CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 2080540rig15000 SUMMARY REVIEW Division Director Summary Review NDA 208054, Axumin (Fluciclovine 18) Libero Marzella MD, Division Director Summary Review for Regulatory Action Date 5/10/2016 From Libero Marzella MD, Subject Division Director Summary Review 208054 Supplement 0 Applicant Blue Earth Diagnostics Date of Submission 9/28/2015 PDUFA Goal Date 5/27/2016 Proprietary Name Axrmrin Non-Proprietary Name Fluciclovine F18 Dosage Form(s) Strength(s) Injection 26 mL solution of 335-8200 (9-221 mCi/an ?uciclovine 18 Applicant Proposed PET imaging of men with suspected prostate cancer recrurence based on elevated PSA levels Action/Recommended Action for NME: Recommend approval Approved/Recommended Indication/Population(s) Axurnin is a radioactive diagnostic agent indicated for positron emission tomography (PET) imaging in men with suspected prostate cancer recurrence based on elevated blood prostate speci?c antigen (PSA) levels following prior treatment. Material Reviewed/Consulted 0ND Action Package, including: Names of discipline reviewers Medical Of?cer Review Phillip Davis MD Reference ID: 3929291 Division Director Summary Review NDA 208054, Axumin (Fluciclovine F 18) Libero Marzella MD, PhD Statistical Review Pharmacology Toxicology Review OPQ Reviews: Drug substance Drug Product (DP) Facility Environmental assessment Microbiology Review Clinical Pharmacology Review CDTL Review Labeling Review OPDP OSE/DMEPA OSE/DRISK Anthony Mucci PhD Yanli Ouyang MD PhD Benjamin D. Stevens PhD Ravindra K. Kasliwal PhD Tony Wilson James Laurenson PhD Eric Adeeku PhD Christy John PhD Nushin Todd MD, PhD Michele Fedowitz MD Adam George PharmD Michelle Rutledge PharmD Mona Patel PharmD OND=Office of New Drugs OPQ=Office of Pharmaceutical Quality OPDP=Office of Prescription Drug Promotion CDTL=Cross-Discipline Team Leader OSE= Office of Surveillance and Epidemiology DEPI= Division of Epidemiology DMEPA=Division of Medication Error Prevention and Analysis DRISK=Division of Risk Management 1. Benefit-Risk Assessment Benefit-Risk Summary and Assessment Recurrence of prostate cancer after treatment with curative intent of the primary cancer is an important public health concern. Often the only evidence of recurrence is a rise in the levels of prostate specific antigen and standard imaging modalities fail to localize the site of recurrence. New imaging modalities are needed to improve the accuracy and early detection of cancer recurrence. Improvements in diagnostic performance are important to guide patient management and improve clinical outcomes. 2 Reference ID: 3929291 Division Director Summary Review NDA 208054, Axumin (Fluciclovine F 18) Libero Marzella MD, PhD Fluciclovine F -18 is a radiolabeled amino acid analogue designated as a new molecular entity in the diagnostic radiopharmaceutical product class for use with positron emission tomography imaging. Fluciclovine F 18 is transported across cell membranes by amino acid transporters that are upregulated in cancer cells. Fluciclovine F 18 is taken up to a greater extent in prostate cancer cells compared with surrounding normal tissues. The efficacy of Axumin was evaluated in two studies in men with suspected recurrence of prostate cancer based on rising PSA levels following radical prostatectomy and/or radiotherapy. I relied on a study conducted at Emory University (published by Schuster et al, J Urol 191: 14461453, 2014) for the primary evidence of efficacy and on a second study conducted at the University of Bologna (published by Nanni et al, Clin Nucl Med, 40 (8): 386-391, 2015) for supportive efficacy. The Applicant re-analyzed the studies and conducted blinded, independent, re-reads of the images to verify the original clinical site interpretation of the images. The Emory study evaluated 105 Axumin scans in comparison to histopathology obtained by biopsy of the prostate bed and biopsies of lesions suspicious by imaging. The study met its primary efficacy endpoint of positive predictive value and these results were consistent with multiple additional analyses of performance. At the subject level seven of ten patients with lesions detected by Fluciclovine F18 (71%) had prostatic cancer metastases and nearly all (97%) patient with metastases had Fluciclovine F 18 detections verified as positive by histology. The performance of Axumin is affected by PSA levels. Among the 16 scans in patients with PSA levels less than or equal to 1 ng/mL, there were 4 false positive scans and 1 false negative scan. Among the 83 scans in patients with PSA levels greater than 1 ng/mL, there were 13 false positive scans and no false negative scans. The results of the independent reads were generally consistent with one another and confirmed the results of the on-site reads. The Bologna study evaluated the concordance between 96 Axumin and Choline C 11 scans. The agreement values between the Axumin and Choline C11 reads were 61%, 67% and 77% respectively. I conclude that the studies establish the utility of Fluciclovine F 18 for the detection of metastases of prostatic cancer in patients with recurrent disease. The risks of Axumin are associated with radiation exposure and with image interpretation errors. Axumin use contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer. Incorrect image interpretation is possible because. Fluciclovine F 18 uptake is not specific for prostate cancer and may occur with other types of cancer and benign prostatic hypertrophy in primary prostate cancer. Therefore a positive image does not confirm the presence of recurrent prostate cancer and a negative image does not rule out the presence of recurrent prostate cancer. Clinical correlation, which may include histopathological evaluation of the suspected recurrence site, is recommended. Given the clinical importance of early and accurate detection of metastatic disease in patients suspected of having recurrent prostatic cancer, the 3 Reference ID: 3929291 Division Director Summary Review NDA 208054, Axumin (Fluciclovine F 18) Libero Marzella MD, PhD risks are acceptable. I conclude that the risk benefit of Fluciclovine F 18 is favorable and recommend approval of this new drug application. Dimension Analysis of Condition Current Treatment Options Evidence and Uncertainties  Patients who have undergone curative treatment of primary carcinoma of the prostate by radical prostatectomy or radiotherapy are followed clinically by testing that includes the measurement of prostate specific antigen (PSA). Patients who develop elevated PSA are suspected of having cancer recurrence. Localization of the recurrent cancer is critical for patient management and prognosis.  Prostatic cancer is the second most commonly diagnosed cancer in the US. It is estimated that ten percent of patients experience cancer recurrence after primary treatment. Accurate staging is an important objective in improving management and outcomes in primary and recurrent cancer.  Magnetic resonance imaging, computed tomography ultrasonography, single photon emission tomography and positron emission tomography are imaging procedure that might be done to localize recurrent prostatic cancer.  Blind biopsy of the prostatic bed region, lesion biopsy directed by findings on one or more imaging modality and clinical follow up are used to localize and verify the recurrence of the tumor and to develop a patient management plan.  The diagnostic accuracy of standard imaging for tumor detection is low. Enhanced performance characteristics and greater commercial distribution potential than provided by the currently marketed radiopharmaceuticals are needed. Conclusions and Reasons Primary and recurrent prostatic carcinoma is a major public health issue in the US. The standard imaging modalities have limitations. New diagnostic options are needed for this serious condition. 4 Reference ID: 3929291 Division Director Summary Review NDA 208054, Axumin (Fluciclovine 18) Libero Marzella MD, Dimension Evidence and Uncertainties Conclusions and Reasons The data analyses from two prospective studies in the original publications and the re-analyses performed after blinded central interpretation of the Axrunin images yielded favorable and consistent results. 0 The Emory study provided acceptable estimates of positive predictive values (PPV) and lesion detection rates compared to a histology truth standard. However PPV is in?uenced by the prevalence of disease The truth standard is dependent on lesions detected by test, active control, or other imaging introducing veri?cation bias and dif?culty in verifying true negative status. 0 The Bologna study provided supportive evidence of concordance of Axrunin and Choline C11. 0 Accurate staging of prostatic cancer in primary and recurrent prostatic cancer is an important medical need. Insuf?cient information was presented to establish that no important differences in tumor detection exist between patients with primary and patients with recurrent cancer. 0 Both ef?cacy studies of Axurnin included an active diagnostic comparator. one In the study that included a truth standard, the lesion detection rates were numerically higher for Axumin compared to 1 lIn-capromab pendetide. Standard accru'acy measures (sensitivity and speci?city) cannot be used to evaluate cancer recurrence. PPV met its prespeci?ed threshold but the estimate is in?uenced by disease prevalence. ?Sensitivity? de?ned as proportion of patients with histology positive lesions who had these lesions detected by ?uciclovine was very high. The most meaningful data are considered to be patient and region-level estimates of true positive and false negative rates as determined by central readers. (m4) 0 Radiation exposure, misinterpretation of clinical images, hypersensitivity reactions are the most important safety concerns. 0 Axrunin contributes to a patient overall radiation exposm?e. Long term crunulative exposru?e increases the risk of cancer. The effective radiation absorbed dose is approximately 6 The radiation exposure is consistent with that of other radiopharmaceutical diagnostic agents. Dosimetry tables will be provided in the labeling. Reference ID: 3929291 Division Director Summary Review NDA 208054, Axumin (Fluciclovine F 18) Libero Marzella MD, PhD Dimension Risk Management Evidence and Uncertainties  Image interpretation errors can occur with Axumin PET imaging. A negative image does not rule out the presence of recurrent prostate cancer and a positive image does not confirm the presence of recurrent prostate cancer. Fluciclovine F 18 uptake is not specific for prostate cancer and may occur with other types of cancer and benign prostatic hypertrophy in primary prostate cancer.  Diagnostic imaging agents as a class do not pose clinical risks that warrant the use of postmarketing risk management procedures. Conclusions and Reasons Imaging results need to be verified by additional clinical testing including histology; the labeling will address this risk No action is needed 6 Reference ID: 3929291 Division Director Summary Review NDA 208054, Axrunin (Fluciclovine 18) Libero Marzella MD, 2. Background On September 28, 2015 the Applicant (Blue Earth Diagnostics Ltd) submitted a 505(b)(1) new drug application (NDA) for the new molecular entity Fluciclovine 18. This diagnostic radiopharmaceutical is proposed for use in PET imaging of men with suspected prostate cancer recrurence based on elevated PSA levels. This review srunmarizes my assessment of the approvability of the NDA. Fluciclovine 18 (mm at Emory University and was subsequently developed as a PET radiopharmaceutical by (low and GE Healthcare. The Applicant acquired the rights to the data and did not conduct new preclinical studies or new clinical trials. The clinical reviewer (Dr. Davis) and the cross discipline team leader (Dr. Todd) provide an overview of the public health importance of the clinical condition, namely prostatic cancer recrurence after cru?ative therapy of a primary prostate cancer. The study patients are men who experience cancer recrurence based on rising prostate speci?c antigen (PSA) levels and who have negative standard diagnostic imaging studies. The application was granted a priority review status because Fluciclovine 18 was judged to have the potential to improve the diagnostic accuracy for a serious condition for which an accurate diagnosis is critical for patient management and improved outcome. Standard imaging modalities for evaluation of recrurence have generally low accuracy. The clinical reviewers srmimarize the available diagnostic options including the two radiopharmaceuticals indicated for use in this patient population. Indirun 111 capromab pendetide (Prostascint), a single photon emission computerized tomography (SPEC T) agent, was approved in 1999 for the diagnostic imaging of patient with primary prostate cancer at high risk of metastasis and in patient with a rising PSA post-prostatectomy. PET imaging with Choline 11 was approved in 2012, for use in patients with suspected prostatic cancer recrurence; however, the 20 minute half-life of 11C limits the use of this agent to medical centers with on-site production capability. There were no major scienti?c disagreements with the Applicant. The applicant reached agreement with the Division in pre-submission meetings on how to verify the results of the image interpretation performed on?site site for each of two prospective independent published studies for which they acquired the rights. There was general agreement among all the primary and secondary reviewers regarding the overall adequacy of quality information and of data from preclinical and clinical studies. The ef?cacy study design considerations and analyses for Axmnin are typical for diagnostic medical imaging products. No major statistical analysis issues arose during the review and no important safety issue were identi?ed. There are no class effects of particular concern for the product. No non-clinical safety signals, novel or incompletely resolved safety concerns were Reference ID: 3929291 Division Director Summary Review NDA 208054, Axumin (Fluciclovine 18) Libero Marzella MD, identi?ed. No postmarketing requirements and no risk evaluation and mitigation strategies are needed. I concm? with the unanimous recommendation for a regulatory action of approval of the NDA made by all the review disciplines. 3. Product Quality I concur with the MC reviewer Dr. Kasliwal that all the quality aspects, the drug substance, the drug product, the manufacturing process, the microbiological aspects and the environmental assessment have been reviewed and are f01md to be adequate to support approval of the application. The drug substance, ?uciclovine 18, is produced as an aqueous solution (mm The MC reviewer considers the products of the 09(4) modules to be equivalent. The manufacturing site for M0 the three drug product manufactruing site were inspected for confomrity with .The review of the manufactru?ing facilities has been completed and no signi?cant risks were identi?ed. The ?nal recommendation that the facilities are adequate for the operations proposed in the submission was issued. The NDA contains (m4) for the manufactlu?e of ?uciclovine F18 injection drug product subsequent to the approval of the NDA. The proposed proprietary name for the product is Axrunin. Fluciclovine (18F) is the International Non-proprietary Name for the active substance anti-1-amino-3-[18F] ?uorocyclobutane-l-carboxylic acid. Fluciclovine 18 is the proposed United States Approved Name (U SAN). I concur with the recommendation by Dr. Adeeku that suf?cient sterility assurance has been provided. The PET drug product is a sterile unpreserved solution for intravenous administration. Three manufacturing sites have been designated. No microbiology de?ciencies were identi?ed. 4. Nonclinical Pharmacology/Toxicology I concur with the recommendation by the pharmacology/toxicology reviewer Dr. Ouyang that the application be approved based on adequate nonclinical safety evaluations and the safety pro?le for the intended use. Reference ID: 3929291 Division Director Summary Review NDA 208054, Axumin (Fluciclovine 18) Libero Marzella MD, Fluciclovine 19, a non-radioactive formulation of the ?uciclovine 18 injection drug product with an equivalent impurity pro?le, was used in nonclinical studies. Dr. Ouyang summarizes the pharmacology toxicology ?ndings as follows. Process impurity The major issue was the presence of an impurity in the drug product. Nonclinical safety of the impurity was evaluated in the nonclinical studies conducted for formulation (containing M0) or for M0 alone. The lot used in the 14 day repeat dose toxicity studies contained 1.8 mcg/mL anti-FAC BC and (mo . The calculated ratio of anti-FAC BC M4) was (our The NOAELs for (W) are calculated using this ratio based on NOAELS for anti-FAC BC . Adequate safety margins for now were established (HMD (4) In?itancy Paravenous injection of ?uciclovine induces pain and mild in?ammation in the subcutaneous tissues. In a study in rabbits 3 of 6 animals struggled vigorously during and immediately after subcutaneous injection of cold ?uciclovine. This reaction was attributed to pain caused by low pH (3.1) and high osmotic pressure (515 mOsm/kg). In addition, slight cellular in?ltration in the subcutis was noted and resolved by Day 14. On the other hand, ?uciclovine did not induce vascular irritancy in rabbits following intravenous injection. No hemolytic activity was identi?ed. The Applicant agreed to change pH to 4 upon the recommendation. Pharmacology uptake peaked at 5 to 30 minutes in ?ve hrunan prostate adenocarcinoma cell lines. The uptake by the cancer cell lines was higher than that by normal human prostate epithelial cell line at early time points (2 to 9 times higher at 5 and 15 minutes). 18F-anti- FACBC in tumor bearing mice achieved the highest tumor/tissue ratios at 5 minutes post- dosing. Safety pharmacology In assays, mol/L (the highest concentration tested) of anti-FAC BC had minimal effect on the crurent amplitude compared with the controls (91% of the control value). Intravenous administration of 43 mcg/kg FAC BC in rats produced no remarkable effect on behavior, body temperature, and respiratory function. Intravenous infusion of 5.4 meg/kg FAC BC to conscious dogs did not elicit biologically signi?cant changes in blood pressure, heart rate, ECG, and interval. Following a single intravenous injection of BC in rats, the highest concentration of radioactivity was found in the pancreas, thymus gland, kidneys, muscle, stomach, and bone marrow. Anti-[18F] FAC BC was mainly excreted through urine Anti-[14C] FAC BC or anti-[18F] FAC BC was not metabolized in vivo (less than and in vitro in rat, dog, monkey, or human liver microsomes. General toxicology Reference ID: 3929291 Division Director Summary Review NDA 208054, Axumin (Fluciclovine F 18) Libero Marzella MD, PhD Fourteen day intravenous toxicity studies of anti-FACBC in rats and dogs established NOAELs at 22 and 10.8 mcg/kg/day respectively (dose multiples of 21X or 35X based on body surface area). Genetic toxicology (b) (4) Both anti-FACBC (the active ingredient) and (the major impurity) were negative in the in vitro reverse mutation assay in bacteria (Ames), in the in vitro chromosomal aberration assay, and in vivo micronucleus assay. 5. Clinical Pharmacology I concur with the recommendation by the clinical pharmacology reviewer Dr. John that the application be approved. The following is a summary of Dr. John’s findings. Mechanism of action Fluciclovine F 18 is a synthetic amino acid transported across mammalian cell membranes by amino acid transporters, such as LAT-1 and ASCT2, which are upregulated in prostate cancer cells. Fluciclovine F 18 is taken up to a greater extent in prostate cancer cells compared with surrounding normal tissues. Pharmacodynamics Following intravenous administration, the tumor-to-normal tissue contrast is highest between 4 and 10 minutes after injection, with a 61 % reduction in mean tumor uptake at 90 minutes after injection Pharmacokinetics and metabolism Fluciclovine F 18 does not undergo significant metabolism. There was no measurement of active moieties in any of the studies on imaging performance. Assessment of Fluciclovine F 18 activity in healthy subjects showed the distribution to be mostly uniform throughout the body with the exceptions of the brain, red bone marrow, liver, and pancreas. There was very little brain uptake (1.6%). The four organs with the highest initial uptake of 18F were the liver (14%), red bone marrow (11 %), lung (7%), and pancreas (4%). The critical organ (i.e., that with the highest absorbed dose per unit administered activity) was the pancreas, with a mean absorbed dose of 103 microGy/MBq. Recommended dose Clinical trials from various institutions (Oslo University, Bologna University, and Emory University) studied doses of 18F-Fluciclovine varying from 162 - 485 MBq (4.4 to 13.1 mCi). The investigators from Oslo University used a dose of 200 MBq and concluded that ineffective images were obtained. The basis for selecting doses does not appear in the submission or in the literature. No dose finding studies appeared in the literature or were conducted by the applicant. The proposed package insert recommends a dose of 370 MBq or 10 mCi by intravenous injection in a total volume not exceeding 5 mL. The mass dose of 10 Reference ID: 3929291 Division Director Summary Review NDA 208054, Axumin (Fluciclovine F 18) Libero Marzella MD, PhD Fluciclovine F 18 is 2 mcg/mL (max of 10 mcg). While there is no assurance that an optimal dose has been identified, the proposed dose is effective. Process impurity Pharmacokinetic studies quantitated only parent drug. The main impurity present in the (b) (4) formulation intended for marketing, , has a similar uptake profile to fluciclovine, although its affinity for amino acid transporter is much lower than that of fluciclovine. The (b) (4) impurity is similarly not incorporated into proteins. is unlikely to have any impact on the uptake of fluciclovine at the clinical dose. The maximum chemical concentrations of (b) (4) (b) (4) fluciclovine and in the drug product are 2mcg/mL respectively. Based on the maximum recommended dose volume of 5mL, this is equivalent to maximum (b) (4) concentrations in plasma (assuming a 5 L blood volume) of 15nM respectively, which are orders of magnitude lower than the concentrations at which the in vitro uptake of (b) (4) (b) (4) fluciclovine is saturated (Km of 64mcM) or inhibited by (IC50 of ). The effective radiation dose resulting from the administration of 370 MBq Fluciclovine F 18 for an adult weighing 75 kg is approximately 6 mSv. A comparable effective dose for Choline C 11 is 2.6 mSv and the effective dose for Indium 111 capromab pendetide is 27 mSv. QT effects The mass of Fluciclovine F 18 injected is about 10 mcg. The drug is injected only once, thus the likelihood of QT or QTc prolongation is remote. There were no significant effects of 18FFluciclovine injection on ECG interval changes in mean values or shifts from baseline in ECG parameter. Food effects Because fluciclovine is an amino acid, the reviewer considered whether a high protein meal might alter distribution. Ingestion of a high protein meal elevates plasma amino acid levels by ~25% during the first 1-2 hours following the meal, with levels returning to pre-prandial levels after 4-8 hours, It is very unlikely that the a 25% increase in total circulating amino acids would have any significant effect on transport and resulting image quality. In the clinical studies patients fasted (4 hrs) before the administration of Fluciclovine F 18. 6. Clinical Microbiology This section is not applicable to radiopharmaceuticals intended for diagnostic use. 7. Clinical/Statistical-Efficacy I concur with the clinical and statistical reviewers’ assessment that in men with recurrent prostate cancer Fluciclovine F 18 is useful for the detection of metastases as verified by histopathology and patient follow up. 11 Reference ID: 3929291 Division Director Summary Review NDA 208054, Axumin (Fluciclovine F 18) Libero Marzella MD, PhD The primary and secondary clinical reviewers (Dr. Davis and Dr. Todd) and the primary and secondary statistical reviewers (Dr. Mucci and Dr Zalkikar) focused their reviews on a study conducted at Emory University (published by Schuster et al, J Urol 191: 1446-1453, 2014) for the primary evidence of efficacy and on a second study conducted at the University of Bologna (published by Nanni et al, Clin Nucl Med, 40 (8): 386-391, 2015) for supportive efficacy. The Applicant conducted re-analyses of the studies and conducted blinded, independent, centralized re-reads of the images to verify the original clinical site interpretation of the images. The reviewers agreed in their assessment of the Emory study and in the importance of various primary and secondary efficacy analyses for demonstrating utility. The reviewers evaluated several performance characteristics and found them generally consistent with each other. The reviewers highlighted the following aspects.         Value of histology as truth standard to validate lesion detection Lack of independent ascertainment of truth standard precludes the use of standard accuracy measures (sensitivity and specificity) to evaluate cancer recurrence Re-read of images in a blinded fashion useful to validate the image interpretation at the clinical site Most clinically useful definition of efficacy is with respect to subject and anatomic region classifications for recurrence of disease Weakness of positive predictive value as a primary endpoint due to influence of this estimate on the prevalence of disease. Need to couple positive predictive value with a measure that lesion detections are generally positive by histology Consistency of favorable results among the initial study publication, the re-analysis study and the re-read study The labeling will provide subject and region levels summary statistics showing true/false positive and negative lesion detections The Emory study met its primary efficacy endpoint of PPV. Dr Mucci determined that at the subject level seven of ten patients (71%) with lesions detected by Fluciclovine F 18 had prostatic cancer metastases and nearly all (97%) patient with metastases had Fluciclovine F 18 detections verified as positive by histology. I agree with the reviewer that these results are persuasive. Dr. Davis points out that the original publication showed Fluciclovine F 18 detected more lesions than the active comparator. Table 1 summarizes the principal efficacy outcomes of the Emory study. 12 Reference ID: 3929291 Division Director Summary Review NDA 208054, Axumin (Fluciclovine F 18) Libero Marzella MD, PhD Table 1: Performance of Axumin in Patients with Biochemically Suspected Recurrent Prostate Cancer, at the Patient Level and in the Prostate Bed and Extraprostatic Regions Levels Reader 1 Reader 2 Reader 3 Patient N = 104 N = 105 N = 99 True Positive 75 72 63 False Positive 24 23 13 True Negative 5 7 15 False Negative 0 3 8 Prostate Bed True Positive False Positive True Negative False Negative N = 98 58 29 10 1 Extraprostatic N = 28 True Positive 25 False Positive 2 True Negative 0 False Negative 1 N = number of patient scans evaluated N = 97 56 26 12 3 N = 96 47 15 24 10 N = 28 26 2 0 0 N = 25 22 2 0 1 The performance of Axumin is affected by PSA levels. Among the 16 scans in patients with PSA levels less than or equal to 1 ng/mL, there were 4 false positive scans and 1 false negative scan. Among the 83 scans in patients with PSA levels greater than 1 ng/mL, there were 13 false positive scans and no false negative scans. I agree with the FDA reviewers that the study conducted at the University of Bologna is generally supportive. The study evaluated the concordance between 96 Axumin and Choline C 11 scans in patients with median PSA value of 1.44 ng/mL (interquartile range = 0.78 to 2.8 ng/mL). The Choline C 11 scans were read by on-site readers. The Axumin scans were read by the same three blinded independent readers used for the reread of the Emory study. The agreement values between the Axumin and Choline C11reads were 61%, 67% and 77% respectively. . 8. Safety I concur with Dr. Davis’ assessment that in the intended population and clinical use, the safety database of 877 subjects, including 797 men diagnosed with prostate cancer is adequate to assess the safety of Fluciclovine F18 injection. Most patients received a single administration of Axumin, a small number of subjects (N = 50) received up to five administrations of the drug. The mean administered activity was 370 MBq. Safety evaluations included treatment emergent adverse events, pre and post treatment changes in laboratory hematology, 13 Reference ID: 3929291 Division Director Summary Review NDA 208054, Axumin (Fluciclovine F 18) Libero Marzella MD, PhD biochemistry and urinalysis, safety evaluations, pre and post treatment 12 lead ECGs, as well as vital signs pre and post dose during imaging sessions. No deaths or serious adverse reactions were reported. Adverse reactions occurred in < 1% study subjects. The most common were injection site pain and dysgeusia. The risks of Axumin are associated with radiation exposure and with image interpretation errors. Axumin use contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer. A negative image does not rule out the presence of recurrent prostate cancer and a positive image does not confirm the presence of recurrent prostate cancer. The performance of Axumin is affected by PSA levels. Fluciclovine F 18 uptake is not specific for prostate cancer and may occur with other types of cancer and benign prostatic hypertrophy in primary prostate cancer. Clinical correlation, which may include histopathological evaluation of the suspected recurrence site, is recommended. Hypersensitivity reactions including anaphylaxis are a potential risk in patients who receive Axumin. Emergency resuscitation equipment and personnel should be immediately available. 9. Advisory Committee Meeting The application did not raise regulatory or scientific issues. The approval of another radiopharmaceutical (Choline C 11) was based on similar study design and endpoint (lesion localization rates verified by histopathology) in the same patient population (patients with elevated PSA levels suspected of cancer recurrence). For these reasons no advisory committee meeting was necessary. 10. Pediatrics The Applicant requested a waiver. Prostate cancer is most frequently diagnosed among older men with median age at diagnosis as 66 years. Therefore, pediatric studies were waived based on the indicated population. 11. Other Relevant Regulatory Issues I concur with the assessment by Dr. Rutledge that the proposed proprietary name does not misbrand the product or raise concerns about the potential for medication errors. I concur with the assessment of the reviewer from the Office of Prescription Drug Promotion. Dr. Adam reviewed the final versions of the prescribing information and the carton and container labeling and found them to be acceptable. 14 Reference ID: 3929291 Division Director Summary Review NDA 208054, Axrunin (Fluciclovine 18) Libero Marzella MD, 12. Labeling The following is a srumnary of the consensus views of the review team and re?ects the input by Drs. Todd and Fedowitz who led the review of the labeling for content and consistency with the regulations. 0 INDICATIONS AND USAGE section: I agree with the Applicant on the indicated population namely patients with recurrent prostate cancer based on elevated levels of PSA after primary treatment. Broadening the indicated population to include patients with 09(4) was considered. However insuf?cient supportive information on diagnostic performance of Axrunin in patients (m4) prostate cancer was available. An adequate study of Axrunin in patients (W) could provide the necessary performance data. No limitations for use statements were considered necessary. 0 DOSAGE AND ADMINISTRATION section: The recommended dose is effective. However no dose ranging studies were performed to optimize the Axrunin dose. 0 WARNINGS AND PRECAUTIONS sections: The risks associated with Axrunin are due to radiation absorbed dose from the 18 radioisotope and errors in image interpretation. These risks are described in the warnings section. It is also mentioned that interpretation of the scans is dependent on PSA levels. 0 CLINICAL STUDIES section: The Emory study was the principal ef?cacy study establishing the diagnostic performance of Axrunin. The most important diagnostic information was considered to be the Axumin cancer detection rate at the patient level de?ned as the proportion of true positive patients among the true positive and false negatives. Performance at the region level (prostate bed and extraprostatic bed) was also presented. Performance at the lesion level was not included as it did not add more useful clinical information. Only the results of the blinded reads were presented because the results were similar to those of the site readers and provided information on the level of agreement of the readers. M4) 13. Postmarketing A review by The Division of Risk Management (DRISK) determined whether a risk evaluation and mitigation strategy (REMS) for this new molecular entity (Axrunin, ?uciclovine) is necessary to wane the bene?ts of this product outweigh its risks. As a class, diagnostic radiopharmaceuticals have not required a REMS for approval. The applicant did not submit a proposed REMS or risk management plan with this application. I concru? with Dr. 15 Reference ID: 3929291 Division Director Suimnary Review NDA 208054, Axumin (Fluciclovine 18) Libero Marzella MD, Patel?s assessment that none are needed. I concur with the recommendation by the CMC and Pharmacology/Toxicology reviewers that the applicant investigate the feasibility of reducing the amount of the process impurity (I?m in the drug product. The Applicant has agreed (Jan 11 2016 amendment) to perform preliminary development work and to report the results to the Agency. The objective is to achieve a reduction within 12 months of NDA approval. Based on the data from 21 batches made by the ?nal manufacturin rocess, the M0 concentrations were much lower (range: Therefore the CMC team proposed speci?cation of as M0 is reasonable. 16 Reference ID: 3929291 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------LIBERO L MARZELLA 05/10/2016 Reference ID: 3929291