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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. Standard Disclaimers.

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fda regulatory issues and ophthalmic drug development

FDA Regulatory Issues andOphthalmic Drug Development

Pharmaceutical Education Associates

4th Annual Ophthalmic Drug Development & Delivery Summit

September 2008

Del Mar, California

standard disclaimers
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.
fda path new and old hurdles
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
the fda path start to finish
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
two drugs how they progressed
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
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

pre ind submission and package
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
investigational new drug exemption ind
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
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

Phase 1
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

Phase 2
end of phase eop 2 meeting
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
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

Phase 3
phase 31
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


Two virtually identically designed studies


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

Phase 3 …
pre nda bla filing meeting
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.
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

NDA/BLA Filing
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

Review Clock
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

Advisory Committee
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


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


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

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


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

Approval …
Used prior to FDAAA

Memorialized by FDAAA

Can take many forms


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

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


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.

Post-Marketing Commitments
a few tips of the trade
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
a few tips of the trade1
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
  • FDA website –
    • Drug Approval Process --
    • Drugs @ -- 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. 2007 – available from Michael Swit by request


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

about your speaker
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, 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.

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.

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