CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
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`203284Orig1s000
`
`ADMINISTRATIVE and CORRESPONDENCE
`DOCUMENTS
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`

`

`.
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`EXCLUSIVITY SUMMARY
`
`
`NDA # 203284
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`SUPPL #
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`HFD # 180
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`Trade Name RAVICTI
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`Generic Name glycerol phenylbutyrate
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`Applicant Name Hyperion Therapeutics
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`Approval Date, If Known January 31, 2013
`
`PART I
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`1. An exclusivity determination will be made for all original applications, and all efficacy
`supplements. Complete PARTS II and III of this Exclusivity Summary only if you answer "yes" to
`one or more of the following questions about the submission.
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`IS AN EXCLUSIVITY DETERMINATION NEEDED?
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`a) Is it a 505(b)(1), 505(b)(2) or efficacy supplement?
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` YES
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`NO
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`If yes, what type? Specify 505(b)(1), 505(b)(2), SE1, SE2, SE3,SE4, SE5, SE6, SE7, SE8
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`505(b)(2)
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`c) Did it require the review of clinical data other than to support a safety claim or change in
`labeling related to safety? (If it required review only of bioavailability or bioequivalence
`data, answer "no.")
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` YES
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`NO
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`If your answer is "no" because you believe the study is a bioavailability study and, therefore,
`not eligible for exclusivity, EXPLAIN why it is a bioavailability study, including your
`reasons for disagreeing with any arguments made by the applicant that the study was not
`simply a bioavailability study.
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`If it is a supplement requiring the review of clinical data but it is not an effectiveness
`supplement, describe the change or claim that is supported by the clinical data:
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`Reference ID: 3256908
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`Page 1
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`d) Did the applicant request exclusivity?
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`7 years – orphan designation
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`If the answer to (d) is "yes," how many years of exclusivity did the applicant request?
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` YES
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`NO
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`e) Has pediatric exclusivity been granted for this Active Moiety?
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` YES
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`NO
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` If the answer to the above question in YES, is this approval a result of the studies submitted in
`response to the Pediatric Written Request?
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`IF YOU HAVE ANSWERED "NO" TO ALL OF THE ABOVE QUESTIONS, GO DIRECTLY TO
`THE SIGNATURE BLOCKS AT THE END OF THIS DOCUMENT.
`
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`2. Is this drug product or indication a DESI upgrade?
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` YES
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`NO
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`If "yes," identify the approved drug product(s) containing the active moiety, and, if known, the NDA
`#(s).
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` YES
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`NO
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`IF THE ANSWER TO QUESTION 2 IS "YES," GO DIRECTLY TO THE SIGNATURE BLOCKS
`ON PAGE 8 (even if a study was required for the upgrade).
`
`
`FIVE-YEAR EXCLUSIVITY FOR NEW CHEMICAL ENTITIES
`PART II
`(Answer either #1 or #2 as appropriate)
`
`1. Single active ingredient product.
`
`Has FDA previously approved under section 505 of the Act any drug product containing the same
`active moiety as the drug under consideration? Answer "yes" if the active moiety (including other
`esterified forms, salts, complexes, chelates or clathrates) has been previously approved, but this
`particular form of the active moiety, e.g., this particular ester or salt (including salts with hydrogen
`or coordination bonding) or other non-covalent derivative (such as a complex, chelate, or clathrate)
`has not been approved. Answer "no" if the compound requires metabolic conversion (other than
`deesterification of an esterified form of the drug) to produce an already approved active moiety.
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`Reference ID: 3256908
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`Page 2
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`NDA# 20572 and 20573
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`NDA#
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`NDA#
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`Buphenyl
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`THREE-YEAR EXCLUSIVITY FOR NDAs AND SUPPLEMENTS
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`Reference ID: 3256908
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`Page 3
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`2. Combination product.
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`If the product contains more than one active moiety(as defined in Part II, #1), has FDA previously
`approved an application under section 505 containing any one of the active moieties in the drug
`product? If, for example, the combination contains one never-before-approved active moiety and
`one previously approved active moiety, answer "yes." (An active moiety that is marketed under an
`OTC monograph, but that was never approved under an NDA, is considered not previously
`approved.)
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`YES
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`NO
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`If "yes," identify the approved drug product(s) containing the active moiety, and, if known, the NDA
`#(s).
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`NDA#
`NDA#
`NDA#
`
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`IF THE ANSWER TO QUESTION 1 OR 2 UNDER PART II IS "NO," GO DIRECTLY TO THE
`SIGNATURE BLOCKS ON PAGE 8. (Caution: The questions in part II of the summary should
`only be answered “NO” for original approvals of new molecular entities.)
`IF “YES,” GO TO PART III.
`
`
`PART III
`
`To qualify for three years of exclusivity, an application or supplement must contain "reports of new
`clinical investigations (other than bioavailability studies) essential to the approval of the application
`and conducted or sponsored by the applicant." This section should be completed only if the answer
`to PART II, Question 1 or 2 was "yes."
`
`
`1. Does the application contain reports of clinical investigations? (The Agency interprets "clinical
`investigations" to mean investigations conducted on humans other than bioavailability studies.) If
`the application contains clinical investigations only by virtue of a right of reference to clinical
`investigations in another application, answer "yes," then skip to question 3(a). If the answer to 3(a)
`
`

`

`is "yes" for any investigation referred to in another application, do not complete remainder of
`summary for that investigation.
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`YES
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`NO
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`IF "NO," GO DIRECTLY TO THE SIGNATURE BLOCKS ON PAGE 8.
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`2. A clinical investigation is "essential to the approval" if the Agency could not have approved the
`application or supplement without relying on that investigation. Thus, the investigation is not
`essential to the approval if 1) no clinical investigation is necessary to support the supplement or
`application in light of previously approved applications (i.e., information other than clinical trials,
`such as bioavailability data, would be sufficient to provide a basis for approval as an ANDA or
`505(b)(2) application because of what is already known about a previously approved product), or 2)
`there are published reports of studies (other than those conducted or sponsored by the applicant) or
`other publicly available data that independently would have been sufficient to support approval of
`the application, without reference to the clinical investigation submitted in the application.
`
`
`(a) In light of previously approved applications, is a clinical investigation (either conducted
`by the applicant or available from some other source, including the published literature)
`necessary to support approval of the application or supplement?
`
`
` YES
`
`
`If "no," state the basis for your conclusion that a clinical trial is not necessary for approval
`AND GO DIRECTLY TO SIGNATURE BLOCK ON PAGE 8:
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`NO
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`(b) Did the applicant submit a list of published studies relevant to the safety and
`effectiveness of this drug product and a statement that the publicly available data would not
`independently support approval of the application?
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` YES
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`NO
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`(1) If the answer to 2(b) is "yes," do you personally know of any reason to disagree
`with the applicant's conclusion? If not applicable, answer NO.
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` YES
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`NO
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` If yes, explain:
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`(2) If the answer to 2(b) is "no," are you aware of published studies not conducted or
`sponsored by the applicant or other publicly available data that could independently
`demonstrate the safety and effectiveness of this drug product?
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` YES
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`NO
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`Reference ID: 3256908
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`Page 4
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` If yes, explain:
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`(c)
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`If the answers to (b)(1) and (b)(2) were both "no," identify the clinical
`investigations submitted in the application that are essential to the approval:
`
`Investigation #1: Study HPN-100-006, Randomized, Double-Blind, Cross-Over,
`Active-Controlled Study of the Efficacy and Safety of HPN-100 for the treatment of
`adults with Urea Cycle Disorders
`Investigation #2: UP1204-003 Open-Label, Switch-Over, Dose-Escalation Study of
`the safety and tolerability of HPN-100 compared to Buphenyl in patients with Urea
`Cycle Disorders
`Investigation #3: Study HPN-100-007, Long term (12 months) open-label study to
`assess ammonia control and safety in adult and pediatric patients’ (cid:149)6 years with
`Urea Cycle Disorders.
`Investigation #4: Study HPN-100-005, Open-label switch over study in pediatric
`patients 6 to 17 years old with Urea Cycle Disorders to evaluate safety,
`tolerability and pharmacokinetics of Ravicti compared to Buphenyl. The switch
`over part of this study was 7 days on each drug.
`Investigation#5: Study HPN-100-005SE, Long term (12 months) safety extension
`study that evaluated ammonia control and safety in pediatric patients ages 6 to 17
`years old with Urea Cycle Disorders.
`Investigation #6: Study HPN-100-012, Open-label switch over study in pediatric
`patients 29 days to <6 years with Urea Cycle disorders currently being treated
`with Buphenyl to assess PK, safety and ammonia control. No patients younger
`than 2 months were enrolled.
`Investigation #7: Study HPN-100-012SE, Long term (12 months) safety extension
`study. The study is ongoing, (data cutoff date 01 March 2012.
`
`
`
`Studies comparing two products with the same ingredient(s) are considered to be bioavailability
`studies for the purpose of this section.
`
`
`3. In addition to being essential, investigations must be "new" to support exclusivity. The agency
`interprets "new clinical investigation" to mean an investigation that 1) has not been relied on by the
`agency to demonstrate the effectiveness of a previously approved drug for any indication and 2) does
`not duplicate the results of another investigation that was relied on by the agency to demonstrate the
`effectiveness of a previously approved drug product, i.e., does not redemonstrate something the
`agency considers to have been demonstrated in an already approved application.
`
`
`a) For each investigation identified as "essential to the approval," has the investigation been
`relied on by the agency to demonstrate the effectiveness of a previously approved drug
`product? (If the investigation was relied on only to support the safety of a previously
`approved drug, answer "no.")
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`Reference ID: 3256908
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`Page 5
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`Investigation #1
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`Investigation #2
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`Investigation #3
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`Investigation #4
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`Investigation #5
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`Investigation #6
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`Investigation #7
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`YES
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`YES
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`YES
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`YES
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`YES
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`YES
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`YES
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`NO
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`NO
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`NO
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`NO
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`NO
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`NO
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`NO
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`If you have answered "yes" for one or more investigations, identify each such investigation
`and the NDA in which each was relied upon:
`
`
`b) For each investigation identified as "essential to the approval", does the investigation
`duplicate the results of another investigation that was relied on by the agency to support the
`effectiveness of a previously approved drug product?
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`YES
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`YES
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`YES
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`NO
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`NO
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`NO
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`YES
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`YES
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`YES
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`NO
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`NO
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`NO
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`Investigation #1
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`Investigation #2
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`Investigation #3
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`Investigation #4
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`Investigation #5
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`Investigation #6
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`Investigation #7
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`If you have answered "yes" for one or more investigation, identify the NDA in which a
`similar investigation was relied on:
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`YES
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`NO
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`c) If the answers to 3(a) and 3(b) are no, identify each "new" investigation in the application
`
`
`Reference ID: 3256908
`
`
`Page 6
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`or supplement that is essential to the approval (i.e., the investigations listed in #2(c), less any
`that are not "new"):
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`
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`All investigations listed in #2(c) were necessary for approval.
`
`
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`4. To be eligible for exclusivity, a new investigation that is essential to approval must also have
`been conducted or sponsored by the applicant. An investigation was "conducted or sponsored by"
`the applicant if, before or during the conduct of the investigation, 1) the applicant was the sponsor of
`the IND named in the form FDA 1571 filed with the Agency, or 2) the applicant (or its predecessor
`in interest) provided substantial support for the study. Ordinarily, substantial support will mean
`providing 50 percent or more of the cost of the study.
`
`
`Investigations #1 thru #7
`
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`IND # 73,480
`YES
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`a) For each investigation identified in response to question 3(c): if the investigation was
`carried out under an IND, was the applicant identified on the FDA 1571 as the sponsor?
`
`
`
`
`
`NO
`
`Explain:
`There was a change in the sponsor in the middle of
`the NDA review cycle. Applicant has right of
`reference and notes in their updated exclusivity
`request, dated 1/8/13, that they are now the sponsor
`named on the 1571 for IND 43780. Please see
`additional comments at end of document for more
`information.
`
`
`
`
`(b) For each investigation not carried out under an IND or for which the applicant was not
`identified as the sponsor, did the applicant certify that it or the applicant's predecessor in
`interest provided substantial support for the study?
`
`Investigations #1 thru #7
`
`
`
`YES
`
`Explain:
`
`
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`!
`
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`!
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`! NO
`! Explain:
` No certification was found in the NDA. Please
`see additional comments below.
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`
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`(c) Notwithstanding an answer of "yes" to (a) or (b), are there other reasons to believe that
`the applicant should not be credited with having "conducted or sponsored" the study?
`
`
`Reference ID: 3256908
`
`
`Page 7
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`(Purchased studies may not be used as the basis for exclusivity. However, if all rights to the
`drug are purchased (not just studies on the drug), the applicant may be considered to have
`sponsored or conducted the studies sponsored or conducted by its predecessor in interest.)
`
`
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`YES
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`NO
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`If yes, explain:
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`Additional information:
`In 2007, Hyperion entered into a Research and Collaboration Agreement with Ucyclyd Pharma
`(Medicis), original sponsor of IND 73480 and NDA 203284, regarding its products Buphenyl,
`Ammonul and glycerol phenylbutryate. In 2007, the agreement granted Hyperion the sole right
`and responsibility to developed glycerol phenylbutyrate for urea cycle disorders and hepatic
`encephalopathy (INDs 73,480
`, respectively), this included all regulatory
`responsibilities for the INDs. The ownership of the INDs remained with Ucyclyd/Medicis and
`Hyperion was designated as the regulatory agent with all responsibilities for the INDs transferred
`to Hyperion (see IND 73,480 serial number 011). Under the 2007 agreement, Hyperion’s
`responsibilities also included the sole responsibility to write and manage the future NDA
`submission and FDA review for UCD on behalf of Ucyclyd/Medicis. The agreement also
`included a pre-negotiated option to purchase the full license rights to glycerol phenybutyrate
`(and potentially Buphenyl and Ammonul), which was to be triggered based on the PDUFA date
`for the glycerol phenylbutyrate NDA for UCD, with ownership of all corresponding applications
`for glycerol phenylbutryate (INDs and NDAs) being transferred to Hyperion upon execution of
`the purchase rights.
`
`Per the Research and Collaboration Agreement, Hyperion submitted NDA 203284 in December
`2011 on behalf of Uclyclyd/Medicis as the regulatory agent, and at that time, since the NDA was
`a Ucyclyd/Medicis application, a full right of reference to sodium phenylubyrate was made on
`the 356h form because Ucyclyd/Medicis owned both the glycerol phenylbutyrate and the
`Buphenyl (sodium phenylbutyrate) applications.
`
`In the late 2011/early 2012, the agreement between Ucylcyd/Medicis and Hyperion was re-
`negotiated to an Asset Purchasing Agreement, which allowed Hyperion to purchase the full
`rights of glycerol phenylbutryate immediately, before the PDUFA date, with the option to
`purchase Buphenyl and Ammonul set for a later date. Hyperion executed the purchase right
`in March 2012 and at that time the ownership of the glycerol phenylbutyrate NDA 20-3284 and
` INDs 73,480
` were transferred to Hyperion (see NDA 20-3284 amendment, dated
`March 23, 2012; IND 73,480 dated April 17, 2012).
`
`=================================================================
`
`Name of person(s) completing form: Melanie Blank, M.D.
`Title: Acting Cross Discipline Team Leader, DGIEP
`Date: January 28, 2013
`
`
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`Reference ID: 3256908
`
`
`Page 8
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`(b) (4)
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`(b) (4)
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`

`

`Nancy Snow, D.O. Medical Reviewer Feb. 1, 2013
`
`Name of Office/Division Director signing form: Donna Griebel, M.D.
`Title: Division Director, DGIEP
`
`
`
`Form OGD-011347; Revised 05/10/2004; formatted 2/15/05; removed hidden data 8/22/12
`
`
`
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`Reference ID: 3256908
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`
`Page 9
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`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`JESSICA M BENJAMIN
`02/07/2013
`
`DONNA J GRIEBEL
`02/07/2013
`
`Reference ID: 3256908
`
`

`

`1.3.
`
`ADMINISTRATIVE INFORMATION
`
`3.
`
`DEBARMENT CERTIFICATION
`
`Ucyclyd Pharma Inc., a wholly owned subsidiary of Medicis Pharmaceutical Inc., certifies that it
`did'not andwill not use in any capacity the services of any person debarred‘under section 306 of
`the F era! Food, Drug, an Cosmetic Act in connection with this application.
`
`
`
`/Ira LawrenCe,
`
`cc and Sr. Vice Research and
`Chief Medica
`
`
`)2~Ye/Z
`Date
`
`Development
`
`Ucyclyd Pharma lnc.
`7720 North Dobson Road
`
`Scottsdale, AZ 85256
`
`Phone: (480) 291-5629
`
`Email: ilawrence@medicis.com
`
`Hyperion Therapeutics certifies that it did not and will not use in any capacity the services of any
`
`
`
`Klara A. Dickinson
`
`Date
`
`Sr. Vice President Regulatory Affairs and Compliance
`
`Hyperion Therapeutics, Inc.
`60] Gateway Boulevard, Suite 200
`South San Francisco, CA 94080
`
`Phone: (650) 745-7820
`
`Email: klara.dickinson@hyperiontx.com
`
`NDA 29-3284
`Ravicti M (glycerol phenylbutyrate) Liquid
`
`1
`
`Confidential
`
`

`

`ACTION PACKAGE CHECKLIST
`
`NDA # 203284
`
`NDA Supplement #
`BLA Supplement #
`
`Proprietary Name: RAVICTI
`Established/Proper Name: glycerol phenylbutyrate
`oral liquid
`Dosage Form:
`
`.
`IfNDA, Efficacy Supplement Type.
`
`Applicant: Hyperion Therapeutics
`Agent for Applicant (if applicable):
`
`RPM: Jessica M. Benjamin
`
`Division: DGIEP
`
`NDAs and NDA Efficag Supplements:
`
`505
`
`2 Ori ' al NDAs and 505
`
`2 NDA su
`
`lements:
`
`NDA Application Type: D 505(b)(1) E 505(b)(2) Listed drug(s) relied upon for approval (include NDA #(s) and drug
`Efficacy Supplement: D 505(b)(1) D 505(b)(2)
`name(s)):
`
`(A supplement can be either a (b)(l) or a (b)(2)
`regardless of whether the original NDA was a (b)(l)
`or a (b)(2). Consult page 1 of the 505(b)(2)
`Assessment or the Appendix to this Action Package
`Checklist.)
`
`Provide a brief explanation of how this product is different from the listed
`drug.
`
`0 User Fee Goal Date is 1/23/213
`
`E This application does not reply upon a listed drug.
`X This application relies on literature.
`I] This application relies on a final OTC monograph.
`D This application relies on (explain)
`
`For ALL (b112, applications, two months prior to EVERY action,
`review the information in the 50512112] Assessment and submit the
`draft2 to CDER 0ND 10 for clearance. Finalize the 505(b)(2)
`Assessment at the time of the approval action.
`
`On the day of approval, check the Orange Book again for any new
`patents or pediatric exclusivity.
`
`D No changes
`
`[I Updated Date of check:
`
`If pediatric exclusivity has been granted or the pediatric information in
`the labeling of the listed drug changed, determine Whether pediatric
`information needs to be added to or deleted from the labeling of this
`drug.
`
`0
`°.° Actions
`
`0
`
`Proposed action
`
`0
`
`Previous actions (spectfi type and datefor each action taken)
`
`1 The Application Information Section is (only) a checklist. The Contents of Action Package Section (beginning on page 5) lists
`the documents to be included in the Action Package.
`2 For resubmissions. (b)(2) applications must be cleared before the action, but it is not necessary to resubmit the draft 505(b)(2)
`Assessment to CDER 0ND IO unless the Assessment has been substantively revised (e.g., nrew listed drug, patent certification
`revised).
`
`Version: 1/27/12
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`Reference ID: 3257643
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`

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`NDA # 203284
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`Page 2
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`'3'
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`Ifaccelerated approval or approval based on efficacy studies in animals, were promotional
`materials received?
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`D Received
`
`Note: Promotional materials to be used within 120 days after approval must have been
`submitted (for exceptions, see
`ht_tp://www fda.gov/downloads/Drugs/GuidanceConmlianceRegiilatoglnfomiation/Guida
`nces/ucm069965.-
`. Ifnot submitted, -
`lain
`O
`9.. Application Characteristics 3
`
`
`
`|Z| Standard El Priority
`Review priority:
`Chemical classification (new NDAs only):
`
`E Fast Track
`El Rolling Review
`E Orphan drug designation
`
`[I Rx-to-OTC full switch
`[I Rx—to-OTC partial switch
`El Direct-to-OTC
`
`NDAs: Subpart H
`D Accelerated approval (21 CFR 314.510)
`[I Restricted distribution (21 CFR 314.520)
`Subpart I
`[I Approval based on animal studies
`
`BLAs: Subpart E
`I] Accelerated approval (21 CFR 601.41)
`E] Restricted distribution (21 CFR 601.42)
`Subpart H
`El Approval based on animal studies
`
`I] Submitted in response to a PMR
`El Submitted in response to a PMC
`El Submitted in response to a Pediatric Written Request
`
`Comments:
`
`REMS: I] MedGuide
`I] Communication Plan
`D ETASU
`IX] MedGuide w/o REMS
`El REMS not required
`
`03° BLAs only: Ensure RMS—BLA Product Infomlation Sheetfor TBP and RMS—BLA Facility
`Information Sheetfor TBP have been completed and forwarded to OPI/OBI/DRM (Vicky
`Carter
`
`El Yes, dates
`
`'2' BLAs only: Is the product subject to oflicial FDA lot release per 21 CFR 610.2
`(approvals only)
`
`
`‘2' Public communications (approvals only)
`
`0 Ofiice of Executive Programs (OEP) liaison has been notified of action
`
`0
`Press Office notified of action (by OEP)
`
`0
`
`Indicate what types (if any) of information dissemination are anticipated
`
`
`
`FDA Talk Paper
`CDER Q&As
`Other
`
`3 Answer all questions in all sections in relation to the pending application, i.e., if the pending application is an NDA or BLA
`supplement, then the questions should be answered in relation to that supplement, not in relation to the original NDA or BLA. For
`example, if the application is a pending BLA supplement, then a new RMS—BLA Product Information Sheetfor TBP must be
`completed.
`
`Version: “27/12
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`Reference ID: 3257643
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`

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`NDA # 203284
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`Page 3
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`O
`°.° Exclusivity
`
`0
`
`Is approval of this application blocked by any type of exclusivity?
`
`E No
`
`D Yes
`
`0 NDAs and BLAs: Is there existing orphan drug exclusivity for the “same”
`drug or biologic for the proposed indication(s)? Refer to 21 CFR
`31 6.3(b)(13) for the definition of "same drug”for an orphan drug (i.e.,
`active moiety). This definition is NOT the same as that usedfor ADA
`chemical classification.
`
`o
`
`(b)(2) NDAs only: Is there remaining S-year exclusivity that would bar
`efiecfive approval of a 505 (b)(2) application)? (Note that, even ifexclusivity
`remains, the application may be tentatively approved iit is otherwise ready
`
`for approval.)
`
`o
`
`(b)(2) NDAs only: Is there remaining 3—year exclusivity that would bar
`efiecfive approval of a 505(b)(2) application? (Note that, even ifexclusivity
`remains, the application may be tentatively approved ‘y‘it is othenvise ready
`for approval.)
`
`I] Yes
`E No
`If, yes, NDA/BLA #
`date exclusivity expires:
`
`If yes, NDA #
`exclusivity expires:
`
`and date
`
`D Yes
`ENO
`If yes, NDA #
`and date
`exclusivity expires:
`
`o
`
`(b)(2) NDAs only: Is there remaining 6—month pediatric exclusivity that
`would bar effective approval of a 505(b)(2) application? (Note that, even if
`If yes, NDA #
`exclusiw'ty remains, the application may be tentatively approved ifit is
`exclusivity expires:
`otherwise readyfor approval.)
`
`and date
`
`
`
`
`
`El Yes
`o NDAs only: Is this a single enantiomer that falls under the 10-year approval E No
`limitation of 505(u)? (Note that, even ifthe 10-year approval limitation
`.
`_
`.
`_
`_
`_
`_
`_
`Ifyes, NDA #
`and date 10-
`.
`perlod has not expired, the application may be tentatively approved IfIt Is
`-
`-
`-
`_
`year hmrtatron expires.
`,
`_
`.
`_
`'
`otherwise I eadyfor app] oval.)
`
`IX] Verified
`D Not applicable because drug is
`an old antibiotic.
`
`2 1 CFR 314.50(i)(1)(i)(A)
`D Verified
`
`21 CFR 314.50(i)(l)
`
`E No paragraph III certification
`Date patent will expire
`
`‘3‘ Patent Information (NDAs only)
`
`0
`
`Patent Information:
`
`Verify that form FDA-35423 was submitted for patents that claim the drug for
`which approval is sought.
`If the drug is an old antibiotic, skip the Patent
`
`Certification questions.
`
`0
`
`Patent Certification [505(b)(2) applications]:
`Verify that a certification was submitted for each patent for the listed drug(s) in
`the Orange Book and identify the type of certification submitted for each patent.
`
` O
`
`[505(b)(2) applications] If the application includes a paragraph 111 certification,
`it cannot be approved lmtil the date that the patent to which the certification
`pertains expires (but may be tentatively approved if it is otherwise ready for
`approval).
`
`o
`
`[505(b)(2) applications] For each paragraph IV certification, verify that the
`applicant notified the NDA holder and patent owner(s) of its certification that the E N/A (no paragraph Iv certification)
`patent(s) is invalid, unenforceable, or will not be infringed (review
`'3 Verified
`documentation of notification by applicant and documentation of receipt of
`notice by patent owner and NDA holder). (Ifthe application does not include
`any paragraph IV certifications, mark "N/A " and skip to the next section below
`(Summary Reviews».
`
`Reference ID: 3257643
`
`Version: 1/27/12
`
`

`

` Yes
`
` No
`
` Yes
`
` No
`
` Yes
`
` No
`
` Yes
`
` No
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`
`
`Version: 1/27/12
`
`
`
`NDA # 203284
`Page 4
`
`
` •
`
`
`
`[505(b)(2) applications] For each paragraph IV certification, based on the
`questions below, determine whether a 30-month stay of approval is in effect due
`to patent infringement litigation.
`
`Answer the following questions for each paragraph IV certification:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(1) Have 45 days passed since the patent owner’s receipt of the applicant’s
`notice of certification?
`
`
`
`(Note: The date that the patent owner received the applicant’s notice of
`certification can be determined by checking the application. The applicant
`is required to amend its 505(b)(2) application to include documentation of
`this date (e.g., copy of return receipt or letter from recipient
`acknowledging its receipt of the notice) (see 21 CFR 314.52(e))).
`
` If “Yes,” skip to question (4) below. If “No,” continue with question (2).
`
`(2) Has the patent owner (or NDA holder, if it is an exclusive patent licensee)
`submitted a written waiver of its right to file a legal action for patent
`infringement after receiving the applicant’s notice of certification, as
`provided for by 21 CFR 314.107(f)(3)?
`
`
`If “Yes,” there is no stay of approval based on this certification. Analyze the next
`paragraph IV certification in the application, if any. If there are no other
`paragraph IV certifications, skip the rest of the patent questions.
`
`If “No,” continue with question (3).
`
`
`(3) Has the patent owner, its representative, or the exclusive patent licensee
`filed a lawsuit for patent infringement against the applicant?
`
`
`
`(Note: This can be determined by confirming whether the Division has
`received a written notice from the (b)(2) applicant (or the patent owner or
`its representative) stating that a legal action was filed within 45 days of
`receipt of its notice of certification. The applicant is required to notify the
`Division in writing whenever an action has been filed within this 45-day
`period (see 21 CFR 314.107(f)(2))).
`
`
`If “No,” the patent owner (or NDA holder, if it is an exclusive patent licensee)
`has until the expiration of the 45-day period described in question (1) to waive
`its right to bring a patent infringement action or to bring such an action. After
`the 45-day period expires, continue with question (4) below.
`
`(4) Did the patent owner (or NDA holder, if it is an exclusive patent licensee)
`submit a written waiver of its right to file a legal action for patent
`infringement within the 45-day period described in question (1), as
`provided for by 21 CFR 314.107(f)(3)?
`
`If “Yes,” there is no stay of approval based on this certification. Analyze the next
`paragraph IV certification in the application, if any. If there are no other
`paragraph IV certifications, skip to the next section below (Summary Reviews).
`
`If “No,” continue with question (5).
`
`
`
`
`Reference ID: 3257643
`
`

`

`NDA # 203284
`
`Page 5
`
`(5) Did the patent owner, its representative, or the exclusive patent licensee
`bring suit against the (b)(2) applicant for patent infringement within 45
`days of the patent owner’s receipt of the applicant’s notice of
`certification?
`
`(Note: This can be determined by confirming whether the Division has
`received a written notice from the (b)(2) applicant (or the patent owner or
`its representative) stating that a legal action was filed within 45 days of
`receipt of its notice of certification. The applicant is required to notify the
`Division in writing whenever an action has been filed within this 45-day
`period (see 21 CFR 314.107(t)(2)). Ifno written notice appears in the
`NDA file, confirm with the applicant Whether a lawsuit was commenced
`within the 45-day period).
`
`If "No, " there is no stay ofapproval based on this certification. Analyze the
`nart paragraph IV certification in the application, Vany. Ifthere are no other
`paragraph IV certifications, skip to the next section below (Summary
`Reviews).
`
`If "Yes, " a stay ofapproval may be in eflect. To determine ifa 30—month stay
`is in eflect, consult with the 0ND ADRA and attach a summary ofthe
`response.
`
`Copy of this Action Package Checklist4
`
`List of oflicers/employees who participated in the decision to approve this application and
`consented to be identified on this list (approvals only)
`
`Documentation of consent/non-consent by oflicers/employees
`
`2/1/13
`
`Copies ofall action letters (including approval letter withfinal labeling)
`
`git/12°:1(3) and date(s): A” val
`
`Package Insert (write submission/communication date at upper right offirstpage ofPI)
`
`Most recent draft labeling. Ifit is division-proposed labeling, it should be in
`track-changes format.
`
`Original applicant-proposed labeling
`Example of class labeling, if applicable
`
`.
`.
`12/23/201-1
`Buph-yl April 2008
`
`‘
`
`O0
`
`..
`
`O9
`
`..
`
`O
`0.0
`
`o
`0..
`
`‘ Fill in blanks with dates ofreviews, letters, etc.
`
`Version: 1/27/12
`
`Reference ID: 3257643
`
`

`

`NDA # 203284
`
`Page 6
`
`Medication Guide/Patient Package Insert/Instructions for Use/Device Labeling (write
`submission/communication date at upper right offirstpage ofeach piece)
`
`Most-recent drafi labeling. Ifit is division-proposed labeling, it should be in
`track-changes format.
`
`Original applicant-proposed labeling
`
`Example of class labeling, if applicable
`
`Labels (full color carton and immediate-container labels) (write
`submission/communication date on upper right offirstpage ofeach submission)
`
`0 Most-recent draft labeling
`
`Proprietary Name
`Acceptability/non-ac