1. The US Regulatory Environment for Non-Rx Drugs Linda Bowen Head of US Regulatory Policy and Intelligence Sanofi 13 August 2013 (DIA RA Community RI WG TC)

2. What do the following products have in common? Advil (ibuprofen) Imodium A-D (loperamide) Aleve (naproxen) Claritin (loratadine) MiraLAX (PEG 3350) Zegerid (omeprazole and sodium bicarbonate) Alli (orlistat) Allegra (fexofenadine HCl) Oxytrol for Women 2

3. Durham-Humphrey Amendments The 1951 Durham-Humphrey Amendments revised the Federal Food Drug and Cosmetic Act to establish criteria for Rx/OTC status : Habit-forming characteristics Need for physician supervision Limitations established as part of the product’s marketing approval 3

4. Prescription versus Nonprescription Under section 503(b)(1)(A) of the FD&C Act, a drug must be dispensed only by prescription if, ‘‘because of its toxicity or other potentiality for harmful effect, or the method of its use, or the collateral measures necessary to its use, [it] is not safe for use except under the supervision of a practitioner licensed by law to administer such drug.’’503(b)(1)(A) 4

5. Additional OTC Drug legislation 1966 Fair Packaging and Labeling Act 1970 Poison Prevention & Packaging Act 1983 Federal Anti-Tampering Act 2006 Dietary Supplement and NonRx Drug Consumer Protection Act The Federal Trade Commission Act The Lanham Act State Laws 5

6. Regulatory Framework Two regulatory mechanisms exist for the legal marketing of OTC drug products: NDA (regulations described in 21 CFR Part 314) OTC drug monograph (regulations described in 21 CFR Part 330) OTC drug products marketed under either mechanism must meet established standards for safety and effectiveness. Neither mechanism establishes higher standards for safety or effectiveness than the other. Under both mechanisms, products must be manufactured according to current good manufacturing practices as defined in 21 CFR Part 210 and must comply with the labeling content and format requirements in 21 CFR Part 201 Subpart C. 6

7. Regulatory Framework – NDA/ANDA Legal marketing is under the authority of an approved product-specific NDA or ANDA. An OTC drug product with active ingredients, dosage form, dosage strength, or route of administration new to the OTC marketplace is regulated under the NDA process. Rx-to-OTC switches Direct-to-OTC Generic Monograph deviations via NDA (d-NDA) 7

8. Regulatory Framework – Monograph Monographs specify the active ingredients that can be contained within OTC drug products. An OTC drug product containing ingredients that comply with standards established in an applicable monograph is considered to be “generally recognized as safe and effective” (GRASE) and does not require specific FDA approval before marketing. 8

9. Regulatory Framework – Monograph A monograph can be likened to a recipe book. It includes: Allowable active ingredients Dosage form Dosage strength Indications Warnings Allowable combinations 9

10. Drugs Facts Labeling In the Federal Register of March 17, 1999, FDA published a final regulation (21 CFR 201.66), establishing standardized content and format for the labeling of OTC drug products.Federal Register of March 17, 199921 CFR 201.66 Standardized labeling for OTC drug products is intended to make it easier for consumers to read and understand OTC drug products safely and effectively. The labeling regulations in 21 CFR 201.66 cover all OTC drug and drug-cosmetic products, whether marketed under a 505(b)(1) application, a 505(b)(2) application, abbreviated new drug application, or an OTC drug monograph. Standardized labeling 21 CFR 201.66 10

11. Drugs Facts Labeling 11

12. OTC Drug Review Implementation of the 1962 Kefauver-Harris Amendments included a review of the efficacy and safety of all drug products on the market prior to 1972 (DESI Review). There were so many OTC products on the market that the FDA decided to divide the products in to categories and evaluate them based on their active ingredients. FDA chose to ban over 500 compounds from the market, and ultimately determined that only 270 or so active ingredients were generally recognized as both safe and effective (GRAS/E) for their intended uses 12

13. OTC Drug Review Evaluations were done by committees established by FDA for each category. Based upon each committee’s recommendations, FDA published an ANPR (Advanced Notice of Proposed Rulemaking) inviting comment. At this stage, ingredients were classified as Category I (GRASE), Category II (not GRASE), or Category III (additional data needed).GRASE 13

14. OTC Drug Review FDA reviewed the comments made on the ANPR and published a Tentative Final Monograph (TFM or proposed rule) which requested further comment. At the end of the comment review, a Final Monograph (final rule) was published in the Federal Register. These are codified annually in to the Code of Federal Regulations (21 CFR Parts 330 – 358).Code of Federal Regulations 14

15. How do you make changes to an OTC Monograph? Citizen Petition can be submitted if the product was marketed in the U.S. prior to 1975. Time and Extent Application (TEA) under 21 CFR 330.14; over the counter drugs initially marketed in the United States after the OTC drug review began in 1972 and OTC drugs without any U.S. marketing experience can be considered for inclusion in the OTC drug monograph system. (Link to rulemaking history of time and extent applications). The TEA final guidance was issued September 2011.LinkTEA final guidance 15

16. OTC Monograph System Public process Class-specific regulations No data confidentiality No potential for marketing exclusivity No necessary clinical development costs No user fees under PDUFA No mandated FDA review timelines 16

17. OTC Cough Cold Monograph 21 CFR 341 Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic drug products for OTC use 21 CFR 341 Subpart B--Active Ingredients § 341.12 - Antihistamine active ingredients. § 341.14 - Antitussive active ingredients. § 341.16 - Bronchodilator active ingredients. § 341.18 - Expectorant active ingredient. § 341.20 - Nasal decongestant active ingredients. § 341.40 - Permitted combinations of actives Subpart B--Active Ingredients§ 341.12§ 341.14§ 341.16§ 341.18§ 341.20§ 341.40 17

18. Recent Addition to the Cough Cold Monograph Bayer petitioned FDA to add “phenylephrine bitartrate” as GRASE in an effervescent tablet to the nasal decongestant section of the Cold, Cough, Allergy, Bronchodilator, and Anti-asthmatic Monograph. FDA meeting held 2002 Bayer Citizen’s Petition to FDA 2002 Advanced Notice of Proposed Rulemaking 02-Nov- 2004. Bayer’s comment to the docket 28-Jan-2005. Inclusion of phenylephrine bitartrate to USP/NF 01- August-2005 Final Monograph/Final rule published 01-August-2006. 18

19. Regulatory Framework – Rx to OTC Switch Rx-to-OTC switch refers to the transfer of proven prescription drugs to nonprescription, over-the- counter status. The Rx-to-OTC switch process is a data-driven, scientifically rigorous, and highly regulated process that allows consumers to have OTC access to a growing range of medicines. For a medicine to be granted OTC status, it must have a wide safety margin and be effective, and must bear understandable labeling to ensure proper use. More than 700 OTC products on the market today use ingredients or dosages available only by prescription less than 30 years ago. 19

20. Regulatory Framework – Rx to OTC Switch An efficacy supplement is submitted to an approved NDA for a Rx product if the sponsor plans to switch the drug product covered under the NDA to OTC marketing status in its entirety without a change in the previously approved dosage form or route of administration. A new NDA is submitted if the sponsor is proposing to convert some but not all of the approved prescription indications to OTC marketing status. An original NDA needs to be submitted if the sponsor plans to market either a new product OTC whose active substance, indication, or dosage form has never previously been marketed OTC. 20

21. Regulatory Framework – Rx to OTC Switch Does the product have an acceptable safety and efficacy profile for the OTC setting, in the potential absence of a learned intermediary? Does the product have low potential for misuse and abuse? Does the benefit of OTC availability of the proposed product outweigh the potential consequences of some consumers not complying with label directions and warnings or inappropriately self-selecting the product? Can the condition be adequately self-recognized? Can the consumer appropriately select and use the product in accordance with product labeling? 21

22. Regulatory Framework – Rx to OTC Switch Consumer Behavior Studies Label Comprehension Studies Self Selection Studies A self-selection study assesses the ability of consumers to apply drug labeling information to their personal health situation to make correct decisions about whether or not it is appropriate for them to use a drug product. Human Factors Studies Actual Use Studies Assess self-selection or de-selection in accordance with materials, and safety in simulated real world setting 22

23. Can FDA initiate a switch? Theoretically, FDA could make a recommendation to switch a product; however, the agency would need to follow a resource-intensive, complex process. There are unresolved and debated questions concerning such an approach, including the use of proprietary data, formal hearing rights, under what authority FDA would seek to do so, and the lack of regulations. 23

24. Can the switch process go in reverse? If FDA acquires evidence of a significant safety problem with a product or ingredient, the Agency can transfer it back to prescription-only status or remove it from the market all together, e.g., antimicrobial hexachlorophene in 1977, the antihistamine methapyrilene in 1979 and the laxative danthron in 1987. 24

25. What is Behind the Counter (BTC) A third class or BTC class of drugs does not currently exist in the United States. In general, when most people talk about a third class of drugs, they are referring to a category of medicines available without a prescription, but only in pharmacies or through a pharmacist. Under this system, some nonprescription medicines would not be available in other convenient retail outlets, such as grocery stores without a pharmacy. 25

26. BTC History Opinions on BTC Class of Drugs 6/74 FR 12/84 CP 4/93 CP Nonprescription Drugs: Value of a Pharmacist- Controlled Class (1995) – GAO Report Nonprescription Drugs: Value of a Pharmacist- Controlled Class Part 15 hearing 6/28/2000 Part 15 hearing 11/14/2007 Nonprescription Drugs: Considerations regarding a Behind-the Counter Drug Class (2009) – GAO Report Nonprescription Drugs: Considerations regarding a Behind-the Counter Drug Class 26

27. The future of switches The current concept of self care is limited to conditions that can be self-diagnosed and self- treated based on the information in the drug facts labeling on the non-prescription drug combined with common knowledge and commonsense. The question being addressed at the hearing was can we broaden the assistance that a consumer gets, for example by augmenting the drug facts labeling with information technology approaches or by utilizing pharmacist assistance to help the consumer understand the condition or the treatment better, and thus increase the types of medicines that potentially could be available non-prescription? 27

28. Nonprescription Safe Use Regulatory Expansion (NSURE) Initiative Given limitations in the tools available for risk mitigation of nonprescription products, the NSURE initiative is focused on developing innovative approaches for nonprescription drugs in order for patients to appropriately self-select drug products. The objective is to make drugs more widely accessible through conditions of safe use. FDA is currently developing the conceptual framework for NSURE and is seeking to obtain expert feedback and input. 28

29. March 22-23, 2012 FDA Public Hearing “Using Innovative Technologies and other Conditions of Safe Use to Expand Which Drug Products Can Be Considered Nonprescription” 30+ speakers providing broad representation of different views – industry, consumers, trade associations, academia, patient advocacy Panel representation included FDA and CMS Oral presentations or comments to public docket which closed May 7, 2012 29

30. March 22-23, 2012 Public Hearing Topics Types of Technology and Conditions of Safe Use: Mobile, desktop and store-based devices Pharmacy, Consumer, and Health Care Provider Issues: Types of drugs and conditions, reduce burden on healthcare system Other Related Issues: Insurance coverage, out- of-pocket costs, liability, competitive barriers

31. Brookings NSURE Meetings The Engelberg Center for Health Care Reform at Brookings, supported by a cooperative agreement with FDA, has convened two workshops to seek expert stakeholder feedback on the NSURE initiative and to explore potential practical strategies for conditions of safe use. November 8, 2012: 9 AM - 12:30 PM May 9, 2013 9 AM – 4 PM Fall 2013 (Reimbursement)

32. Open Issues Scope of authority – is legislation needed? Technology classification Can the definition of labeling be expanded (beyond DFL) Protection (patent and/or data exclusivity) for technology Regulatory Pathway to approval; are these considered combination products? Pharmacist Gatekeeper akin to BTC class

33. The future of switches Product categories that might be available under this new paradigm: High blood pressure High Cholesterol Diabetes/Pre-diabetes Asthma (especially relief inhalers) Epinephrine Auto Injectors Migraine BPH Urinary Incontinence Nexium, Rhinocort Aqua (licensed by Pfizer) 33

34. The future of regulatory convergence

35. Regulatory Cooperation Council - OTC On February 4, 2011, President Barack Obama and Prime Minister Stephen Harper announced the creation of the United States-Canada Regulatory Cooperation Council (RCC) to increase regulatory transparency and coordination between the two countries. The Joint Action Plan was released in December 2011.United States-Canada Regulatory Cooperation Council The RCC will undertake efforts to better align the regulatory environment between the United States and Canada through a variety of tools such as enhanced technical collaboration, mutual recognition of standards, and joint work sharing, in an effort to address root causes of regulatory misalignments, develop lasting solutions, and avoid future misalignments from developing. 35

36. Regulatory Cooperation Council - OTC One of the goals was a joint collaboration between Health Canada and the FDA to better align our regulatory systems, reduce unnecessary duplications and differences, and, to the extent feasible, better leverage resources to help both agencies meet their public health missions within the parameters allowed by prevailing laws and regulations subject to available human and financial resources. 36

37. Regulatory Cooperation Council - OTC One of the Joint Action Plan Initiatives is to develop and adopt common monographs for routine over-the-counter drugs.common monographs The objectives of the RCC monograph alignment working group (regulators) are to conduct a pilot program to develop aligned monograph elements for a selected over-the-counter drug category (e.g. aligned directions, warnings, indications and conditions of use). And subsequently, develop recommendations to determine the feasibility of an ongoing mechanism for alignment in review and adoption of these OTC drug monograph elements. 37

38. Regulatory Cooperation Council - OTC Although regulator driven, various stakeholders have been involved and met via TC May 2012: Consumer Health Products Canada (CHP) Consumer Healthcare Products Association (CHPA) Canadian Cosmetic, Toiletry and Fragrance Association (CCTFA) Personal Care Products Council (PCPC) Groupement Provincial de l'Industrie du Médicament (GPIM) National Association of Pharmacy Regulatory Authorities (NAPRA) Canadian Pharmacists Association (CPA) 38

39. References Rule-making history for OTC drug products Rule-making history OTC active ingredients (alphabetically)alphabetically OTC active ingredients (by monograph)monograph OTC active ingredients (excel sheet)excel sheet Rx-to-OTC switch listswitch list FAQ on the OTC regulatory process FAQ Slides and Testimony (March 2012 meeting) Slides and Testimony Transcript Day 1 (March 2012 meeting) Transcript Day 1 Transcript Day 2 (March 2012 meeting) Transcript Day 2 CHPA-Booz & Co. Report January 2012 “The Value of OTC medicine to the United States” 39