Michael A. Swit, Esq. Vice President

1. Michael A. Swit, Esq.Vice President

2. Selected Regulatory Issues inOphthalmic Drug Development Pharmaceutical Education Associates 5th Annual Ophthalmic Drug Development & Delivery Summit September 2009 Del Mar, California

3. Standard Disclaimers Views expressed here are solely mine and do not reflect those of my firm or any of its clients. This presentation supports an oral briefing and should not be relied upon solely on its own to support any conclusion of law or fact.

4. What We Will Cover • 505(b)(2) NDAs – How They Differ • Key Regulatory Tips • Some Recent Ophthalmic Approval Examples • FDA Regulation of Combination Products

5. Statutory 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)}

6. How is 505(b)(2) Different? • The applicant and FDA may rely on prior FDA safety and efficacy determinations, based on studies conducted by someone else even though the applicant does not have a right of reference to the data. 21 U.S.C. § 355(b)(2) • Safety and efficacy can also be supported by published reports – resembles, in part, FDA’s 1978 “Paper NDA” policy

7. Types of 505(b)(2) NDAs • New Chemical Entity (rarely) • Changes to a Previously Approved Drug • New dosage form, dosing regimen, strength, or route of administration • New indication • New active ingredient • New inactive ingredient that requires studies beyond limited confirmatory studies • Rx  OTC switch (Claritin) • Rarely -- duplicates of approved drugs that cannot be approved under an ANDA (e.g., due to changes in inactives in parenteral products) • May get Exclusivity under Waxman-Hatch

8. Pfizer/Pharmacia Petition Statement of Grounds • Reliance on proprietary data not authorized by FDCA for 505(b)(2) NDAs • Published Studies vs. • Proprietary Data vs. • FDA Findings of Safety/Efficacy • Reliance on proprietary data would be an unconstitutional “taking” • “A” ratings not permitted for 505(b)(2) drugs

9. Pfizer/Pharmacia Petition: FDA Reply • Denied on October 14, 2003 – 38 pages • “Validated” the 505(b)(2) approach that FDA has been using • “A” ratings – made clear would be available if products are pharmaceutical equivalents and shown to bioequivalence -- leaves open issue of bioequivalence on “generic biologics” if approved via 505(b)(2) process

10. Recent 505(b)(2) Ophthalmic Approval • Akten (lidocaine hydrochloride) Ophthalmic Gel • Akorn, Inc.; Oct. 7, 2008 • Topical, ocular anesthetic formulation for use in ocular procedures that require a topical anesthetic agent. • Reference drug: their own ANDA for a lidocaine jelly • Key data required/waived • Single clinical study in 208 subjects (3 strengths vs. sham) • No nonclinical studies required • Secured waiver of bioavailability requirements • Safety • The clinical study • Literature references • Exclusivity awarded? Yes – 3 years as a new dosage form (NDF)

11. 505(b)(2) Does Not Mean It’s Easy • Misconception – the 505(b)(2) is the quick way to get an approval (don’t be fooled by Akten®) • Have to carefully assess how your product differs from approved product; for example: • Acute to chronic – may trigger new tox studies • New indications for old moieties – can trigger complex studies depending on the indication selected • New dosage forms – first see if can do under an ANDA Suitability Petition – if can, must • Drug delivery systems – often approved under 505(b)(2), but can present various challenges • Also may be “Combination Products” if married to a medical device

12. Overall Comparison of 3 Pathways *Either clinical or PD study required with topical product or some non-systemically effective drugs for ANDA. Do not always need clinical for 505(b)(2). In very rare occasions, new clinicals not needed for a 505(b)(1) NDA (e.g., with a right of reference) 12

13. Tips of the Trade • Non-standard Manufacturing Process • Specialized pharmaceutical dosage forms (certain modified release preparations) • Incorporation of new technology into a conventional process • Specialized processes involving new technologies • Nonstandard methods of sterilization • If non-standard process, may require validation data on 3 production scale batches at time of NDA • If using a drug delivery system (device), provide Risk Analysis on the device (ISO 14971) – required in some countries in the EU before the CTA can be approved • Some EU countries require a Risk Minimization Plan for the CTA and also for the MAA

14. Tips of the Trade … • Emerging trends in FDA demands: • endothelial cell counts • comfort studies • endotoxin testing for all ophthalmic drugs, not just ones used during surgery.  Can change: • how excipients and actives are handled • may require upgrades to manufacturing water systems. • DMFs – make sure updates, especially for new USP residual solvents requirements • Degradation products - if concentration of your ophthalmic preparations is low -- and thus the exposure itself is low– may be more degradation products needing quantitation as above the ICH limit. • Be prepared to justify your specifications

15. Recent Ophthalmic Approvals • Zirgan (ganciclovir) Ophthalmic Gel • Date of Approval: September 15, 2009 • Company: Sirion Therapeutics, Inc. • Treatment for: Keratitis • Zirgan (ganciclovir ophthalmic gel) is a topical ophthalmic antiviral preparation for the treatment of acute herpetic keratitis (dendritic ulcers). • Bepreve (bepotastine) Ophthalmic Solution • Date of Approval: September 8, 2009 • Company: ISTA Pharmaceuticals, Inc. • Treatment for: Allergic Conjunctivitis • Bepreve (bepotastine ophthalmic solution) is an antihistamine and mast cell stabilizer for treatment of the symptoms of allergic conjunctivitis.

16. Recent Ophthalmic Approvals … • Acuvail (ketorolac tromethamine) Ophthalmic Solution • Date of Approval: July 22, 2009 • Company: Allergan, Inc. • Treatment for: Postoperative Ocular Inflammation • Acuvail (ketorolac tromethamine) is a preservative-free formulation of ketorolac, a nonsteroidal anti-inflammatory drug (NSAID) indicated for the treatment of pain and inflammation following cataract surgery. • Ozurdex (dexamethasone) Intravitreal Implant • Date of Approval: June 17, 2009 • Company: Allergan, Inc. • Ozurdex (dexamethasone intravitreal implant) is a sustained-release, potent steroid implant for the treatment of macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO).

17. Recent Ophthalmic Approvals … • Besivance (besifloxacin) Ophthalmic Suspension • Date of Approval: May 28, 2009 • Company: Bausch & Lomb • Treatment for: Bacterial Conjunctivitis • Besivance (besifloxacin ophthalmic suspension) is a topical quinolone antimicrobial for the treatment of bacterial conjunctivitis, commonly referred to as "pink eye.“ • Latisse (bimatoprost) Ophthalmic Solution • Date of Approval: December 24, 2008 • Company: Allergan, Inc. • Treatment for: Hypotrichosis of Eyelashes • Latisse (bimatoprost ophthalmic) is a prostamide indicated for the treatment of hypotrichosis (or reduced amount of hair) of the eyelashes. Growth of the eyelashes is a well documented side effect of bimatoprost which is currently approved as Lumigan for the treatment of glaucoma.

18. Resources FDA Website: “Drugs @” -- for info on individual drug approvals such as links to reviews, approval letters, etc. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm

19. More Resources … • FDA website – (more …) • Drug Approval Process -- http://www.fda.gov/Drugs/DevelopmentApprovalProcess/default.htm • FDA listservs – updates on key CDER regulatory issues – visithttp://www.fda.gov/Drugs/ucm136245.htm • “Regulatory Pitfalls in Product Development” – Presentation by Michael Swit at PEA Pipeline to Product Conference, November 2007 – available from Michael Swit by request • “Regulatory Considerations in the Development of Ophthalmic Drugs.” Presentation by Michael Swit at PEA 4th , Ophthalmic Drug and Delivery Summit, Sept. 2008 – available from Michael Swit by request • “Regulatory Considerations in the Development of Ophthalmic Sustained Drug Delivery Systems.” Susan Caballa, Vice President, Alimera Biosciences. PEA 3rd Annual Ophthalmic Drug and Delivery Summit, Sept. 2007 – available from Michael Swit by request

20. Combination Product Regulation

21. What Is a Combination Product? • As defined in 21 CFR § 3.2(e), the term combination product includes: • (1) A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity; • (2) Two or more separate products packaged together in a single packageor as a unit and comprised of drug and device products, device and biological products, or biological and drug products; • (3) A drug, device, or biological product packaged separatelythat according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose; or • (4) Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect.

22. Devices PMA/510(k)/IDE QSR MDR The Combination Galaxy Drugs • NDA/IND • cGMP • AERS Biologics • BLA/IND • cGMP+ • AERS+ Primary Mode of Action Consultation Regulations

23. A Brief History of Combinations • Combination products statutorily recognized in Safe Medical Device Act of 1990 • Required assignment to lead center based on primary mode of action • Implemented by Chief Mediator and Ombudsman

24. A Brief History … • Office of Combination Products (“OCP”) • Created by Medical Device User Fee and Modernization Act (MDUFMA) • Office established on December 24, 2002 • OCP given broad oversight responsibilities covering the regulatory life cycle of combination products. • Coordinate reviews among FDA Centers • Ensure consistency among similar reviews

25. Section 503(g) of the Act • FDA is required to assign a combination product to a lead Center based on its "primary mode of action" • PMOA was not defined in the statute or regulations • For some products, PMOA is difficult to identify • Early in development (just don't know) • Products that have two (or more) completely different modes of action, neither of which is subordinate to other

26. PMOA -- Determining Which Center Leads • PMOA = Primary Mode of Action; not defined in statute, but in regulations • Final Rule – 8/25/2005; 70 Fed. Reg. 49848 • http://www.fda.gov/OHRMS/DOCKETS/98fr/05-16527.pdf • Mode of Action: the means by which a product achieves an intended therapeutic effect or action. 21 CFR 3.2(k) • Three types of modes of action: biological product, device, drug • Combination products typically have more than one identifiable mode of action

27. PMOA … Primary mode of action is the single mode of action of a combination product that provides the most important therapeutic action of the combination product. The most important therapeutic action is the mode of action expected to make the greatest contribution to the overall intended therapeutic effects of the combination product. Source: 21 CFR 3.2(m)

28. Final PMOA Rule: “Constituent Parts” • A constituent part of a combination product has a: • Biological product mode of action if it acts by means of a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product applicable to the prevention, treatment, or cure of a disease or condition of human beings… • Device mode of action if it meets the definition of device…, it does not have a biological product mode of action, and it does not achieve its primary intended purposes through chemical action within or on the body….and is not dependent on being metabolized for the achievement of its primary intended purposes • Drug mode of action if it meets the definition of drug…and it does not have a biological product or device mode of action.

29. The PMOA Decision Tree If unable to determine most important therapeutic action with reasonable certainty, consider: • Consistency: is there an agency component that regulates other combination products presenting similar questions of S & E with regard to the combination product as a whole? • Safety and Effectiveness: which agency component has the most expertise related to most significant S&E questions presented by combination product?

30. Not Sure – Requests for Designations (RFDs) • Voluntary Formal Process under 21 CFR Part 3 • Seeks to determine: • Classification • Assignment • Clarification of Regulatory Pathway • If don’t file, FDA may stay review clock while a determination is made • When: • Before any application for premarket review • As soon as enough info exists for FDA to make a decision

31. RFD’s … • Contents: • Sponsor information • Product description • Proposed use and indications • Description of primary mode of action • Recommendation on product classification and Center with primary jurisdiction • Source: 21 CFR §3.7(c) • Guidance on How to Write a RFD (8/2005) • http://www.fda.gov/oc/combination/Guidance-How%20to%20Write%20an%20RFD.pdf

32. RFD’s … • Key sections to focus on: • What is your product? • Why would your product be used? • How does your product work? • What is your product’s most important therapeutic action? • What is the basis for your PMOA analysis? • How do you think your product should be assigned?Why? Use assignment algorithm if appropriate.

33. RFD’s … • OCP reviews RFD’s for completeness • If complete, OCP sends acknowledgement letter to sponsor, and copy of RFD’s to three Center Liaisons • Center recommendations due to OCP in 21 days • Consultation among OCP, Centers and Office of Chief Counsel • Decision reached, response letter prepared, necessary clearances obtained • Decision must issue within 60 days; if not YOUR recommendation wins!!

34. RFD’s … • Request for Reconsideration • Submit within 15 days • Less than 5 page submission, no new information • FDA response within 15 days • FDA has been known to change a decision upon reconsideration • Effect of RFD Letter – designated FDA Center can only be changed without your consent to protect the public health or another compelling reason. • Source: 21 CFR 3.9(b)

35. Jurisdictional Decisions -- Examples • BreathTest Combinations • http://www.fda.gov/oc/combination/breathtest.html • Minimal Manipulation of Structural Tissue • http://www.fda.gov/oc/combination/Minimal%20Manipulation%20JU%20(Final%209-19-06).pdf • Heparin Catheter Lock-Flush Solutions • Federal Register of 8/17/2006 -- http://www.fda.gov/OHRMS/DOCKETS/98fr/E6-13509.htm • Summary -- http://www.fda.gov/oc/combination/catheter.html • Metered Dose Inhalers, Spacers and Other Accessories • http://www.fda.gov/oc/combination/mdiupdate.html • Drug/Biologic Combinations • http://www.fda.gov/oc/combination/biologic.html

36. Which GMP Rules Apply? • Guidance on GMPS for Combination Products • http://www.fda.gov/oc/combination/OCLove1dft.pdf • Sets forth broad framework for application of cGMP to combination products • Each constituent part (drug, device, and/or biological product) of a combination product is subject to its governing cGMP regulations before combination

37. GMPs … • During and after combination, both sets of cGMP regulations apply (single entity and co-packaged products*) • Recognizes that many manufacturing facilities operate under one type of manufacturing system • cGMP and QS regulations are generally similar

38. GMPs … • Each regulation also contains key elements based upon the unique characteristics of the types of products were designed to address • Compliance with both sets of regulations can generally be achieved by using either regulation • e.g., by using the system in place at a facility and paying special attention to key issues

39. GMPs … • If properly implemented, parallel operating systems (e.g., cGMP and QS) should not be necessary • Reasoning: possible to implement a practice under a general requirement in one set, for example, that complies with a more specific requirement of other set

40. GMPs … • Guidance -- identifies key provisions of cGMP and QS regulations that differ in specificity and that should be carefully considered by manufacturer • For example, if operating under Device cGMP Quality System: • Design controls (21 CFR 820.30) • Purchasing controls (21 CFR 820.50) • CAPA (820.100)

41. GMPs … • For example, if operating under Drug GMP system: • Testing and approval/rejection of components (21 CFR 211.84) • Calculation of yield (21 CFR 211.103) • Expiration dating (21 CFR 211.137) • Stability testing (21 CFR 211.166) • Containers and closures (21 CFR 211.84) • Ultimately – the two systems are being harmonized

42. How Many Applications? • Concept Paper on Marketing Applications for Combination Products • http://www.fda.gov/oc/combination/singlesepconpaper.pdf • Basics: • PMOA does not ensure application status; but lead Center • Single application usually is sufficient • Exceptions • One component is already approved, but labeling will need to be changed • Biologics – legally can have separate apps. for components • When the components are “separate and complex” – e.g., a device in combination with a new molecular entity drug/biologic • Where needed to “apply mechanisms to ensure appropriate regulation or unique regulatory requirements” not available under one app. • Example: gene therapy

43. How Many Applications?... • You Might Want Two – perhaps: • To qualify for Waxman-Hatch Exclusivity • Orphan Drug Status • To protect proprietary data if 2 firms are involved • Complex decision tree suggested in concept paper on how these are handled

44. User Fees – Can I Pay the Least Amount? • Guidance on User Fees for Combination Products – April 2005 • http://www.fda.gov/oc/combination/userfee.pdf • Basics • Depends on type and # of applications (see prior slide) • If two applications submitted voluntarily, pay two fees • If two applications REQUIRED, still pay two fees • “Innovative Product Waiver” – consider seeking

45. Resources • List of Jurisdictional Determinations – By Assigned Center • http://www.fda.gov/oc/combination/determinations.html • Guidance on Early Development Considerations for Innovative Combination Products (9/2006) • http://www.fda.gov/oc/combination/innovative.pdf • Guidance on How to Write a RFD (8/2005) • http://www.fda.gov/oc/combination/Guidance-How%20to%20Write%20an%20RFD.pdf • Final Rule on “Primary Mode of Action” – 8/25/2005; 70 Fed. Reg. 49848 • http://www.fda.gov/OHRMS/DOCKETS/98fr/05-16527.pdf • Concept Paper on Handling of Adverse Events • http://www.fda.gov/oc/combination/adveventconpaper.pdf

46. Resources … • Overview of the Office of Combination Products • http://www.fda.gov/oc/combination/overview.html • Frequently Asked Questions on Combination Products • http://www.fda.gov/oc/combination/faqs.html#_Toc88444686 • Other Types of Combinations (e.g., Drug/Cosmetic) • http://www.fda.gov/oc/combination/other_combinations.html • List of Recent Combination Product Approvals • http://www.fda.gov/oc/combination/approvals.html • Recent Presentations by FDA on Combination Products • http://www.fda.gov/oc/combination/presentations/default.htm

47. Questions? 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

48. About your speaker… Michael A. Swit, Esq., is a Vice President at THE WEINBERG GROUP, where he develops and ensures the execution of a broad array of regulatory and other services to drug, biologics and medical device/diagnostic clients seeking to market products in the United States. His expertise includes product 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, he received his law degree from Emory University Law School and is a member of the California, D.C. and Virginia bars.

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