CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`202570Orig1s000
`
`ADMINISTRATIVE and CORRESPONDENCE
`DOCUMENTS
`
`
`
`
`
`
`

`

`a) Is it a 505(b)(1), 505(b)(2) or efficacy supplement?
`
`
`
`
`
` YES
`
`
`
`If yes, what type? Specify 505(b)(1), 505(b)(2), SE1, SE2, SE3,SE4, SE5, SE6, SE7, SE8
`
`
`
`
`
`NO
`
`
`
`EXCLUSIVITY SUMMARY
`
`
`NDA # 202570
`
`
`
`
`
`SUPPL #
`
`
`
`
`
`HFD # 150
`
`Trade Name Xalkori Capsules, 200 mg and 250 mg.
`
`Generic Name crizotinib
`
`
`
`
`
`Applicant Name Pfizer Inc.
`
`Approval Date, If Known August 26, 2011
`
`
`
`
`
`
`
`PART I
`
`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.
`
`
`
`
`
`
`IS AN EXCLUSIVITY DETERMINATION NEEDED?
`
`505(b)(1)
`
`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.")
`
`
`
`
`
` YES
`
`
`
`NO
`
`
`
`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.
`
`
`
`
`
`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:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3005166
`
`Page 1
`
`

`

`d) Did the applicant request exclusivity?
`
`
`
`
`
` YES
`
`
`
`NO
`
`
`
`
`If the answer to (d) is "yes," how many years of exclusivity did the applicant request?
`
`
`5
`
`
`
`e) Has pediatric exclusivity been granted for this Active Moiety?
`
`
` YES
`
`
`
`NO
`
`
`
`
`
`
` 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?
`
`
`
`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
`
`
`
`NO
`
`
`
`
`
`If "yes," identify the approved drug product(s) containing the active moiety, and, if known, the NDA
`#(s).
`
`
`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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` YES
`
`
`
`NO
`
`
`
`
`
`
`
`
`
`Reference ID: 3005166
`
`Page 2
`
`

`

`NDA#
`
`
`
`NDA#
`
`
`
`NDA#
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`If "yes," identify the approved drug product(s) containing the active moiety, and, if known, the NDA
`#(s).
`
`NDA#
`NDA#
`NDA#
`
`
`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
`
`
`
`
`
`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 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.)
`
`YES
`
`
`
`NO
`
`
`
`
`
`
`
`
`
`
`
`THREE-YEAR EXCLUSIVITY FOR NDAs AND SUPPLEMENTS
`
`
`
`Reference ID: 3005166
`
`Page 3
`
`

`

`summary for that investigation.
`
`
`
`
`
`YES
`
`
`
`NO
`
`
`
`
`IF "NO," GO DIRECTLY TO THE SIGNATURE BLOCKS ON PAGE 8.
`
`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:
`
`
`
`NO
`
`
`
`
`
`
`
`
`
`(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?
`
`
` YES
`
`
`
`NO
`
`
`
`
`
`
`(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.
`
`
`
`
`
`
`
`
`
`
` YES
`
`
`
`NO
`
`
`
` If yes, explain:
`
`
`
`
`
`(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?
`
`
`
`
`
`
`
` If yes, explain:
`
`
`
`
`
` YES
`
`
`
`NO
`
`
`
`
`
`Reference ID: 3005166
`
`Page 4
`
`

`

`
`
`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.
`
`
`
`
`(c)
`
`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:
`
`
`
`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
`
`YES
`
`
`
`
`
`NO
`
`NO
`
`
`
`
`
`If you have answered "yes" for one or more investigations, identify each such investigation
`and the NDA in which each was relied upon:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Investigation #1
`
`Investigation #2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`YES
`
`YES
`
`
`
`
`
`NO
`
`NO
`
`
`
`
`
`
`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?
`
`
`
`
`
`
`
`
`If you have answered "yes" for one or more investigation, identify the NDA in which a
`
`
`
`Reference ID: 3005166
`
`Page 5
`
`

`

`
`
`
`
`
`
`similar investigation was relied on:
`
`
`
`c) If the 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 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.
`
`
`Investigation #1
`
`
`
`IND #
`
`
`
`
`
`
`
`
`
`YES
`
`
`Investigation #2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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:
`
`
`
`!
`!
`
`! NO
`! Explain:
`
`
`IND #
`
`
`
`
`
`
`
`
`
`
`
`
`
`(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?
`
`
`YES
`
`
`
`
`
`
`
`
`
`
`Investigation #1
`
`YES
`
`
`
`
`
`
`
`
`
`
`
`
`
`!
`!
`! NO
`
`
`
`
`
`Reference ID: 3005166
`
`Page 6
`
`

`

`
`
`Explain:
`
`
`
`Investigation #2
`
`
`YES
`Explain:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`! Explain:
`
`
`
`!
`!
`
`! NO
`! 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, 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.)
`
`
`
`
`
`
`YES
`
`
`
`NO
`
`
`
`If yes, explain:
`
`
`
`
`
`
`
`
`=================================================================
`
`Name of person completing form: Frank Cross
`Title: Chief, Project Management Staff
`Date: 8/23/11
`
`
`Name of Office/Division Director signing form: Robert L. Justice, M.D., M.S.
`Title: Director, Division of Drug Oncology Products
`
`
`
`Form OGD-011347; Revised 05/10/2004; formatted 2/15/05
`
`
`
`
`Reference ID: 3005166
`
`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/
`----------------------------------------------------
`
`DIANE C HANNER
`08/26/2011
`
`FRANK H CROSS
`08/26/2011
`
`ROBERT L JUSTICE
`08/26/2011
`
`Reference ID: 3005166
`
`

`

`Page 1 of 3
`
`Hanner, Diane
`
`From: Hanner, Diane
`Sent:
`Tuesday, August 23, 2011 12:09 PM
`To:
`'Domingo, Ron'
`Subject: RE: NDA 202570 IR
`
`Hi,
`I believe since we have deleted the IRR responses from the label that we will no longer need
`you to e-mail the tables.
`Regards,
`Diane
`
`
`
`
`
`From: Domingo, Ron [mailto:Ron.Domingo@pfizer.com]
`Sent: Tuesday, August 23, 2011 9:52 AM
`To: Hanner, Diane
`Subject: RE: NDA 202570 IR
`
`Hi Diane,
`
` 
`Do you still need us to email the IRR DR tables today?  Based on the FDA’s labeling feedback yesterday it seemed 
`as though it may not be needed anymore.  Please confirm.
`
` 
`Thanks,
`Ron
`
` 
`Ron Domingo, MS, RAC
`Worldwide Regulatory Strategy
`
`
`Global Research & Development
`La Jolla Laboratories, Pfizer Inc.
`10646 Science Center Drive (CB10)
`San Diego, CA 92121
`Phone: 858-622-3234
`Cell: 858-722-3065
`Fax: 877-481-0933
`Email: ron.domingo@pfizer.com
`
` 
`From: Hanner, Diane [mailto:Diane.Hanner@fda.hhs.gov]
`Sent: Monday, August 22, 2011 12:26 PM
`To: Domingo, Ron
`Subject: FW: NDA 202570 IR
`
`
`Hi,
`I was instructed to convey the following:
`
`It is acceptable to submit IRR duration of response information tomorrow.
`
`
`Reference ID: 3006555
`8/25/2011
`
`

`

`Page 2 of 3
`
`Regards,
`Diane
`
`
`
`From: Domingo, Ron [mailto:Ron.Domingo@pfizer.com]
`Sent: Monday, August 22, 2011 3:12 PM
`To: Hanner, Diane
`Subject: FW: NDA 202570 IR
`
`Hi Diane,
` 
`In response to your query below please see the attached files for studies 1001 and 1005.  This information will 
`be submitted to the NDA tomorrow.
`
` 
`Can you please confirm if the Agency still needs the IRR Duration of Response output?
`
` 
`Thanks,
`Ron
`
` 
`Ron Domingo, MS, RAC
`Worldwide Regulatory Strategy
`
`
`Global Research & Development
`La Jolla Laboratories, Pfizer Inc.
`10646 Science Center Drive (CB10)
`San Diego, CA 92121
`Phone: 858-622-3234
`Cell: 858-722-3065
`Fax: 877-481-0933
`Email: ron.domingo@pfizer.com
`
` 
`From: Hanner, Diane [mailto:Diane.Hanner@fda.hhs.gov]
`Sent: Monday, August 22, 2011 10:38 AM
`To: Domingo, Ron
`Subject: NDA 202570 IR
`Importance: High
`
`
`
`Hi,
`Please address the following Information Request regarding NDA 202570:
`
`
`Patients who are not evaluable for IRR due to missing scans should be included in
`response rate calculation. IRR response rate should be based on 136 treated patients.
`We note that the patient (ID 11051040), who was not response-evaluable by investigator,
`was included in the 128 IRR response-evaluable population.
`
`
`Please submit IRR response rate with 95% CI and response duration for both studies by
`3:00pm today.
`
`
`Please submit SAS dataset for IRR response data including response duration for both
`studies by COB August 23, 2011.
`
`
`
`Reference ID: 3006555
`8/25/2011
`
`

`

`Page 3 of 3
`
`Thank you.
`Regards,
`Diane
`
`
`CDR Diane Hanner
`Senior Program Management Officer
`FDA/CDER/OODP/DDOP
`10903 New Hampshire Avenue
`Bldg. 22/Room 2119
`Silver Spring, Maryland 20993
`(301) 796-2330
`FAX (301) 796-9845
`E-mail: diane.hanner@fda.hhs.gov
`
`
`
`
`Reference ID: 3006555
`8/25/2011
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DIANE C HANNER
`08/25/2011
`
`Reference ID: 3006555
`
`

`

`FOOD AND DRUG ADMINISTRATION
`
`____________________________________________________
`
`
`
`Meeting Date and Time:
`Meeting Type:
`Meeting Category:
`Meeting Location:
`
`
`Application Number:
`
`Product Name:
`
`
`Received Briefing Package
`Sponsor Name:
`
`
`Meeting Requestor:
`Meeting Chair:
`Meeting Recorder:
`
`August 22, 2011 3:30 p.m.
`Teleconference
` N/A
`Bldg. 22, Room 2376
`NDA 202570
`Crizotinib
`N/A
`Dr. Udayan Guha (SGE)
`CDR Diane Hanner
`Shakun Malik, M.D., Medical Officer, DDOP
`CDR Diane Hanner, Senior Program Management Officer,
`DDOP
`
`
`Meeting Attendees:
`Attendee from NIH
`• Udayan Guha, M.D.
`FDA Attendees
`• Robert Justice, M.D., M.S., Director DDOP
`• Anthony J. Murgo, M.D., M.S., FACP., Associate Director for Regulatory Science
`• Shakun Malik, M.D., Ph.D., Medical Officer
`• CDR Diane Hanner, M.P.H., M.S.W., Senior Program Management Officer, DDOP
`BACKGROUND
`Pfizer originally submitted NDA 202570 to the Division of Oncology Drug Products for NSCLC on
`March 30, 2011. On August 22, 2011, the Division of Oncology Drug Products and Dr. Guha Special
`Government Employee (SGE), held a teleconference to discuss his advice regarding his consultative
`review of crizotinib.
`
`
`
`
`
`
`Reference ID: 3005159
`
`

`

`
`
`Confidential
`
`Division of Drug Oncology Products- SGE meeting
`NDA 202570
`
`
`
`
`
`
`DISCUSSION:
`
`FDA solicited the advice from the consultants regarding the following:
`
`FDA asked Dr. Udayan Guha to discuss the benefit: risk ratio of crizotinib for the treatment of patients
`with locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC) based on
`response rate and the toxicities noted in two single arm nonrandomized clinical trials.
`Dr. Guha responded that based on the ORR and the toxicities presented in the two single arm
`nonrandomized studies, the benefit/risk ratio of crizotinib for the treatment of locally advanced or
`metastatic ALK rearrangement-positive NSCLC is favorable. However, the existing randomized Phase
`III trials will eventually demonstrate whether crizotinib will be beneficial to current standard of care.
`At this time there is no treatment available that is specific to the ALK rearranged patients.
`An ORR of more than 40% is a significant improvement to current treatments available.
`He was however, concerned about the standardization of the diagnostic test. The FDA responded that
`we at the OODP believe that the test will be readily available to the community physicians soon after
`the approval. We will confirm this after consulting with the CDRH team and then convey it to Dr
`Guha.
`Dr Guha believed that he as a physician will not have any hesitations in using Crizotinib as first line
`therapy in patients who are found to have ALK positive NSCLC unless they fit in a clinical trial. He
`believed that the toxicity profile and the high response rate is clinically meaningful in these patients.
`
`Reference ID: 3005159
`
`Page 2 of 2
` Meeting Minutes
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DIANE C HANNER
`08/23/2011
`
`SHAKUNTALA M MALIK
`08/23/2011
`
`Reference ID: 3005159
`
`

`

`FOOD AND DRUG ADMINISTRATION
`
`____________________________________________________
`
`
`
`August 19, 2011 12:00 p.m.
`Teleconference
` N/A
`Bldg. 22, Room 2376
`NDA 202570
`Crizotinib
`N/A
`Dr. Wyndaham Wilson (SGE)
`Diane Hanner
`Shakun Malik, M.D., Medical Officer, DDOP
`Diane Hanner, Senior Program Management Officer, DDOP
`
`
`Meeting Date and Time:
`Meeting Type:
`Meeting Category:
`Meeting Location:
`
`
`Application Number:
`
`Product Name:
`
`
`Received Briefing Package
`Sponsor Name:
`
`
`Meeting Requestor:
`Meeting Chair:
`Meeting Recorder:
`Meeting Attendees:
`Attendee from NIH
`• Wyndaham Wilson, M.D.
`FDA Attendees
`• Richard Pazdur, M.D., Office Director, OODP
`• Robert Justice, M.D., M.S., Director DDOP
`• Shakun Malik, M.D., Ph.D., Medical Officer
`• Diane Hanner, M.P.H., M.S.W., Senior Program Management Officer, DDOP
`BACKGROUND
`Pfizer originally submitted NDA 202570 to the Division of Oncology Drug Products for NSCLC on
`March 30, 2011. On August 19, 2011, the Division of Oncology Drug Products and Dr. Wilson,
`Special Government Employee (SGE), held a teleconference to discuss his advice regarding his
`consultative review of crizotinib.
`
`
`
`
`
`
`
`Reference ID: 3003626
`
`

`

`
`
`Confidential
`
`Division of Drug Oncology Products- SGE meeting
`NDA 202570
`
`
`
`
`
`DISCUSSION:
`
`FDA solicited the advice from the consultants regarding the following:
`
`FDA asked Dr. Wilson to discuss the benefit: risk ratio of crizotinib for the treatment of patients with
`locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC) based on response
`rate and the toxicities noted in two single arm nonrandomized clinical trials.
`
`Dr. Wilson responded that the response rate (50% - 61%), and the duration of response in patients with
`locally advanced or metastatic ALK-positive NSCLC, treated with crizotinib is clinically meaningful.
`Therefore, I support accelerated approval of crizotinib.
`
`The toxicity spectrum is a bit worrisome especially pneumonitis, vision disorders and hepatic
`toxicities. However, it is not possible to differentiate if pneumonitis was caused by the underlying lung
`cancer or if it was drug related. Most of the liver and visual toxicities noted were reversible.
`
`
`Reference ID: 3003626
`
`Page 2 of 2
` Meeting Minutes
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DIANE C HANNER
`08/22/2011
`
`SHAKUNTALA M MALIK
`08/22/2011
`
`Reference ID: 3003626
`
`

`

`Page 1 of 1
`
`Hanner, Diane
`
`From:
`Hanner, Diane
`Sent:
`Friday, August 12, 2011 10:13 AM
`To:
`'Domingo, Ron'
`Subject:
`FDA response regarding NDA 202570
`Follow Up Flag: Follow up
`Flag Status:
`Red
`
`Hi,
`I have been instructed to convey the following regarding NDA 202570:
`
`
`You plan to accrue 20 patients with ALK negative NSCLC (the majority of patients with lung cancer) over a 33
`month period. Given the RR demonstrated in the 23 patients with ALK negative NSCLC treated with crizotinib, we
`do not think it will be difficult to recruit these patients. From your previous response, the reason for this long
`period of accrual is unclear. Please state the number of sites that will conduct this protocol, the number of patients
`with ALK negative NSCLC seen at those sites each month, and the number of patients that are estimated to
`participate in this trial. Please reply by Friday, August 12.
`
`
`Regards,
`Diane
`
`Reference ID: 3006550
`8/25/2011
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DIANE C HANNER
`08/25/2011
`
`Reference ID: 3006550
`
`

`

`Hanner, Diane
`
`From:
`Sent:
`To:
`Subject:
`
`Hanner, Diane
`Thursday, August 18, 2011 2:56 PM
`'Domingo, Ron'
`Label revisions regarding NDA 202570
`
`Attachments:
`
`Crizotinib USPI_FDA comments 8-3-11 and 8-11-11_final tracked.doc
`
`Hi,
`Please click on the attachment and view the latest version of the Crizotinib (NDA 202570) label.
`
`I need you to pay particular attention to the following regarding the attached label changes located in
`Section 6; Table 3:
`
`"Please revise the table to include treatment emergent as well as treatment adverse reactions in
`more than 10% of patients all grades as well grades 3 and 4."
`
`Please let me know if you have any questions and please send back the final label by c.o.b. Friday,
`8/19, tomorrow. Also, please remember to send me a clean and tracked version of the label.
`
`Regards,
`Diane
`
`Crizotinib
`_FDA commen
`
`Reference ID: 3006551
`
`1
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DIANE C HANNER
`08/25/2011
`
`Reference ID: 3006551
`
`

`

`Page 1 of 3
`
`Hanner, Diane
`
`From: Hanner, Diane
`Sent:
`Thursday, August 11, 2011 3:14 PM
`To:
`'Domingo, Ron'
`Subject: RE: FDA clarifications regarding PMRs
`
`Hi,
`CDER would like an explanation for why the timeline for their ELK negative PER (two years of
`accrual) is so long? Also, please clarify where the ELK testing would be taking place.
`Thank you.
`Regards,
`Diane
`
`
`From: Domingo, Ron [mailto:Ron.Domingo@pfizer.com]
`Sent: Thursday, August 11, 2011 9:48 AM
`To: Hanner, Diane
`Subject: RE: FDA clarifications regarding PMRs
`
`Dear Diane,
`
` 
`Please see the attached document for our responses to the queries received on August 9, 2011.  This 
`information will be submitted to the NDA later today.  Please contact me if you have any questions.
`
` 
`Regards,
`Ron
`
` 
`Ron Domingo, MS, RAC
`Worldwide Regulatory Strategy
`
`
`Global Research & Development
`La Jolla Laboratories, Pfizer Inc.
`10646 Science Center Drive (CB10)
`San Diego, CA 92121
`Phone: 858-622-3234
`Cell: 858-722-3065
`Fax: 877-481-0933
`Email: ron.domingo@pfizer.com
`
` 
`From: Hanner, Diane [mailto:Diane.Hanner@fda.hhs.gov]
`Sent: Monday, August 08, 2011 7:08 AM
`To: Domingo, Ron
`Subject: FW: FDA clarifications regarding PMRs
`Importance: High
`
`
`Please verify that you have received this e-mail.
`Thanks.
`Diane
`
`______________________________________________
`ne
`
`Reference ID: 3001449
`8/16/2011
`
`

`

`Page 2 of 3
`
`ust 08, 2011 10:07 AM
`'
`arifications regarding PMRs
`Hi,
`
`
`Per your August 03, 2011, request regarding the clinical pharamcology PMRs, FDA has the following
`clarifications:
`PMR 2. Conduct a multiple dose trial in humans to determine how to adjust the crizotinib dose
`when it is coadministered with a strong CYP3A inhibitor (e.g., ketoconazole).
`PMR 3. Conduct a multiple dose trial in humans to determine how to adjust the crizotinib dose
`when it is coadministered with a strong CYP3A inducer (e.g., rifampin).
`Applicant’s response to PMR 2 and 3:
`Due to the likely difficulties associated with the conduct of the proposed studies, Pfizer would like to
`discuss the trials with the FDA. The conduct of multipledose studies in healthy volunteers is not feasible
`due to crizotinib’s adverse event profile. Additionally, performing multiple-dose CYP3A inhibition and
`induction studies in cancer patients will be very difficult to recruit and complete. The conduct of
`multiple-dose CYP3A inhibition and induction studies in ALK-positive NSCLC patients poses concerns
`with regards to the possibility of sub-therapeutic and supratherapeutic crizotinib exposures. As the
`proposed USPI advises patients to avoid the concomitant use of crizotinib with strong CYP3A inhibitors
`or inducers, Pfizer does not believe that formal drug-drug interaction studies would be necessary.
`Please provide more clarity on the population in which the Agency proposes that Pfizer conduct these
`CYP3A drug interaction trials. Additionally, please provide the draft labeling sections related to the
`CYP3A inhibitors/inducers so that we can consider the FDA’s request in light of the marked-up product
`label.
`FDA clarification:
`We agree with you that strong CYP3A inducers and inhibitors should be avoided at this time. However,
`in order to determine the dose adjustments in patients who have to take crizotinib with CYP3A inducers
`or inhibitors, a multiple dose trial with a strong CYP3A inducer (e.g., rifampin) or a strong CYP3A
`inhibitor (e.g., ketoconazole) must be conducted in patients with cancers. We recommend that you use
`PBPK modeling and simulations (or other useful tools) and real-time PK to help the study design and
`conduct so that the exposure can be matched in the test condition to that in the reference condition (250
`mg BID without coadministration of strong CYP3A inhibitors or inducers).
`Draft labeling language will be available after August 11, 2011.
`PMR 6. Conduct a multiple dose trial in humans to determine how to dose crizotinib with regard
`to gastric pH elevating agents (i.e., a proton-pump inhibitor, an H2-receptor antagoist, and an
`antacid).
`Applicant Response:
`Pfizer does not believe it is possible to conduct a multiple-dose study in healthy volunteers due to
`crizotinib’s adverse event profile. Pfizer believes that a popPK/PD approach would be a proper
`alternative to evaluate how to dose crizotinib with regard to gastric pH elevating agents.
`Please provide clarity on the population in which the Agency proposes that Pfizer conduct this trial with
`a pH-elevating agent. Additionally, please provide the draft labeling sections related to to pH-elevating
`agents so that we can consider the FDA’s request in light of the marked-up product label.
`FDA clarification:
`This multiple dose trial should be conducted in patients with cancers to explicitly determine how to dose
`
`Reference ID: 3001449
`8/16/2011
`
`

`

`Page 3 of 3
`
`crizotinib with regard to gastric pH elevating agents. Single dose trial in healthy subjects or a population
`PK/PD approach may not provide explicit conclusions on the dosing strategies with regard to gastric pH
`elevating agents, though they may provide helpful information on the study design of the multiple dose
`trial in patients with cancers.
`Draft labeling language will be available after August 11, 2011.
`
`
`Regards,
`Diane
`
`
`
`Reference ID: 3001449
`8/16/2011
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DIANE C HANNER
`08/16/2011
`
`Reference ID: 3001449
`
`

`

`Page 1 of 2
`
`Hanner, Diane
`
`From: Hanner, Diane
`Sent:
`Thursday, August 11, 2011 2:34 PM
`To:
`'Domingo, Ron'
`Subject: FW: NDA 202570- Crizotinib
`
`Hi,
`
`
`Below is the FDA response to your inquiry regarding the rationale for changing the Pregnancy
`Category from
` to D.
`
`
`Pregnancy Category D was considered appropriate for this drug for the following reasons:
`(cid:122) Positive findings of post-implantation loss and low fetal weight in animals at exposures sim