Full Press Release Details
Phathom Pharmaceuticals, Inc.
Florham Park, NJ 07932
This letter responds to your citizen petition submitted on behalf of Phathom Pharmaceuticals, Inc. (Phathom), and received on December 11, 2024
(Petition). In the Petition, you request that the Food and Drug Administration (FDA or Agency) correct the publication, Approved Drug Products with Therapeutic Equivalence Evaluations (the Orange Book ), to accurately reflect
the statutorily-required 10-year period of non-patent new chemical entity ( NCE ) exclusivity in the Orange Book listing for Voquezna (vonoprazan
fumarate) new drug application (NDA) 215151 (Petition at 1).
Specifically, Phathom argues that Voquezna should benefit from the NCE and Generating
Antibiotic Incentives Now (GAIN) (NCE*GAIN) exclusivity granted to Voquezna Triple Pak (co-package of vonoprazan fumarate, amoxicillin, and clarithromycin) NDA 215152 and Voquezna Dual Pak (co-package of vonoprazan fumarate and amoxicillin) NDA 215153 (collectively, the Voquezna Paks). Vonoprazan, the active moiety first approved in the Voquezna Paks, was recognized as a NCE upon approval. The
Voquezna Paks received qualified infectious disease product (QIDP) designation and, pursuant to the GAIN provisions, the NCE exclusivity recognized for the Voquezna Paks was extended by 5 years, resulting in a total of 10 years of NCE*GAIN
exclusivity with respect to the active moiety vonoprazan. Phathom contends that under FDA s umbrella policy, this exclusivity should extend to Voquezna because it contains the same active moiety (vonoprazan), despite Voquezna not
independently being designated as a QIDP.1, 2
FDA has carefully considered the Petition, including
the public comments submitted to the docket. For the reasons described below, the Petition is granted.
U.S. Food & Drug Administration
Silver Spring, MD 20993
The Hatch-Waxman Amendments provide incentives for pharmaceutical innovation in the form of exclusivities, including
5-year exclusivity, to protect qualified drugs submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(b)) from competition from certain 505(b)(2) NDAs and
abbreviated new drug applications (ANDAs) for varying periods of time depending on the factual circumstances.
5-year exclusivity statutory provision provides:
If an application submitted under subsection
(b) for a drug, no active moiety (as defined by the Secretary in section 314.3 of title 21, Code of Federal Regulations (or any successor regulations)) of which has been approved in any other application under subsection (b), is
approved after [September 24, 1984], no application which refers to the drug for which the subsection (b) application was submitted and for which the investigations described in subsection (b)(1)(A)(i) and 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 may be submitted under
subsection (b) before the expiration of five years from the date of the approval of the application under subsection (b), except that such an application may be submitted under subsection (b) after the
expiration of four years from the date of the approval of the subsection (b) application if it contains a certification of patent invalidity or noninfringement described in clause (iv) of subsection
In this provision, the first clause (italicized text) describes which drugs
are NCEs (eligibility clause), and thus eligible for 5-year NCE exclusivity, and the second clause (bold text) describes the applications that are blocked by such exclusivity (bar clause). The eligibility
clause commands a 5-year exclusivity period for a drug, no active moiety . . . of which has been approved in any other application under [section 505(b) of the FD&C Act]. The Agency has
interpreted the term drug in both the eligibility and bar clauses to mean drug substance that contains an active moiety.4
Once a drug has met the requirements of the eligibility clause, the bar clause prevents the submission of any ANDA or 505(b)(2) NDA that refers to the
drug for which the [505(b)] application was submitted (emphasis added). This exclusivity generally has been interpreted to prevent an applicant from submitting a 505(b)(2) NDA or ANDA for a drug that contains the same active moiety
approved in the protected drug for a 5-year period from the date of approval of the protected drug.5 Five-year NCE exclusivity does not block submission or
review of stand-alone 505(b)(1) NDAs.
In the 1989 proposed rule Abbreviated New Drug Application Regulations, the Agency addressed how it would interpret certain statutory exclusivity
provisions, including the 5-year exclusivity statutory provisions, to operationalize these valuable incentives.6 The Agency chose an interpretation that
allowed for this exclusivity to protect all drug products containing the novel active moiety during the 5-year pendency of the exclusivity period under the umbrella of the exclusivity recognized for the
first approval of the novel active moiety. The Agency explained:
The language of sections 505(c)(3)(D) and 505(j)(4)(D) of the [FD&C
Act] is ambiguous as to which ANDAs or 505(b)(2) applications are affected by an innovator s exclusivity. The statutory language allows at least two interpretations. The narrower interpretation of the protection offered by exclusivity is that
exclusivity covers only specific drug products and therefore protects from generic competition only the first approved version of a drug . . . . Under this interpretation, an innovator s exclusivity could lose its value as soon as FDA approved
a second full new drug application for a version of the drug, because an ANDA could be approved by reference to the second approved version of the drug, which would not be covered by exclusivity.
The broader interpretation of the coverage of exclusivity is that it covers the active moieties in new chemical entities . . . rather than
covering only specific drug products. Thus exclusivity would protect the new active moiety of a new chemical entity . . . from generic competition even after FDA had approved subsequent full new drug applications for subsequent versions of the drug.
Under this theory, an ANDA or 505(b)(2) application for a drug with the same active moiety as the innovator s new chemical entity . . . could not be approved until the innovator s exclusivity expired, even if the ANDA or 505(b)(2)
application relied on another approved version of the innovator s drug.7
interpretation, FDA explained that the term drug in the bar clause of the 5-year NCE exclusivity provisions meant drug substance.8 Under this
interpretation, now referred to as the umbrella policy, after a drug product becomes eligible for 5-year NCE exclusivity, certain drug products subsequently developed and approved that contain the same active
moiety would also benefit from the original drug product s 5-year NCE exclusivity until the exclusivity period for the original drug product has
expired.9 Alternatively said, under the umbrella policy, 5-year exclusivity attaches to the previously unapproved active moiety, and thus, not only to the
first approved drug product that was eligible for 5-year NCE exclusivity, but also to other drug products containing the same active moiety. Thus, the scope of
5-year exclusivity is the NCE (new active moiety).10
Accordingly, under the umbrella policy, 5-year NCE exclusivity will
apply not just to the first approved drug product containing no previously approved active moiety but also to any subsequently approved drug product developed that contains the same new active moiety as in the first drug product and that is approved
during the 5-year period. Such a subsequently approved drug product will be protected for the balance of the 5-year period, which runs from the date of approval of the
first approved drug product.
The goal of the umbrella policy is to encourage further development and improvement of drug products containing the NCE
without compromising the innovator s exclusivity period by allowing the innovator to market different drug products containing the same active moiety and to benefit from the 5-year protection while doing
so. FDA explained its reasoning for adopting the broader interpretation of the coverage of exclusivity as follows:
[I]f FDA adopted the
narrower interpretation that exclusivity covers only a specific drug product and does not prevent ANDAs from copying subsequent versions of the innovative product, a manufacturer of a new chemical entity (entitled to 5 years of exclusivity), could
not make improvements in the drug, e.g., by making a new dosage form of the drug, without destroying the value of its exclusivity. Approval of a new dosage form, and certain other changes in approved drugs, require the submission of a new drug
application; once approved, the new dosage form would become a new drug product that an ANDA application could copy, without being subject to the exclusivity covering the original drug product.
For the same reasons, an innovator whose drug was entitled to exclusivity could not license another company to make a copy of the pioneer drug
without losing the value of its exclusivity. Under the narrow theory of exclusivity, once the licensed company s product was approved, ANDA applicants could copy the licensed product, without regard to the innovator s exclusivity.
The agency does not believe that Congress intended the exclusivity provisions to discourage innovators from making improvements in their drug
products nor from authorizing the marketing of competitive products. Accordingly, FDA has concluded that the broader interpretation of the scope of exclusivity should be applied to all types of exclusivity conferred by sections 505(c)(3)(D) and
505(j)(4)(D) of the [FD&C Act].11
Notably, the umbrella policy is also an important legal and
policy consideration in the Agency s statutory interpretations regarding the eligibility of 5-year NCE exclusivity for certain fixed-combination drug products containing a new active moiety in combination
approved active moiety (or moieties), a fact recognized by Federal courts,12 including for fixed-combinations containing old antibiotics in combination with new active moieties (such as the Voquezna Paks).
Section 505E of the FD&C Act provides for a 5-year extension of exclusivity periods upon approval of certain
applications for drug products that have been designated as QIDPs. Specifically, section 505E(a) states that the applicable 3-year, 5-year, or 7-year exclusivity period for a QIDP-designated drug shall be extended by 5 years (GAIN Extension).13 Title VIII of the Food and Drug Administration
Safety and Innovation Act (FDASIA) (Public Law 112-144), entitled Generating Antibiotic Incentives Now, amended the FD&C Act to add section 505E. This section was intended to address the public
health threat of antimicrobial drug resistance by incentivizing the development of new antibacterial and antifungal drugs for the treatment of serious or life-threatening infections.14
The term QIDP is defined in section 505E(g) of the FD&C Act to mean:
a drug . . . including an antibacterial or antifungal drug, for human use that
(1) acts on bacteria or fungi or on substances produced by such bacteria or fungi; and
(2) is intended to treat a serious or life-threatening infection, including such an infection caused by
(A) an antibacterial or antifungal resistant pathogen, including novel or emerging infectious pathogens; or
(B) qualifying pathogens listed by the Secretary under subsection (f).15
Section 505E(c) of the FD&C Act (Limitations) lists the following limitations to the GAIN
Extension of section 505E(a):
Subsection (a) does not apply to the approval of
(1) a supplement to an application under section 505(b) for any qualified infectious disease product for which an extension described in
subsection (a) is in effect or has expired;
(2) a subsequent application filed with respect to a product approved under section 505
for a change that results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device, or strength;
(3) a product that does not meet the definition of a qualified infectious disease product under subsection (g) based upon its approved
(4) an application pursuant to section 351(a) of the Public Health Service Act.
Voquezna (NDA 215151) contains the single active moiety vonoprazan, which belongs to a new class of acid-inhibitory agents called potassium-competitive acid
blockers.16 The active moiety vonoprazan was first approved by FDA on May 3, 2022, in the Voquezna Paks for the treatment of Helicobacter pylori (H. pylori) infection in adults.17
Because vonoprazan had never been approved as an active moiety in any other application, FDA
recognized 5-year NCE exclusivity for the Voquezna Paks. The Orange Book lists this exclusivity expiring on May 3, 2027. Additionally, because the Voquezna Paks were designated as QIDPs, in part because
of their indication to treat H. pylori in adults,18 the 5-year NCE exclusivity period recognized with respect to the new active moiety, vonoprazan,
was extended for an additional 5 years pursuant to the GAIN Extension of section 505E(a) of the FD&C Act.19
This NCE*GAIN exclusivity is listed in the Orange Book for the Voquezna Paks expiring on May 3, 2032.
On November 1, 2023, FDA approved Voquezna (NDA 215151), a drug product containing the single active ingredient, and single active moiety,
vonoprazan. In addition to being approved for the treatment of H. pylori infection in adults (in combination with amoxicillin and clarithromycin), Voquezna is also approved for three indications: (1) for healing of all grades of erosive
esophagitis and relief of heartburn associated with erosive esophagitis in adults, (2) to maintain healing of all grades of erosive esophagitis and relief of heartburn associated with erosive esophagitis in adults, and (3) for the relief
of heartburn associated with nonerosive gastroesophageal reflux disease in adults.20 Voquezna was not designated as a QIDP.21 The Orange Book