ANDAs – Key Regulatory and Legislative Issues

1
ANDAs Key Regulatory and Legislative Issues

• September 19, 2002
• PLI Biotechnology Law ConferenceSan Francisco,
  California

2
PART I Power

• Protecting and PreservingA Drug Franchise Under
  Waxman-Hatch
• Exclusivity and the 30-month Stay

3
Market Protections Available

• Patents (and extensions)
• Traditional enforcement
• Listing patents in FDA's "Orange Book"
• Statutory exclusivities/extensions under
  Waxman-Hatch
• Other strategies

4
Listing Patents in FDA's "Orange Book"

• 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.

5
Statutory Exclusivities Under Waxman-Hatch

• New Chemical Entity (NCE) Exclusivity
• 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.
• (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."

6
Statutory Exclusivities

• 3-Year Exclusivity
• Available for NDAs which contain
• 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

• Orphan Drug Exclusivity
• 7 year exclusivity
• Drugs for rare conditions (lt200,000 people in
  U.S.)
• Pediatric Exclusivity
• 6-month extension of existing patent or
  Waxman-Hatch exclusivity
• 180-day generic (ANDA) exclusivity

8
Generic Drug Strategies

• Generic industry -- diverse in sizes and
  approaches of companies
• Business factors influencing drug selection
• 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

9
Generic Defense Strategies

• Patent listing, litigation
• Development of follow-on/ancillary patents
• Strategy may be impacted by pending legislation
• Amendments seeking 3-year exclusivity
• New indication for original product (limited
  utility)
• Changed dosage form
• New dosing regimen
• New strength(s)

10
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

11
Abbott Geneva 2000

• Drug Hytrin (terazosin HCl)
• Alleged antitrust violation Abbott paid Geneva
• to not sell an approved capsule version while the
  companies litigated patent issues on the tablet
  version
• not transfer or relinquish Genevas 180-Day ANDA
  Exclusivity rights thus, keeping other
  generics off the market
• Resolution consent order

12
Abbott Geneva

• Consent order
• bars agreements that
• 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

13
Schering AHP/ESI Upshur-Smith

• Drug K-Dur (potassium chloride)
• Alleged antitrust violation agreements to
  settle patent litigation
• 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

14
Hoechst-Marion-Rousell Andrx

• Drug Cardizem CD
• Alleged antitrust violation agreements to
  settle patent litigation by which, for
• Andrx agreed to stay off the market
• Andrx agreed to not relinquish its 180-day
  Exclusivity rights
• Resolution consent order --

15
Hoechst-Marion-Rousell Andrx

• Consent order (similar to Hytrin)
• 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

16
Other Alleged Nefarious Activity Biovail Patent
Listing Case

• Drug Tiazac (diltiazem)
• Alleged violative activity
• 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)

17
Other Alleged Nefarious Activity Biovail Patent
Listing Case

• Resolution consent order
• 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.

18
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

• 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.

20
Results of 1984 Compromise

• 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.

21
McCain-Schumer "Findings"

• 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

22
Orange Book Listing

• 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)

23
Late Listing Penalty

• Failure of NDA holder to timely list will bar
  patent holder (who may be different person) from
  enforcing the patent against any person who
• has filed an ANDA or 505(b)(2) NDA, or
• manufactures, uses, or sells an approved generic
  or 505(b)(2) drug.

24
Listing Challenges

• ANDA applicants can bring civil lawsuit seeking
  correction or removal of listed patent
  information.
• Only pending applicants may sue.
• Only applies to patents listed at time of NDA
  approval.
• No "damages" allowed.

25
Claim-by-Claim -IV Certifications

• For patents that
• 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.

26
30-Month Stay Limitation

• 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.

27
One-Shot Patent Enforcement

• 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.

28
Generic Exclusivity Eligibility

• Reverts to prior FDA requirement that first
  Paragraph IV applicant must be sued to get
  exclusivity.
• Appears to maintain patent-by-patent exclusivity
  approach.

29
Generic Exclusivity Triggers

• 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

• 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

31
"Rolling" Generic Exclusivity

• 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.

32
Bioequivalence Provisions

• 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."

33
Part IV the Future Generic Biologics???

• No consensus view exists that any current legal
  mechanism can be used to support approval of a
  generic biologic
• Why?
• Legally, biologics licensed under Public Health
  Service Act, not Waxman-Hatch
• Difficulty (alleged?) in characterization

34
Generic Biologics

• "One cannot completely characterize the
  biological product and that in itself is an
  issue, and quite frankly with biological products
  you really dont 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

35
Generic Biologics Under 505(b)(2)?

• 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

36
What is a 505(b)(2) Product ?

• Not a completely new product,
• Not a generic,
• 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?

• 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

38
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)
• Duplicates of approved drugs that cannot be
  approved under an ANDA

39
Patent and Exclusivity Issues

• 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.

40
Patent and Exclusivity Issues

• A 505(b)(2) product may itself qualify for 3 or 5
  years of new drug exclusivity
• 3-year exclusivity requires
• 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"
• NCEs can be old drugs (i.e., ingredient never
  approved under an NDA)

41
Patent and Exclusivity Issues

• 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.
• 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.

42
Legal Challenges andOpportunities Under
505(b)(2)

• 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?"

43
Pfizer/Pharmacia's Challenge To FDA's 505(b)(2)
Approach

• 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

44
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

45
Which Way is the Generic Biologics Wind Blowing ??

• 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?

46
A Few Predictions and Questions

• 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?

47
A Few Predictions and Questions

• Where does the science of characterization and
  replication stand on large molecules?
• How will bioequivalence be judged?
• Are the drug models relevant?
• If not, will generic biologics always require
  comparative clinical studies?

48
Questions?

• Call, e-mail, fax or writeMichael 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_at_fdacounsel.com
• http//www.fdacounsel.com

49
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 companys 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 firms 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.