Daiichi Sankyo, Inc.HER3-Dxd

BLA 761366 COMPLETE RESPONSE

Daiichi Sankyo, Inc.

Attention: Anandika Dhaliwal, PhD, RAC Associate Director, Regulatory Affairs 211 Mount Airy Road

Basking Ridge, NJ 07920

Dear Dr. Dhaliwal:

Please refer to your biologics license application om

or HER3-Dxd.

We have completed our review of this application, as amended, and have determined that we cannot approve this application in its present form. We have described our reasons for this action below and, where possible, our recommendations to address these issues.

FACILITY INSPECTIONS 1. Following pre-license inspection of Ch)

, listed in this application, FDA conveyed deficiencies to the representative of the facility. The facility should provide satisfactory responses to these deficiencies to the FDA office indicated on the FDA Form 483 prior to your resubmission of the application. Your resubmission should include the date(s) of the facility’s response to the FDA Form 483. The assessment of application approvability and the resolution of inspection deficiencies will be evaluated upon receipt of the resubmission and may include re-inspection of the facility. Please work with the facility in resolving the related deficiencies.

PRESCRIBING INFORMATION

2. We reserve comment on the proposed labeling until the application is otherwise adequate. We encourage you to review the labeling review resources on the Prescription Drug Labeling Resources! and Pregnancy and Lactation Labeling Final Rule? websites, including regulations and related guidance documents and

1 https:/Awww.fda.gov/drugs/laws-acts-and-rules/prescription-drug-labeling-resources 2 https://www.fda.gov/drugs/labeling-information-drug-products/pregnancy-and-lactation-labeling-drugs- final-rule

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the Selected Requirements for Prescribing Information (SRPI) - a checklist of important format items from labeling regulations and guidances.

If you revise labeling, use the SRPI checklist to ensure that the Prescribing Information conforms with format items in regulations and guidances. Your response must include updated content of labeling [21 CFR 601.14(b)] in structured product labeling (SPL) format as described at FDA.gov.?

CARTON AND CONTAINER LABELING

3. We reserve comment on the proposed labeling until the application is otherwise adequate.

MEDICATION GUIDE

4. Add the following bolded statement or appropriate alternative to the carton and container labeling per 21 CFR 208.24(d): "ATTENTION PHARMACIST: Each patient is required to receive the enclosed Medication Guide."

PROPRIETARY NAME

5. Please refer to correspondence dated om , which addresses the proposed proprietary name, |). This name was found conditionally acceptable pending approval of the application in the current review cycle. Please resubmit the proposed proprietary name when you respond to all of the application deficiencies that have been identified in this letter.

SAFETY UPDATE

When you respond to the above deficiencies, include a safety update. The safety

update should include data from all nonclinical and clinical studies/trials of the product

under consideration regardless of indication, dosage form, or dose level.

6. Describe in detail any significant changes or findings in the safety profile.

7. When assembling the sections describing discontinuations due to adverse events, serious adverse events, and common adverse events, incorporate new

safety data as follows:

e Present new safety data from the studies/clinical trials for the proposed indication using the same format as in the original submission.

3 http://www.fda.gov/Forlndustry/DataStandards/StructuredProductLabeling/default.htm

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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BLA 761366 Page 3

e Present tabulations of the new safety data combined with the original application data.

e Include tables that compare frequencies of adverse events in the original application with the retabulated frequencies described in the bullet above.

e For indications other than the proposed indication, provide separate tables for the frequencies of adverse events occurring in Clinical trials.

8. Present a retabulation of the reasons for premature trial discontinuation by incorporating the drop-outs from the newly completed trials. Describe any new trends or patterns identified.

9. Provide case report forms and narrative summaries for each subject who died during a Clinical trial or who did not complete a trial because of an adverse event. In addition, provide narrative summaries for serious adverse events.

10. Describe any information that suggests a substantial change in the incidence of common, but less serious, adverse events between the new data and the original application data.

11. Provide updated exposure information for the clinical studies/trials (e.g., number of subjects, person time).

12. Provide a summary of worldwide experience on the safety of this product. Include an updated estimate of use for product marketed in other countries.

13. Provide English translations of current approved foreign labeling not previously submitted.

ADDITIONAL COMMENTS

We have the following comments/recommendations that are not approvability issues:

Product Quality

(b) (4)

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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(b) (4)

Clinical

16. We note that the proposed confirmatory study, Study U31402-A-U301 (HERTHENA-Lung02, HL-02, Study U301) did not meet the pre-specified efficacy boundary for PFS at the interim analysis (data cut-off date oe

). We recommend that you request a post-action meeting with FDA (e.g., Type A) prior to application resubmission to discuss alternative trial(s) that may verify clinical benefit after a potential accelerated approval.

OTHER

Within one year after the date of this letter, you are required to resubmit or take other actions available under 21 CFR 601.3(b)). If you do not take one of these actions, we may consider your lack of response a request to withdraw the application under

21 CFR 601.3(c). You may also request an extension of time in which to resubmit the application.

A resubmission must fully address all the deficiencies listed in this letter and should be clearly marked with "RESUBMISSION" in large font, bolded type at the beginning of the cover letter of the submission. The cover letter should clearly state that you consider this resubmission a complete response to the deficiencies outlined in this letter. A partial response to this letter will not be processed as a resubmission and will not start a new review cycle.

You may request a meeting or teleconference with us to discuss what steps you need to take before the application may be approved. If you wish to have such a meeting, submit your meeting request as described in the draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products.

The product may not be legally marketed until you have been notified in writing that this application is approved.

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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Page 5 If you have any questions, contact

Sincerely,

{See appended electronic signature page}

rug Evaluation and Researc!

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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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.

(b) (4)

06/26/2024 03:58:39 PM

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