations

  • Pediatric drug development regulatory considerations (focus on

BPCA and PREA)

  • Safeguards for children in clinical investigations (ethics,

extrapolation)

  • Pediatric utilization of opioid analgesic products (outpatient only)
  • Trends going down since 2011
  • Immediate release 99.5%; extended release 0.5%
  • OxyContin prescriptions dropped, including through April 2016
  • Current approaches to studying opioids analgesics in pediatric

patients

  • Clinical pharmacology considerations

FDA advisory meeting: Additional presentations

  • Rohit Shenoi: AAP perspective
  • Charles Berde: Pharmacotherapy of pain in infants
  • Maturation of pain responses and analgesic actions
  • Scope of pediatric acute, recurrent and chronic pain and palliative care
  • Analgesics commonly prescribed in pediatrics
  • Risk-benefit considerations and roles for opioids
  • Harold van Bosse: Pediatric orthopedic patients
  • Chris Feudtner: Ethical framework for pediatric opioid policy
  • Two groups with desperate and disparate needs
  • Taking opioids in a prohibited and harmful manner
  • Enduring inadequately relieved severe pain
  • Focus on patients (individual) versus persons (population)
  • Product labeling
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FDA advisory meeting: Additional presentations

  • Steven Weisman: Challenges of conducting opioid trials in

pediatrics

  • Population challenges
  • Appropriate pain models
  • Chronic pain in adults versus chronic pain in children
  • New pain taxonomy for acute and chronic pain syndromes
  • Risks to investigators
  • Sharon Levy: Opioid misuse and opioid use disorders in

adolescents

  • Adolescents are developmentally primed to use drugs and vulnerable

to substance use disorders

  • Substance use disorders rarely start with opioids
  • Access to opioids: the “opioid reservoir” and diversion from others--

(84.2%)

Summary

  • Change in clinical practice is often a slow process
  • Multiple forces of change
  • Regulatory
  • Evidence based practice
  • Ethics
  • Public demand
  • Humaneness
  • Individual
  • Institutional
  • Organizational (e.g. SPA, IASP, APS)
  • State and provincial initiatives
  • Federal plans and guidelines
  • International efforts

Another sage

“A dream you dream alone is only a dream. A dream you dream together is reality.”

  • John Lennon