The Feinstein Institute for Medical ResearchFluorodopa F 18 Injection

NDA 200655 COMPLETE RESPONSE

The Feinstein Institute for Medical Research Attention: Thomas Chaly, Ph.D., FAIC

Chief, Cyclotron — Radiochemistry Department 350 Community Drive

Manhasset, NY 11030

Dear Dr. Chaly:

Please refer to your New Drug Application (NDA) dated October 29, 2009, received October 30, 2009, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for Fluorodopa F 18 Injection, 0.42 mCi/mL to 8.33 mCi/ml.

We acknowledge receipt of your amendment dated December 15, 2015, which constituted a complete response to our October 22, 2013, action letter.

We acknowledge receipt of your major amendment dated April 11, 2016, which extended the goal date by three months.

We also acknowledge receipt of your amendment dated August 31, 2016, which was not reviewed for this action. You may incorporate applicable sections of the amendment by specific reference as part of your response to the deficiencies cited in this letter.

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.

CLINICAL / STATISTICAL

Your resubmitted application contained the report of the prospectively designed “Study #17” which aimed to evaluate Fluorodopa F 18 for: 1) sensitivity, specificity, and clinical utility in the differential diagnosis of Parkinsonian syndromes, 2) inter-reader reliability, 3) quantitative correlation with Parkinson’s disease diagnosis, and 4) safety by monitoring for adverse events. This study does not provide sufficient confirmatory evidence of effectiveness and the Fluorodopa F 18 PET scan’s performance is not adequately characterized.

In Study #17, 45 movement disorder patients were imaged with Fluorodopa F 18. Of these patients,

32 had images interpreted as positive for visualization of a loss of dopaminergic neurons in striatum and 13 were interpreted as negative.

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Out of these 13 patients, only 5 patients had undergone a clinical follow up which was to serve as a standard of reference and only 1 of these patients had a clinical follow up at a pre-defined time interval following the Fluorodopa F 18 PET scan (>1 year). Some patients had an interval as short as one or two weeks. Therefore, out of 13 patients with no loss of dopaminergic neurons in striatum as visualized with Fluorodopa F 18, only 1 patient had this interpretation adequately verified.

Additionally, the image interpretations were known to the clinicians providing follow-up prior to their determination of the clinical diagnosis. Because the clinician was responsible for making the assessment of the clinical diagnosis, which served as the standard of reference, it is possible that the results of the test influenced their a: s is not acceptable as a standard of reference and is not adequate for support of the proposed visualization claim.

Furthermore, we note that in patients with “positive” images, only 20 patients had a standard of reference obtained | year or more following imaging with Fluorodopa F 18. Most patients did not have 1 year of follow-up. This is also inadequate.

The three readers agreed with each other on the interpretation of the scans in 98% (44 of 45 images) of the patients. It is not clear what clinical information was provided to the readers or the amount of independence from each other they had in making the reads.

Going forward, it is important to develop a plan to address these deficiencies. It will need to include a method to make a clinical assessment of the patients’ clinical diagnosis that is not influenced by the results of the image reads. This will include obtaining complete follow up on all of the subjects. You may extend Study #17 to enroll additional patients who will also go on to have a clinical follow up at a pre-defined interval as an adequate standard of reference. The deficiencies with the study protocol and conduct of the study will need to be corrected as you go forward. You should also clearly document which clinical features in each patient were consistent with Parkinsonian or non-Parkinsonian syndrome.

You may consider requesting a meeting to discuss the design of an appropriate statistical analysis plan for the completion and extension of Study #17.

PRESCRIBING INFORMATION

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(1)(1)(i)] in structured product labeling (SPL) format as described at http://www.fda.gov/ForIndustry/DataS tandards/StructuredProductLabeling/default.htm

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SAFETY UPDATE

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

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

2. When assembling the sections describing discontinuations due to adverse events, serious adverse events, and common adverse events, incorporate new safety data as follows:

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

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.

3. 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.

4. 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.

5. 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.

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

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

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

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ADDITIONAL COMMENTS We have the following comment which is not an approvability issue:

As per your amendment dated April 14, 2016, we remind you of your commitment to provide information regarding (4)

. You agreed to submit this information in a Prior Approval Supplement if NDA 200655 is approved. However, we acknowledge your amendment dated August 31, 2016, containing chemistry information to address this commitment. As noted above, your August 31, 2016 amendment was not reviewed for this action and may be incorporated by specific reference if you decide to resubmit this application.

OTHER

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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If you have any questions, contact Ms. Thuy M. Nguyen, M.P.H., Senior Regulatory Health Project Manager at (301) 796-1427 or Thuy.Nguyen @fda.hhs.gov.

Sincerely,

{See appended electronic signature page} Charles J. Ganley, M.D.

Director

Office of Drug Evaluation IV Center for Drug Evaluation and Research

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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.

THUY M NGUYEN 09/15/2016

CHARLES J GANLEY 09/15/2016

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