1. THE DRUG PRICE COMPETITION AND PATENT TERM RESTORATION ACT OF 1984: THE BASICS OF THE WAXMAN-HATCH ACT Michael A. Swit, Esq. Vice President Center for Professional Advancement Generic Drug Approvals Course

2. Why The 1984 Law Was Created  Difficulty in obtaining an ANDA for post-1962 drugs  Erosion of patent protection for pioneer drugs due to lengthy FDA approval process  Increased pressure for competitive pricing  Federal government’s role as major drug purchaser

3. Statute Sections - NDAs FDCA § 505(b)(1) “Any person may file with the Secretary [FDA] an application with respect to any [new] drug...” {21 U.S.C. § 355(b)(1)} FDCA § 505(b)(2) “An application... for a [new] drug for which the [safety and effectiveness] investigations... relied upon by the applicant for approval of the application were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted...” {21 U.S.C. § 355(b)(2)}

4. Post-1984 NDA Requirements  Preclinical and Clinical Data  For New Chemical Entity, New Indication, or New Formulation  Submission of Patent Information  Eligibility for Patent Extension or Market Exclusivity  Pediatric Use Assessment

5. User Fees & Review Schedule – FY2009  Application with Clinical Data = $1,247,200  Application without Clinical Data/ Supplement with Clinical Data = $623,600  60 Days – FDA Determines if NDA is Accepted for Filing  180 Days – FDA Presents all Major Deficiencies  10 Months – 1st Target Date for Approval  12 Months – 2nd Target Date for Approval

6. Post-1984 ANDA Requirements  Based on a “Reference Listed Drug” (RLD)  Bioequivalence Data  Manufacturing Information  Approval is Limited by Patent Extension and/or Market Exclusivity  Limited Eligibility for Market Exclusivity – 180 Days  No User Fees

7. Safe Harbor for ANDA R&D on Patent-Protected RLD  History: Court held “patent infringement” includes precommercial testing of product (flurazepam/Dalmane®) (Roche v. Bolar, Federal Circuit, 1984)  Waxman Hatch Act -- Overturned the court decision, specifically declaring that precommercial testing is NOT an infringement (35 USC Section 271(e)(1))  Statute Language: Person may make, use or sell a patented drug during the patent life if solely for uses reasonably related to the development and submission of information under a federal law which regulates the manufacture, use or sale of drugs

8. Safe Harbor for ANDA R&D on Patent- Protected RLD  Safe Harbor -- applies to innovator and generic firms (Bristol-Myers Squibb v. Rhone-Poulenc Rorer, S.D.N.Y. 2001, aff’d, 3 rd Circuit, 2003)  “Reasonably Related” -- means having a decent prospect that the “use” would generate the kind of information relevant to FDA approval requirements  Construed:  Intermedics v. Ventritex, N.D.Ca. 1991, aff’d, Federal Circuit, 1993 – clinical trials on intermediates, yes  Medtronic v. Lohr, U.S. Supreme Court, 1996 – applies to medical devices  Integra Life Sciences v. Merck, U.S. Supreme Court, 2005 – preclinical research to identify future candidate, yes

9. Basic Requirements for Securing ANDA Approval  “Listed Drug”  Conditions of use  Active ingredient(s)  Route of administration, dosage form and strength  Bioequivalent  Labeling  CMC  Certification to patents  May be delayed by RLD’s market exclusivity

10. The Concept of the Listed Drug  Required for ANDA Approval  Generic must be the same as the RLD  Before 1984 – Federal Register Notices Declared DESI Drugs to be “Effective”  Now Appear in FDA’s Orange Book, updated monthly

11. Electronic Orange Book Approved Drug Products with Therapeutic Equivalence Evaluations Current through March 2008 Preface FAQ Search by Active Ingredient Search by Applicant Holder Search by Proprietary Name Search by Application No. The products in this list have been approved under section 505 of the Federal Food, Drug, and Cosmetic Act. Drug question email: DRUGINFO@CDER.FDA.GOVDRUGINFO@CDER.FDA.GOV U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research Office of Pharmaceutical Science Office of Generic Drugs Updated: May 1, 2008

12. Electronic Orange Book  Search in 3 Databases  Rx  OTC  Discontinued  Request FDA Determination that RLD Was Not Withdrawn from the Market for Reasons of Safety or Efficacy  FDA Answers: Approved Discontinued Drug Products Safety and Effectiveness DeterminationsApproved Discontinued Drug Products Safety and Effectiveness Determinations

13. “Same As” RLD  Conditions of Use, Route of Administration, Dosage Form and Strength  Exception: Suitability Petition Requests Approval of Differences  FDA Must Approve Before ANDA Is Filed  Examples  Advantages/Disadvantages  Effect of Pediatric Study Rule – Denial or Waiver

14. Bioequivalence  Clinical Comparison of Generic and RLD  No Significant Difference in the Rate and Extent to which the Active Ingredient Becomes Available at the Site of Drug Action  Details in Next Lecture

15. Labeling  Same as RLD Except for Certain Differences:  Changes Permitted Under Suitability Petition  Based on Different Manufacturer  Based on Patents or Market Exclusivity  Electronic Version Required As Of June 8, 2004 (21 CFR 314.94(d); 68 FR 69009 (12/11/03))  Problem Areas  Copyright -- Trade Name  Trademark/Trade Dress-- USP Specs  Indication “Carve Out”-- “Same”?

16. Chemistry, Manufacturing & Controls  Include List of Articles Used as Components of the Drug  Full Statement of Composition of the Drug  Full Description of Methods, Facilities, and Controls Used in Manufacturing, Processing, and Packaging the Drug  Samples of the Drug and Components, If Requested

17. Inactive Ingredients  Listed on the Product Label and Labeling  Need Not Be the Same as the RLD  Exceptions: Parenterals, Ophthalmics, Otics, Topicals  ANDA may be delayed if formulation contains inactives never before included in an approved drug of that route of administration (Qualitative) – Q1  Or inactives at a higher concentration (Quantitative) – Q2  If different as to Q1 or Q2, applicant must submit information to demonstrate the difference has no effect on the drug’s safety

18. CDER Inactive Ingredient Search for Approved Drug Products Inactive IngredientRoute; Dosage FormMaximum Potency Apricot Kernel Oil PEG-6 Esters Topical; Emulsion, Cream 2.94% Apricot Kernel Oil PEG-6 Esters Vaginal; Emulsion, Cream 2.94% Corn Oil PEG-6 Esters Oral; Capsule, Soft Gelatin 300 mg Glyceryl Stearate /PEG Stearate Oral; Tablet 1.8 mg Glyceryl Stearate /PEG Stearate Oral; Tablet, Coated 1.8 mg Glyceryl Stearate /PEG Stearate Rectal; Suppository 36.85 mg Search Results for “peg”

19. Organizational Structure of OGD  Office of the Director  Division of Bioequivalence  Divisions of Chemistry (3)  Division of Labeling and Program Support  Review Queue – 1st In, 1st Reviewed, But For  First generic products for which there are no blocking patents or exclusivities on the RLD  Clusters of ANDAs for same active ingredient  Expertise of Reviewers

20. Statutory Exclusivities Under Waxman- Hatch  New Chemical Entity (NCE) Exclusivity  Prohibits the filing of an ANDA (or 505(b)(2) NDA) for a product that contains the NCE for 5 years after approval of the first NDA.  (4 years if ANDA includes a Paragraph IV challenge to listed patent)  NCE: "a drug that contains no active moiety that has been approved by FDA in any other [NDA]."

21. Statutory Exclusivities …  3-Year Exclusivity  Available for NDAs which contain:  Reports of "new" "clinical trials"  That were "essential to approval" of the NDA  Conducted or sponsored by the applicant  FDA may not approve an ANDA or 505(b)(2) NDA for 3 years after approval  Applies for new indications, Rx  OTC switch, new dosing regimen, and some other labeling changes.

22. Statutory Exclusivities -- Other  Orphan Drug Exclusivity  7 year exclusivity  Drugs for rare conditions (<200,000 people in U.S.)  Pediatric Exclusivity  6-month extension of existing patent or Waxman-Hatch exclusivity  180-day generic (ANDA) exclusivity

23. “180-Day” or “ANDA” Exclusivity  Basics:  First person to file an ANDA with a Paragraph IV certification gets 180 days during which no other ANDA can be approved for that drug  Must either (a) not be sued by brand co. in 45-day period or (b) prevail in litigation (or get favorable settlement)  180 days starts from earlier of:  Date of first commercial marketing (changed in 2003; used to peg to a court decision as well)

24. Present Goals of OGD  Decrease Time to Approval & Review Backlogs  Now called GIVE - the Generic Initiative for Value and Efficiency  Use existing resources to help modernize & streamline  Hire and train new reviewers  Enhanced use of electronic programs for handling submissions and internal documents  Identify low-risk manufacturing changes that do not require an intense review  Educate consumers on safety and low-cost of generics  Timely Foreign Inspections (APIs/DMFs)  Implement changes under FDAAA and MMA

25. FDA Amendments Act of 2007 (FDAAA)  Post Labeling of RLD 21 days after approval  Post Approval Package 30 days after approval  Database For Authorized Generic Drugs  FDA must publish a complete list on its Internet site of all authorized generic drugs, updated quarterly  Drug trade name, brand manufacturer, and date the authorized generic drug entered the market  Drugs marketed, sold, or distributed directly or indirectly to retail class of trade with either labeling, packaging, product code, labeler code, trade name, or trade mark that differs from that of the RLD

26. FDA Amendments Act of 2007 (FDAAA)  Clinical Trial Registry Databank  Not required for blood-level bio studies  May be required for clinical bio studies (e.g., topical dosage forms) - controversial  Citizen Petitions  Shall not delay ANDA approvals unless necessary for public health  If delay, 30-day notice to ANDA applicant  Denial permitted based on Petitioner’s intent to delay  Certify that Info became known on XX date

27. OGD Statistics YearANDAs Received ANDAs Approved Plus Tentative Approvals Median Approval Times 200130724131018.4 Months 200236129636418.3 Months 200344928437317.3 Months 200456332041316.3 Months 200576636146716.3 Months

28. What’s in a Name?  Drug Price Competition and Patent Term Restoration Act of 1984  “Waxman-Hatch Act” – universally called that until 1994  1994 – Republicans take control of Congress – “Hatch- Waxman Act”  2006 – Democrats take control of Congress  So what do you call it now? – well, the first part of the statutory name – Drug Price Competition – relates to Waxman’s role; and the second part – Patent Term Restoration – refers to Hatch’s role in pushing the 1984 compromise.  What do you think?

29. Numerous FDA Guidance Documents  CDER Guidance Documents on Generic Drugs  www.fda.gov/cder/guidance/index.htm www.fda.gov/cder/guidance/index.htm  OGD Guidance Documents for ANDAs  www.fda.gov/cder/regulatory/applications/anda.htm www.fda.gov/cder/regulatory/applications/anda.htm  CDER Manual of Policies and Procedures (MAPP)  www.fda.gov/cder/mapp.htm www.fda.gov/cder/mapp.htm

30. Call, e-mail, fax or write: Michael A. Swit, Esq. Vice President The Weinberg Group Inc. 336 North Coast Hwy. 101 Suite C Encinitas, CA 92024 Phone 760.633.3343 Fax 760.454.2979 Cell 760.815.4762 michael.swit@weinberggroup.com www.weinberggroup.com Questions?

31. About your speaker… Michael A. Swit, Esq., is a Vice President at The Weinberg Group Inc., where he develops and ensures the execution of a broad array of regulatory and other services to drug and biologics clients seeking to market products in the United States. His expertise includes FDA development strategies, compliance and enforcement initiatives, recalls and crisis management, submissions and related traditional FDA regulatory activities, labeling and advertising, and clinical research efforts. Mr. Swit has been addressing critical FDA legal and regulatory issues since 1984. His multi-faceted experience includes serving for three and a half years as corporate vice president, general counsel and secretary of Par Pharmaceutical, a prominent, publicly-traded, generic drug company and, thus, he brings an industry and commercial perspective to his work with FDA-regulated companies. Mr. Swit then served for over four years as CEO of FDANews.com, a premier publisher of FDA regulatory newsletters and other specialty information products for the FDA-regulated community. His private FDA regulatory law practice has included service as Special Counsel in the FDA Law Practice Group in the San Diego office of Heller Ehrman White & McAuliffe and with the Food & Drug Law practice at McKenna & Cuneo, both in the firm’s Washington office and later in San Diego. He first practiced FDA regulatory law with the D.C. office of Burditt & Radzius. Mr. Swit has taught and written on a wide variety of subjects relating to FDA law, regulation and related commercial activities, including, since 1989, co-directing a three-day intensive course on the generic drug approval process and editing a guide to the generic drug approval process, Getting Your Generic Drug Approved. A former member of the Food & Drug Law Journal Editorial Board, he also has been a prominent speaker at numerous conferences sponsored by such organizations as RAPS, FDLI, and DIA. A magna cum laude graduate of Bowdoin College, with high honors in history, he received his law degree from Emory University Law School and is a member of the California, D.C. and Virginia bars.