ANDAs – Key Regulatory and
Legislative Issues
September 19, 2002
PLI Biotechnology Law Conference
San Francisco, California
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PART I – Power
Protecting and Preserving
A Drug Franchise Under Waxman-Hatch
– Exclusivity and the 30-month Stay
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Market Protections Available
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Patents (and extensions)
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Traditional enforcement
Listing patents in FDA's "Orange Book"
Statutory exclusivities/extensions under
Waxman-Hatch
Other strategies
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Listing Patents in FDA's
"Orange Book"
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Requires patent certification by generic
competitors
If approval sought pre-expiration,
generic must notify sponsor of bases for
alleged invalidity or non-infringement.
Sponsor may sue for infringement and
impose 30-month stay of generic
approval.
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Statutory Exclusivities Under
Waxman-Hatch
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New Chemical Entity (NCE) Exclusivity
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Prohibits the filing of an ANDA (or
505(b)(2) NDA) for a product that contains
the NCE for 5 years after approval of the
first NDA.
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(4 years if ANDA includes a Paragraph IV
challenge to listed patent)
NCE: "a drug that contains no active
moiety that has been approved by FDA in
any other [NDA]."
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Statutory Exclusivities …
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3-Year Exclusivity
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Available for NDAs which contain:
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Reports of "new" "clinical trials"
That were "essential to approval" of the NDA
Conducted or sponsored by the applicant
FDA may not approve an ANDA or 505(b)(2) NDA for
3 years after approval
Applies for new indications, Rx  OTC switch, new
dosing regimen, and some other labeling changes.
Carve out for pediatric labeling.
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Statutory Exclusivities -- Other
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Orphan Drug Exclusivity
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Pediatric Exclusivity
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7 year exclusivity
Drugs for rare conditions (<200,000 people
in U.S.)
6-month extension of existing patent or
Waxman-Hatch exclusivity
180-day generic (ANDA) exclusivity
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Generic Drug Strategies
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Generic industry -- diverse in sizes and
approaches of companies
Business factors influencing drug selection
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Market size, pricing of innovator product
Patent landscape
Strategic "fit" with production capabilities,
therapeutic or technical areas of focus (if any)
Chance of 180-day exclusivity; other generic entry
Ease of marketing
Other – some firms are dosage form oriented
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Generic Defense Strategies
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Patent listing, litigation
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Development of follow-on/ancillary patents
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Strategy may be impacted by pending legislation
Amendments seeking 3-year exclusivity
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New indication for original product (limited utility)
Changed dosage form
New dosing regimen
New strength(s)
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PART II – Problems with
Power
Federal Trade Commission Oversight
of Patent Litigation Settlements
Between Big Pharma and the
Generic Industry
and
Other Alleged Nefarious Activity
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Abbott – Geneva – 2000
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Drug: Hytrin® (terazosin HCl)
Alleged antitrust violation – Abbott paid
Geneva
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to not sell an approved capsule version while the
companies litigated patent issues on the tablet
version
not transfer or relinquish Geneva’s 180-Day “ANDA
Exclusivity” rights – thus, keeping other generics
off the market
Resolution: consent order
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Abbott – Geneva
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Consent order …
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bars agreements that:
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restrict ANDA applicant from giving up 180-day
exclusivity; or
restrict ANDA applicant from entering the market with a
non-infringing product
agreements to pay to stay off market done to
settle patent litigation need court OK and FTC
chance to comment
required Geneva to waive its 180-day exclusivity
rights on a Hytrin tablet so other generics could
enter market
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Schering – AHP/ESI & UpshurSmith
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Drug – K-Dur® (potassium chloride)
Alleged antitrust violation – agreements to
settle patent litigation
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Upshur-Smith: for $$, agreed to stay off market;
as first to file a Para. IV patent cert., had 180-day
Exclusivity; its delay in marketing meant
subsequent ANDA filers could not go to market
Resolution – July 2002 – an FTC
administrative law judge threw out the FTC
action; saying deal was really procompetitive
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Hoechst-Marion-Rousell &
Andrx
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Drug – Cardizem CD
Alleged antitrust violation – agreements
to settle patent litigation by which, for
$$:
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Andrx agreed to stay off the market
Andrx agreed to not relinquish its 180-day
Exclusivity rights
Resolution – consent order --
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Hoechst-Marion-Rousell &
Andrx …
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Consent order … (similar to Hytrin®)
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barred from agreeing to NOT relinquish 180-day
exclusivity rights (which, if kept, can preclude
subsequent generic filers from marketing even if
approved and even if patent expired)
barred from agreeing to restrictions on entering
market with a non-infringing generic
Interim patent litigation settlements involving
payments to generics require Court OK and notice
to FTC
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Other Alleged Nefarious Activity –
Biovail Patent Listing Case
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Drug – Tiazac® (diltiazem)
Alleged violative activity:
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filing a patent in Orange Book (O.B.) that
did not claim marketed drug – effectively
kept generic off due to need to certify to
new patent
illegal exclusive marketing license with
patent holder (differed from Biovail)
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Other Alleged Nefarious Activity –
Biovail Patent Listing Case …
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Resolution – consent order:
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Biovail to divest part of exclusive patent
license
Biovail to not enforce any rights that would
trigger a 30-month Waxman-Hatch
barred from wrongfully listing patents in
O.B.
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Part III – Statutory Solutions
to Power Problems
An Overview of McCain-Schumer –
“The Greater Access to Affordable
Pharmaceuticals Act of 2001”
S. 812
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The 1984 Compromise
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Strengthen incentives for innovative
research by partially restoring patent
time lost due to FDA approval delays.
Facilitate generic competition by
establishing ANDA process and allowing
patent challengers to receive 180-day
generic exclusivity period.
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Results of 1984 Compromise
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Generic share of total Rx has
skyrocketed (19% - 43%).
Cost of innovation has skyrocketed as
new therapies become more elusive.
Legal challenges have scrambled FDA's
implementing regulations, leading to
costly uncertainty and allegations of
abuse.
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McCain-Schumer "Findings"
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Drug costs rising at "alarming rate"
More generic competition will lower
prices
More generic competition needed
FTC has found restraints of trade
between companies
No finding re research incentives
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Orange Book Listing
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Patents that "claim the drug for which
the application was approved," or
Patents that claim an approved method
of use,
Must be submitted to FDA within 30
days of NDA approval, or 30-days of
issuance (if issued post-approval)
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Late Listing Penalty
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Failure of NDA holder to timely list will
bar patent holder (who may be different
person) from enforcing the patent
against any person who
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has filed an ANDA or 505(b)(2) NDA, or
manufactures, uses, or sells an approved
generic or 505(b)(2) drug.
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Listing Challenges
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ANDA applicants can bring civil lawsuit
seeking correction or removal of listed
patent information.
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Only pending applicants may sue.
Only applies to patents listed at time of
NDA approval.
No "damages" allowed.
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Claim-by-Claim ¶-IV Certifications
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For patents that
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Include both product claim and method of
use claim(s), or
Contain multiple method of use claims,
Paragraph IV Certifications, and "viii
statements" must be claim-specific.
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30-Month Stay Limitation
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The 30-month stay of Paragraph IV ANDA
approval may only be imposed with respect to
patents listed at time of initial NDA approval,
not post-approval patents.
For "other patents" "not described in clause
(iii)"** but listed in the Orange Book,
innovator must seek PI within 45 days; If PI
denied, immediate approval possible. If PI
granted, approval delayed until case resolved.
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One-Shot Patent Enforcement
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In addition to not being able to enforce
late-listed patents, if no lawsuit is
brought within 45 days of a Paragraph
IV Notification to a listed patent, a
patent owner is "barred from bringing a
civil action for infringement" with
respect to drug under the ANDA.
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Generic Exclusivity Eligibility
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Reverts to prior FDA requirement that
first Paragraph IV applicant must be
sued to get exclusivity.
Appears to maintain patent-by-patent
exclusivity approach.
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Generic Exclusivity Triggers
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Reverts to "final" court decision trigger
rule to start 180-day exclusivity period.
Adds settlement or consent decree as a
triggering event if it contains a specific
finding of invalidity/non-infringement.
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Generic Exclusivity Forfeiture
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Failure to market w/in 60 days of final
approval or court decision (whichever is later)
Withdrawal of ANDA
Amendment from ¶IV to ¶III
Failure to obtain tentative approval w/in 30
months.
Failure to challenge newly listed patents.
FTC finds unlawful conduct by applicant
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"Rolling" Generic Exclusivity
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If first challenger forfeits exclusivity, all
subsequent ANDAs eligible for approval.
If first subsequent ANDA to get
effective approval was also the first
subsequent filer (i.e., second overall
filer), then it receives exclusivity.
No other subsequent ANDA eligible.
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Bioequivalence Provisions
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The 1992 amendments to 21 C.F.R. Part 320
"shall continue in effect as an exercise of
authorities under [FDCA] sections 501, 502,
505, and 701," but may be amended by FDA.
"This section shall not be construed to alter
the authority of [HHS] to regulate biological
products under the [FDCA] (21 U.S.C. § 301
et seq.). Any such authority shall be exercised
under that Act as in effect on the day before
the date of enactment of this Act."
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Part IV – the Future –
Generic Biologics???
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No consensus view exists that any
current legal mechanism can be used to
support approval of a generic biologic
Why?
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Legally, biologics licensed under Public
Health Service Act, not Waxman-Hatch
Difficulty (alleged?) in characterization
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“Generic” “Biologics”
"One cannot completely characterize the biological
product and that in itself is an issue, and quite
frankly with biological products you really don’t have
a homogeneous product, you have a defined range of
biological components for which you find consistency
in a particular clinical outcome. The challenges of
analytical technology are still very great for
characterizing biologics."
-- Katherine Zoon, CBER
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“Generic” “Biologics”
Under 505(b)(2)?
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For Biologics originally approved under an
NDA, FDA will accept a 505(b)(2) for a
“generic” version
Examples include naturally-derived active
ingredients (from animal or botanical sources)
or those derived from recombinant
technology (e.g., insulin, HGH)
For BLA-approved products, no generic
approval pathway
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What is a 505(b)(2) Product ?
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Not a completely new product,
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Not a generic,
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A product with some differences from a
previously approved product.
Approval requires clinical data, but the
studies may have been conducted by
others.
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How is 505(b)(2) Different?
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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
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Types of 505(b)(2) NDAs
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New Chemical Entity (rarely)
Changes to a Previously Approved Drug
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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)
Duplicates of approved drugs that cannot be
approved under an ANDA
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Patent and Exclusivity Issues
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505(b)(2) NDA must include patent
certification(s).
505(b)(2) NDA must also list any relevant
patent(s).
Same Paragraph IV challenge system as
ANDAs, EXCEPT, no 180-day exclusivity
period.
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Patent and Exclusivity Issues
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A 505(b)(2) product may itself qualify for 3 or
5 years of new drug exclusivity
3-year exclusivity requires:
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New clinical studies (other than BE studies)
Conducted by the applicant
Essential to the approval of the application
5-year exclusivity for "New Chemical Entities"
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NCEs can be old drugs (i.e., ingredient never
approved under an NDA)
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Patent and Exclusivity Issues
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Waxman-Hatch Exclusivities block ANDAs and
505(b)(2) NDAs, but cannot block a "full" NDA.
3-year exclusivity blocks other pending 505(b)(2)s,
regardless of filing date; creates race to approval.
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Only the first 505(b)(2) for a change can receive exclusivity.
Studies for later applications deemed not essential for
approval.
5-year exclusivity does not block other 505(b)(2)s
that were filed before first approval.
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Legal Challenges and
Opportunities Under 505(b)(2)
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Has FDA Expanded § 505(b)(2) Beyond
the Scope Intended by Congress?
What Opportunities and Pitfalls Await
the 505(b)(2) Applicant?
Is 505(b)(2) A Viable Pathway for
"Generic Biologics?"
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Pfizer/Pharmacia's Challenge
To FDA's 505(b)(2) Approach
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Requests amendment of 505(b)(2)
Guidance and 21 C.F.R. 314.54
Requests FDA not to approve any
505(b)(2) NDA based on proprietary
data
Requests FDA to not assign “A” rating to
any approved 505(b)(2) Drug
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Pfizer/Pharmacia Petition Statement of
Grounds
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Reliance on proprietary data not authorized
by FDCA for 505(b)(2) NDAs
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Published Studies vs.
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Proprietary Data vs.
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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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Which Way is the Generic Biologics
Wind Blowing ??
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No 505(b)(2) approved yet for a biotech
product
FDA Guidance on “Well-Characterized
Biologics” – a manifesto for action?
Transfer of CBER therapeutics review
divisions to CDER – a harbinger of a
bureaucracy being repositioned to handle
generic biologics?
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A Few Predictions and Questions
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FDA will not do it on its own; will
require statutory authorization
McCain-Schumer will not be the vehicle,
but may be regarded by some as
necessary itself to be enacted before
tackling generic biologics
Is the generic industry ready to
challenge technologically?
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A Few Predictions and Questions …
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Where does the science of
characterization and replication stand
on large molecules?
How will bioequivalence be judged?
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Are the “drug” models relevant?
If not, will generic biologics always require
comparative clinical studies?
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Questions?
Call, e-mail, fax or write:
Michael A. Swit, Esq.
Law Offices of Michael A. Swit
539 Samuel Ct., Suite 229
Encinitas, California 92024
760-815-4762 ♦ 760-454-2979 (fax)
mswit@fdacounsel.com
http://www.fdacounsel.com
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About the speaker ...
Michael A. Swit has extensive experience in all aspects of FDA regulation with a particular emphasis on
drugs and medical device regulation. In addition to his regulatory law experience, Mr. Swit also
served for three and a half years as vice president and general counsel of Pharmaceutical Resources,
Inc. (PRI) a prominent generic drug company and, thus, brings an industry and commercial
perspective to his representation of FDA-regulated companies. While at PRI from 1990 to late
1993, Mr. Swit spearheaded the company’s defense of multiple grand jury investigations, other
federal and state proceedings, and securities litigation stemming from the acts of prior management.
Mr. Swit then served from 1994 to 1998 as CEO of Washington Business Information, Inc. (WBII) a
premier publisher of FDA regulatory newsletters and other specialty information products for the
FDA publishing company. Before starting FDACounsel.com, he was with Heller Ehrman from
May 2001 to May 2003, and also twice in private practice with McKenna & Cuneo, from 1988 to
1990 and, most recently, from 1999 to 2001, first in that firm’s D.C. office and most recently, in its
San Diego office. He first practiced FDA regulatory law with the D.C. office of Burditt & Radzius
from 1984 to 1988. Mr. Swit has taught and written on a wide variety of subjects relating to FDA
law including, since 1989, co-directing a three-day intensive course on the generic drug approval
process, serving on the Editorial Board of the Food & Drug Law Journal, and editing a guide to the
generic drug approval process, Getting Your Generic Drug Approved, published by WBII. Mr. Swit
holds an A.B., magna cum laude, with high honors in history, in 1979, from Bowdoin College, and
earned his law degree from Emory University in 1982. He is a member of the California, Virginia
and District of Columbia bars.
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