CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
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`APPLICATION NUMBER:
`208700Orig1s000
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`OTHER ACTION LETTERS
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 208700
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`Food and Drug Administration
`Silver Spring MD 20993
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`COMPLETE RESPONSE
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`Advanced Accelerator Applications USA, Inc.
`Attention: Victor G. Paulus, Ph.D.
`Head of Regulatory Affairs
`350 Fifth Avenue, Suite 6902
`New York, NY 10118
`
`Dear Dr. Paulus:
`
`Please refer to your New Drug Application (NDA) dated April 27, 2016, received April 28,
`2016, and your October 18 and 19, 2016, amendments, submitted under section 505(b)(1) of the
`Federal Food, Drug, and Cosmetic Act for LUTATHERA (177Lu-DOTA0-Tyr3-Octreotate),
`Injection for Intravenous Infusion; 370 MBq/mL single-use vial.
`
`We have completed our review of this application 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.
`
`CLINICAL/STATISTICAL
`
`1.
`
`FDA is not able to verify the data submitted in NDA 208700 due to missing data,
`uninterpretable data, data errors and unusable datasets. In order for FDA to evaluate the
`safety and effectiveness of 177Lu-DOTA0-Tyr3-Octreotate, and to verify data proposed in
`product labeling, submit datasets from all studies included in the NDA submission that
`are accurate, complete, and internally consistent in order to allow FDA inspection,
`review, and archiving. A comprehensive review of all data submitted in the NDA was
`not possible due to the deficiencies catalogued above; therefore, additional deficiencies
`may exist that were not discovered during the course of the review.
`
`In addition to providing accurate, complete, and internally consistent datasets, ensure that
`the following deficiencies are addressed in your resubmission:
`
`a.
`
`b.
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`Provide datasets with English characters, including variable names (for example,
`the variable names were in Chinese character Adverseeventsm1 data under SN
`22).
`The legacy raw datasets appeared to be modified after the clinical data cut-off
`date (for example, DM information was last modified on November 14, 2015, and
`the most recent tumor evaluation was modified on September 23, 2016). Ensure
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`Reference ID: 4028661
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`NDA 208700
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`Page 2
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`c.
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`d.
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`e.
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`f.
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`g.
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`iii.
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`iv.
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`that the raw data used to generate the datasets have been audited for
`completeness, missing data and errors, and provide cleaned and locked data up to
`the time of database lock.
`Minimize missing data or provide justification for why these data are not
`included. For example:
`i.
`Essential variables for tumor assessments were missing.
`ii.
`Baseline CrCl values or dosing information for several patients in the
`fdaclinpharmreqbaselab dataset were missing. Dosing information (for
`example, tdosemci) was missing even though organ radiation exposure and
`blood concentration (Cmax, AUC) data were provided.
`Demographic and baseline patient characteristics data were missing (for
`example, in the fdaclinpharmreqbaselab dataset).
`Laboratory parameters and organ exposure information was missing from
`clinical pharmacology datasets in the Erasmus PK study folder.
`The datasets contained values that appeared to be incorrect or invalid. For
`example, some laboratory test results appeared to be grossly out of range and
`incompatible with other reported data for the same patient. Furthermore, some lab
`test values did not have measurement units associated with them to permit an
`understanding of the meaning of the value. Ensure that the data are reviewed for
`errors and provide appropriate units of measurement for all data values.
`The datasets are missing unique subject IDs and study IDs. Ensure that all
`datasets submitted in the NDA include these variables and assign each patient a
`single unique subject identification (USUBJID) across the entire submission.
`Ensure that consistent doses are recorded across datasets (for example, for patient
`BE01-002: 7.541 GBq in fdaclinpharmreqbaselab and 7.274 GBq for pktp
`datasets). Provide consistent data across datasets or justify why there are different
`doses provided.
`In order to confirm the derived values/parameters, provide the following variables
`(sampled, timefadm, measurdt, bloodvol, sampvol, collvol, countval, countvau,
`activcon, pepticon, activity, percia, and percumia) in the Erasmus datasets, or
`justify why the variables cannot be provided: pp, pc, supppc, and supppp datasets.
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`2.
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`3.
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`Submit revised clinical study reports (CSR) that contain data and analyses based on the
`datasets submitted to address item number 1.
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`As required per 21 CFR 314.50, provide safety and efficacy subgroup analyses for
`gender, age, and racial subgroups. Also provide subgroup analyses based on stratification
`factors and any other important disease characteristics.
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`NDA 208700
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`FACILITIES
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`4.
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`During recent inspections of the manufacturing facilities for this NDA, our field
`investigator observed objectionable conditions at the Advanced Accelerator
`Applications, Meldola, Italy (FEI#3010469290); Advanced Accelerator Applications,
`Colleretto Giacosa, Ivrea, Italy (FEI#3010175147); and IDB Radiopharmacy B.V.,
`Netherlands (FEI#3010293768) facilities and conveyed the information to the
`representatives of each of the facilities at the close of the inspections. Satisfactory
`resolution of the observations is required from each of the facilities before this NDA may
`be approved.
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`ADDITIONAL COMMENTS
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`5.
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`Submit the following in your response:
`
`a.
`
`b.
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`DSMB meeting minutes from the NETTER and ERASMUS trials; and,
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`A study data reviewer’s guide and an analysis data reviewer’s guide for the legacy
`raw data and analysis data, respectively.
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`In order to facilitate re-submission of the datasets, refer to the “Study Data Technical
`Conformance Guide: Technical Specifications Document,” available at:
`http://www.fda.gov/downloads/ForIndustry/DataStandards/StudyDataStandards/UCM38
`4744.pdf, and “Providing Regulatory Submissions In Electronic Format-Standardized
`Study Data and Data Standards Catalog,” available at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
`ances/UCM292334 and
`http://www.fda.gov/forindustry/datastandards/studydatastandards/default.htm.
`
`To facilitate FDA’s review of the application, we recommend that you use the standards
`specified in the FDA’s Data Standards Catalog.
`
`Traceability permits an understanding of the relationships between the analysis results
`tables, listings and figures (TLFs) in the CSR, and the analysis datasets, tabulation
`datasets, and source data. To ensure data traceability, map variables in the case report
`forms (CRFs) to the corresponding variables in the datasets (for example, sex was
`reported as 916576 and 920197 but reported as Male and Female in aCRF for variable
`DM.DMSEX). Additionally, provide information necessary to allow FDA to understand
`the provenance of the data (i.e., traceability of the analysis results back to the annotated
`CRF).
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`Provide a define file that allows reviewers to understand the variables and derivations in
`the datasets. Additionally, ensure that the define file has sufficient comments, adequate
`bookmarks, and hyperlinks to the xpt files, CRFs, controlled terminologies, and
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`6.
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`7.
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`8.
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`9.
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`NDA 208700
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`10.
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`11.
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`12.
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`13.
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`14.
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`15.
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`16.
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`computational methods. The define files submitted to the NDA were missing metadata
`and there were inconsistencies between output variables and the assigned code.
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`Provide consistent definitions and patient numbers between datasets or explain why the
`discrepancies should be accepted (for example, “A” indicates treatment in
`fdaclinpharmreqbaselab database, but “AO” is listed as treated in the PK sub study in
`summpat database).
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`Provide consistent controlled terminology across datasets (for example, yes vs. no value
`was coded as no vs. yes; the treatment arms were coded as A vs. B in PFS.treat and 1 vs.
`2 in PFS.treatx without control terminology for PFS.SAS7bdat).
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`Provide all necessary SAS programs, SAS macro, SAS format library, and adequate
`documents in order to duplicate the analysis datasets derivation from the raw dataset and
`the analysis results in the CSR and USPI.
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`Provide an explanation for why the calibration factor
` is used in the gamma detection
`of 177Lu-DOTA0-Tyr3-Octreotate for the following patients in the pktp dataset: DE01-
`006, DE01-009, DE01-010, and DE01-014, as other patients in this dataset have a
`calibration factor ranging from
` to
`.
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`Provide the analysis for patient ID NETTER-1-UK06-003 in the pp and supppp datasets.
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`The submitted datasets had many missing essential variables precluding our ability to
`accurately assess efficacy. Ensure that efficacy datasets include stratification variables
`based on IVRS in addition to those based on the CRFs. In addition, include age, race,
`gender and important disease characteristics as variables.
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`Provide datasets in XPT format to allow FDA to process, review and archive the data.
`Specifically, ensure that the following issues are addressed in the submission.
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`
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`
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`Split datasets to ensure that datasets are no larger than 5 GB [four datasets
`(Labblood, eortc, laburinem2, and adverseeventm1) were greater than 5 GB in
`size].
`To reduce file size, set the allotted length for each variable to the maximum
`length of variables used across the entire submission.
`Include one dataset per transport file with the same name.
`Set the maximum length in characters for dataset and variable names to 8.
`Set the maximum length in characters for dataset and variable labels to 40.
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`17.
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`Use American Standard Code for Information Interchange (ASCII) text codes. We
`recommend that you utilize the default SAS coding system, wlatin1 (i.e., western world
`encoding) because the encoding system you used to generate the datasets (utf-8 Unicode)
`resulted in reading errors.
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`Reference ID: 4028661
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`NDA 208700
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`
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`
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`Exclude punctuation, dashes, spaces, non-alphanumerical symbols, and special
`characters in variable and dataset names.
`Exclude user-defined SAS format libraries. Instead, you may provide this
`information in the Controlled Terminologies.
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`SAFETY UPDATE
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`When you respond to the above deficiencies, include a safety update as described at
`21 CFR 314.50(d)(5)(vi)(b). 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.
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`18.
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`Describe in detail any significant changes or findings in the safety profile.
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`19. When assembling the sections describing discontinuations due to adverse events, serious
`adverse events, and common adverse events, incorporate new safety data as follows:
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`a. Present new safety data from the studies/clinical trials for the proposed indication
`using the same format as in the original submission.
`b. Present tabulations of the new safety data combined with the original application
`data.
`Include tables that compare frequencies of adverse events in the original application
`with the retabulated frequencies described in the bullet above.
`d. For indications other than the proposed indication, provide separate tables for the
`frequencies of adverse events occurring in clinical trials.
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`c.
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`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.
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`Provide case report forms and narrative summaries for each patient 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.
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`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.
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`Provide updated exposure information for the clinical studies/trials (e.g., number of
`subjects, person time).
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`Provide a summary of worldwide experience on the safety of this product. Include an
`updated estimate of use for product marketed in other countries.
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`Provide English translations of current approved foreign labeling not previously
`submitted.
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`20.
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`21.
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`22.
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`23.
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`24.
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`25.
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`NDA 208700
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`PRESCRIBING INFORMATION
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`We reserve comment on the proposed labeling until the application is otherwise adequate.
`
`We encourage you to review the labeling review resources on the PLR Requirements for
`Prescribing Information and Pregnancy and Lactation Labeling Final Rule websites, including
`regulations and related guidance documents and 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 314.50(l)(1)(i)] in structured product labeling (SPL) format as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.
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`OTHER
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`Within one year after the date of this letter, you are required to resubmit or take other actions
`available under 21 CFR 314.110. 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 314.65. 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 FDA Guidance for Industry, “Formal Meetings Between
`FDA and Sponsors or Applicants,” May 2009 at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM153222.pdf.
`
`The drug product may not be legally marketed until you have been notified in writing that this
`application is approved.
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`PDUFA V APPLICANT INTERVIEW
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`FDA has contracted with Eastern Research Group, Inc. (ERG) to conduct an independent interim
`and final assessment of the Program for Enhanced Review Transparency and Communication for
`NME NDAs and Original BLAs under PDUFA V (“the Program”). The PDUFA V Commitment
`Letter states that these assessments will include interviews with applicants following FDA action
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`NDA 208700
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`on applications reviewed in the Program. For this purpose, first-cycle actions include approvals,
`complete responses, and withdrawals after filing. The purpose of the interview is to better
`understand applicant experiences with the Program and its ability to improve transparency and
`communication during FDA review.
`
`ERG will contact you to schedule a PDUFA V applicant interview and provide specifics about
`the interview process. Your responses during the interview will be confidential with respect to
`the FDA review team. ERG has signed a non-disclosure agreement and will not disclose any
`identifying information to anyone outside their project team. They will report only anonymized
`results and findings in the interim and final assessments. Members of the FDA review team will
`be interviewed by ERG separately. While your participation in the interview is voluntary, your
`feedback will be helpful to these assessments.
`
`If you have any questions, call Susan Truitt, Regulatory Health Project Manager, at (240) 402-
`3656.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Richard Pazdur, M.D.
`Director
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
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`Reference ID: 4028661
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`RICHARD PAZDUR
`12/19/2016
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`Reference ID: 4028661
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`