CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`'
`
`APPLICA TION NUMBER:
`
`NDA 22-249
`
`ADMINISTRATIVE and CORRESPONDENCE
`
`DOCUMENTS
`
`

`

`EXCLUSIVITY SUMMARY
`
`NDA # 22—249
`
`V
`
`,SUPPL #
`
`HFD # 150
`
`Trade Name TREANDA® for Injection, for intravenous infusion
`
`Generic Name bendamustine hydrochloride
`
`Applicant Name Cephalon, Inc.
`
`Approval Date, If Known March 20, 2008
`
`PART I
`
`IS AN EXCLUSIVITY DETERMINATION NEEDED?
`
`1. An exclusivity determination will be made for all original applications, and all efficacy
`V supplements. Complete PARTS II and III of this Eirclusivity Summary only if you answer'"yes" to
`one or more of the following questions about the submission.
`
`a) Is it a 505(b)(l), 505(b)(2) or efficacy supplement?
`
`YES 12]
`
`NO El
`
`Ifyes, what type? Specify 505(b)(1), 505(b)(2), SE1, SE2, SE3,SE4, SE5, SE6, SE7, SE8
`
`505(b)(2)
`
`0) 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.")
`
`YES IE
`
`NO [:1
`
`Ifyour 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.
`
`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:
`
`Page 1
`
`

`

`(1) Did the applicant request exclusivity?
`
`'YESEI
`
`NOE]
`
`If the answer to (d) is "yes," how many years of exclusivity did the applicant request?
`
`e) Has pediatric exclusivity been granted for this Active Moiety?
`YEslj
`
`NolZI
`
`Ifthe answer to the above question in YES, is this approval a result of the studies submitted in
`response to the Pediatric Written Request?
`
`IF YOU HAVE ANSWERED "NO" TO ALL OF THE ABOVE QUESTIONS, GO DIRECTLY TO
`THE SIGNATURE BLOCKS AT THE END OF THIS DOCUMENT.
`
`2. Is this drug product or indication a DESI upgrade?
`
`YES 1:]
`
`No
`
`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 ofthe 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, chelatc, 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.
`
`YESE]
`
`NOIXI
`
`If "yes," identify the approved drug product(s) containing the active moiety, and, ifknown, the NDA
`#(s).
`
`Page 2
`
`

`

`NDA#
`
`NDA#
`
`NDA#
`
`2. Combination product.
`
`'
`
`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 a_ny 9% of the active moieties in the drug
`product? If, for example, the combination contains one never-before—approved active moiety and
`one previously approved activemoiety, answer "yes." (An activemoiety that is marketed under an
`OTC monograph, but that was never approved under an NDA, is considered not previously
`approved.)
`E]
`D
`If"yes," identify the approved drug product(s) containing the active moiety, and, ifknown, the NDA
`#(s).
`-
`.
`
`YES
`
`NO
`
`NDA#
`
`NDA#
`
`NDA#
`
`IF THE ANSWER TO QUESTION 1 OR 2 UNDER PART H IS "NO," GO DIRECTLY TO THE
`SIGNATURE BLOCKS ON PAGE 8. (Caution: The questions in part H of the summary should
`only be answered “NO” for original approvals of new molecular entities.)
`IF “YES,” GO TO PART 1]].
`
`PART III
`
`THREE-YEAR EXCLUSIVITY FOR NDAs AND SUPPLEMENTS
`
`To qualify for three years ofexclusivity, an application or supplement must contain "reports ofnew
`clinical investigations (other than bioavailability studies) essential to the approval ofthe application
`and conducted or sponsored by the applicant." This section should be completed only ifthe answer
`to PART 11, Question 1 or 2 was "yes."
`
`1. Does the application contain reports ofclinical 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). Ifthe answer to 3(a)
`is "yes" for any investigation referred to in another application, do not complete remainder of
`
`Page 3
`
`

`

`summary for that investigation.
`
`YES El
`
`NO [I
`
`IF "NO," GO DIRECTLY TO THE SIGNATURE BLOCKS ON PAGE 8.
`
`2. A clinical investigation is "essential to the approval" ifthe 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 ofwhat'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 ofpreviously 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 El
`
`NOD
`
`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:
`
`(b) Did the applicant submit a list ofpublished studies relevant to the safety and effectiveness
`ofthis drugproduct and a statement that the publicly available data would not independently
`support approval of the application?
`
`YES 1:]
`
`NO 1:]
`
`(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.
`
`YESEI
`
`NOE]
`
`If yes, explain:
`
`(2) Ifthe answer to 2(b) is "no," are you aware ofpublished 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?
`
`YES 1:]
`
`NO 1:!
`
`Page 4
`
`

`

`If yes, explain:
`
`(c)
`
`Ifthe answers to (b)( l) and (b)(2) were both "no," identify the clinical investigations
`submitted in the application that are essential to the approval:
`
`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 ofanother 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.")
`
`Investigation #1
`
`Investigation #2
`
`YES I:
`
`NO El
`
`.
`
`YES 1:]
`
`NO El
`
`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?
`
`Investigation #1
`
`Investigation #2
`
`YES [:1
`
`NO El
`
`YES E]
`
`NO [:1
`
`Page 5
`
`

`

`If you have answered "yes" for one or more/investigation, identify the NDA in which a
`similar investigation was relied on:
`'
`
`c) Ifthe answers to 3(a) and 3(b) are no, identify each "new" investigation in the application
`or supplement that is essential to the approval (i.e., the investigations listed in #2(c), less any
`that are not "new"):
`
`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 ofthe 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.
`'
`
`a) For each investigation identified in response to question 3(0): if the investigation was
`carried out under an 1ND, was the applicant identified on the FDA 1571 as the sponsor?
`
`!
`!
`
`1 NO E]
`' Explain‘
`
`! !
`
`! NO El
`! Explain:
`
`Investigation #1
`-
`
`IND #
`
`YES 1:]
`
`Investigation #2
`
`,
`
`1ND#
`
`YES [:|
`
`(b) For‘each investigation not carried out under an 1ND 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?
`
`Page 6
`
`

`

`zo 1:]
`.
`. Explain:
`
`! !
`
`1 NO 1:!
`! Explain:
`
`Investigation #1
`
`YES E]
`Explain:
`
`Investigation #2
`
`YES E]
`Explain:
`
`(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?
`(Purchased studies may not be used as the basis for exclusivity. However, ifall 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.)
`
`YEslj
`
`iNoEII
`
`If yes, explain:
`
`
`
`Name of person completing form: Frank Cross
`Title: Project Manager
`Date: March 19, 2008
`
`Name of Office/Division Director signing form: Robert Justice, M.D.
`Title: Division Director
`
`Form OGD-011347; Revised 05/10/2004; formatted 2/15/05
`
`Page 7
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/S/
`
`Robert Justice
`
`3/20/2008 10:12:25 AM
`
`

`

`PEDIATRIC PAGE
`(Complete for all filed original applications and efficacy supplements)
`
`NDA/BLA # :
`
`22-249
`
`I
`
`Supplement Type (e.g. SE5):
`
`Supplement Number:
`
`Stamp Datezi 9-20-07
`
`PDUFA Goal Date: 3-20-08
`
`HFD -150
`
`Trade and generic names/dosage form: Treanda' {bendamustine HCl) inj
`
`Applicant: Ce halon 5010100 ' , '1 Therapeutic Class:
`
`
`
`
`
`
`
`
`
`
`
`plication provide for new active ingredient(s), new indication(s), new dosage form, new dosing regimen, or new
`Does this
`route of _ dministration? *
`,
`Yes. Please proceed to the next question.
`V D. No PREA does not apply. Skip to signature block.
`
`* SE5, SE6, and SE7 sabmissi'ons may also trigger PREA. Ifthere are questions, please contact the. Rosemary Addy or: Grace Carmouze.‘
`
`Indication(s) previously approved. (please complete this section for supplements only):
`_
`'
`Each indication covered by current application under review must have pediatric studies: Completed, Deferred, and/or Waived.
`
`Number of indications for this application(s):
`
`1
`
`Indication #1:
`
`CLL
`
`Is this an orphan indication?
`
`D/Yes; PREA does not apply. Skip to signature block.
`
`E! No. Please proceed to the next question.
`
`Is there a full waiver for this indication (check one)?
`
`El Yes: Please proceed to Section A.
`
`D .No: Please check all that apply:
`
`Partial Waiver
`
`Deferred
`
`Completed
`
`NOTE: More than one may apply
`
`Please proceed to Section B, Section C, and/or Section ‘D and complete as necessary.
`
` Section A: Fully Waived Studies
`
`Reason(s) for full waiver:
`
`Products in this class ‘for this indication have been studied/labeled for pediatric population
`Disease/condition does not exist in children
`
`UCIDUU
`
`Too few children with disease to study
`There are safety concerns
`Other:
`
`Ifstudies arefully waived, then pediatric information is. completefiJr this indication. Ifthere is another indication, please see
`Attachment A. Otherwise, this Pediatric Page is complete and should be entered into DFS.
`
`

`

`NDA ##W
`
`Page 2
`
`'
`
`Section B: Partially Waived Studies
`
`Age/weight range being partially waived (fill in applicable criteria below):
`
`kg
`Min
`kg
`,
`Max .
`_Reason(s) for partial waiver:
`
`mo.
`mo.
`
`yr.
`yr.
`
`Tanner Stage
`Tanner Stage
`
`Products in this class for this indication have been studied/labeled for pediatric population
`Disease/condition does not exist in children
`Too few children with disease to study
`There are safety concerns
`
`Adult studies ready for approval.
`Formulation needed
`Other.
`
`.ananub
`
`- Lfstudies aredeferred, proceed to Section C. Ifstudies are completed,proceed to SectionD. Otherwise, this Pediatric Pageis
`completeandshould be entered intoDFS
`'
`~
`~
`Section C: Deferred Studies
`
`Age/weight range being. deferred (fill in applicable criteria below):
`
`I Min »
`Max'
`
`kg
`kg .
`
`mo. A
`mo.
`
`yr.
`yr.
`
`Tanner Stage
`Tanner Stage
`
`Reason(s) for deferral:
`
`El Products in this class for this indication have been studied/labeled for pediatric population
`CI Disease/condition does not exist in children
`El Too fewchildren with disease to study
`[I ' There are safety concerns
`I
`CI Adult studies ready for approval
`Cl Formulation needed
`Othezr
`
`' Date studies are due (mm/dd/yy):
`
`Ifstudies are completed, proceed to Section D. Otherwise, this Pediatric Page is complete and should be entered into DFS.
`
`. S
`
`ection D: Completed Studies
`
`Age/weight range of completed studies (fill in applicable criteria below):
`
`Min
`Max
`
`kg
`kg .
`
`‘ mo.
`mo.
`
`yr.
`yr.
`
`
`Tanner Stage
`Tanner Stage
`
`Comments:
`
`Ifthere are additional indications, please proceed to Attachment A. Otherwise, this Pediatric Page is complete and should be entered
`into DFS.
`
`

`

`NBA ##4##
`
`Page 3
`
`' This page was completed by:
`i
`
`
`
`
`
`< ~: :1 ~3::s.=.-*-: ,- ~ ans”:-
`
`Dotti Pease, Regulatory Project Manager
`
`FOR- QUESTIONS ON COMPLETING THIS FORM CONTACT THE 55' ‘3'"?
`
`v
`
`3
`
`3"
`
`. (Revised: 10/10/2006)
`
`

`

`NDA new
`
`Page 4
`
`(This attachment is to be completed for those applications with multiple indications only.)
`
`Attachment A
`
`Indication #2:
`
`Is this an orphan indication?
`
`El Yes. PREA does not apply. Skip to signature block.
`D No. Please proceed to the next question.
`.
`
`ls therea full waiver for this indication (check one)?
`
`El Yes: Please proceed to Section‘A,
`
`Completed
`Deferred
`' Partial Waiver
`El No: Please check allv‘that apply:
`'
`’
`'
`'
`'
`. NOTE: More than one may apply
`Please proceed to Section .B’ Section .C, and/or Section D and-complete as necessary.
`
`‘
`
` Section A: Fully Waived Studies
`
`Reason(s) for full Waiver:
`
`D Products in this class for this indication have been studied/labeled for pediatric population
`D Disease/condition does not exist in children
`
`El Too few children with disease to study
`Cl There are safety concerns
`D Other:
`
`‘Ifstudies arefixlly waiv'ed, then pediatric information is completefor this indication. Ifthere' is another indication, please see
`Attachment A. Otherwise, this Pediatric Page is complete and should be entered into DFS.
`
` Section B: Partially Waived Studies
`
`Age/Weight range being partially waivedv(fill in applicable criteria below)::
`
`Min
`Max
`
`kg
`kg
`
`mo.
`mo.
`
`'
`
`yr.
`yr.
`
`Tanner Stage
`Tanner Stage
`
`Reason(s) for partial waiver:
`
`[3000000
`
`Products in this class for this indication have been studied/labeled for pediatric population
`Disease/condition does not exist in children
`Too few children with disease to study
`There are safety concerns
`Adult studies ready for approval
`Formulation needed
`Other:
`
`1
`
`Ifstudies are deferred, proceed to Section C. Ifstudies are completed, proceed to Section D. Otherwise, this Pediatric Page is
`
`

`

`NDA ##W
`
`Page 5
`
`complete and should be entered into DFS.
`
`Section C: Deferred Studies
`
`Age/weight range being deferred (fill in applicable criteria below)::
`
`Min
`_ Max
`
`V kg'
`kg.
`
`_
`
`Reason(s_) for deferral:
`
`-mo.
`mo.
`
`yr.
`yr.
`
`Tanner Stage
`Tanner Stage
`
`DBDDDUD
`
`Products in this class for this indication have been studied/labeled for pediatric population
`._'DiseaSe/condition does. not exist in children
`Too few children with disease to study
`There are safety concerns .
`Adult studies ready for approval
`“Formulation needed ‘
`'
`Other:
`
`Date studies are due (mm/dd/yy):
`
`
`
`~ Ifstudies are completed,- proceed to Section D. Otherwise, this Pediatric Page is complete and should be entered into DFS.
`
` Section D: Completed Studies
`
`
`Age/weight range of completed studies (fill in applicable criteria below):
`
`Min
`' Max
`
`'
`
`V
`
`kg
`kg .
`
`-
`
`-
`
`mo.
`mo.
`
`_ yr.
`yr.
`
`' Tanner Stage
`
`Tanner Stage
`
`Comments;
`
`' Ifthere are additional indications, please copy thefields above and completepediatric information as directed. Ifthereare no
`other indications, this Pediatric Page is complete and should be entered into DFS.
`
`This page 'was completed by:
`
`m.“
`
`Regulatory Project Manager
`
`FOR QUESTIONS ON COMPLETING THIS FORM CONTACT THE
`
`(Revised: 10/10/2006)
`
`

`

`This'Is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/S/
`
`Dotti-Pease
`1/25/2008 02:45:37 PM
`
`

`

`Cephaton®
`NDA 22-249
`Bendamustine h drochloride CEP-18083
`
`l
`
`CONFIDENTIAL
`
`Debarrnent Certification
`
`Debarment Certification
`
`Cephalon, Inc. hereby certifies that it did not and will not use in any capacity the services
`of any person debarred under Section 306 of the Federal Food, Drug, and Cosmetic Act
`in connection with this application.
`
`[
`
`~ //1/’/ Mm,
`
`
`Carol S. Marchione
`
`Senior Director and Group Leader
`Regulatory Affairs
`Cephalon, Inc.
`
`$4,127! 740 Z
`
`Date
`
`

`

`ACTION PACKAGE CHECKLIST
`
`BLA STN#
`
`NDA Supplement #
`
`IfNDA, Efficacy Supplement Type
`
`Established Name: bendamustine hydrochloride
`Dosage Form:
`for injection
`
`Applicant: Cephalon, Inc.
`
`‘
`NDAs:
`NDA Application Type: C] 505(b)(1) X 505(b)(2)
`Efficacy Supplement:
`CI 505(b)(l) E] 505(b)(2)
`
`,
`
`505(b)(2) NDAs and 505(b)(2) NDA supplements:
`Listed drug(s) referred to in 505(b)(2) application (NDA #(s), Drug
`name(s)):
`
`(A supplement can be either a (b)(1) or a (b)(2) regardless
`of whether the original NDA was a (b)(l) or a (b)(2).
`Consult page 1 ofthe NDA Regulatory Filing Review for
`this application or Appendix A to this Action Package
`Cheeklist‘)
`
`'
`
`Published literature on reproductive toxicity ofbendamustine.
`’
`'
`Provide a briefexplanation ofhow this product is different from the
`listed drug. Same compound.
`
`
`
`C] Ifno listed drug, check here and explain:
`
`Review and confirm the information previously provided in
`Appendix B to the Regulatory Filing Review. Use this Checklist to
`update any information (including patent certification
`information) that is no longer correct.
`'
`
`XConfinned
`Date: 3/19/08
`
`D Corrected
`
`User Fee Goal Date
`Action Goal Date (if different)
`
`Advertising (approvals only)
`Note: If accelerated approval (21 CFR 314.510/601.41), advertising must have been
`submitted and reviewed (indicate dates ofreviews)
`
`Version: 7/ 1 2/06
`
`

`

`Page 2
`
`Application Characteristics
`
`6 v
`
`1:] Standard E Priority
`Review priority:
`Chemical classification (new NDAs only):
`
`NDAs, BLAs and Supplements;
`Cl Fast Track
`CI Rolling Review
`E] CMA Pilot 1
`[I CMA Pilot 2
`
`X Orphan drug designation
`
`NDAs: SubpartlH
`D Accelerated approval (21 CFR 314.510)
`1] Restricted distribution (21 CFR 314.520)
`Subpart I
`C] Approval based on animal studies
`
`BLAs: Subpart E
`'
`D Accelerated approval (21 CFR 601.41)
`D Restricted distribution (21 CFR 601.42)
`Subpart H
`D Approval based on animal studies
`
`NDAs and NDA Supplements:
`D OTC drug
`'
`
`Other:
`
`Other comments:
`
`'3‘ Application Integrity Policy (AIP)
`
`0 Applicant is on the AIP
`
`0
`
`This application is on the'AIP
`
`0
`
`Exception for review (file Center Director’s memo in Administrative
`- Documents section)
`
`Yes
`
`B
`
`D
`
`
`
`0 OC clearance for approval (file communication in Administrative
`.
`Documents section)
`¢
`‘3 Public communications (approvals only)
`
`0 Office of Executive Programs (OEP) liaison has been notified of action
`X Yes D No
`‘
`0
`Press Office notified of action
`X Yes D No
`
`1:] None
`X FDA Press Release
`
`Not an AP action
`
`0.
`
`Indicate what types (if any) of information dissemination are anticipated
`’
`‘
`
`[:1 FDA Talk Paper
`[:1 CDER Q&As
`X Other - Burst
`
`Version: 7/12/2006
`
`

`

`Page 3
`O
`2‘ Exclus'ivity
`0 NDAs: Exclusivity Summary (approvals only) (file Summa; in Administrative
`
`'
`
`,-
`
` 0
`
`Is approval of this application blocked by any type of exclusivity?
`
`Documents section) X Included
`
`
`0 NDAs/BLAs: Is there existing orphan drug exclusivity for the “same” drug
`or biologic for the proposed indication(s)? Refer to 21 CFR 3I 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 usedfar NDA chemical classification.
`
`0 NDAS: Is there remaining 5-year exclusivity that would bar effective
`approval of a 505(b)(2) application? (Note that, even ifexclusivity remains,
`the application may be tentatively approved ifit is otherwise readyfi)r
`approval.)
`
`0
`
`NDAs:‘ Is there remaining3-year eX'clusivity that would bar effective
`approval of a 505(b)(2) application? (Note that, even ifexclusivity remains,
`the application may be tentatively approved ifit is otherwise readyfor
`approval.)
`.-
`
`0 NDAs: Is there remaining 6-month pediatric exclusivity that would bar
`effective approval of a 505(b)(2) application? (Note that, even ifexclusivity
`remains, the application may be tentatively approved ifit is otherwise ready
`for approval.)
`
`and
`
` X No i D Yes
`If, yes, NDA/BLA #
`
`
`date exclusivity expires:
`
`
`
`X No
`D Yes
`If yes, NDA #
`
`
`
`exclusivity expires:
`
`
`X No
`El Yes
`If yes, NDA #
`'
`
`exclusivity expires:
`
`C] Yes _
`X No
`If yes, NDA #
`
`
`‘ exclusivity expires:
`
`and date
`
`
`
`.9
`Patent Information (NDAs and NDA supplements only)
`0
`Patent Information:
`
`'\»a/'
`
`Verify that form FDA-3542a 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.
`
`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.
`
`X Verified
`
`D Not applicable because drug is
`
`
`
`an old antibiotic.
`CI Verified
` 21 CFR 3 14.50(i)( 1)
`
`
`
`
`[505(b)(2) applications] If the application includes a paragraph III certification,
`
`it cannot be approved until 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
`patent(s) is invalid, unenforceable, or will not be infringed (review
`documentation of notification by applicant and documentation ofreceipt 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)).
`
` -
`
`21 CFR 314.50(i)(l)(i)(A)
`
`0
`
`0
`
`[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 infiingement litigation.
`
`Answer the following questions for each paragraph IV certification:
`Version: 7/ 1 22006
`
`X (ii) D (iii) Note: there is
`published literature on ‘
`reproductive toxicity of
`bendamustine
`.
`X No paragraph III certification
`Date patent will expire
`
`X N/A (no paragraph [V certification)
`
`[:1 Verified
`
`

`

`Page 4
`
`(1) Have 45 days passed since the patent owner’s receipt of the applicant’s
`notice of certification?
`
`D Yes
`
`
`
`(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 ‘ers, ” 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
`infiingement after receiving the applicant’s notice of certification, as
`provided for by 21 CFR 314.107(t)(3)?
`
`_
`
`DYes’
`
`If “Yes, ” there is no stay ofapproval based on this certification. Analyze the next
`paragraph IV certification in the application, ifany. Ifthere are no other
`paragraph IV certifications, skip to the next section below (Summary Reviews).
`
`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?
`
`D Yes
`
`(Note: This can be determined by confirming whether the Division has
`received a written notice ‘fiom 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))).
`
`If “No, ” the patent owner (or NDA holder, if it is an exclusive patent licensee)
`has until the expiration ofthe 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
`infiingement within the 45-day period described in question (1), as
`provided for by 21 CFR 314.107(t)(3)?
`
`[:1 Yes
`
`If “Yes, ” there is no stay ofapproval based on this certification. Analyze the next
`paragraph IV certification in the application. ifany. Ifthere are no other
`paragraph IV certifications, skip to the next section below (Summary Reviews).
`
`If “No, ” continue with question (5).
`
`(5) Did the patent owner, its representative, or the exclusive patent licensee
`bring suitlagainst the (b)(2) applicant for patent infringement within 45
`days of the patent owner’s receipt of the applicant’s notice of
`certification?
`
`C] Yes
`
`(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
`
`Version: 7/ l 2/2006
`
`

`

`Page 5
` . period (see 21 CFR 314.107(t)(2)). If no written notice appears in the
`NDA file, confirm with the applicant whether a lawsuit was commenced
`within the 45-day. period).
`
`Nip,
`
`..-,
`
`If “No, ” there is no stay ofapproval based on this certification. Analyze the
`next paragraph IVcertification in the application, ifany Ifthere are no other
`paragraph IVcertifications, 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 Director, Division ofRegulatory Policy II, Oflice
`_ ofRegulatory Policy (HFD—00 7) and attach a summary ofthe response.
`
` 0 Most recent division-proposed labeling (only if generated after latest applicant
`
`>
`
`}
`
`0 v
`
`0 Original applicant-proposed labeling
`0 Other relevant labeling (e.g., most recent 3 in class, class labeling), if applicable
`Patient Package Insert
`
`9/ 19/07
`
`
`
`0 Most-reCent division-proposed labeling (only if generated afier latest applicant
`
`A
`submission of labeling)
`
`0 Most recent applicant-proposed labeling (only if subsequent division labeling
`
`does not show a . . licant version)
`_ _
`0 Original applicant-proposed labeling
`'
`0
`Other. relevant labeling (e.g, most recent 3in class, class labeling), if applicable
` ‘30 Medication Guide
`
`
`0 Most recent division—proposed labeling (only if generated afier latest applicant
`submission of labeling)
`
`
`'Most recent applicant-proposed labeling (only—if subsequent division labeling
`
`
`
`does not show applicant version)
`'
`
`0 Original applicant-proposed labeling
`
`
`Other relevant labeling (e.g., most recent 3 in class, class labeling)
`
`
`‘3' Labels (full color carton and immediate—container labels)
`o Most-recent division-proposed labels (only if generated after latest applicant
`submission)_
`
`0 Most recent applicant-proposed labeling 3/ 13/08
`
`0
`
`Version: 7/12/2006
`
`3/7/08 (P/l‘); 3/19/08 (CMC)
`3/19/08 (Clin - DD);_3/20/08 (OD)
`
`-
`
`submission of labeling)
`0 Most recent applicant-proposed labeling (only if subsequent division labeling
`
`does not show applicant version)
`.
`
`-
`
`

`

`Page 6
`
`meetings)
`
`
`'1' Labeling reviews and minutes ofany labeling meetings (indicate dates ofreviews and
`
`X DMETS 3/10/08;3/18/08
`X DDMAC 3/3/08
`
`X SEALD 2/25/08
`
`Other reviews
`
`D Memos of Mtgs
`
`
`
`
`-
`21
`:5,
`_ Am
`mama-aca’ikma
`
`
`Administrative Reviews (RPM Filing Review/Memo ofFiling Meetmg; ADRA) (indicate
`
`
`date ofeach review)
`
`
`NDA and NDA supplement approvals only Exclusivity Summary (signed by Division
`Director)
`,
`
`
`
`02° AlP-related documents
`0
`Center Director’s Exception for Review memo
`
`
`
`
`0
`If AP: 0C clearance for approval
`
`
`1/25/08
`
`X Included '
`
`
`
`I
`
`X Included
`
`'3’ Pediatric Page (all actions)
`
`Debarment certification (original applications only): verified that qualifying language was
`not used1n certification and that certifications fi'om foreign applicants are cosigned by
`U.S agent. (Include certification.)
`
`Postmarketing Commitment Studies
`0 Outgoing Agency request for post—marketing commitments (zflocated elsewhere
`March 19, 2008, PMC Tab
`‘ acka e, state where located)
`'
`
`acceptable
`
` X Verified, statement is
`
`March 19, 2008, PMC Tab
`
`°:' Outgoing correspondence (letters including previous action letters, emails, faxes, telecons)
`
`0:0
`
`Internal memoranda, telecoms, email, etc.
`Minutes of Meetings
`
`Pre—Approval Safety Conference (indicate date; approvals only)
`2/28/08
`Pre—NDA/BLA meeting (indicate date)
`_
`—-
`C] No mtg
`April 12, 2007
`
`
`EOP2 meeting (indicate date).
`C] No mtg
`May 9, 2005
`-
`Other (e.g., EOP2a, CMC pilot programs)
`_
`
`1
`Advisory Committee Meeting
`X No AC meeting
`0 Date of Meeting
`
`Yes
`
`o
`
`48-hour alert or minutes, if available
`
`
`
`0:“ Reviews by other disciplines/divisions/Centers requested by CMC/product reviewer
`(indicate datefor each review)
`
`E] Categorical Exclusion (indicate review date)(all original applications and
`allegflicacy sugglements_that couldincrease the patientpopulation)___
`I D Review & FONSI (indicate date of review)
`0 Cl Review & Environmental Impact Statement (indicate date ofeach review)
`1
`
`
`'3‘ NDAs: Microbiology reviews (sterility & apyrogeiiicity) (indicatedate ofeach review)
`
`
`
`2/27/08
`
`10/18/07; 12/17/07; 2/6/2008
`
`1
`
`0
`
`Version: 7/12/2006
`
`

`

`Page 7
`
` L I
`[I Notaparenteralproduct'
`O
`_ 13' Facilities Review/Inspection
`‘
`Date completed: 3/18/08
`
`_
`
`~
`
`L ‘2‘ NDAs: Facilities inspections (include EER printout)
`
`X Acceptable
`
`E] Withhold recommendation
`
`
`O
`
`3‘ BLAs: Facility—Related Documents
`
`Facility review (indicate date(s))
` D Requested
`Compliance Status Check (approvals only, both original and supplemental
`C] Accepted
`applications) (indicate date completed, must be wi