1 Michael A. Swit, Esq. Vice President

FDA Regulatory Issues and Ophthalmic Drug Development Pharmaceutical Education Associates 4 th Annual Ophthalmic Drug Development & Delivery Summit September 2008 Del Mar, California

3 Standard Disclaimers  Views expressed here are solely my own and do not necessarily reflect those of my firm or any of our clients.  These slides support an oral briefing and may not be relied upon solely on their own to support any conclusion of law or fact.

4 FDA Path – New and Old Hurdles  New Hurdles  Changed realities –  Drug Safety focus – post-Vioxx  Pressure on use of accelerated approvals  Pressure on use of priority reviews  Impact of FDAAA – new FDA weaponry and company duties  REMS  Clinical Trial Registries  PDUFA  Pediatric studies  Old Hurdles  Traditional challenges of regulatory path – will be our focus today, with an emphasis on taking a look at a couple recent ophthalmic approvals for guidance  Speaking of guidance – there is not much out of FDA in the ophthalmic arena

5 The FDA Path – Start to Finish  Lab Studies (most) – not FDA regulated – not our concern today  Preclinical aka Tox – beginning of FDA concern  Pre-IND Submission and Package  IND  Phase 1  Phase 2  End of Phase 2 Meeting  Phase 3  Pre-NDA/BLA Filing Meeting  NDA/BLA Filing  Review Clock  Advisory Committee  Approval  Post-Marketing Commitments – commonly:  Pediatric Study  REMS

6 Two Drugs – How They Progressed  Lucentis (ranibizumab injection) -- for treatment of patients with neovascular (wet) age-related macular degeneration – June 2006  Macugen (pegaptanib sodium injection) – for treatment of wet age-related macular degeneration – -- December 2004

7 Preclinical/Tox  Goal – to develop sufficient data to support an IND to institute human studies  Lucentis – key issue – appropriate animal model – because Lucentis was thought to act on vascular endothelial growth factor (VEGF) – chose cynomologous monkey model – 99% homology to human VEGF  Macugen –  Able to secure a waiver of carcinogenicity studies by showing low systemic absorption and negative SHE cell assays  Consistent with ICH guidance

8 Pre-IND Submission and Package  Key Step in Development  Need to lay out both tox work done and best statement of rest of development plan  Trying to secure “buy-in” for Phase 1 and 2, if possible  Essential that it be very well-prepared and asks the questions in the best way as to assure FDA provides the correct reply  Actual meeting  Rehearse, rehearse, rehearse  Be careful who you bring  Coordinate with EU “scientific advice” process – despite “harmonization,” never assume what FDA wants will satisfy the EMEA or member states

9 Investigational New Drug Exemption -- IND  If you did the pre-IND well, this will follow easily  Remember – is not an “approval” – is a notice system.  30 days  If FDA has a problem, will issue “clinical hold” letter  Exemptions – limited –  marketed products under some circumstances  Even if marketed product, will need IND if seeking to change new claims

10 Phase 1  Goal – establish the pharmacology, safety, and, occasionally, preliminary evidence of effectiveness  Safety – of different dosages and to see if there are any dose- limiting toxicities  Dose selection – commonly – those with fewest reactions go to Phase 2 and 3  Lucentis – instead of volunteers, used AMD patients due to the risk linked to the intravitreal injection  Macugen – 4 different Phase 1/2 studies – an aggregate of about 60 individuals

11 Phase 2  Goal – determine minimum dose that is maximally effective in target populations  Lucentis – key issue – tested various doses and dosing regimens  Macugen – did four Phase 1/2 studies for dose ranging – relatively small number of patients

12 End of Phase (EOP) 2 Meeting  Critical Meeting –  Forms basis for Phase 3 approach – get input on design of Phase 3 pivotal clinicals  Some will use to obtain a SPA – Special Protocol Assessment – that (theoretically) binds FDA to not change the rules  Challenges of an SPA  Can lock you into a format that might restrict your ability to adjust the clinical as you learn more about the drug  If you miss on study endpoints, you may have less of an ability to use sound science as to why the studies may still support an approval of an appropriate indication

13 Phase 3  Goal – perform two “adequate and well- controlled” clinical investigations  Result – will satisfy “substantial evidence” requirement of Federal Food, Drug, and Cosmetic Act needed to support NDA approval (parallel legal requirements for BLA licensing)  Lucentis –  Multi-center, randomized, double blind with sham injection as an inactive control  Bias – minimized by using separate treating and evaluating physicians  Strict inclusion/exclusion criteria  Two different treatment doses to look for dose response  Study endpoints – AMD  Visual acuity – FDA -- doubling of visual angle – 15 letters on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart measured at 4 m or more = clinically relevant  Surrogates (e.g., retinal thickness) – must be validated to clinical effect

14 Phase 3 …  Goal – perform two “adequate and well- controlled” clinical investigations  Result – will satisfy “substantial evidence” requirement of Federal Food, Drug, and Cosmetic Act needed to support NDA approval Note: legal requirements for BLA licensing are worded differently, but essentially enforced same  Macugen  Two virtually identically designed studies  Patients  EOP1003 – 622 patients --  EOP1004 – 586 patients –  Design – multi-center, randomized, sham- injection controlled, double blind, dose finding (.3, 1 or 3 mg.)  Study endpoints – AMD – same as Lucentis  Visual acuity – FDA -- doubling of visual angle – 15 letters on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart measured at 4 m or more = clinically relevant

15 Pre-NDA/BLA Filing Meeting  Vital meeting  To ensure that key issues related to data for filing are properly addressed  REMS – get buy-in from FDA on any remaining safety signals and how they might be addressed by the panoply of options articulated in FDAAA, such as:  Studies (non-clinical)  Clinical trials (e.g., Phase 4)  Patient registries  Education programs  Dispensing restrictions (e.g., only if certain test results filed), etc.

16 NDA/BLA Filing  Goal – ensure that the submission is sufficiently complete that it is “accepted for filing”  Worst scenario – RTF or “refuse to file”  Lucentis –  Had separate clinical and CMC pre-filing meetings  Macugen –  filed as a rolling submission  Did not have a pre-NDA meeting

17 Review Clock  Goal – if possible, secure fastest review cycle  Priority – significant therapeutic advance over available therapies – 6 month  Standard – 10 months  Lucentis – did get priority review – as regarded as an improvement on existing therapies (not clear how)  Macugen – Fast Track status awarded (similar treatment to priority review) – unmet medical need

18 Advisory Committee  Goal – to provide expert guidance to FDA on key safety or clinical issues presented by filed applications  New Rule – as of 10/07, most new molecular entities will need an Adv. Com. meeting  Lucentis – no unique safety or effectiveness issue – thus, did not require an Advisory Committee  Macugen – did go through as it was first in class and route of administration for atypical  Made the recommendation on educating on aseptic handling

19 Approval  Standard – NDA -- “substantial evidence” of effectiveness and drug can be safely used per labeling  BLA – “safe, pure and potent” – but basic approach is same as with NDA  FDA Review Responses  RTF – refuse to file  Complete Response – that the review period has completed  Approval July 10, 2008 – Final Rule issued on FDA replies to NDAs/BLAs – 73 Fed. Reg  Lucentis – Two efficacy studies:  FVF2598g –  Sham control  Monthly injections  Minimally classic or occult  FVF2587g  Active control – verteporfin PDT  Monthly injections  Predominantly classic AMD  Result – nearly 95% of subjects maintained their vision at 12 months  Approval – based on 12-month data; but studies were planned as 24-month  FVF3192g – studied dosing of Lucentis every 3 months

20 Approval …  Standard – NDA -- “substantial evidence” of effectiveness and drug can be safely used per labeling  BLA – “safe, pure and potent” – but basic approach is same as with NDA  FDA Review Responses  RTF – refuse to file  Complete Response – that the review period has completed  Approval July 10, 2008 – Final Rule issued on FDA replies to NDAs/BLAs – 73 Fed. Reg  Macugen –  Approval based on 1 year data from a 2-year study and partial 2 nd year data  Four-arm study  3 treatment groups .3 pegaptanib  1 mg.  3 mg  Sham group

21 REMS  Used prior to FDAAA  Memorialized by FDAAA  Can take many forms  Labeling  Patient education  Doctor education  Testing requirements  Inclusion criteria for patients (e.g., negative pregnancy test for Accutane)  Lucentis -- none  Macugen – Educate medical providers of the aseptic conditions required for the drug’s administration to reduce risk to patients

22 Post-Marketing Commitments  Goal – may vary – commonly to track a safety signal identified in earlier studies, particularly Phase 3  May now be required by FDA as part of a REMS  Will include timelines for completion  Lucentis –  Develop and validate assays to characterize immune response to ranibizumab from banked serum in Phase 3 trials to try to determine potential antibody response effects  More characterization of dosing regimen  CMC data to reflect mfg. data and stability  Macugen  2-year study (minimum) – see if any degenerative effects on neurosensory retina following intravitreal admin.  1-year study (minimum) – adverse effects on the corneal endothelium  2-year study (minimum) – safety & effectiveness of 2 additional doses below 0.3 mg.

23 A Few 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

24 A Few 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

25 Resources  FDA website –  Drug Approval Process  -- for info on individual drug approvals such as links to reviews, approval letters, etc.  FDA listservs – updates on key CDER regulatory issues -- visit  “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 Sustained Drug Delivery Systems.” Susan Caballa, Vice President, Alimera Biosciences. PEA Ophthalmic Drug and Delivery Summit, Sept – available from Michael Swit by request

26 Call, , fax or write: Michael A. Swit, Esq. Vice President The Weinberg Group Inc. 336 North Coast Hwy. 101 Suite C Encinitas, CA Phone Fax Cell Questions?

27 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 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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