Product & Portfolio

Enhancement for Generics

June 30, 2009

Avoiding the
Commoditization of
Your Generic Products
Vincent P. Andolina
VP Regulatory Affairs
 Overview
• Enhancing opportunities through 505(b)(2) NDAs:
Changes from the reference listed drug beyond what can
be approved under an ANDA
• Case study of successful 505(b)(2) NDA:
Product development, submission, approval, and sale
• Enhancing opportunities through ANDA suitability
petitions: Changes from the reference listed drug that may
be approved under an ANDA
• Niche product strategies: Low volumes, high margins
 Enhancing opportunities
through 505(b)(2) NDAs
• Definitions / background information:
ƒ A full NDA is submitted under §505(b)(1) of the FD&C
Act and contains full reports of safety and efficacy
studies for which the NDA applicant has a right of
reference
ƒ A 505(b)(2) NDA provides for a change from the full
NDA product beyond what may be approved under an
ANDA. Approval of the 505(b)(2) relies on FDA’s
conclusions with regard to the full NDA product and
additional information to support the differences.
 Enhancing opportunities
through 505(b)(2) NDAs
• Types of changes requiring a 505(b)(2) NDA
(based on 21 CFR §314.54 and FDA Oct. 1999 draft guidance):
ƒ Change in dosage form, route of administration,
strength, dosing regimen, change of one active
ingredient in a combination product, new combination of
previously-approved drugs
ƒ Intentional differences in rate/extent of absorption
[cannot submit a failed bio study under a 505(b)(2)]
ƒ New indication, Rx-OTC switch, etc.
 Enhancing opportunities
through 505(b)(2) NDAs
§ 314.54 Procedure for submission of an application requiring investiga-
tions for approval of a new indication for, or other change from, a listed
drug.
(a) The act does not permit approval of an abbreviated new drug application for a new
indication, nor does it permit approval of other changes in a listed drug if
investigations, other than bioavailability or bioequivalence studies, are essential to
the approval of the change. Any person seeking approval of a drug product that
represents a modification of a listed drug (e.g., a new indication or new dosage
form) and for which investigations, other than bioavailability or bioequivalence
studies, are essential to the approval of the changes may, except as provided in
paragraph (b) of this section, submit a 505(b)(2) application. This application need
contain only that information needed to support the modification(s) of the listed
drug.
.....
(b) An application may not be submitted under this section for a drug product whose
only difference from the reference listed drug is that:
(1) The extent to which its active ingredient(s) is absorbed or otherwise made available
to the site of action is less than that of the reference listed drug; or
(2) The rate at which its active ingredient(s) is absorbed or otherwise made available to
the site of action is unintentionally less than that of the reference listed drug.
 Enhancing opportunities
through 505(b)(2) NDAs
• Types of changes requiring a 505(b)(2) NDA
(based on 21 CFR §314.54 and FDA Oct. 1999 draft guidance):
ƒ Formulation differences that cannot be submitted under
an ANDA [see 21 CFR § 314.94(a)(9)(iii), (iv) and (v)]
ƒ Change in source of the drug substance such as natural
source vs. previously-approved synthetic source NDA
product; or any drug substance produced using rDNA
technology for which innovator was approved under an
NDA (not a BLA)
 Enhancing opportunities
through 505(b)(2) NDAs
(iii) Inactive ingredient changes permitted in drug
products intended for parenteral use.
Generally, a drug product intended for parenteral use shall
contain the same inactive ingredients and in the same
concentration as the reference listed drug identified by the
applicant under paragraph (a)(3) of this section. However,
an applicant may seek approval of a drug product that
differs from the reference listed drug in preservative,
buffer, or antioxidant provided that the applicant
identifies and characterizes the differences and provides
information demonstrating that the differences do not affect
the safety or efficacy of the proposed drug product.
 Enhancing opportunities
through 505(b)(2) NDAs
(iv) Inactive ingredient changes permitted in drug products
intended for ophthalmic or otic use.
Generally, a drug product intended for ophthalmic or otic use shall
contain the same inactive ingredients and in the same concentration as
the reference listed drug identified by the applicant under paragraph
(a)(3) of this section. However, an applicant may seek approval of a
drug product that differs from the reference listed drug in preservative,
buffer, substance to adjust tonicity, or thickening agent provided
that the applicant identifies and characterizes the differences and
provides information demonstrating that the differences do not affect
the safety or efficacy of the proposed drug product, except that, in a
product intended for ophthalmic use, an applicant may not change a
buffer or substance to adjust tonicity for the purpose of claiming a
therapeutic advantage over or difference from the listed drug, e.g., by
using a balanced salt solution as a diluent as opposed to an isotonic
saline solution, or by making a significant change in the pH or other
change that may raise questions of irritability.
 Enhancing opportunities
through 505(b)(2) NDAs
(v) Inactive ingredient changes permitted in drug products
intended for topical use.
Generally, a drug product intended for topical use,
solutions for aerosolization or nebulization, and nasal
solutions shall contain the same inactive ingredients as the
reference listed drug identified by the applicant under
paragraph (a)(3) of this section. However, an abbreviated
application may include different inactive ingredients
provided that the applicant identifies and characterizes the
differences and provides information demonstrating that
the differences do not affect the safety or efficacy of the
proposed drug product.
 Enhancing opportunities
through 505(b)(2) NDAs
“Follow-on” protein products approved
via 505(b)(2) NDAs
• Fortical (calcitonin salmon recombinant) Nasal Spray
• GlucaGen (glucagon recombinant for injection)
• Amphadase (hyaluronidase)
• Hylenex (hyaluronidase recombinant human)
• Hydase (hyaluronidase)
• Omnitrope (somatropin [rDNA origin])
Source: Janet Woodcock testimony before House Committee on Oversight and
Government Reform, March 26, 2007
 Enhancing opportunities
through 505(b)(2) NDAs
• Protecting your 505(b)(2) NDA product from
generic competition:
ƒ Orange Book patent listing
ƒ Potential 3-year Hatch/Waxman exclusivity if clinical
studies (other than bio studies) essential to approval
ƒ Potential 5-year Hatch/Waxman NCE exclusivity
ƒ Potential pediatric exclusivity
ƒ Potential orphan drug exclusivity for new indication
 Case study of
successful 505(b)(2) NDA
• GeneraMedix Epoprostenol for Injection
ƒ April 2006 – Licensing opportunity identified
ƒ ~ June 2006 – Licensing agreement signed
ƒ Dec. 2006 – NDA batches manufactured
ƒ June-Aug. 2007 – Pre-NDA discussions with FDA
ƒ Aug. 2007 – NDA submitted
ƒ June 2008 – NDA approved
ƒ Feb. 2009 – Agreement with Actelion Ltd. for purchase
of NDA
 Case study of
successful 505(b)(2) NDA
• Lessons Learned
ƒ Drug used in critically ill patients (PAH)
ƒ Perceived patient benefits rather than simply “different”
ƒ Caution regarding FDA interaction with KOLs
ƒ Reversal of FDA peripheral administration study
requirement
ƒ Change in marketing strategy
Note: FDA review documents available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/02
2260_epoprostenol_toc.cfm
 Enhancing opportunities through
ANDA suitability petitions
• Definitions / background information:
ƒ Citizen petition requesting permission to submit an
ANDA for a product which differs from the reference
listed drug in route of administration, dosage form, or
strength, or change in one active ingredient of a
combination RLD product [21 CFR § 314.93]
ƒ FDA will deny any ANDA suitability petition if clinical
studies (other than bio studies) would be required to
show safety & effectiveness, or if significant labeling
changes would be required
 Enhancing opportunities through
ANDA suitability petitions
§ 314.93 Petition to request a change from a listed drug.
(a) The only changes from a listed drug for which the agency will
accept a petition under this section are those changes described in
paragraph (b) of this section. Petitions to submit abbreviated new
drug applications for other changes from a listed drug will not be
approved.
(b) A person who wants to submit an abbreviated new drug
application for a drug product which is not identical to a listed drug
in route of administration, dosage form, and strength, or in which
one active ingredient is substituted for one of the active ingredients
in a listed combination drug, must first obtain permission from FDA
to submit such an abbreviated application.
 Enhancing opportunities through
ANDA suitability petitions
• Advantages:
ƒ Regulation requires FDA approval or denial within 90
days (raise eyebrows here)
ƒ Low-cost method of developing a product with
presumably some desirable feature, typically
convenience (e.g., ready-to-use injectable solution)
ƒ Theoretically may be patented, although patent(s) will
not be Orange Book listed
ƒ Typically at least 1-2 years of de facto exclusivity
 Enhancing opportunities through
ANDA suitability petitions
• Disadvantages:
ƒ Citizen petitions are publicly available on
regulations.gov
ƒ Product not pharmaceutically equivalent to the RLD and
thus not eligible for generic substitution
ƒ May not warrant a significant price differential above
A-rated generics
ƒ If patented, but patents are “weak,” may not deter
litigious competitors
 Enhancing opportunities through
ANDA suitability petitions
• ANDAs for duplicates of discontinued innovator
products:
ƒ Submit citizen petition requesting a determination that
the Reference Listed Drug was not discontinued for
reasons of safety or effectiveness
ƒ May be expedient if innovator replaced discontinued
formulation with a patent-protected formulation
ƒ Best case (my opinion) – may yield a low volume, high
margin niche product
 Niche product strategies:
Low volume, high margin
• Purchase distribution rights to “senior”
approved niche innovator product:
ƒ A well-established strategy is to purchase distribution
rights to a niche NDA product with low volume and
low sales, then implement repeated substantial price
increases (to support development of the marketer’s
portfolio of lifesaving innovative products).
ƒ Initial protection from generic competition by virtue of
small total market for the drug
 Niche product strategies:
Low volume, high margin
• Purchase development and marketing rights to
“castoff” unapproved innovator product:
ƒ A few companies have successfully completed
development of products licensed from the innovator,
who may have halted work on the project for clinical,
CMC or commercial reasons.
ƒ Excellent relatively recent example is Cubist
Pharmaceuticals’ Cubicin® (daptomycin for
injection), licensed from Lilly