The Marketed
Unapproved Drugs Initiative
CDR Lori Cantin, R.Ph., Pharm.D.
Marketed Unapproved Drugs Enforcement Team
Office of Unapproved Drugs and Labeling Compliance (OUDLC)
Office of Compliance (OC)
Center for Drug Evaluation and Research (CDER)
U.S. Food and Drug Administration
June 21, 2012
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Overview
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What the OUDLC MUD-E team does…
Why do unapproved drugs exist?
Why are unapproved drugs a public health problem?
Scope/legal description of the “Unapproved
Universe”
• The Unapproved Drugs Initiative
• Enforcement Priorities/Actions
• What can you do about unapproved drugs?
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What the OUDLC MUD-E team
does…
• Oversight of all prescription drug products with
respect to Section 505 of the Federal Food Drug and
Cosmetic Act (FD&C Act).
• Oversight of prescription drug labeling with respect
to Sections 502, 503, and 505 of the FD&C Act.
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FD&C Act Section 505
• Section 505 requires pre-approval of most drugs prior to
marketing
– Paragraph (a) no person may introduce a *“new
drug” into interstate commerce without an approved
application, repeated in the prohibited acts section at
301(d)
– NDA under section 505(b); ANDA under section
505(j)
• Drugs are approved based on data showing safety,
efficacy, adequacy of manufacturing methods, and
labeling
*”New Drug” as defined within section 201(p) of the FD&C Act
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Why Are There
Unapproved Drugs?
• Progressive changes over time to drug laws to address tragedies
– Elixir of Sulfanilamide Tragedy
 107 deaths
 1938 FD&C Act – approval for safety required
– Thalidomide Disaster
 Thousands of birth defects
 Highlighted need for stronger drug regulation
 1962 Amendments – required that drugs be proven
effective, as well as safe, prior to marketing
• Unapproved drugs are marketed as if the law never changed
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Why Are Unapproved Drugs a
Public Health Problem?
• Drugs may be unsafe
– Affirmative safety problems
 Quinine – 93 deaths
 Carbinoxamine – 21 deaths
– Unknown safety problems: there may not always
be a documented safety risk
 E-Ferol – 40 deaths
Lesson Learned: the absence of proof of a problem is
not proof of the absence of a problem
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Why Are Unapproved Drugs a
Public Health Problem (cont’d)?
• Drugs may be ineffective
– Trimethobenzamide HCl suppositories
• Potential for labeling deficiencies
– Ergotamine
– Endacof
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Why Are Unapproved Drugs a
Public Health Problem (cont’d)?
• Challenge the integrity of the drug approval
system
– Codeine sulfate tablets
• Limited post-market surveillance;
no periodic reporting
• Potential for drug quality deficiencies
– E.g., Nitroglycerin Sublingual Tablets
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Misconceptions about
Marketed Drugs
• All marketed drugs are FDA-approved, and
therefore assumed to be safe and effective
• Drugs listed in reference books & commercial
databases are approved: Don’t assume that just
because a drug is listed in commonly used references
that it is approved!!!
• Unapproved drugs are generic drugs
• Assignment of an NDC number is equivalent to
FDA approval
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Some Unapproved Prescription
Drugs
May Surprise You!
• Phenobarbital
• ‘Crash cart’ drugs (epinephrine, vasopressin)
• Prenatal Vitamins
• Calcium Gluconate Injection
• Sodium Phosphate Injection
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Scope of the
Unapproved Universe
• Thousands of prescription and nonprescription
drugs are marketed without approval
– Relatively broad range of drugs
(approved/unapproved versions)
– Some firms specialize in marketing unapproved
drugs
– Actual number of marketed unapproved drugs
is a moving target
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“Unapproved Universe”
Legal & Historical Background
All drugs must have FDA approval or must
comply with an Over the Counter (OTC)
monograph
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Statutory Exceptions
• GRAS/E (Generally Recognized as Safe
and Effective)
– A GRAS/E determination requires a consensus among
experts that the product is safe and effective based
on published scientific literature regarding the
finished drug product of the same quality and
quantity needed to approve a drug.
• Grandfathered
– Product is identical in formulation, strength, dosage
form, route of administration, indications, intended
patient population, and other conditions of use to its
pre-1938 or 1962 formulation
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Policy Exceptions
• DESI pending
– Final determination of efficacy has not yet been
made; some proceedings are still open
– Enforcement discretion may be applied to
marketed DESI pending products
• OTC monograph pending
– Do not meet an OTC monograph but are pending
final review
– Enforcement discretion may be applied to
marketed OTC monograph pending products
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Unapproved Drugs Initiative
• Marketed Unapproved Drugs — Compliance Policy Guide
(CPG):
www.fda.gov/downloads/Drugs/GuidanceComplianceReg
ulatoryInformation/Guidances/UCM070290.pdf
– Initial CPG released June 2006; Revised in September
2011
• Outlines the FDA’s enforcement policies aimed at efficiently and
rationally bringing unapproved drugs into the approval process
• Provides official notice that any illegally marketed product is subject
to FDA enforcement at any time
• Clarifies that the FDA intends to use a risk-based approach to
enforcement for those products marketed before 9/19/11
• Drugs entering the market after 9/19/2011 are subject to immediate
enforcement action at any time, without prior notice and without
regard to the enforcement priorities set forth in the CPG
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CPG Enforcement Priorities
• Apply to all unapproved drugs commercially used or sold AS OF
9/19/11
– Drugs with potential safety risks
– Drugs that lack evidence of effectiveness
– Fraudulent drugs
– Unapproved drugs that directly compete with an approved drug
– Drugs from firms that are otherwise violating the Act (e.g. GMP
violations, ADE reporting violations)
– Drugs with formulation changes made as a pretext to avoid
enforcement
• Do not apply to unapproved drugs entering the market AFTER
9/19/11 (No enforcement discretion)
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Enforcement Actions—Drug Class
Carbinoxamine (June 8, 2006)
• 21 infant deaths
Quinine sulfate (December 15, 2006)
• 665 reports of adverse events including 93 deaths; labeling lacked necessary warnings and
safe dosing information
Ergotamine (March 1, 2007)
• Labeling did not include critical warnings regarding the potential for serious, possibly fatal
interactions with other drugs
Trimethobenzamide suppositories (April 6, 2007)
• Lacked evidence of effectiveness
Timed-release drug products containing
Guaifenesin (May 25, 2007)
• Directly competed with approved products
• Dose dumping
Hydrocodone (September 29, 2007)
• Inadequate safety related labeling
• Improperly suggested the drug was safe for young children
Colchicine injectable (February 8, 2008)
• 50 reports of adverse events including 23 deaths
Topical Papain Products (September 23, 2008)
• Hypersensitivity and anaphylactic reactions; cross-reactivity in patients with latex allergies
Balanced Salt Solution (September 23, 2008)
• Various adverse events, many leading to permanent loss of vision due to product
contamination and product defects
Narcotics (Hydromorphone tabs; Oxycodone IR
tabs; MSO4 oral solution 20 mg/mL) (March 31,
2009)
• No approved versions marketed in the U.S.
• FDA exercised enforcement discretion to avoid imposing a hardship on palliative care
patients
Codeine Sulfate tablets (October 13, 2009)
• Competed with FDA-approved versions of the drug product
Nitroglycerin sublingual tablets (March 16, 2010)
• Unapproved NTG SL tablets competed with FDA-approved version
Epinephrine 0.3 mg injection (June 9, 2010)
•Injection for use in emergency situation without safety or efficacy confirmed
Colchicine tablets (October 1, 2010)
Safety issues related to dosing and drug interactions
Rx Cough/Cold/Allergy (March 3, 2011)
•Unapproved CCA drugs marketed for children and infants; compete with OTC monographcompliant CCA drugs and FDA-approved Rx drugs
Ophthalmic Drug Products (Fluorescein
injection; Freshkote ophthalmic solution)
(November 16, 2011)
•Unapproved ophthalmic drug products competed with FDA approved versions of the drug.
Enforcement Actions
• To view more detailed information on these actions:
http://www.fda.gov/Drugs/GuidanceComplianceRegulato
ryInformation/EnforcementActivitiesbyFDA/SelectedEnfor
cementActionsonUnapprovedDrugs/ucm238675.htm
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Multi-pronged Initiative
• 19 class actions = 1000+ drugs ordered removed from
the market and over 200 firms affected
• 90 WLs sent to firms for violations of the Act (cGMPs,
ADEs) and marketing unapproved drugs
• 5 seizures (totaling approximately $40 million)
• 9 injunctions
• 122 applications for previously marketed drugs without
approval are now approved (92 ANDAs and 30 NDAs)
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Education and Outreach
• Increase awareness and understanding about unapproved drugs
• Educate consumers and health care providers about risks
• Unapproved Drugs Website
– Information included:
 Bringing an Unapproved Drug into Compliance WebLearn
 Unapproved Drugs Video News Release
 Podcasts on XM Radio/Reach MD
• Webinar on Marketed Unapproved Drugs
–
http://www.fda.gov/AboutFDA/WorkingatFDA/FellowshipInternshipGraduateFacultyPrograms/Ph
armacyStudentExperientialProgramCDER/ucm253355.htm
• CMS
– Regular communication regarding regulatory status of drugs
– Collaboration to cease payment for unapproved drugs post-class
action
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Determining Drug Approval
Status: Resources
• The Orange Book
– www.accessdata.fda.gov/scripts/cder/ob/default.cfm
• Drugs@FDA
– www.accessdata.fda.gov/scripts/cder/drugsatfda/index
.cfm
• NDC Directory
– www.fda.gov/Drugs/InformationOnDrugs/ucm142438.
htm
• DailyMed
http://dailymed.nlm.nih.gov/dailymed/about.cfm
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The Orange Book
(Approved Drug Products with
Therapeutic Equivalence Evaluations)
Includes:
 A listing of Rx and OTC drug products with
approved NDAs and ANDAs
 Discontinued products
Does not include:
 Over-the-counter (OTC) products marketed under
a final or pending monograph
 Products withdrawn from the market for safety or
efficacy reasons, e.g., Seldane.
 Animal drug products
 Biologic drug products
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Drugs@FDA
Contains a listing of most FDA-approved drug
products, including:
 Prescription and over-the-counter human drugs with
an approved drug marketing application (NDA or
ANDA).
 Most therapeutic biologic products (approved BLA)
Drug products not included are:
 Over-the-counter (OTC) products marketed under a
final or pending monograph
 Biologic products regulated by the Center for
Biologics Evaluation and Research (CBER)
 Dietary supplements (do not require FDA approval)
 Animal Drugs
 Unapproved Drugs, e.g., Phenobarbital Tablets
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NDC (National Drug Code)
Directory
• Contains a listing of all human
prescription drugs and insulin products
in commercial distribution
• The Marketing Category will state
“Unapproved Drug Other” if the drug
does not have an approved the
NDA/ANDA application
• NDC number ≠ FDA approval !!!
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DailyMed
• Public service provided by the National
Library of Medicine (do not accept
advertising)
• Contains drug labeling for marketed
drugs based on what has been most
recently submitted by drug companies to
FDA as drug listing information
• Provides firm-reported approval status
for drugs, Rx and OTC: approved, not
approved, OTC monograph final, OTC
monograph not final
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What can YOU do about
Unapproved Drugs??
• Know your state’s pharmacy laws. Are there laws in
the state in which you plan to practice pharmacy
that regulate the dispensing of Unapproved Drugs?
• Check to see if a drug product is approved prior to
dispensing it.
• Consult with healthcare providers that prescribe
unapproved drugs; work to find an approved
alternative whenever possible.
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What can YOU do about
Unapproved Drugs??
• Work with your employer to eliminate or minimize
the number of unapproved drugs on your
pharmacy’s shelves or on your institution’s
formulary, to the extent possible
– Increase awareness/knowledge to formulary
decision makers regarding unapproved drugs
– Evaluate drugs for approval status when
considering addition to formulary/pharmacy
shelves
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Take home messages
• Unapproved drugs pose safety risks to patients
• There is no confirmation that unapproved drugs are effective
or deliver the active ingredient/s in their labeled amount and
timeframe
• Unapproved drugs may not be manufactured according to
current good manufacturing practice (cGMP) regulations
• Unapproved drug labeling may be incomplete, confusing,
and/or ungrounded in evidence
• Unapproved drugs do not have an ANDA, are not generic
drugs and are not proven to be bioequivalent to a sponsor
product
• FDA actions against unapproved drugs help to secure the
nation’s drug supply
• Pharmacists can play a vital role
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Questions?
Thanks!
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