Transcript Slide 1

Michael A. Swit, Esq.
Vice President
Selected Regulatory Issues in
Ophthalmic Drug Development
Pharmaceutical Education Associates
5th Annual Ophthalmic Drug Development & Delivery Summit
September 2009
Del Mar, California
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.
What We Will Cover
 505(b)(2) NDAs – How They Differ
 Key Regulatory Tips
 Some Recent Ophthalmic Approval Examples
 FDA Regulation of Combination Products
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)}
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
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
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
 May get Exclusivity under Waxman-Hatch
Pfizer/Pharmacia Petition Statement of Grounds
 Reliance on proprietary data not authorized by FDCA for 505(b)(2)
 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
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
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)
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
Overall Comparison of 3 Pathways
Manufacturing / Stability / Controls
FDA Meeting (pre-IND)
PK Study
Clinical Trial
FDA Meeting (pre-NDA)
User Fees
*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)
Tips of the Trade
 Non-standard Manufacturing Process
 Specialized pharmaceutical dosage forms (certain modified release
 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
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
 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
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.
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).
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.
FDA Website: “Drugs @” -- for info on individual drug approvals such as links to
reviews, approval letters, etc.
More Resources …
 FDA website – (more …)
 Drug Approval Process --
 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 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
Combination Product Regulation
What Is a Combination Product?
 As defined in 21 CFR § 3.2(e), the term combination product
 (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 package or 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 separately that 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.
The Combination Galaxy
Primary Mode of Action
 PMA/510(k)/IDE
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
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
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
PMOA -- Determining Which Center Leads
 PMOA = Primary Mode of Action; not defined in statute, but in
 Final Rule – 8/25/2005; 70 Fed. Reg. 49848
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
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)
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.
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?
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
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)
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.
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
Decision must issue within 60 days; if not YOUR recommendation
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)
Jurisdictional Decisions -- Examples
 BreathTest Combinations
 Minimal Manipulation of Structural Tissue
 Heparin Catheter Lock-Flush Solutions
Federal Register of 8/17/2006 --
Summary --
 Metered Dose Inhalers, Spacers and Other Accessories
 Drug/Biologic Combinations
Which GMP Rules Apply?
 Guidance on GMPS for Combination Products
 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
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
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
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
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
 Design controls (21 CFR 820.30)
 Purchasing controls (21 CFR 820.50)
 CAPA (820.100)
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
How Many Applications?
 Concept Paper on Marketing Applications for Combination
 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
 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
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
User Fees – Can I Pay the Least Amount?
 Guidance on User Fees for Combination Products – April 2005
 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
 List of Jurisdictional Determinations – By Assigned Center
 Guidance on Early Development Considerations for Innovative
Combination Products (9/2006)
 Guidance on How to Write a RFD (8/2005)
 Final Rule on “Primary Mode of Action” – 8/25/2005; 70 Fed. Reg.
 Concept Paper on Handling of Adverse Events
Resources …
 Overview of the Office of Combination Products
 Frequently Asked Questions on Combination Products
 Other Types of Combinations (e.g., Drug/Cosmetic)
 List of Recent Combination Product Approvals
 Recent Presentations by FDA on Combination Products
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
[email protected]
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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