Joan Bergstrom Henkel Consumer Goods, Inc. Fundamentals of Regulatory Affairs, 8th edition Ch. 14 Patents and Exclusivity Joan Bergstrom Henkel Consumer Goods, Inc.

Introduction Hatch-Waxman Act of 1984 gave brand-name drug companies incentives to do new drug research including: Patent term extension for time lost during Regulatory review Listing patent in Orange Book Eligibility for a period of non-patent exclusivity Additional incentives created by other laws including: Orphan Drug Act – drug development for rare diseases Best Pharmaceuticals for Children Act – developing medicine for kids

Patents and Exclusivity Affords right to prevent competitor from making same Granted by the Patent and Trademark office Awarded anytime during development of a drug Usual duration is 17-20 years Affords manufacturer exclusive marketing rights Granted by the FDA Awarded upon approval of a drug (NDA) A statutory provision, if requirements are met Duration varies

Patents and Exclusivity Patents can be expired before drug approval, issued after drug approval, and anywhere in between Exclusivity is granted upon approval of a drug product if the statutory requirements are met Some drugs have both patent and exclusivity protection while others have just one or none Patents and exclusivity may or may not run concurrently and may or may not encompass the same claims Exclusivity is not added to the patent life

Patent-Related Market Exclusivity Patent generally keeps other companies from making same product for a period of time, protecting the $ investments by patent holder Time is lost during regulatory review of a product is an issue Regulatory Review Time = Testing Phase Time + Review Phase Time Period from submission to approval of NDA Hatch-Waxman Act of 1984 says patent term may be extended Extension = ½ Testing Phase time + Review Phase time Assuming due diligence is maintained! Not to exceed 14 years after date of approval of marketing application

Patent Term Extension Law Definition: “Drug Product” is active ingredient (AI) of a new drug, and salts or esters, as a single entity or in combination with other AI Law provides that patent for drug may be extended from original issue date IF: Term of patent has not expired Patent not previously been extended Extension application submitted by owner w/in 60 days of NAD approval Product in Reg. Review before it is commercially available NDA is first permitted commercial use of drug product

Orange Book Approved Drug Products with Therapeutic Equivalence Evaluations (commonly known as the Orange Book) Lists drug products approved on the basis of safety and effectiveness by the FDA under the Federal Food, Drug, and Cosmetic Act First published in 1980, now electronic database Orange Book Data updated Monthly Generic Drug Product Information updated Daily Patent Information updated Daily

Orange Book Patent Listing Patent information is required to be submitted with all new drug applications at the time of NDA submission Patent information is published in the Orange Book after approval of NDA, upon receipt of FDA form 3542 For patents issued after approval of the NDA, the applicant holder has 30 days in which to file the patent to have it considered as a timely filed patent. Patents may still be submitted beyond the 30 day timeframe, but the patent is not considered a timely filed patent. Expired patents and exclusivity are not included in the published list

Non-Patent Statutory Market Exclusivity Five Year Exclusivity 5-year exclusivity granted to sponsor of a drug not previously approved under NDA, referring to a New Chemical Entity Sometimes called “NCE Exclusivity”, prevents approval of a generic equivalent for 5 years Three Year Exclusivity 3-year exclusivity granted to sponsor of a drug previously approved under NDA, but reports New Clinical Investigations (studies) Must be studies essential to approval Must be studies conducted by same sponsor Called the “NCI Exclusivity” or “New Use Exclusivity”

Non-Patent Statutory Market Exclusivity (cont.) Pediatric Exclusivity Provides an additional 6 months exclusivity to sponsor that conducts acceptable and beneficial Pediatric Studies Submit Pediatric Written Request (PWR) to FDA Applies to ALL indications of the drug or formulation, not just pediatric Orphan Drug Exclusivity Grants 7 year exclusivity to sponsor of a drug for a “rare disease or condition” Affects fewer than 200,000 people or sponsor shows inability to recover development or marketing costs Other or subsequent drugs must be “different” or “clinically superior” to be approved within the 7 years

Duration of Drug Exclusivity How long is exclusivity granted for? It depends on what type of exclusivity is granted: New Chemical (NCE) - 5 years Orphan Drug (ODE) - 7 years New Clinical Investigation (NCI) - 3 years, if criteria are met Pediatric (PED) - 6 months added to existing Patents/Exclusivity Patent Challenge (PC) – 180 days (this exclusivity is for ANDAs only) See 21 C.F.R. 314.108 New Drug Product Exclusivity

Patent Filing Leahy-Smith America Invents Act (AIA) of 2011 significantly modified the patent filing process AIA went into effect March 2013 Grants the patent to the entity “first to file” the application regardless of any previous publications Caused defensive publication planning by many companies Requires greater diligence of competitive landscape

Joan Bergstrom Henkel Consumer Goods, Inc. Fundamentals of Regulatory Affairs, 8th edition Ch. 15 Over-the-Counter Drug Products Joan Bergstrom Henkel Consumer Goods, Inc.

Introduction Over-the-counter (OTC) drugs play increasingly important role Durham-Humphrey Amendment to the FD&C Act in 1951 established three criteria for Prescription status drugs Habit forming drugs Not safe for use unless supervised by healthcare professional Limited to prescription use under NDA All drugs that did not meet these criteria = OTC drugs

Regulation of OTC Drugs Regulations applicable to Rx drugs also apply to OTC drugs All aspects of drug manufacture and testing (GMP’s) Facility listing and inspections Drug registrations Clinical trials and safety oversight Both review and approval of OTC drugs done by FDA Center for Drug Evaluation and Research’s (CDER) office Two main avenues to receive approval for an OTC drug OTC Monograph route – Safety and efficacy data known, using approved active ingredients and labeling NDA / ANDA route – submit safety and efficacy data

OTC Monograph Route In 1972, FDA initiated OTC Drug Review Process Encompassed review of safety and efficacy of products on the market Started by grouping products into therapeutic categories and evaluating the active ingredients rather than each product FDA now reviews active ingredients and labeling for more than 80 therapeutic classes of drugs (monographs, not all finalized) OTC Monograph is developed and published in the Federal Register

OTC Monograph Review Process Review of safety and efficacy data done by therapeutic category specific Advisory Panels, subject matter experts Advisory Panel recommended active ingredients be classified as Category I – generally regarded as safe and effective, not misbranded Category II – not generally regarded as safe and effective, or is misbranded Category III – insufficient data to permit classification After comment periods, FDA published conclusions as Tentative Final Monographs (Proposed Rule) Final Monograph (Final Rule) No defined timelines to move from TFM to FM, can be lengthy process Can market products under TFMs FDA can amend FMs as new information is available

NDA Route Products not covered by OTC monographs are subject to NDA process prior to marketing Four NDA Routes Direct-to-OTC NDA – same requirements as Rx NDA, PLUS demonstration product can be safely used without healthcare professional supervision Rx-to-OTC Switch – used when Rx shows it can be safely used without healthcare professional supervision NDA Monograph Deviation – used when a drug product deviates in any aspect from the OTC Monograph, like dosage form. NDA submitted with S&E data. Generic (ANDA) - same requirements as Rx NDA, with bioequivalence data

OTC NDA Products and Specific Studies Manufacturers must conduct Safety, Efficacy, and Preclinical studies Additional studies for OTC products: Label comprehension – evaluate extent to which a consumer can understand and apply information on OTC label when making drug product use decisions Open label and uncontrolled No drug product is used Self-selection – evaluate whether consumer makes correct decision on use/no use based on label information and knowledge of personal medical history No drug product used Suitable label based on comprehension should be created before test Actual use test (AUT) or Simulation Trial – evaluate consumer behavior Conducted under an IND “all comers” study with actual product

Labeling of OTC Drugs Primary responsibility over OTC drug labeling belongs to FDA In 1999, “Drug Facts” labeling rule became effective Standardized format, content, headings, graphics, and min. type size Ensure product information is easy to find and understand when used by ordinary people

Drug Facts Label Regulation 21 CFR 201.66 Specific information on OTC label: Active ingredient Uses Warnings Inactive ingredients Purpose Directions

OTC Drug Packaging Requirements Tamper evident packaging has become standard Regulation 21 CFR 211.132 Statement on both inner and outer pack show tamper-evident features Must comply with child-resistant package requirements Requirements as defined in the Poison Prevention Packaging Act (PPPA) of 1970 Consumer Product Safety Commission (CPSC) enforces child-resistant package requirements

FDA Oversight All OTC drug manufacturing activities must comply with 21 CFR 210 and 211 Drug manufacturing sites are required to register with the FDA Subject to prior approval inspections for NDA products and other routine inspections All OTC drug products must be drug listed, though NDC number not required on OTC drug product label Mandated safety reporting per the Dietary Supplement and Nonprescription Drug Consumer Protection Act of 2006

Assigning a Product Class Classified based on intended use as defined by FD&C Act Intended use determined by: Product claims ex. Cleans Consumer perception Drug ingredients ex. Fluoride Products can be both cosmetics and drugs – if two intended uses Examples: Antidandruf shampoo, antibacterial hand soap Must comply with requirements for either/both drugs and cosmetics

Advertising Since 1971, Regulated by the Federal Trade Commission (FTC) No requirement to submit advertising to FTC before use FTC has policy guides on advertising that must be consulted National Advertising Division (NAD) of the Better Business Bureau is the investigative arm of the voluntary self-regulation program NAD casework includes competitive challenges from other advertisers self-monitoring traditional and new media Ensure all claim support data is available before advertising