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Michael A. Swit, Esq.Vice President

FDA Regulatory Issues andOphthalmic Drug Development

Pharmaceutical Education Associates 4th Annual Ophthalmic Drug Development &

Delivery Summit

September 2008Del Mar, California

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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.

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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.

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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

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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

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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

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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

ApprovalJuly 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

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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

ApprovalJuly 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

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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

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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.

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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

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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

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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

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Call, e-mail, fax or write:

Michael A. Swit, Esq.Vice President

The Weinberg Group Inc.336 North Coast Hwy. 101

Suite CEncinitas, CA 92024

Phone 760.633.3343Fax 760.454.2979Cell 760.815.4762

michael.swit@weinberggroup.comwww.weinberggroup.com

Questions?

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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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