This document summarizes the FDA approval process for two ophthalmic drugs - Lucentis and Macugen. It outlines the key steps, including preclinical studies, clinical trials (Phase 1-3), NDA/BLA submission and review, potential for priority or accelerated review, post-approval commitments like pediatric studies or REMS programs. For Lucentis and Macugen specifically, it details considerations around clinical trial design, endpoints, advisory committees and basis for approval based on available data. The presentation provides guidance on navigating the FDA regulatory process for ophthalmic drug development and approval.

1. 1
Michael A. Swit, Esq.
Vice President

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

3. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 39588
 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. 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. 39588
 Macugen –
 Approval based on 1 year data from a 2-year study
and partial 2nd year data
 Four-arm study
 3 treatment groups
 .3 pegaptanib
 1 mg.
 3 mg
 Sham group

21. 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. 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. 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. 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. 25
Resources
 FDA website –
 Drug Approval Process --
http://www.fda.gov/cder/regulatory/applications/
 Drugs @ -- for info on individual drug approvals such as links to reviews,
approval letters, etc.
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/
 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. 2007 –
available from Michael Swit by request

26. 26
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?

27. 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 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.

28. 28
For more than twenty-five years, leading companies have
depended on The Weinberg Group when their products are
at risk. Our technical, scientific and regulatory experts
deliver the crucial results, using sound science, to get
products to the market and keep them there.
Washington, D.C. ♦ San Francisco ♦ Brussels ♦ Edinburgh