U. S. Regulatory Actions and Marketing History
13.3.3.3. Appendix
Table 59. Summary of Baseline Demographic Information (Categorical) in the PPK Dataset.
Property Type Count % Property Type Count %
* Renal Impairment
Normal 553 93.4
# Hepatic Impairment
Normal 462 78
Mild 33 5.6 Mild 124 20.9
Moderate 3 0.5 Moderate 4 0.7
Missing 3 0.5 Severe 1 0.2
Cancer Type
Healthy Volunteer 200 33.8 Missing 1 0.2
Breast Cancer 307 51.9
Race
American Indian / Alaska Native 2 0.3
Colorectal Cancer 21 3.5 Asian 141 23.8
Gastric Cancer 2 0.3 Black for African American 61 10.3
Glioblastoma Cancer 4 0.7 Hispanic 4 0.7
HNSCC 1 0.2 Pacific Islander 5 0.8
NSCLC 39 6.6 Other Multi-racial 2 0.3
Ovarian Cancer 6 1 Unknown 13 2.2
Pancreatic Cancer 2 0.3 White 364 61.5
Renal Cancer 3 0.5 Sex Female 369 62.3
Other 7 1.4 Male 223 37.7
* Renal Impairment: defined by BSA-indexed creatinine clearance, as Normal (> 60 mL/min), Mild ([40, 60) mL/min), Moderate (([20, 40) mL/min), and Missing.
# Hepatic Impairment: defined as Normal (Bili ≤ ULN & AST ≤ ULN), Mild (Bili ≤ ULN & AST ≥ ULN, or, 1x ULN < Bili <
1.5x ULN), Moderate (1.5x ULN < Bili < 3x ULN), Severe (Bili >3x ULN), and Missing.
Source: POPPK report: an update, Table 4
Table 60. Summary of Baseline Demographic Information (Continuous) in the PPK Dataset.
Source: POPPK report: an update, Table 5
Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) 174
Reference ID: 4125095
NDA/BLA Multi-disciplinary Review and Evaluation NDA 208051 NERLYNX (neratinib)
Table 61. Analysis of Safety Endpoints and Steady State Exposures Adjusted by Average Daily Dose of Neratinib (Neratinib Arm in Studies A1-102, A1-104, A1-201, and A2-3003)
Ctrough,ss (ng/mL) AUCss (ng*h/mL) Cmax,ss (ng/mL)
Odds Ratio P-Value Odds Ratio P-Value Odds Ratio P-Value
>Grade 1 Diarrhea 1.018 (1.000, 1.037) 0.055 1.001 (1.000, 1.001) 0.033 1.013 (1.001, 1.025) 0.034
>Grade 2 Diarrhea 1.000 (0.990, 1.010) 0.956 1.000 (1.000, 1.000) 0.537 0.997 (0.990, 1.004) 0.368
>Grade 3 Diarrhea 1.003 (0.992, 1.014) 0.632 1.000 (1.000, 1.000) 0.901 0.998 (0.991, 1.006) 0.655
>Grade 3 Fatigue 1.002 (0.975, 1.029) 0.901 1.000 (0.999, 1.001) 0.969 1.000 (0.982, 1.018) 0.993 Rash 0.996 (0.983, 1.009) 0.521 1.000 (0.999, 1.000) 0.475 0.997 (0.988, 1.006) 0.474 Elevated Liver
Enzyme Level 0.998 (0.987, 1.008) 0.646 1.000 (1.000, 1.000) 0.770 0.999 (0.992, 1.006) 0.799 Source: Adapted from Response to Population Pharmacokinetic Information Request, Table 4-21
Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) 175
Reference ID: 4125095
APPEARS THIS WAY ON ORIGINAL
(
NDA/BLA Multi-disciplinary Review and Evaluation NDA 208051 NERLYNX (neratinib)
14 Division Director (DHOT)
{See appended electronic signature page}
John Leighton, PhD
Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) 176
Reference ID: 4125095
NDA/BLA Multi-disciplinary Review and Evaluation NDA 208051 NERLYNX (neratinib)
15 Division Director (OCP)
{See appended electronic signature page}
Nam Atiqur Rahman, PhD
Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) 177
Reference ID: 4125095
NDA/BLA Multi-disciplinary Review and Evaluation NDA 208051 NERLYNX (neratinib)
16 Division Director (OB)
{See appended electronic signature page}
Rajeshwari Sridhara, PhD
Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) 178
Reference ID: 4125095
NDA/BLA Multi-disciplinary Review and Evaluation NDA 208051 NERLYNX (neratinib)
17 Division Director (Clinical)
{See appended electronic signature page}
Julia Beaver, MD
Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) 179
Reference ID: 4125095
NDA/BLA Multi-disciplinary Review and Evaluation NDA 208051 NERLYNX (neratinib)
18 Office Director (or designated signatory authority)
This application was reviewed under the auspices of the Oncology Center of Excellence (OCE) per the OCE Intercenter Agreement. My signature below represents an approval recommendation for the clinical portion of this application under the OCE.
{See appended electronic signature page}
Richard Pazdur, MD
Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) 180
Reference ID: 4125095
---This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature.
---/s/
---PAMELA I BALCAZAR
07/17/2017
XIANHUA W CAO 07/17/2017
QI LIU 07/17/2017
NAM ATIQUR RAHMAN 07/17/2017
I concur.
KIMBERLY R RINGGOLD 07/17/2017
JOHN K LEIGHTON on behalf of TODD R PALMBY 07/17/2017
JOHN K LEIGHTON 07/17/2017
JOYCE H CHENG 07/17/2017
SHENGHUI TANG 07/17/2017
RAJESHWARI SRIDHARA 07/17/2017
WILLIAM F PIERCE 07/17/2017
B HARPREET SINGH
Reference ID: 4125095
07/17/2017
AMANDA J WALKER 07/17/2017
LALEH AMIRI KORDESTANI 07/17/2017
JULIA A BEAVER 07/17/2017
RICHARD PAZDUR 07/17/2017
Reference ID: 4125095
Clinical Review – Memo
NDA: 208051
Drug Name: NERLYNX (neratinib)
Indication: Extended adjuvant treatment of adult patients with early stage ERBB2-positive breast cancer who have received prior adjuvant trastuzumab-based therapy
Applicant: Puma Biotechnology Receipt Date:
PDUFA Goal Date:
July 19, 2016 July 19, 2017 Review Priority: Standard
Medical Division: OHOP/DOP1
Clinical Team: Amanda Walker, M.D., Clinical Reviewer Harpreet Singh, M.D., Clinical Reviewer
Laleh Amiri-Kordestani, M.D., Clinical Review Team Leader Julia Beaver, M.D., Division Director
Project Manager: Pamela Balcazar, M.S.
The clinical safety review is complete and has been added to the Multi-disciplinary Review and Evaluation. My recommendation for this application is to approve.
Reference ID: 4120458
---This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature.
---/s/
---AMANDA J WALKER
07/05/2017
Reference ID: 4120458
CLINICAL FILING CHECKLIST FOR NDA/BLA or Supplement
File name: 5_Clinical Filing Checklist for NDA_BLA or Supplement 010908 1
NDA/BLA Number: 208051 Applicant: Puma Biotechnology
Stamp Date: July 19, 2016 Drug Name: Neratinib NDA/BLA Type: NME
On initial overview of the NDA/BLA application for filing:
Content Parameter Yes No NA Comment
FORMAT/ORGANIZATION/LEGIBILITY
1. Identify the general format that has been used for this application, e.g. electronic common technical document (eCTD).
X
2. Is the clinical section legible and organized in a manner to allow substantive review to begin?
X 3. Is the clinical section indexed (using a table of contents)
and paginated in a manner to allow substantive review to begin?
4. For an electronic submission, is it possible to navigate the application in order to allow a substantive review to begin (e.g., are the bookmarks adequate)?
X
5. Are all documents submitted in English or are English
translations provided when necessary? X
LABELING
6. Has the applicant submitted a draft prescribing information that appears to be consistent with the Physician Labeling Rule (PLR) regulations and guidances (see
http://www.fda.gov/Drugs/GuidanceComplianceRegulatory Information/LawsActsandRules/ucm084159 htm
X
SUMMARIES
7. Has the applicant submitted all the required discipline
summaries (i.e., Module 2 summaries)? X
8. Has the applicant submitted the integrated summary of
safety (ISS)? X
9. Has the applicant submitted the integrated summary of efficacy (ISE)?
X 10. Has the applicant submitted a benefit-risk analysis for the
product? X
11. Indicate if the Application is a 505(b)(1) or a 505(b)(2). 505(b)(1) 505(b)(2) Applications
12. If appropriate, what is the relied upon listed drug(s)? X 13. Did the applicant provide a scientific bridge demonstrating
the relationship between the proposed product and the listed drug(s)/published literature?
X
14. Describe the scientific bridge (e.g., BA/BE studies) X DOSAGE
15. If needed, has the applicant made an appropriate attempt to determine the correct dosage regimen for this product (e.g., appropriately designed dose-ranging studies)?
CLINICAL FILING CHECKLIST FOR NDA/BLA or Supplement
File name: 5_Clinical Filing Checklist for NDA_BLA or Supplement 010908 2
Content Parameter Yes No NA Comment
16. Do there appear to be the requisite number of adequate and well-controlled studies in the application?
Pivotal Study #1 3004
Indication: Extended adjuvant therapy of HER2+ breast cancer with prior adjuvant trastuzumab-based therapy
X
17. Do all pivotal efficacy studies appear to be adequate and well-controlled within current divisional policies (or to the extent agreed to previously with the applicant by the Division) for approvability of this product based on proposed draft labeling?
X
18. Do the endpoints in the pivotal studies conform to previous Agency commitments/agreements? Indicate if there were not previous Agency agreements regarding
primary/secondary endpoints.
X
19. Has the application submitted a rationale for assuming the applicability of foreign data to U.S. population/practice of medicine in the submission?
X
SAFETY
20. Has the applicant presented the safety data in a manner consistent with Center guidelines and/or in a manner previously requested by the Division?
X
21. Has the applicant submitted adequate information to assess the arythmogenic potential of the product (e.g., QT interval studies, if needed)?
X
22. Has the applicant presented a safety assessment based on all current worldwide knowledge regarding this product?
X 23. For chronically administered drugs, have an adequate
number of patients (based on ICH guidelines for exposure1) been exposed at the dosage (or dosage range) believed to be efficacious?
X
24. For drugs not chronically administered (intermittent or short course), have the requisite number of patients been exposed as requested by the Division?
X
25. Has the applicant submitted the coding dictionary2 used for mapping investigator verbatim terms to preferred terms?
X 26. Has the applicant adequately evaluated the safety issues that
are known to occur with the drugs in the class to which the new drug belongs?
X
1 For chronically administered drugs, the ICH guidelines recommend 1500 patients overall, 300-600 patients for six months, and 100 patients for one year. These exposures MUST occur at the dose or dose range believed to be efficacious.
2 The “coding dictionary” consists of a list of all investigator verbatim terms and the preferred terms to which they were mapped. It is most helpful if this comes in as a SAS transport file so that it can be sorted as needed; however, if it is submitted as a PDF document, it should be submitted in both directions (verbatim -> preferred and preferred -> verbatim).
Reference ID: 4119804
CLINICAL FILING CHECKLIST FOR NDA/BLA or Supplement
File name: 5_Clinical Filing Checklist for NDA_BLA or Supplement 010908 3
Content Parameter Yes No NA Comment
27. Have narrative summaries been submitted for all deaths and adverse dropouts (and serious adverse events if requested by the Division)?
X
OTHER STUDIES
28. Has the applicant submitted all special studies/data requested by the Division during pre-submission discussions?
X
29. For Rx-to-OTC switch and direct-to-OTC applications, are the necessary consumer behavioral studies included (e.g., label comprehension, self selection and/or actual use)?
X
PEDIATRIC USE
30. Has the applicant submitted the pediatric assessment, or provided documentation for a waiver and/or deferral?
X PREGNANCY, LACTATION, AND FEMALES AND
MALES OF REPRODUCTIVE POTENTIAL USE
31. For applications with labeling required to be in Pregnancy and Lactation Labeling Rule (PLLR) format, has the applicant submitted a review of the available information regarding use in pregnant, lactating women, and females and males of reproductive potential (e.g., published literature, pharmacovigilance database, pregnancy registry) in Module 1 (see
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/D evelopmentResources/Labeling/ucm093307 htm)?
X
ABUSE LIABILITY
32. If relevant, has the applicant submitted information to
assess the abuse liability of the product? X
FOREIGN STUDIES
33. Has the applicant submitted a rationale for assuming the applicability of foreign data in the submission to the U.S.
population?
X
DATASETS
34. Has the applicant submitted datasets in a format to allow
reasonable review of the patient data? X
35. Has the applicant submitted datasets in the format agreed to
previously by the Division? X
36. Are all datasets for pivotal efficacy studies available and
complete for all indications requested? X
37. Are all datasets to support the critical safety analyses available and complete?
X 38. For the major derived or composite endpoints, are all of the
raw data needed to derive these endpoints included? X CASE REPORT FORMS
39. Has the applicant submitted all required Case Report Forms in a legible format (deaths, serious adverse events, and adverse dropouts)?
X
40. Has the applicant submitted all additional Case Report Forms (beyond deaths, serious adverse events, and adverse drop-outs) as previously requested by the Division?
X
FINANCIAL DISCLOSURE
41. Has the applicant submitted the required Financial
Disclosure information? X
GOOD CLINICAL PRACTICE
Reference ID: 4119804
CLINICAL FILING CHECKLIST FOR NDA/BLA or Supplement
File name: 5_Clinical Filing Checklist for NDA_BLA or Supplement 010908 4
Content Parameter Yes No NA Comment
42. Is there a statement of Good Clinical Practice; that all clinical studies were conducted under the supervision of an IRB and with adequate informed consent procedures?
X
IS THE CLINICAL SECTION OF THE APPLICATION FILEABLE? _____Yes ___
If the Application is not fileable from the clinical perspective, state the reasons and provide comments to be sent to the Applicant.
Please identify and list any potential review issues to be forwarded to the Applicant for the 74-day letter.
Harpreet Singh/ Amanda Walker 9/17/2016
Reviewing Medical Officer Date
Clinical Team Leader Date
Reference ID: 4119804
---This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature.
---/s/
---B HARPREET SINGH
07/03/2017
Uploaded 7/3/17, however completed at time of filing meeting, 9/15/16 AMANDA J WALKER
07/05/2017
LALEH AMIRI KORDESTANI 07/05/2017
Reference ID: 4119804
DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION NONCLINICAL STUDIES – MEMO
Application number: 208051 Supporting document/s: 1
Applicant’s letter date: 7/18/2016 CDER stamp date: 7/19/2016 PDUFA goal date: 7/19/2017
Product: Nerlynx (neratinib maleate)
Indication: Extended adjuvant treatment of adult patients with early stage ERBB2-positive breast cancer who have received prior trastuzumab-based therapy
Applicant: Puma Biotechology, Inc.
10880 Wilshire Blvd Los Angeles, CA United States
Review Division: Division of Hematology Oncology Toxicology (Division of Oncology Products 1)
Reviewers: Kimberly Ringgold, PhD Supervisor: Todd Palmby, PhD
Division Director: John Leighton, PhD, DABT (DHOT) Julia Beaver, MD (DOP1, acting) Project Manager: Pamela Balcazar
Disclaimer
The Pharmacology/Toxicology review is complete and has been added to the Multi-disciplinary Review and Evaluation, which will be uploaded to DARRTS when it is finalized. Refer to the Multi-disciplinary Review and Evaluation for additional details. There are no nonclinical findings that would preclude the approval of NERLYNX for the proposed indication.
Reference ID: 4116985
---This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature.
---/s/
---KIMBERLY R RINGGOLD
06/29/2017
TODD R PALMBY 06/30/2017
Reference ID: 4116985
NDA-208051 (Neratinib maleate) Page 2 of 14
Table of Contents
1. Background ...3
2. Study Design and Analysis ...3
2.1. Sponsor's analyses ...4
2.1.1. Survival analysis ...4
Sponsor’s findings ...4
2.1.2. Tumor data analysis ...4
Adjustment for multiple testing ...5
Sponsor’s findings ...5
2.2. Reviewer's analyses ...5
2.2.1. Survival analysis ...5
Reviewer’s findings ...5
2.2.2. Tumor data analysis ...6
Adjustment for multiple testing ...6
Reviewer’s findings ...7
3. Summary ...7
4. Appendix ...9
Table 1A: Intercurrent mortality rate in male mice Table 1B: Intercurrent mortality rate in female mice Table 2A: Tumor rates and p-values for trend and pairwise comparisons in male mice Table 2B: Tumor rates and p-values for trend and pairwise comparisons in female mice Figure 1A: Kaplan-Meier survival functions for male mice Figure 1B: Kaplan-Meier survival functions for female mice 5. References ...14
Reference ID: 4118155
NDA-208051 (Neratinib maleate) Page 3 of 14