CENTER FOR DRUG EVALUATION AND RESEARCH...mail from DO 1 (Sherry Hou) on November 5, 2019, and are...

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

761139Orig1s000

OTHER REVIEW(S)

FOOD AND DRUG ADMINISTRATION Center for Drug Evaluation and ResearchOffice of Prescription Drug Promotion

****Pre-decisional Agency Information****

Memorandum Date: November 25, 2019

To: Preeti Narayan, MD, Clinical Reviewer Division of Oncology Disease 1 (DO 1)

Sherry Hou, PharmD, Regulatory Project Manager, DO 1

William Pierce, PharmD, Associate Director for Labeling, DO 1

From: Maritsa Serlemitsos-Day, PharmD, BCPS, Regulatory Review Officer Office of Prescription Drug Promotion (OPDP)

CC: Kevin Wright, PharmD, Team Leader, OPDP

Subject: OPDP Labeling Comments for Enhertu™ (fam-trastuzumab deruxtecannxki) for injection, for intravenous use

BLA: 761139

In response to DO 1’s consult request dated August 30, 2019, OPDP has reviewed the proposed product labeling (PI), Medication Guide, and carton and container labeling for the original BLA submission for Enhertu™ (fam-trastuzumab deruxtecan-nxki) for injection, for intravenous use (Enhertu).

OPDP’s comments on the proposed labeling are based on the draft PI received by electronic mail from DO 1 (Sherry Hou) on November 5, 2019, and are provided below.

A combined OPDP and Division of Medical Policy Programs (DMPP) review was completed, and comments on the proposed Medication Guide were sent under separate cover on November 25, 2019.

OPDP has reviewed the attached proposed carton and container labeling submitted by the Sponsor to the electronic document room on November 22, 2019, and we do not have any comments.

Thank you for your consult. If you have any questions, please Maritsa Serlemitsos-Day at (301) 796-1760 or [email protected].

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Reference ID: 4525408

mailto:[email protected]

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Signature Page 1 of 1

This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record.

/s/

MARITSA SERLEMITSOS-DAY 11/25/2019 10:48:03 PM


Department of Health and Human Services Public Health Service

Food and Drug Administration Center for Drug Evaluation and Research

Office of Medical Policy

PATIENT LABELING REVIEW

Date: November 25, 2019

To: Julia Beaver, MD Director Division of Oncology Products 1 (DOP 1)

Through: LaShawn Griffiths, MSHS-PH, BSN, RN Associate Director for Patient Labeling Division of Medical Policy Programs (DMPP)

Barbara Fuller, RN, MSN, CWOCN Team Leader, Patient Labeling Division of Medical Policy Programs (DMPP)

From: Susan Redwood, MPH, BSN, RN Patient Labeling Reviewer Division of Medical Policy Programs (DMPP) Maritsa Serlemitsos-Day, PharmD, BCPS Regulatory Review Officer Office of Prescription Drug Promotion (OPDP)

Subject: Review of Patient Labeling: Medication Guide (MG)

Drug Name (established name):

ENHURTU (fam-trastuzumab deruxtecan-nxki)

Dosage Form and Route:

for injection, for intravenous use

Application Type/Number:

BLA 761139

Applicant: Daiichi Sankyo, Inc.


1 INTRODUCTION On August 29, 2019 Daiichi Sankyo, Inc., submitted for the Agency’s review an original Biologics License Application (BLA) 761139 for ENHURTU (famtrastuzumab deruxtecan-nxki) for injection, for intravenous use. The proposed indication for ENHURTU (fam-trastuzumab deruxtecan-nxki) is (b) (4)

(b) (4)

This collaborative review is written by the Division of Medical Policy Programs (DMPP) and the Office of Prescription Drug Promotion (OPDP) in response to a request by the Division of Oncology Products 1 (DOP 1) on August 30, 2019, for DMPP and OPDP to review the Applicant’s proposed Medication Guide (MG) for ENHURTU (fam-trastuzumab deruxtecan-nxki) injection, for intravenous use.

2 MATERIAL REVIEWED

• Draft ENHURTU (fam-trastuzumab deruxtecan-nxki) injection MG received on August 29, 2019, revised by the Review Division throughout the review cycle, and received by DMPP and OPDP on November 5, 2019.

• Draft ENHURTU (fam-trastuzumab deruxtecan-nxki) injection Prescribing Information (PI) received on August 29, 2019, revised by the Review Division throughout the review cycle, and received by DMPP and OPDP on November 5, 2019.

3 REVIEW METHODS To enhance patient comprehension, materials should be written at a 6th to 8th grade reading level, and have a reading ease score of at least 60%. A reading ease score of 60% corresponds to an 8th grade reading level Additionally, in 2008 the American Society of Consultant Pharmacists Foundation (ASCP) in collaboration with the American Foundation for the Blind (AFB) published Guidelines for Prescription Labeling and Consumer Medication Information for People with Vision Loss. The ASCP and AFB recommended using fonts such as Verdana, Arial or APHont to make medical information more accessible for patients with vision loss. In our collaborative review of the MG we: • simplified wording and clarified concepts where possible • ensured that the MG is consistent with the Prescribing Information (PI) • removed unnecessary or redundant information • ensured that the MG is free of promotional language or suggested revisions to

ensure that it is free of promotional language • ensured that the MG meets the Regulations as specified in 21 CFR 208.20. • ensured that the MG meets the criteria as specified in FDA’s Guidance for

Useful Written Consumer Medication Information (published July 2006)


4 CONCLUSIONS The MG is acceptable with our recommended changes.

5 RECOMMENDATIONS

• Please send these comments to the Applicant and copy DMPP and OPDP on the correspondence.

• Our collaborative review of the MG is appended to this memorandum. Consult DMPP and OPDP regarding any additional revisions made to the PI to determine if corresponding revisions need to be made to the MG.

Please let us know if you have any questions.

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/s/

SUSAN W REDWOOD 11/25/2019 08:30:36 AM

MARITSA SERLEMITSOS-DAY 11/25/2019 08:37:01 AM

BARBARA A FULLER 11/25/2019 09:00:02 AM

LASHAWN M GRIFFITHS 11/25/2019 11:12:52 AM


MEMORANDUM REVIEW OF REVISED LABEL AND LABELING

Division of Medication Error Prevention and Analysis (DMEPA) Office of Medication Error Prevention and Risk Management (OMEPRM)

Office of Surveillance and Epidemiology (OSE) Center for Drug Evaluation and Research (CDER)

Date of This Memorandum: November 15, 2019

Requesting Office or Division: Division of Oncology 1 (DO1)

Application Type and Number: BLA 761139

Product Name and Strength: Enhertu (fam-trastuzumab deruxtecan-nxki) for Injection, 100 mg/vial

Applicant/Sponsor Name: Daiichi Sankyo, Inc

OSE RCM #: 2019-1565-2

DMEPA Safety Evaluator: Tingting Gao, PharmD

DMEPA Team Leader: Chi-Ming (Alice) Tu, PharmD

1 PURPOSE OF MEMORANDUM Daiichi Sankyo submitted revised container label and carton labeling received on November 13, 2019 for Enhertu. Division of Oncology 1 (DO1) requested that we review the revised container label and carton labeling for Enhertu (Appendix A) to determine if it is acceptable from a medication error perspective. The revisions are in response to recommendations that we made during a previous label and labeling review.a

2 CONCLUSION Daiichi Sankyo implemented all of our recommendationsb and we have no additional recommendations at this time.

a Gao, T. Label and Labeling Review for Enhertu (BLA 761139). Silver Spring (MD): FDA, CDER, OSE, DMEPA (US); 2019 Nov 7. RCM No.: 2019-1565-1. b Response to Information Request Dated November 7, 2019 – Carton/Container Labeling. Basking Ridge (NJ): Daiichi Sankyo, Inc. 2019 Nov 13. Available from: \\cdsesub1\evsprod\bla761139\0049\m1\us\12-cover-letters\cover.pdf.

1


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/s/

TINGTING N GAO 11/15/2019 04:23:17 PM

CHI-MING TU 11/15/2019 04:49:06 PM


MEMORANDUM REVIEW OF REVISED LABEL AND LABELING

Division of Medication Error Prevention and Analysis (DMEPA) Office of Medication Error Prevention and Risk Management (OMEPRM)

Office of Surveillance and Epidemiology (OSE) Center for Drug Evaluation and Research (CDER)

Date of This Memorandum: November 7, 2019

Requesting Office or Division: Division of Oncology Products 1 (DOP1)


Product Name and Strength: Enhertu (fam-trastuzumab deruxtecan-nxki) for Injection, 100 mg/vial


OSE RCM #: 2019-1565-1



1 PURPOSE OF MEMORANDUM The Applicant submitted revised container label and carton labeling received on October 28, 2019 for Enhertu. Division of Oncology Products 1 (DOP1) requested that we review the revised container label and carton labeling for Enhertu (Appendix A) to determine if it is acceptable from a medication error perspective. The revisions are in response to recommendations that we made during a previous label and labeling review.a

2 DISCUSSION The Applicant implemented all of our recommendations. However, we noted that the barcode on the container label was presented in a horizontal position on a 10-mL vial, which may impact scannability of the barcode. Therefore, we recommend Daiichi Sankyo to confirm that the horizontally oriented barcode can be easily scanned. Furthermore, per the General Advice Letter dated November 7, 2019b, we recommend the Applicant to revise the nonproprietary name on all labels and labeling to incorporate the FDA-designated nonproprietary name suffix, -nxki, appended to the core name, fam-trastuzumab

a Gao, T. Label and Labeling Review for Enhertu (BLA 761139). Silver Spring (MD): FDA, CDER, OSE, DMEPA (US); 2019 Oct 22. RCM No.: 2019-1565. b Harris, D. General Advice Letter for BLA 761139. Silver Spring (MD): FDA, CDER, OSE, DMEPA (US); 2019 Nov 7.

1


deruxtecan so that the proper name appears as fam-trastuzumab deruxtecan-nxki throughout the labels and labeling.

3 CONCLUSION The revised container label and carton labeling may be improved to ensure safe medication use. We provide our specific recommendations in Section 4 below.

4 RECOMMENDATIONS FOR DAIICHI SANKYO, INC We recommend the following be communicated to Daiichi Sankyo.

A. Container label and carton labeling 1. Revise the nonproprietary name on all labels and labeling to incorporate the

FDA-designated nonproprietary name suffix, -nxki, appended to the core name, fam-trastuzumab deruxtecan so that the proper name appears as famtrastuzumab deruxtecan-nxki throughout the labels and labeling. This recommendation was communicated to you in the November 7, 2019 General Advice Letter.

B. Container Label 1. Ensure that the horizontally oriented barcode can be easily scanned. If the vial

cannot be easily scanned, consider reorienting the linear barcode to a vertical position to improve the scannability of the barcode. Barcodes placed in a horizontal position may not scan due to vial curvature.


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/s/

TINGTING N GAO 11/07/2019 04:05:30 PM

CHI-MING TU 11/07/2019 04:22:39 PM


(b) (4)

Clinical Inspection Summary BLA 761139 for fam-trastuzumab deruxtecan

Clinical Inspection Summary

Date November 4, 2019 From Yang-min (Max) Ning, M.D., Ph.D.

Aisha Johnson, M.D., M.P.H., M.B.A. Kassa Ayalew, M.D., M.P.H. GCPAB/OSI/CDER/FDA

To Preeti Narayan, M.D. Harpreet Singh, M.D. Sherry Hou, Pharm. D. DOP1/OHOP/OCE/FDA

BLA # 761139 Applicant Daiichi Sankyo, Inc. Drug Fam-trastuzumab deruxtecan NME (Yes/No) Yes Therapeutic Classification Proposed Indication(s)

Consultation Request Date

Antibody conjugate

July 17, 2019 Summary Goal Date November 22, 2019 Action Goal Date December 22, 2019 PDUFA Date April 29, 2020

I. OVERALL ASSESSMENT OF INSPECTIONAL FINDINGS AND RECOMMENDATIONS

Clinical data from an open-label Phase 2 study (DS8201-A-U201) were submitted to the Agency in support of this Biologics License Application (BLA) for fam-trastuzumab deruxtecan. Three study sites (#1002, 1004, and 8108) were selected for clinical inspection.

The inspectional findings verified the Applicant’s reported clinical data with source records at the three study sites. There were no substantial Good Clinical Practice (GCP) compliance deficiencies identified at these sites.

Based on the results of these inspections, the data reported by these investigator sites appear acceptable and supportive of this BLA.



BLA 761139 for fam-trastuzumab deruxtecan

II. BACKGROUND

Fam-trastuzumab deruxtecan is a human epidermal growth factor receptor 2 (HER2)-targeted antibody drug conjugate. It is comprised of a humanized anti-HER2 IgG1 conjugated to deruxtecan, a topoisomerase I inhibitor. The investigational drug name of this product was DS8201a.

To support the proposed indication in the current Biologics License Application (BLA), the Applicant submitted clinical data from the Study DS8201-A-U201 (NCT03248492), titled “A Phase 2, Multicenter, Open-Label Study of DS-8201a, an Anti-HER2-Antibody Drug Conjugate (ADC) for HER2-Positive, Unresectable and/or Metastatic Breast Cancer Subjects Previously Treated with T-DM1”. This study had 2 parts: Part 1 for defining the recommended Phase 2 Dose (RP2D), Part 2 for expansion in subjects to be treated at the RP2D. The primary endpoint was “confirmed objective response rate (ORR)” in study subjects, which was assessed by independent central review (ICR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1).

Study treatment with DS-8201a was administered as an intravenous infusion once every three weeks (on Day 1 of each 21-day cycle), and continued until disease progression, death, withdrawal of consent, or unacceptable toxicity. Tumor assessments were based on computed tomography (CT) or magnetic resonance imaging (MRI) scans which were performed at baseline and then every 6 weeks (±7 days). All on-study scans were required to be submitted to the designated facility for ICR.

From 09/25/2017 through 03/21/2019 (the data cutoff date for analysis), the study enrolled 253 subjects from 72 study sites in 8 countries. Of the enrolled subjects, 180 received DS-8201a at a dose of 5.4 mg/kg (the same dose recommended for use of fam-trastuzumab deruxtecan in this BLA) and were pooled for the reported efficacy analysis irrespective of their study part allocation (Part 1 or 2). The rest of subjects in Part 1 who received study treatment at other doses (e.g., 6.4 mg/kg or 7.4 mg/kg) were not included in the efficacy analysis and the proposed product label.

Three clinical investigator sites were selected for clinical inspection. These sites had a relatively high number of subjects enrolled and/or responders reported among all clinical investigator sites. Relative to other site, one site (Site 1002) had fewer serious adverse events reported.

III. RESULTS

1. Dr. Ian Krop, Site # 1002

This clinical investigator site was inspected between August 8 and August 26, 2019 as a data audit for the Study DS8201-A-U201. For the investigator, this was the initial FDA inspection. The site enrolled 8 of the 12 screened subjects. Seven subjects received DS8201a at 5.4 mg/kg and one at 7.4 mg/kg. As of the data cutoff date, four




subjects remained on study treatment, one came off due to disease progression, and (b) (6) (b) (6) (b) (6)three (Subjects and at the 5.4 mg/kg dose level, Subject

at the 7.4 mg/kg dose level) were discontinued due to toxicity.

The inspection reviewed study-related documents and source records for all enrolled subjects and compared the records with the site-level data listings submitted to the BLA. The reviewed documents and records included but were not limited to: Institutional Review Board (IRB) documentation and communications, investigator’s agreements, financial disclosures, training records, delegation of authority logs, informed consent forms (ICFs), adverse events, protocol deviation logs, source records, electronic case report forms (eCRFs), study drug accountability, dosing, monitoring logs, and monitoring reports.

The inspection found that the study was adequately conducted at this site. For all the enrolled subjects, the submitted data listings were verifiable with the site’s source records, with no discrepancies reported. Note that the ICR reported tumor response in the data listings were not available at the site. There were no evidence of underreporting of adverse events and protocol deviations.

There was one inspectional observation reported, which led to a Form FDA 483 issued to the investigator. This observation related to nurses’ collection of research blood samples outside of the protocol-required time frames in four study subjects at the

(b) (6)infusion facility. For Subject , the high sensitivity troponin sample was not drawn 2-3 hours after the end of infusion (EOI) as specified in the protocol, but rather

consistent with the protocol-specified time frame of “within 15 minutes after EOI” for PK sampling.

In the written response to the FDA 483, the Investigator acknowledged the observation and stated that corrective and preventive actions have been implemented. These include 1) Immediate Corrective Action: “All staff infusion nurses are required to attend a clinical research course and training on how to read an investigational protocol plan”; 2) Ongoing Corrective Action, which entails “Investigational plan education, a clinical research course (including but not limited to good clinical documentation practice), and one to one re-training continues to occur for all staff infusion nurses”. In addition, standardized investigational plan flowsheets along with training for documentation on flowsheets will be used at the Institute of this study site.

2. Dr. Shanu Modi, Site # 1004

This clinical investigator site was inspected on September 9-12, 2019 as a data audit for the Study DS8201-A-U201. This was the first FDA inspection for Dr. Shanu Modi at Memorial Sloan Kettering Cancer Center (MSKCC). The study was initiated at the site on 11/14/2017 and was ongoing at the time of inspection. As of the data cutoff date, the site enrolled 15 of

“within 15 minutes of EOI” on Day 1 of Cycle 1 and “4 minutes after the EOI” on Day 1 od Cycle 7. For Subjects , their pharmacokinetic (PK) samples were drawn 5 minutes before the EOI on Day 1 of Cycle 1. This is not

(b) (6)




the 28 screened subjects. Eight subjects received DS8201a at 5.4 mg/kg: two were discontinued due to disease progression and six remained on study treatment.

The inspection reviewed all subjects’ source documents and compared them with the data listings submitted to the BLA by the Applicant for the site. The reviewed source documents consisted of records such as data collection worksheets, informed consent forms, medical progress notes, laboratory reports, adverse events, and concomitant medications. At the site, study documentation for study subjects were scanned and uploaded into the hospital’s electronic medical record (EMR) system per the MSKCC written procedures and maintained within the EMR system. The inspection also reviewed the conduct of this study at the site, including the IRB approvals and oversight, clinical site training, delegation of authority, signed financial disclosure and From FDA 1572s, sponsor’s monitoring practices, drug accountability records, and reports to the sponsor.

The inspection found no significant deficiencies, with no Form FDA 483 issued. The submitted data listings for the site were verified with all subjects’ source documents, with no discrepancies reported. Note that the inspection only verified the investigator-assessed best overall response since the ICR results were not available at the site for review. The site remained blinded to the central review assessments. A few issues were noted in source documents and were discussed with the study team at the closeout meeting: 1) there was no clear documentation of medical review of some abnormal laboratory results given lack of signatures; 2) the Subject RECIST Forms (for local use) were not signed by the radiologist and the investigator in a timely manner (e.g., 5-9 months after the scans were performed); 3) The investigator instructed her administrative assistant via email to insert her wet signature image into Notes to File. The investigator and her study team provided explanations and relevant records, and the issues were addressed. Regarding the use of the wet signature image, the investigator stated that she would implement “a better method for electronic signatures that are more compliant with electronic records and signatures regulations (21 CFR Part 11)”.

3. Dr. Toshinari Yamashita, Site # 8108

This foreign clinical investigator site was inspected on October 7-10, 2019 as a data audit for the Study DS8201-A-U201. The inspection report is not currently available.

Based on the inspector’s preliminary summary, the site enrolled 10 of the 11 screened subjects. As of the data cutoff date, six subjects received DS8201a at 5.4 mg/kg and four received DS8201a at 6.4 mg/kg or 7.4 mg/kg. Four of the six subjects at the 5.4 mg/kg dose

(b) (6)

(b) (6)level remained on study treatment and two were discontinued (Subject due to adverse event and Subject at the Investigator’s discretion). At the time of inspection, two subjects continued receiving DS8201a at 5.4 mg/kg (note that the ID of the two subjects was not provided in the preliminary summary).

The inspection audited source documents for all study subjects at the site and found that the efficacy and safety data were verifiable with the source documents. There was no evidence of underpotting of adverse events.




The inspection had no significant observations reported. No Form FDA 483 was issued to the investigator at the end of this inspection. The discussed items were related to documentation at the site: 1) documenting the number of the study kits administered to subjects to ensure that it matches the IWRS-assigned number, 2) signing off each out-ofrange laboratory value to show that the investigator reviewed and assessed the result as opposed to only signing the cover page, 3) documenting the reason for crossing out any adverse events.

Note: An amendment to this inspection summary will be issued if the EIR for Dr. Yamashita’s site contains substantial differences that alter the current GCP assessment or compliance conclusion.




PRIMARY REVIEW: {See appended electronic signature page}

Yang-min (Max) Ning, M.D., Ph.D. Good Clinical Practice Assessment Branch Division of Clinical Compliance Evaluation Office of Scientific Investigations

CONCURRENCE: {See appended electronic signature page}

Aisha Johnson, M.D., M.P.H., M.B.A. Acting Team Lead Good Clinical Practice Assessment Branch Division of Clinical Compliance Evaluation Office of Scientific Investigations

CONCURRENCE: {See appended electronic signature page}

Kassa Ayalew, M.D., M.P.H Branch Chief Good Clinical Practice Assessment Branch Division of Clinical Compliance Evaluation Office of Scientific Investigations

cc:

Central Doc. Rm. BLA 761139 Review Division /Division Director/J Beaver Review Division /Medical Team Leader/H Singh Review Division /Project Manager/S Hou Review Division/Medical Officer/P Narayan OSI/Office Director/D Burrow OSI/DCCE/ Division Director/N Khin OSI/DCCE/Branch Chief/K Ayalew OSI/DCCE/Team Leader/A Johnson OSI/DCCE/GCP Reviewer/YM NING OSI/ GCP Program Analysts/ Joseph Peacock/Yolanda Patague OSI/Database PM/Dana Walters


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/s/

YANGMIN NING 11/04/2019 05:03:43 PM

AISHA P JOHNSON 11/05/2019 05:40:18 AM

KASSA AYALEW 11/05/2019 08:26:55 AM


Interdisciplinary Review Team for Cardiac Safety Studies: QT Consultation Review

Submission BLA761139

Submission Number 002

Submission Date 8/29/2019

Date Consult Received 9/9/2019

Clinical Division DOP1 Note: Any text in the review with a light background should be inferred as copied from the sponsor’s document.

This review responds to your consult regarding the sponsor’s QT evaluation. The QTIRT reviewed the following materials: DS8201-A-J102 statistical analysis plan and clinical trial report (Submission 0002); Nonclinical overview (Submission 0001); Summary of Clinical Pharmacology Studies (Submission 0002); Previous QT-IRT review under IND 127553 dated 03/29/2017 in DARRTS; and Proposed label (Submission 0002).

1 SUMMARY No large mean increases in QTc (i.e., >20 ms) was observed in this QT assessment of ENHERTU.

The effect of ENHERTU (fam-trastuzumab deruxtecan) was evaluated in Study DS8201A-J102. The highest dose evaluated was 6.4 mg/kg administered every 3 weeks, which covers the therapeutic exposures. The data were analyzed using by-timepoint analysis as the primary analysis, which did not suggest that ENHERTU is associated with large mean increases in the QTc interval (refer to section 4.3) – see Table 1 for overall results. The findings of this analysis are further supported by the available nonclinical data (section 3.1), concentration-QTc analysis (section 4.5), and categorical analysis (section 4.4).

Table 1: The Point Estimates and the 90% CIs (FDA Analysis) ECG parameter Treatment Time ∆ (ms) 90% CI (ms)

QTc 6.4 mg/kg every 3 weeks Period 3 hour 7 5.0 (1.2, 8.7)

The observed geometric mean Cmax of MAAA-1181a is 12.3 ng/mL in this study. It covers the maximum therapeutic exposure at the therapeutic dose (8.2 ng/mL, Table 3.4 in the Summary of Clinical Pharmacology Studies). At this time, none of the intrinsic or extrinsic factors being evaluated (i.e., age, sex, race, weight, mild hepatic impairment, mild and moderate renal impairment, and strong inhibition of OATP1B, P-gp, or CYP3A) are expected to result in higher than 30% increase in steady state Cmax of MAAA-1181a.


1

(b) (4) (b) (4)

1.1 RESPONSES TO QUESTIONS POSED BY SPONSOR

Not applicable.

1.2 COMMENTS TO THE REVIEW DIVISION

Not applicable

2 PROPOSED LABEL Below are proposed edits to the label submitted to Submission 0002 from the QT-IRT. Our changes are highlighted (addition, deletion). This is a suggestion only and we defer the final labeling decisions to the Division.

12.2 Pharmacodynamics Cardiac Electrophysiology

The administration of multiple doses of ENHERTU (6.4 mg/kg every 3 weeks) did not show large mean effect (i.e. >20 ms) on the QTc interval in an open label, single-arm study in 51 patients with HER2-expressing metastatic breast cancer.

Reviewer’s comments: The study design is not adequate to exclude small effect (i.e. 10 ms) on the QTc interval. We propose to clarify the scope of the analysis in the label.

3 SPONSOR’S SUBMISSION

3.1 OVERVIEW

Trastuzumab deruxtecan (also known as fam-trastuzumab deruxtecan or DS-8201a) is a HER2-targeted antibody (MAAL-9001) and topoisomerase I inhibitor (MAAA-1181a) conjugate. MAAL-9001 has the same amino acid sequence as trastuzumab. The released drug (or payload), MAAA-1181a, and the GGFG tetra-peptide cleavable linker, form the drug-linker, MAAA-1162a. Each trastuzumab deruxtecan molecule consists of 1 DS8201a conjugated to approximately 8 MAAA-1162a.

The sponsor seeks accelerated approval of ENHERTU (fam-trastuzumab deruxtecan)

The recommended dose of ENHERTU is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (Q3W).

(b) (4)

Study DS8201-A-J102 is a Phase 1, multicenter, open-label, multiple dose study of DSS8201a in 51 patients with HER2-expressing metastatic and unresectable breast cancer. The study was conducted in Japan. The study dose was 6.4 mg/kg as an IV infusion Q3W (first dose administered in approximately 90 min and subsequent doses in 30 min). Triplicate ECG data with matching PK samples were collected on C1D1 and C3D1 at predose, 2, 4, and 7 hours after the start of administration, end-of-infusion on C3D1, predose on Days 8 and 15 in Cycle 1 and 3, C2D1, and Day 1 of subsequent cycles. The sponsor also collected time-matched ECG data (predose, 30 min, 2, 4, and 7 hours after the start of infusion) on the day before C1D1.


2

Previously the QT-IRT suggested that Study DS8201-A-J102 could potentially serve as a substitute of a TQT study and exclude large increases in the QTc interval.

In the current submission, the sponsor used QTcF as the primary endpoint and bytimepoint analysis as the primary analysis. Time-matched baseline was used in the sponsor’s analysis. There were 2 patients excluded due to concomitant use with QT-prolonging drugs.

The reviewers used predose baseline (i.e., the average of baseline ECG collected on the day before C1D1). The 2 patients on QT-prolonging drugs were excluded in the bytimepoint analysis and concentration QTc analysis but were included in the categorical analysis.

In the safety pharmacology study in monkeys treated with a single intravenous dose of DS-8201a, no effects on the cardiovascular system were observed at doses up to 78.8 mg/kg. In the study in hERG transfected CHO cells, MAAA-1181a had no effect on hERG channel current at concentrations up to 10 μmol/L (approximately 5000 ng/mL). Considering a protein binding of 2-3%, the ratio between hERG IC50 and free Cmax is >10000-fold.

3.2 SPONSOR’S RESULTS

3.2.1 By-Time Analysis No large mean increases in QTc (i.e., >20 ms) was observed.

The results of the reviewer’s analysis are similar to the sponsor’s results. Please see section 4.3 for additional details.

3.2.1.1 Assay Sensitivity Not applicable.

3.2.1.1.1 QT bias assessment Not applicable.

3.2.2 Categorical Analysis None of the subjects had a QTcF >480 ms or an increase from baseline >60 ms. The results of the reviewer’s analysis are similar to the sponsor’s results. Please see section 4.4 for additional details.

3.2.3 Safety Analysis There were no TEAEs with an outcome of death and no subject died during the study (i.e., between the first dose of DS-8201a and up to 47 days after the last dose).

There were 2 (3.9%) subjects with serious TEAEs (nausea, and femur fracture) and 2 (3.9%) subjects discontinued treatment with DS-8201a due to TEAEs (pneumonitis and ejection fraction decrease).

Four (7.8%) subjects had TEAEs of ECG QT prolonged, all Grade 1, and were not classified as a serious TEAE. None of the subjects required medication and no action


3

was taken with DS-8201a due to the TEAEs. All subjects recovered and continued on study.

No other subjects had TEAEs in the QT prolongation category, i.e., none had TEAEs of torsades de pointes, ventricular arrhythmias, syncope, seizure, or sudden death.

3.2.4 Exposure-Response Analysis The sponsor conducted linear mixed effect modeling (QTcF ~ 1 + CONC + centered_baseline) to quantify the relationship between the ΔQTcF and the serum concentration of DS-8201a or MAAA-1181a. The reviewer conducted the analysis using MAAA-1181a only because the conjugate and the antibody molecules are not expected to directly interact with cardiac ion channels because of the large molecular size. The results of the reviewer’s analysis are similar to the sponsor’s results. Please see section 4.5 for additional details.

4 REVIEWERS’ ASSESSMENT

4.1 EVALUATION OF THE QT/RR CORRECTION METHOD

The sponsor used QTcF for the primary analysis, which is acceptable as no significant increases or decreases in heart rate (i.e. |mean change| < 10 bpm) were observed (see section 4.3.2).

4.2 ECG ASSESSMENTS

4.2.1 Overall Waveforms from the ECG warehouse were reviewed. Overall ECG acquisition and interpretation in this study appears acceptable.

4.2.2 QT bias assessment Not applicable.

4.3 CENTRAL TENDENCY ANALYSIS

4.3.1 QTc Descriptive statistics were used to describe the QTcF effect for ENHERTU. The study did not include placebo and positive control group. Data from 49 female subjects are included in the by-time analysis. Four subjects had one or more missing data. The sponsor used time-matched baseline. The reviewer’s analysis used baseline averaged within subject.

The following figure displays the time profile of mean ΔQTcF for different treatment groups. The largest upper limits of 90% CI for the ΔQTcF mean is 8.7ms.


4

Figure 1: Mean and 90% CI ΔQTcF Time Course (unadjusted CIs).

4.3.1.1 Assay sensitivity Not applicable.

4.3.2 HR The same statistical analysis was performed based on HR (Figure 2). The largest upper limits of 90% CI for the ΔHR mean is 9.6 bpm.

Figure 2: Mean and 90% CI ΔHR Time Course

4.3.3 PR The same statistical analysis was performed based on PR interval (Figure 3). The largest upper limits of 90% CI for the ΔPR mean is 15.3ms.


5

Figure 3: Mean and 90% CI ΔPR Time Course

4.3.4 QRS The same statistical analysis was performed based on QRS interval (Figure 4). The largest upper limits of 90% CI for the ΔQRS mean is 2.0ms.

Figure 4: Mean and 90% CI ΔQRS Time Course

4.4 CATEGORICAL ANALYSIS

4.4.1 QTc No subject’s QTcF was above 480 ms.

No subject’s change from baseline was above 60 ms.

4.4.2 PR The outlier analysis results for PR are presented in Table 2. One subject had a PR >220 ms and increase from baseline ≥ 25% at 2 visits after receiving DS-8201a 6.4mg/kg. The baseline PR of the subject is 201ms.


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Table 2: Categorical Analysis for PR Actual Total (N) Value <= 220 ms Value > 220 ms & < 25% Value > 220 ms & >= 25%

Treatment # Subj. # Obs. # Subj. # Obs. # Subj. # Obs. # Subj. # Obs.

DS-8201a 6.4 mg/kg 51 621 48

(94.1%) 608

(97.9%) 2

(3.9%) 11

(1.8%) 1

(2.0%) 2

(0.3%)

4.4.3 QRS There are no subjects with QRS > 120ms.

4.4.4 HR The outlier analysis results for HR are presented in Table 3. Five subjects experienced maximum HR > 100 bpm after receiving DS-8201a 6.4mg/kg. Their HR baselines are 63.3, 76.0, 80.3, 88.0 and 98.7 bpm, and change from baseline corresponding to the outliers are ranging from 2.7% to 63.2%

Table 3: Categorical Analysis for HR Actual Treatment Total (N) Value <= 100 beats/min Value > 100 beats/min

Actual Treatment # Subj. # Obs. # Subj. # Obs. # Subj. # Obs.

DS-8201a 6.4 mg/kg 51 631 46 (90.2%)

624 (98.6%)

5 (9.8%)

7 (1.4%)

4.5 EXPOSURE-RESPONSE ANALYSIS

The objective of the clinical pharmacology analysis is to assess the relationship between ΔQTcF and concentration of the payload.

Prior to evaluating the relationship using a linear model, the three key assumptions of the model were evaluated using exploratory analysis: 1) absence of significant changes in heart rate (more than a 10 bpm increase or decrease in mean HR); 2) delay between plasma concentration and ΔQTcF and 3) presence of non-linear relationship. An evaluation of the time-course of drug concentration and changes in ΔΔHR and ΔΔQTcF is shown in Figure 2 and Figure 5, which shows an absence of significant changes in HR and do not appear to show significant hysteresis. Figure 6 shows the relationship between drug concentration and ΔQTcF and supports the use of a linear model. The exposure of MAAA-1181a is not higher with the shorter duration of infusion.


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Figure 5: Time course of drug concentration (top) and QTcF (bottom)

Figure 6: Assessment of linearity of concentration-QTc relationship

Finally, the linear model was applied to the data and the goodness-of-fit plot is shown in Figure 7. Both the slope and the intercept were statistically significant. The predicted QTcF at the geometric mean of observed Cmax in this study (12.3 ng/mL) is 5.6 ms (90% CI: 3.4, 7.9 ms). The analysis supports the exclusion of large mean effect (i.e. >20 ms) on the QTc interval.


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Figure 7: Goodness-of-fit plot for QTc


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/s/

NAN ZHENG 10/31/2019 10:18:57 AM

YU YI HSU 10/31/2019 03:05:10 PM

DALONG HUANG 10/31/2019 03:07:09 PM

MICHAEL Y LI 10/31/2019 03:18:07 PM

DEVI KOZELI on behalf of LARS JOHANNESEN 11/01/2019 10:24:59 AM Signing on behalf of Lars as he is out of the office

CHRISTINE E GARNETT 11/01/2019 10:27:10 AM


LABEL AND LABELING REVIEW Division of Medication Error Prevention and Analysis (DMEPA)

Office of Medication Error Prevention and Risk Management (OMEPRM) Office of Surveillance and Epidemiology (OSE)

Center for Drug Evaluation and Research (CDER)

*** This document contains proprietary information that cannot be released to the public***

Date of This Review: October 22, 2019

Requesting Office or Division: Division of Oncology Products 1 (DOP1)


Product Name, Dosage Form, Enhertu (fam-trastuzumab deruxtecan-xxxx)a for Injection, and Strength: 100 mg/vial

Product Type: Single Ingredient Product

Rx or OTC: Prescription (Rx)


FDA Received Date: August 29, 2019

OSE RCM #: 2019-1565



a Since the proper name for Enhertu has not yet been determined, “fam-trastuzumab deruxtecan-xxxx” is used throughout this review as the nonproprietary name for this product.

1


1 REASON FOR REVIEW

As part of the review process for Enhertu (fam-trastuzumab deruxtecan-xxxx) for Injection, the Division of Oncology Products 1 (DOP1) requested that we review the proposed Enhertu prescribing information (PI), container label, and carton labeling for areas of vulnerability that may lead to medication errors.

2 MATERIALS REVIEWED

We considered the materials listed in Table 1 for this review. The Appendices provide the methods and results for each material reviewed.

Table 1. Materials Considered for this Label and Labeling Review

Material Reviewed Appendix Section (for Methods and Results)

Product Information/Prescribing Information A

Previous DMEPA Reviews B – N/A

Human Factors Study C – N/A

ISMP Newsletters* D – N/A

FDA Adverse Event Reporting System (FAERS)* E – N/A

Other F – N/A

Labels and Labeling G

N/A=not applicable for this review *We do not typically search FAERS or ISMP Newsletters for our label and labeling reviews unless we are aware of medication errors through our routine postmarket safety surveillance

3 OVERALL ASSESSMENT OF THE MATERIALS REVIEWED

3.1 PRESCRIBING INFORMATION (PI)

We reviewed the proposed Enhertu PI and determined that it may be improved to promote the safe use of this product.

3.2 CONTAINER LABEL AND CARTON LABELING

We reviewed the proposed Enhertu container label and carton labeling and determined that they may be improved to promote the safe use of this product and for clarify.

4 CONCLUSION & RECOMMENDATIONS

The proposed PI, container label, and carton labeling received August 29, 2019 may be improved to promote the safe use of this product and for clarity. We provide specific recommendations in Section 4.1 and 4.2 below.

2


4.1 RECOMMENDATIONS FOR THE DIVISION

A. Highlights of Prescribing Information

1. Dosage and Administration Section

a. Consider relocating the statement “Do not substitute ENHERTU for or with trastuzumab or ado-trastuzumab emtansine.” immediately below the Dosage and Administration header to increase the prominence of this important statement. Consider bolding this statement instead of underlining to improve prominence.

B. Full Prescribing Information

1. Dosage and Administration Section

a. Consider relocate the statement “Do not substitute ENHERTU for or with trastuzumab or ado-trastuzumab emtansine.” Immediately below the header 2.1 Recommended Doses and Schedules to increase the prominence of this important statement. Consider bolding this statement instead of underlining to increase prominence.

4.2 RECOMMENDATIONS FOR DAIICHI SANKYO, INC

We recommend the following be implemented prior to approval of this BLA:

A. Container label

1. Add the linear barcode to the container label as required per 21 CFR 201.25. See Product Identifiers under the Drug Supply Chain Security Act - Questions and Answers, available at https://www.fda.gov/regulatory-information/search-fdaguidance-documents/product-identifiers-under-drug-supply-chain-security-actquestions-and-answers.

B. Carton Labeling

1. Consider revising the statement (b) (4)

to “Dosage: See Prescribing Information.” for clarity.

3


https://www.fda.gov/regulatory-information/search-fda

APPENDICES: METHODS & RESULTS FOR EACH MATERIALS REVIEWED APPENDIX A. PRODUCT INFORMATION/PRESCRIBING INFORMATION

Table 2 presents relevant product information for Enhertu received on August 29, 2019 from Daiichi Sankyo, Inc.

Table 2. Relevant Product Information for Enhertu

Initial Approval Date N/A

Nonproprietary Name fam-trastuzumab deruxtecan-xxxx

Indication

Route of Administration Intravenous

Dosage Form for Injection

Strength 100 mg/vial

Dose and Frequency 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

Dose reduction for adverse reactions

Dose Reduction Schedule (Starting dose is 5.4

mg/kg.)

Dose to be administered

First dose reduction 4.4 mg/kg Second dose reduction 3.2 mg/kg Requirement for further dose reduction

Discontinue treatment.

How Supplied Carton of one single-dose vial

Storage Store vials in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF) until time of reconstitution.

Container Closure 10 mL glass vial and sealed with a rubber stopper, and a aluminum

yellow flip-off crimp cap.

(b) (4)

(b) (4) (b) (4)

(b) (4) (b) (4)

4


APPENDIX G. LABELS AND LABELING G.1 List of Labels and Labeling Reviewed

Using the principles of human factors and Failure Mode and Effects Analysis,b along with postmarket medication error data, we reviewed the following Enhertu labels and labeling submitted by Daiichi Sankyo, Inc.

Container label received on August 29, 2019 Carton labeling received on August 29, 2019 Prescribing Information (Image not shown) received on August 29, 2019 available from

\\CDSESUB1\evsprod\BLA761139\0002\m1\us\114-labeling\draft\labeling\us-piclean.docx

G.2 Label and Labeling Images

Container label (b) (4)

b Institute for Healthcare Improvement (IHI). Failure Modes and Effects Analysis. Boston. IHI:2004.

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/s/

TINGTING N GAO 10/22/2019 09:03:49 AM

CHI-MING TU 10/22/2019 09:13:28 AM


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