PGY-2 Legislative Advocacy Presentation February 28, 2012
Lacy-Ann Landell, MD Ryan Morgan, MD Improving Research,
Development, Access, and Safety of Pediatric Drugs and Medical
Devices
Slide 2
Overview Background Barriers to the development and access of
pediatric drugs and devices Regulatory/Legislative History Current
Legislation Future Directions
Slide 3
50-75% of drugs prescribed to children have not been tested in
children Why is this a problem? Medication effects differ in
children compared to adults Overall efficacy Metabolism / Clearance
Side effect profiles differ Effects on growth, development,
fertility, etc. Results are toxicity, drug resistance, longer
illnesses, pain and suffering, morbidity and mortality, and
increased cost to the health care system Different formulations
(liquid solutions, chewable tablets) may be necessary for children
Children are not just small adults!
Slide 4
The Ideal Pediatric Drug An ideal pediatric drug should have
several key features: Age specific Tailored to body weight,
metabolism Pediatric safety profile Researched in children,
addressing pediatric issues like growth and development Variable
administration Easily dissolvable, tasteless, ability to sprinkle
on foods, etc Variable formulations Fixed dose combination pills
for chronic conditions, higher concentration drugs for smaller
doses
Slide 5
Historical Examples of Medications Not Appropriately Tested in
Children Chloramphenicol In 1960s, used off-label in children and
neonates, resulting in serious adverse effects. The immature
UDP-glucoronyl transferase enzyme system in infants livers leads to
inefficient conjugation of the drug The neonatal kidneys are unable
to excrete the unconjugated product Over 2-9 days, infants can
develop vomiting, gray discoloration of the skin, hypotonia,
cyanosis, hypotension, and death
Slide 6
Historical Examples of Medications Not Appropriately Tested in
Children Sulfa drugs displacement of bilirubin from binding sites
jaundice and kernicterus Tetracycline affects growing bone and
teeth and can cause bony abnormalities and permanent teeth
discoloration Aspirin Reyes Syndrome (when given for viral illness)
Rash, vomiting, hypoglycemia, hepatotoxicity, brain injury
Slide 7
Product Labeling The product label contains information about
medication formulation, indications, dosing, and side effect
profile (derived from clinical trials) Because most drugs
prescribed for children have not been tested in pediatric
populations, important information on their risks and appropriate
use for these patients is not available on the product labels.
Off-label use occurs when drugs are prescribed for purposes other
than those included under the terms of the FDA product approval or
in a patient population in whom it has not been studied. Off-label
use of drugs is common in adults but far more prevalent in
children. While such use can be beneficial to the patient, it can
also result in adverse reactions due to a lack of understanding of
the drugs overall profile in the patient population.
Slide 8
Off-label drugs Most medications used on pediatric cardiac
patients are used in an off-label manner Lidocaine, amiodarone,
procainamide, dopamine, dobutamine, norepinephrine, isopril,
milrinone, propanolol, esmolol, sotalol, metoprolol, carvediolol,
labetalol, nitroglycerine, amlodipine, nifedipine Most psych meds
Zoloft, Prozac, etc. ALBUTEROL!!! Not approved for kidsoops
Dexamethasone not approved for pregnant women in premature labor
Bactrim and clindamycin for MRSA infections
Slide 9
The Pediatricians Dilemma: Do I chose to withhold a potentially
effective treatment that is useful in adults or do I expose my
patient to a drug that I dont know is safe?
Slide 10
AAPs Response Off-label use should be based on expert clinical
judgment, published literature and sound scientific evidence.
Physicians who choose to prescribe a medication with limited
pediatric data have a public and a professional responsibility to
assist in the systematic development of the information about that
drug for the benefit of other patients (AAP Policy Statement). FDAs
MedWatch program for reporting serious adverse events.
Slide 11
Barriers to Pediatric Drug Development Economic Ethical
Logistical / Technical Legislative
Slide 12
Economic Barriers to Pediatric Drug Development New drug
approval process requires, on average, $350 million $12.6 billion
investment by the pharmaceutical industry yearly (doubles every 5
years) Testing in children most often requires independent studies
and can double the cost of clinical trials Children tend to be on
medications for shorter durations of time (antibiotics vs. statins)
and tend to have conditions that they outgrow (asthma, ADHD,
frequent infections) Reimbursement from Medicaid and private
insurance companies is lower for some drugs when prescribed for
pediatric rather than adult patients
Slide 13
Barriers to Pediatric Device Development Far fewer children
require implantable devices compared to adults, but the amount of
devices specifically designed for them are disproportionately
lacking When developing a device (i.e. prosthetic heart valve) for
children, multiple sizes must be developed and manufactured. All of
these require independent manufacturing lines, etc., while a
relatively small number of each are actually used. Mass marketing
one-size-fits-all works for adults but not for childrendeveloping
new devices for the treatment of children does not pay. Clinicians
must resort to improvising with existing materials.
Slide 14
The Ethics of Pediatric Drug Development and Research on Minors
Principles Children should not be enrolled in research unless
necessary to answer an important question about health and welfare
of children Research involving children must be characterized by a
balance of risks and potential benefits Research offering no direct
benefit to children must be restricted to that posing minimal
risk
Slide 15
The Ethics of Pediatric Drug Development and Research on Minors
Those at fault: CLINICIANS willing to prescribe off-label drugs,
leading to delays in research PHARMACEUTICALS act in financial
self-interest Pursue clinical trials on children late in a drugs
life cycle, after establishing its market value and the worth of
pursuing pediatric indications Cost considerations trump study
design quality, so studies may not be powered for certain
indications ACADEMIC INSTITUTIONS do not reward their researchers
for participating in clinical trials Want them to be primary
investigators on NIH R01 grants rather than being on a long list of
co-investigators
Slide 16
Logistical/Technical Barriers Lacking infrastructure in which
to conduct pediatric research Few pediatric clinical research
centers Declining number of pediatric pharmacologists Inadequate
teaching of pharmacology / therapeutics in medical school Too few
physician-scientists Lack of pediatric assessment tools
Slide 17
Legislative Barriers to Drug Development: The FDA Drug Approval
Process Average of 12 years and $350 million 1/1000 novel
candidates that enter lab testing make it to human testing After an
average of 3.5 years of lab testing, medications are submitted to
the FDA for the beginnings of clinical trials
Slide 18
Phase I Trial on healthy volunteers (~20-80) to establish a
drugs safety and overall profile (~1 year) Phase II Trial on
100-300 patient volunteers to assess effectiveness (~2 years) Phase
III Trial on ~1000-3000 patients in multiple institutions (likely
randomized) to determine effectiveness and identify adverse
reactions (~3 years) Pharm company submits application (~100,000
pages) to FDA potentially approved after 2-2.5 years, then
available for providers to prescribe Phase IV Post-approval studies
aimed at examining drug in fashion in which it is actually
prescribed
Slide 19
Regulatory and Legislative History In 1992, the BPCA - Best
Pharmaceuticals for Children Act is introduced to Congress. In
1997, the BPCA is enacted as a part of the FDA Modernization and
Accountability Act. In 1998, the Pediatric Rule is declared by the
FDA. In 1999, the Pediatric Rule is enacted. In 2002, the BPCA is
enacted as its own act. In 2003, the PREA - Pediatric Research
Equity Act is introduced to Congress and later that year the
president signs it into law. In 2007, numerous BPCA and PREA
improvements are signed into law as a part of the FDA reforms (Food
and Drug Administration Amendments Act (FDAA).
Slide 20
Pediatric Formulations Platform In 2009, the NIH and the FDA
entered into a Inter-Agency agreement to make an open-source,
publicly available approach to manufacturing pediatric oral meds.
Look for pediatric formulations of commercially available products
Determine best formulations for specific drug categories (based on
solubility, light sensitivity, bitterness)
Slide 21
Current Legislation The two main laws that encourage and
require drug manufacturers to study their products in children are
BPCA and PREA. These laws have been in effect for over a decade
with pediatricians constantly advocating for them. BPCA: Guarantees
six additional months of market exclusivity to pharmaceutical
companies following the completion of pediatric studies requested
by the FDA. PREA: Mandates new pharmaceutical agents to be studied
in children and requires pediatric studies in some drugs already on
the market. The Pediatric Rule requires pharmaceutical companies to
test specific drugs for use in children. Pediatric Medical Device
Safety and Improvement Act of 2007
Slide 22
Other Helpful Steps National Institute of Child Health and
Human Development (NICHD) and the National Institute of General
Medical Sciences (NIGMS) co-funded six pediatric positions under
NIGMS T32 Post Doctoral Programs in Clinical Pharmacology The WHO
launched 'Make medicines child size' initiative in December 2007 to
increase awareness and move toward improving the availability of
safe, effective, quality medicines for children. WHO Model
Formulary for Children contains independent prescriber information
on over 240 medicines based on the WHO Model List of Essential
Medicines for Children. Creation of an online clinical trial
registry for trials involving children and developing guidelines
for conducting these trials in resource-limited settings.
Slide 23
Future directions New problems arise Critical drug shortages
cytarabine for AML; methotrexate for ALL Lower profit margins =
less being made by pharmaceutical companies Drugs losing patents
Medications that are actually approved for children are no longer
profitablethus are not being made Financial crisisdecreasing
numbers of new drugs in the pipeline Current legislation needs to
be re-enacted (October 2012)
Slide 24
Advocate!!! What we can do Call your senator or congressman!
Sen. Kristin Gillibrand - (202) 224-4451 Sen. Charles Schumer -
(202) 224-6542 Congressman Charles Rangel VOTE. Get involved with
the AAP. Participate in clinical trials. Report adverse effects of
off-label medications MedWatch
Slide 25
References AAP Committee on Drugs. Uses of Drugs Not Described
in the Package Insert (Off-Label Uses). Pediatrics.
2002;110(1):181-183 Improving Access to Safe Drugs and Medical
Devices for Children. American Academy of Pediatrics. Retrieved
February 27th, 2012 from
http://www.aap.org/en-us/advocacy-and-policy/federal-advocacy/Pages/Improving-Access-to-Safe-Drugs-and-Medical-Devices-
for-Children.aspx
http://www.aap.org/en-us/advocacy-and-policy/federal-advocacy/Pages/Improving-Access-to-Safe-Drugs-and-Medical-Devices-
for-Children.aspx Medicines: Medicines for Children. World Health
Organization. Fact sheet #341. Retrieved February 27th, 2012 from
http://www.who.int/mediacentre/factsheets/fs341/en/index.html
http://www.who.int/mediacentre/factsheets/fs341/en/index.html
Pediatric Formulations Platform. Best Pharmaceuticals for Children
Act. National Institute of Health. Retrieved February 27th, 2012
from
http://bpca.nichd.nih.gov/collaborativeefforts/initiatives/index.cfmhttp://bpca.nichd.nih.gov/collaborativeefforts/initiatives/index.cfm
Pediatric Product Development. U.S. Food and Drug Administration.
Retrieved February 23 rd, 2012 from
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm049867.htm
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm049867.htm
Addressing the Barriers to Pediatric Drug Development: Workshop
Summary. Institute of Medicine (US) Forum on Drug Discovery,
Development, and Translation. Washington (DC): National Academies
Press (US); 2008.National Academies Press (US) Pasquali, SK, et al.
Off-Label Use of Cardiovascular Medications in Children
Hospitalized With Congenital and Acquired Heart Disease.
Circulation: Cardiovascular Quality and Outcomes. November 2008;
vol. 1 no. 2 74-83.