Transcript CTDOCS-42686-v1-FDAnews_PIV_Disputes_Webinar

How to Align the FDA Approval Process
with PIV Strategy
Chad A. Landmon
[email protected]
90 State House Square
Hartford, CT 06103
(860) 275-8170
June 2, 2011
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Overview
I.
Critical FDA Issues for Market Success
II. Litigation Strategy to Optimize FDA
Results
III. Strategy to Address Exclusivity Grants
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I. Critical FDA Issues for Market Success
• Major factors influencing FDA approval
– Bioequivalence
• Strategies for using the FDA citizen petition process
to optimize success
– Ambien® CR
– ADHD drug citizen petitions
– Abuse of the citizen petition process
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Factors Influencing FDA Approval
• Bioequivalence (BE)
– Required for FDA approval of an ANDA for the generic
version of a brand name drug
– FDA recommends substitution by state formularies only for
bioequivalent products
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Bioavailability
• Bioavailability is the rate and extent to which
the active ingredient becomes available at the
site of drug action.
• Bioavailability is typically measured as AUC
and Cmax.
• Cmax measures the rate of absorption.
• AUC measures the extent of absorption.
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Pharmacokinetic Studies: Key
Measurements
Concentration
Cmax
AUC: Area under the concentration- time curve
Cmax: Maximum concentration
Tmax: Time to maximum concentration
Reference Listed Drug
Generic Version
AUC
Tmax
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Time
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Pharmacokinetic Reference Range
FDA Requirements for Bioequivalence
• Product A is
bioequivalent to the
RLD; its 90%
confidence interval for
AUC and Cmax fall
within 80% to 125%
of the RLD
125%
100%
80%
Product A
Bioequivalent
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Reference
Listed
Drug (RLD)
Product B
Not Bioequivalent
• Product B is not
bioequivalent to the
RLD; its 90%
confidence interval for
AUC and Cmax fall
outside of 80% to
125% of the RLD
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Strategies for Using the FDA Citizen
Petition Process
• The FDA citizen petition (CP) process may be used
in order to delay the approval of generics
– E.g., CP may challenge the BE testing criteria for certain
generic products
– Approval of generic products is delayed while FDA
evaluates the CP
– May be viewed as a less expensive alternative to
litigation
• Generic filers may file a CP so as to adversely affect
another generic competitor
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Ambien CR® Citizen Petition
• Brand company Sanofi-Aventis filed CP in June 2007;
also filed comment on FDA BE Docket on Feb. 2009
– Sanofi argued that FDA should require more extensive BE
measurements, specifically use of partial AUCs: AUC0-3,
AUC3-6, AUC6-inf
• August 2009 BE Guidance
– Required AUC from time 0-1.5 hours after
administration to meet the 80/125 test
– Rationale: this was a sleep medication and effectiveness
in the first 1.5 hours required a BE AUC
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Wellbutrin XL® Citizen Petition
• Biovail argued that FDA should require ANDA
filers to conduct additional BE testing.
– Sought comparisons to Wellbutrin IR and SR, in
addition to Wellbutrin XL®
• FDA rejected Biovail’s argument
• ANDA filers only need to prove BE to RLD.
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ADHD Drug Citizen Petitions
• ADHD drugs: Concerta, extended-release (McNeil);
Metadate ER (CellTech); Adderall® XR (Shire)
– Brand companies filed CPs in 2004 and 2005
• Brand companies: Traditional BE metrics cannot
account for different PK profiles.
– ADHD drugs may appear BE based on standard metrics
but are actually clinically inequivalent.
– Shire: PK profile in the ANDAs must be superimposable
on the profiles of the brand
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ADHD Drug Citizen Petitions
• Brand companies:
– AUCpR is sensitive to early absorption profiles of certain
classes of drugs
• AUCpR = area under the curve to the population median
Tmax of the reference formulation
– Safety concern: AUCpR can account for higher IR:ER ratios
for ER methylphenidate drugs
• Brand companies’ CPs have delayed ANDA approvals
• FDA has not rendered any decisions on these CPs
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Anticompetitive Conduct?
• A meritless CP submitted to impose delay may raise
antitrust issues
– On the eve of ANDA approvals relating to Arava®, SanofiAventis filed a CP for more stringent BE studies; the CP was
denied by FDA six months later.
– Drug wholesaler brought action under § 2 of the Sherman
Act
– Motion to dismiss denied and action allowed to continue
• Louisiana Wholesale Drug Co. v. Sanofi-Aventis, 2008 U.S.
Dist. LEXIS 3611 (S.D.N.Y. Jan. 18, 2008)
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II. Litigation Strategy to Optimize FDA
Results
• Generic and brand strategies to prepare for PIV in
light of FDA approval issues
• Brand company’s efforts to prolong exclusivity using
the FDA process
– Novo Nordisk and repaglinide
• Generic attempts to address various patent issues in
the FDA approval process
– Adding information to an ANDA specification to avoid
infringement
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Brand Strategies
• Evaluate potential FDA issues for generics
– BE
– “sameness”
– labeling issues
• Prepare patent litigation team to issue spot
• Protective order issues regarding use and
dissemination of information
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Generic Strategies
• Fully evaluate ANDA and development history for
FDA issues
• Prepare counsel to issue spot
• Prepare witnesses for FDA issues in depositions
• Protective order issues regarding use and
dissemination of information
• Generic vs. generic strategies
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Novo Nordisk’s Use of Repaglinide
•
Novo Nordisk v. Caraco Pharm. Labs., Ltd., 601 F.3d 1359 (Fed.
Cir. 2010)
– Novo markets Prandin® (repaglinide) for the treatment of diabetes
– Three FDA-approved uses of Prandin: (1) repaglinide by itself; (2)
repaglinide + metformin; and (3) repaglinide + thiazolidinediones
– Novo’s OB-listed patent covers the use of repaglinide + metformin;
patent’s use code was repaglinide + metformin to treat diabetes
– Caraco filed ANDA for repaglinide
• Did not seek approval of repaglinide + metformin → filed
section viii statement
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Novo Nordisk’s Use of Repaglinide
•
Novo Nordisk then updated the OB-listed patent’s use code to broadly
cover the use of repaglinide to treat diabetes
•
Caraco’s proposed carve-out label now overlapped with the OB
patent’s use code → FDA denied Caraco’s section viii statement
•
Caraco brought counterclaim to compel Novo to change the use code
because the new use code was overbroad
–
•
Court: Hatch-Waxman Act did not support such a counterclaim
• The Act authorizes a counterclaim only where the listed patent does not
claim any approved method of using the listed drug
• The statute authorizes a counterclaim to change the “patent information,”
i.e., only the patent number and expiration date, not the use code
July 29, 2010: Federal Circuit denied Caraco’s petition for rehearing
en banc
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Novo Nordisk Use of Repaglinide
• Novo Nordisk: OB Use Codes govern permissibility of
section viii label carve-outs
– Use Codes describing what the patent claims are created by
brand (Forms 3542/3542a); not independently verified by
FDA
• OB Use Codes can be used to thwart carve-outs
– Use Codes can be vague to interfere with label carve-outs
– This practice was sanctioned by Novo Nordisk
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Post-Novo Nordisk Remedies for Use
Code Abuse
• Post-MMA Delisting Counterclaim Provision
– Applicable only where listed patents do not claim a drug
product or any approved methods of use
– Not an immediate remedy; can arise only in conjunction
with PIV litigation
– Counterclaims can only delete patents (or correct patent
numbers and expiration dates); cannot change incorrect
Use Codes
• Implications for the First Filer
– Delisting can satisfy prong of failure-to-market provision
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Adding to the ANDA to Avoid
Infringement
•
Where the ANDA defines it product in a way that directly
addresses the question of infringement, the ANDA product
cannot literally infringe under Section 271(e)(2) as a
matter of law. The Federal Circuit has determined that
the ANDA alone can “mandate[] a finding of no literal
infringement.”
– Bayer AG v. Elan Pharm. Research Corp., 212 F.3d 1241 (Fed.
Cir. 2000)
– Tyco Healthcare Group LP v. Mut. Pharm. Co., No. 07-1299,
2009 U.S. Dist. LEXIS 68176 (D.N.J. Aug. 4, 2009)
•
Hypothetical infringement inquiry is grounded in the
ANDA application.
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III. Strategy to Address Exclusivity
Grants
• Ways to Maximize Exclusivity Strategy
• Challenges to the 180-day Exclusivity Period
– Forfeiture
– 30-month Tentative Approval Issues
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Optimizing a Brand’s Exclusivity
•
Obtain additional patents
– Claims directed to the formulation, PK properties, etc.
•
Adjust the formulation
– Controlled-release
– Abuse-resistant
•
Get approval for additional indications
•
Product switching strategies
– Immediate-release to extended-release dosage form
– Basic drug molecule to a prodrug of the same drug molecule
– Basic formulation to “abuse-resistant” formulation
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Challenges to the 180-day Exclusivity
Period: Forfeiture
•
Failure to Market. The first applicant fails to market the drug by
the later of –
(aa) the earlier of the date that is –
(AA) 75 days after the date on which the approval of the application of the
first applicant is made effective under (B)(iii); or
(BB) 30 months after the date of submission of the application of the first
applicant; or
(bb) with respect to the first applicant or any other applicant (which other applicant
has received tentative approval), the date that is 75 days after the date as of
which, as to each of the patents with respect to which the first applicant
submitted and lawfully maintained a certification qualifying the first applicant
for the 180-day exclusivity period under (B)(iv), at least one of the following
has occurred:
(AA) . . . a court enters a final decision from which no appeal . . . has been or
can be taken that the patent is invalid or not infringed.
(BB) . . . a court signs a settlement order or consent decree that enters a final
judgment that includes a finding that the patent is invalid or not infringed.
(CC) The patent information submitted under (b) or (c) is withdrawn by the
holder of the application approved under (b).
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A First Applicant forfeits 180-day exclusivity if
it fails to market by the later of:
Regulatory Events
THE EARLIER OF:
75 days after final
approval of the first
applicant’s ANDA; or
30 months after
submission of the
first applicant’s
ANDA.
Patent Events
With respect to the first applicant(s), or any
other applicant with tentative approval, and
with respect to each patent for which the first
applicant(s) submitted a Paragraph IV
Certification qualifying it for exclusivity, 75
days after any one of the following “has
occurred":
A court issues a final non-appealable decision
that the patent(s) is/are invalid or not
infringed (whether in an infringement action
or a declaratory judgment action);
A court signs a settlement or consent decree
that includes a finding that the patent(s) is
invalid or not infringed; or
The patent is withdrawn from the Orange
Book
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Other Forfeiture Events
• First applicant withdraws ANDA
• First applicant amends ANDA to withdraw PIV
certifications
• First applicant fails to obtain tentative approval within
30 months from filing, unless the failure is caused by a
change in or review of the approval requirements
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Failure to Obtain Tentative Approval
•
Added by Medicare Modernization Act
•
Forfeiture occurs when “[t]he first applicant fails to
obtain tentative approval of the application within 30
months after the date on which the application is filed,
unless the failure is caused by a change in or a review of
the requirements for approval of the application imposed
after the date on which the application is filed.” 21 U.S.C.
§ 355(j)(5)(D)(i)(IV).
•
Has not yet been litigated by either a first ANDA applicant
who has forfeited 180-day exclusivity on these grounds or
by a subsequent ANDA applicant challenging the first
applicant’s retention of 180-day exclusivity
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Failure to Obtain Tentative Approval
•
In contrast to the “failure to market” provision, the
“failure to obtain tentative approval” provision calculates
the 30-month period from the date the ANDA is filed as
opposed to the date of ANDA submission
– Reasonable to use the date that qualifies the first ANDA
applicant for 180-day exclusivity, i.e., the date that the ANDA is
sufficiently complete to permit substantive review
•
Rationale: 180-day exclusivity provided to the first
applicant “carries with it the requirement that – to
maintain that eligibility – the first applicant must work
diligently to obtain a tentative approval before the 30month period expires.”
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Exceptions to Failure to Obtain
Tentative Approval Provision
• Exception for a change in or a review of the requirements
for approval of the application imposed after the date on
which the application is filed
•
Acarbose:
–
–
–
•
CP filed relating to BE methodology for acarbose products after the 30-month
period had run served to change the BE requirements
Filing and FDA evaluation of CP delayed approval of Cobalt’s ANDA
Cobalt did not forfeit its exclusivity for failure to obtain tentative approval
Nateglinide:
–
–
–
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At least one first ANDA applicant (of many) failed to obtain tentative approval
within 30 months
If a first applicant loses 180-day exclusivity, its ANDA can still be approved during
the 180-day period
Once any first applicant (eligible or ineligible for 180-day exclusivity) gets final
approval and begins commercial marketing, the 180-day clock begins to run.
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Exceptions to Failure to Obtain
Tentative Approval Provision
•
Where tentative approval is not received within 30
months, FDA may nevertheless defer making a decision on
forfeiture unless and until another applicant becomes
eligible for approval within 180 days after the first
applicant begins commercial marketing.
– Example: Triamcinolone Acetonide
• “The agency notes that Barr failed to obtain tentative
approval of this ANDA within 30 months after the date on
which the ANDA was filed. See section 505(j)(5)(D)(i)(IV)
of the Act. However, the agency is not making a formal
determination at this time of Barr's eligibility for 180-day
generic drug exclusivity. It will do so only if another
applicant becomes eligible for approval within 180 days
after Barr begins commercial marketing of Triamcinolone
Acetonide Nasal Spray, 0.055 mg.”
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FDAAA Tolling Provision
• Enacted Sept. 27, 2007
• “[I]f the filing of an application resulted in firstapplicant status . . . and approval of the application
was delayed because of a petition, the 30-month
period . . . is deemed to be extended by a period of
time equal to the period beginning on the date on
which the Secretary received the petition and ending
on the date of final agency action on the petition
(inclusive of such beginning and ending dates),
without regard to whether the Secretary grants, in
whole or in part, or denies, in whole or in part, the
petition.” 21 U.S.C. § 355(q)(1)(G).
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FDAAA Tolling Provision
• Any citizen petition submitted prior to Sept. 27, 2007
will not be subject to the provisions of FDCA
505(q)/21 U.S.C. § 355(q).
– See Guidance for Industry: Citizen Petitions and Petitions
for Stay of Action Subject to Section 505(q) of the
Federal Food, Drug, and Cosmetic Act 4 (Jan. 2009).
• FDA recommends that citizen petitions not be filed
regarding BE guidances; instead, FDA requests
comments on the BE docket (established for
individual BE guidances).
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Any questions?
Chad A. Landmon
[email protected]
(860) 275-8170
(202) 721-5415
AXINN, VELTROP & HARKRIDER LLP
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