The Marketed Unapproved Drugs Initiative

1. The MarketedUnapproved 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

2. Overview • 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?

3. 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.

4. 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

5. 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

6. 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

7. Why Are Unapproved Drugs a Public Health Problem (cont’d)? • Drugs may be ineffective • Trimethobenzamide HCl suppositories • Potential for labeling deficiencies • Ergotamine • Endacof

9. 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

10. Misconceptions aboutMarketed 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

11. Some Unapproved Prescription DrugsMay Surprise You! • Phenobarbital • ‘Crash cart’ drugs (epinephrine, vasopressin) • Prenatal Vitamins • Calcium Gluconate Injection • Sodium Phosphate Injection

12. Scope of theUnapproved 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

13. “Unapproved Universe”Legal & Historical Background All drugs must have FDA approval or must comply with an Over the Counter (OTC) monograph

14. 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

15. 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

16. Unapproved Drugs Initiative • Marketed Unapproved Drugs — Compliance Policy Guide (CPG): www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/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

17. CPG Enforcement Priorities • Apply to all unapproved drugs commercially used or sold AS OF 9/19/11 • Drugs with potential safetyrisks • 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)

18. Enforcement Actions—Drug Class

19. Enforcement Actions • To view more detailed information on these actions: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/SelectedEnforcementActionsonUnapprovedDrugs/ucm238675.htm

20. 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)

21. 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/PharmacyStudentExperientialProgramCDER/ucm253355.htm • CMS • Regular communication regarding regulatory status of drugs • Collaboration to cease payment for unapproved drugs post-class action

22. 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

23. 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

24. 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

25. 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 !!!

26. 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

27. 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. 27

28. 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 28

29. 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

30. Questions? Thanks!