Transcript Slide 1
Michael A. Swit, Esq.
Vice President
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Selected Regulatory Issues in
Ophthalmic Drug Development
Pharmaceutical Education Associates
5th Annual Ophthalmic Drug Development & Delivery Summit
September 2009
Del Mar, California
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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.
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What We Will Cover
505(b)(2) NDAs – How They Differ
Key Regulatory Tips
Some Recent Ophthalmic Approval Examples
FDA Regulation of Combination Products
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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)}
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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
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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
administration
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
products)
May get Exclusivity under Waxman-Hatch
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Pfizer/Pharmacia Petition Statement of Grounds
Reliance on proprietary data not authorized by FDCA for 505(b)(2)
NDAs
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
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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
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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)
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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
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Overall Comparison of 3 Pathways
ANDA
505(b)(2)
505(b)(1)
Formulate
X
X
X
Pre-clinical/Tox
--
Maybe
Usually
Manufacturing / Stability / Controls
X
X
X
FDA Meeting (pre-IND)
--
X
X
PK Study
X
X
X
Clinical Trial
*
*
*
FDA Meeting (pre-NDA)
--
X
X
Submission
X
X
X
User Fees
--
X
X
Exclusivity
Maybe
Usually
Usually
*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)
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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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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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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.
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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).
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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.
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Resources
FDA Website: “Drugs @” -- for info on individual drug approvals such as links to
reviews, approval letters, etc.
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
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More Resources …
FDA website – (more …)
Drug Approval Process --
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/default.htm
FDA listservs – updates on key CDER regulatory issues – visit
http://www.fda.gov/Drugs/ucm136245.htm
“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
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Combination Product Regulation
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What Is a Combination Product?
As defined in 21 CFR § 3.2(e), the term combination product
includes:
(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.
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The Combination Galaxy
Biologics
Drugs
BLA/IND
cGMP+
AERS+
NDA/IND
Primary Mode of Action
Consultation
Regulations
cGMP
AERS
Devices
PMA/510(k)/IDE
QSR
MDR
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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
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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
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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
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PMOA -- Determining Which Center Leads
PMOA = Primary Mode of Action; not defined in statute, but in
regulations
Final Rule – 8/25/2005; 70 Fed. Reg. 49848
http://www.fda.gov/OHRMS/DOCKETS/98fr/05-16527.pdf
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
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PMOA …
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)
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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.
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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?
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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
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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)
http://www.fda.gov/oc/combination/Guidance-How%20to%20Write%20an%20RFD.pdf
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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.
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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
obtained
Decision must issue within 60 days; if not YOUR recommendation
wins!!
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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)
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Jurisdictional Decisions -- Examples
BreathTest Combinations
http://www.fda.gov/oc/combination/breathtest.html
Minimal Manipulation of Structural Tissue
http://www.fda.gov/oc/combination/Minimal%20Manipulation%20JU%20(Final%209-19-06).pdf
Heparin Catheter Lock-Flush Solutions
Federal Register of 8/17/2006 -- http://www.fda.gov/OHRMS/DOCKETS/98fr/E6-13509.htm
Summary -- http://www.fda.gov/oc/combination/catheter.html
Metered Dose Inhalers, Spacers and Other Accessories
http://www.fda.gov/oc/combination/mdiupdate.html
Drug/Biologic Combinations
http://www.fda.gov/oc/combination/biologic.html
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Which GMP Rules Apply?
Guidance on GMPS for Combination Products
http://www.fda.gov/oc/combination/OCLove1dft.pdf
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
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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
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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
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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
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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
System:
Design controls (21 CFR 820.30)
Purchasing controls (21 CFR 820.50)
CAPA (820.100)
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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
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How Many Applications?
Concept Paper on Marketing Applications for Combination
Products
http://www.fda.gov/oc/combination/singlesepconpaper.pdf
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
changed
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.
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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
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User Fees – Can I Pay the Least Amount?
Guidance on User Fees for Combination Products – April 2005
http://www.fda.gov/oc/combination/userfee.pdf
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
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Resources
List of Jurisdictional Determinations – By Assigned Center
http://www.fda.gov/oc/combination/determinations.html
Guidance on Early Development Considerations for Innovative
Combination Products (9/2006)
http://www.fda.gov/oc/combination/innovative.pdf
Guidance on How to Write a RFD (8/2005)
http://www.fda.gov/oc/combination/Guidance-How%20to%20Write%20an%20RFD.pdf
Final Rule on “Primary Mode of Action” – 8/25/2005; 70 Fed. Reg.
49848
http://www.fda.gov/OHRMS/DOCKETS/98fr/05-16527.pdf
Concept Paper on Handling of Adverse Events
http://www.fda.gov/oc/combination/adveventconpaper.pdf
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Resources …
Overview of the Office of Combination Products
http://www.fda.gov/oc/combination/overview.html
Frequently Asked Questions on Combination Products
http://www.fda.gov/oc/combination/faqs.html#_Toc88444686
Other Types of Combinations (e.g., Drug/Cosmetic)
http://www.fda.gov/oc/combination/other_combinations.html
List of Recent Combination Product Approvals
http://www.fda.gov/oc/combination/approvals.html
Recent Presentations by FDA on Combination Products
http://www.fda.gov/oc/combination/presentations/default.htm
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Questions?
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]
www.weinberggroup.com
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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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For more than twenty-five years, leading companies have
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at risk. Our technical, scientific and regulatory experts
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