CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`208700Orig1s000
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
`
`
`
`
`
`

`

`Division of Risk Management (DRISK)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`NDA
`208700
`January 26, 2018
`2017-1540, 2017-1542
`
`Mei-Yean Chen, Pharm.D.
`Elizabeth Everhart, MSN, RN, ACNP
`Cynthia LaCivita, Pharm.D.
`December 8, 2017
`Evaluation of Need for a REMS
`
`177 Lu-DOTA0-Tyr3-Octreotate
`Lutathera
`Advanced Accelerator Applications USA, Inc. (AAA)
`peptide receptor radionuclide
`
`
`Application Type
`Application Number
`PDUFA Goal Date
`OSE RCM #
`
`Reviewer Name(s)
`Team Leader
`Division Director
`Review Completion Date
`Subject
`
`Established Name
`Trade Name
`Name of Applicant
`Therapeutic Class
`Formulation(s)
`Dosing Regimen
`
`
`7.4 GBq (200 mCi) intravenously for 4 doses
`
`
`
`
`Reference ID: 4193058
`
`1
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`

`

`Table of Contents
`
`
`EXECUTIVE SUMMARY ......................................................................................................................................................... 3
`1
`Introduction ..................................................................................................................................................................... 3
`2 Background ...................................................................................................................................................................... 3
`2.1
`Product Information ........................................................................................................................................... 3
`2.2
`Regulatory History............................................................................................................................................... 4
`3
`Therapeutic Context and Treatment Options .................................................................................................... 4
`3.1
`Description of the Medical Condition .......................................................................................................... 4
`3.2
`Description of Current Treatment Options ............................................................................................... 5
`4 Benefit Assessment ....................................................................................................................................................... 6
`5 Risk Assessment ............................................................................................................................................................. 7
`Expected Postmarket Use ........................................................................................................................................... 9
`6
`7 Risk Management Activities Proposed by the Applicant ............................................................................... 9
`8 Discussion of Need for a REMS ................................................................................................................................. 9
`9
`Conclusion & Recommendations ........................................................................................................................... 10
`10
`Appendices ................................................................................................................................................................ 10
`10.1 References ............................................................................................................................................................. 10
`
`
`
`
`
`Reference ID: 4193058
`
`2
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`

`

`EXECUTIVE SUMMARY
`This review by the Division of Risk Management (DRISK) evaluates whether a risk evaluation and
`mitigation strategy (REMS) for the new molecular entity Lutathera (177 Lu-DOTA0-Tyr3-Octreotate) is
`necessary to ensure the benefits outweigh its risks. Advanced Accelerator Applications USA, Inc. (AAA)
`submitted a New Drug Application (NDA) 208700 for Lutathera with the proposed indication for the
`treatment of somatostatin receptor positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs)
`including foregut, midgut, and hindgut neuroendocrine tumors in adults.
`
`DRISK and the Division of Oncology Products 2 (DOP 2) agree that a REMS is not needed to ensure the
`benefits of Lutathera outweigh its risks. The main serious adverse events are due to radiation exposure.
`The critical organs for radiation toxicity with Lutathera are kidney and bone marrow. To mitigate the risk
`of kidney toxicity, the proposed label contains recommendations for administering an amino acid
`solution contain L-lysine and L-arginine as an intravenous infusion 30 mintues before, during, and for at
`least 3 hours following Lutathera infusion. Myelosuppression, secondary myelodysplastic syndrome and
`leukemia, renal toxicity, heptaic toxicity, neuroendocrine hormonal crises, embryo-fetal toxicity, and
`male infertility will be conveyed in Warnings and Precautions. The labeling review is still ongoing at this
`time. If approved, the radiation risks will be in a
` Warnings and Precautions to
`communicate minimizing the risks of radiation exposure consistent with institutional good radiation
`safety practices.
`
`1 Introduction
`This review by the Division of Risk Management (DRISK) evaluates whether a risk evaluation and
`mitigation strategy (REMS) for the new molecular entity (NME) Lutathera (177 Lu-DOTA0-Tyr3-Octreotate)
`is necessary to ensure the benefits outweigh its risks. AAA submitted a New Drug Application (NDA)
`208700 for Lutathera with the proposed indication for the treatment of somatostatin receptor positive
`GEP-NETs including foregut, midgut, and hindgut neuroendocrine tumors in adults. This application is
`under review in the Division of Oncology Product 2 (DOP2). The applicant did not submit a proposed
`REMS or risk management plan with this application.
`
`2 Background
`2.1 PRODUCT INFORMATION
`Lutathera (177 Lu-DOTA0-Tyr3-Octreotate), an NME,a is a radiolabeled somastatin analog proposed for the
`treatment of somatostatin receptor positive GEP-NETs including foregut, midgut, and hindgut
`neuroendocrine tumors in adults. The drug substance lutetium (Lu 177) oxodotreotide is a radionuclide
`chelated to a cyclic peptide by the means of a covalently bound chelator. Lutetium decays to stable
`hafnium (Hf 177) with a half-life of 6.7 days by emiting beta radiation.
`
`Lutathera binds to smatostatin receptors with highest affinity for somastatin subtype 2 receptors
`(SSRT2). Lutathera is administered as intravenous infusion. Once in the blood stream, the molecule
`
`
`a Section 505-1 (a) of the FD&C Act: FDAAA factor (F): Whether the drug is a new molecular entity.
`
`Reference ID: 4193058
`
`
`3
`
`(b) (4)
`
`

`

`binds to the somatostatin receptor expressing cells, including malignant SSRT2-positive tumors, and the
`compound is internalized. The beta emission from Lu 177 induces cellular damage by formation of free
`radicals in SSRT2-positive cells in in neighboring cells. Lutathera is proposed as a solution of 7.4 GBq (200
`mCi) to be given intravenously every 8 week for a total of 4 doses. b Lutathera was approved by the
`European Medicines Agency in September 2017.
`
`2.2 REGULATORY HISTORY
`The following is a summary of the regulatory history for Lutathera relevant to this review:
`
`•
`
`January 12, 2009: Orphan drug designation granted.
`
`• March 31, 2016: Sponsor submitted Lutathera NDA 208700.
`• August 11, 2016: The Sponsor committed to provide the FDA with clean datasets and reviewers
`guide during the mid-cycle meeting.
`
`• December 19, 2016: FDA issued a Complete Response (CR) letter due to the sponsor deficiencies
`in meeting FDA requirements for electronic datasets.
`
`July 26, 2017: The Sponsor resubmitted Lutathera NDA 208700.
`
`•
`• September 29, 2017: The European Commission (EC) approved Lutathera
`
`• October 30, 2017: Midcycle meeting – No major safety concerns identified at this time that
`would require a REMS.
`3 Therapeutic Context and Treatment Options
`3.1 DESCRIPTION OF THE MEDICAL CONDITION
`Neuroendocrine cells are distributed widely throughout the body, and neoplasms of these cells, which
`are termed neuroendocrine tumors (NETs) can arise at many sites. Gastroenteropancreatic
`neuroendocrine tumors (GEP-NETs) are NETs arising usually within the digestive system. Well-
`differentiated carcinoid tumors over-express somatostatin subtype 2 receptors (SSRT2) which is a
`common feature of all GEP-NETs.1
`
`A long-standing classification system divides gastrointestinal (GI) neuroendocrine tumors into foregut,
`midgut and hindgut tumors.2 The classification is based on the embryoinic origin of the different
`tumors. The foregut primaries, which account for up to 25% of cases, arise in the lung, thymus, stomach,
`or proximal duodenum. Midgut tumors, which account for up to 50% of cases, arise in the small
`intestine, appendix, or proximal colon. Hindgut tumors, which account for approximately 15% of cases,
`arise in the distal colon or rectum. Note that some of these locations (lung and thymus) are outside the
`definition of GEP-NETs, so the classification system has contributed to some confusion. A more recent
`World Health Organization (WHO) classficiation system has been developed which is considered more
`clinically relevant.3 The current WHO calssfication specifes 4 subtypes under 2 main categories and is
`relevant for all neuroendocrine tumor types:
`
`b Section 505-1 (a) of the FD&C Act: FDAAA factor (D): The expected or actual duration of treatment with the drug.
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`Reference ID: 4193058
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`• Neuroendocrine neoplasm (well differentiated): grade 1 and grade 2
`
`• Neuroendocrine carcinoma (poorly differentiated ):
`
`1. Grade 3, small cell carcinoma
`
`2. Grade 3, large neuroendocrine carcinoma
`
`GEP-NETs may also be divided into functioning and non-functioning tumors. Functioning tumors
`clinically present with symptoms related to overproduction of biogenic amines and peptide hormones.
`The majority of GEP-NETs does not secrete sufficient levels of biologically active substance to induce
`symptoms and are therefore classified as non-functioning and often present fairly late with symptoms of
`mass effect, or distant metastases. Delayed diagnosis is typical (5-7 years) in patients with non-
`functioning GEP-NETs, resulting in greater morbidity, increased probability of metastatic disease, and
`increaded mortality. At the time of diagnosis, a significant percentage of patients have hepatic
`metastasis.
`
` The classical symptoms of carcinoid syndrome include flushing (80%), diarrhea (70%), abdominal pain
`(40%), valvular heart disease (30-40%), telangiectasia (25), wheezing (15%), and pellagra-like skin lesions
`(5%).c Carcinoid heart disease is characterized by plaque-like fibrous endocardial thickening that
`classically involves the right side of the heart, occurring in 50-70% of patients with a carcinoid syndrome.
`The disease is most likely induced by chronic tumor secretion of serotonin, which binds to cardiac 5-HCT
`receptors. Hemodynamically significant heart disease is seen in about 5-10% of patients.
`
`Among patients with low or intermediate-grade histology and distant disease, survival is highly variable.
`In patients with advanced carcinoid tumors, outcomes are worse for patients with lung and colon
`primary tumors (median survival 17 and 7 months, respectively) and most favorable for tumors arising in
`the jejunum, ileum, and cecum (median survival 55 to 65 months).
`
`The prevalence of neuroendocrine tumors in the United States during 2004 is estimated to be 3.4 per
`100,000 persons 4 and with a living population of 103,312. Adjusting for an annual 4% increase in
`incidence, the living population in the US for 2015 is estimated to be about 159,000.d
`
`3.2 DESCRIPTION OF CURRENT TREATMENT OPTIONS
`The clinical management involves a multi-modal approach including surgery, cytoreductive treatment,
`embolization, chemo-embolisation, radiotherapy, chemotherapy, and somatostain analogues. The FDA
`approved pharmacotherapy is shown in the table below.
`
`
`c Section 505-1 (a) of the FD&C Act: FDAAA factor (B): The seriousness of the disease or condition that is to be
`treated with the drug.
`
`d Section 505-1 (a) of the FD&C Act: FDAAA factor (A): The estimated size of the population likely to use the drug
`involved.
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`Reference ID: 4193058
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` Table: Summary of Treatment Options Relevant to Proposed Indication.
`
`Indication
`
`Dosing
`
`Product Name
`Year of
`Approval
`
`Important Safety and
`Tolerability Issues
`
`Risk
`Management
`Approaches
`
`FDA Approved Treatments
`
`Octreotide
`(Sandostatin
`LAR), 19985
`
`Symptomatic tx
`of meta.
`Carcinoid tumors
`
`20 mg intramuscular
`injection every 4 weeks
`
`10 mg oral once daily
`
`Everolimus
`(Afinitor),
`indication
`pancreatic NET
`approved 2011,
`for GI or lung
`NET approved
`20166
`
`Prog., well-
`diff.,non-
`functional NET of
`GI or lung origin
`that are
`unresectable,
`locally adv.or
`meta. disease
`
`
`
`Sunitinib
`(Sutent),
`approved 2011
`for pancreatic
`NET7
`
`Prog., well-diff.
`pancreatic NET
`that are
`unresectable,
`locally adv. Or
`meta. disease
`
`Warnings &
`Precautions
`
`Warnings &
`Precautions
`
`Gallbladder
`abnormalities, hypo or
`hyperglycemia,
`hypothyroidism,
`bradycardia,
`arrhythmia.
`
`Non-infectious
`pneumontic, infections,
`angioedema, stomatitis,
`renal failure, impaired
`wound healing, embryo-
`fetal toxicity
`
`37.5 mg oral once daily
`
`Boxed warning;
`Warings &
`Precautions
`
`Hepatotoxicity (boxed
`warning), cardiovascular
`events, QT
`prolongation,
`hemorrhagic events,
`tumor lysis syndrome,
`hypertension
`
`Lanreotide
`(Somatuline
`Depot)
`
`20148
`
`unresectble, well
`or moderately-
`diff., locally
`advanced or
`meta. GEP-NETs
`
`120 mg intramuscular
`injection every 4 weeks
`
`Gallstones may occur,
`hypo and/or
`hyperglycemia, and
`decrease heart rate
`
`Warnings &
`Precautions
`
`4 Benefit Assessment
`NETTER-1, a multicenter, open label, and randomized phase 3 study, compared treatment with
`Lutathera (116 patients) with treatment with octreotide LAR (113 patients) in patients with inoperatble,
`progressive, somatostatin receptor positive, midgut carcinoid tumors. Patients were randomized to
`receive Lutathera (7.4 GBq every 8-16 weeks for up to 4 administrations) with octreotide long-acting
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`realease (LAR) (30 mg by intramuscular injection every 4 weeks) or octreotide LAR 60 mg (by
`intramuscular injection every 4 weeks) alone (control arm). Randomization was stratified by OctreoScan
`tumor uptake score and the length of time that patients had been on the most recent constant dose of
`octreotide.
`
`The major efficacy outcome measure was progression free survival (PFS) as determined by a blinded
`independent radiology committee (IRC). The additional efficacy outcome measures were objective
`response rate (ORR) and overall survival (OS). Disease progression was reported in 13% of patients in the
`Lutathera arm versus 54% of patients in the control arm. The median PFS for the Lutathera arm was not
`reached at the time of analysis whereas in the control arm, PFS was 8.5 month with P-value less than
`0.0001. The ORR was 13% in the Lutathera arm versus 4% in the control arm with P-value of 0.0148. The
`OS in the Lutathera arm was not reached whereas in the control arm it was 27.4 months.
`
`The efficacy of Lutathera in patients with GEP-NETs was assessed in the ERASMUS study, a single
`institution, open-label, single-arm trial which enrolled 1,214 patients with somatostain receptor positive
`tumors. Most patients were Dutch (811 patients) with the remaining (403 patients) were residents of
`various European and non-European countires. The main analysis was conducted on 811 Dutch patients
`with different somatostatin receptor positive tumor types. The mean age was 60 years and 56% of
`patients had progressed within 12 months of treatment and 10% had received prior chemotherapy.
`Lutathera 7.4 GBq was administered every 6 to 13 weeks for up to 4 doses concurrently with the
`recommended amino acid solution. Fifty-two percent of patients received Lutathera with octreotide
`LAR. The major efficacy outcome was investigator assessed ORR by SouthWest Oncology Group (SWOG)
`crieteria, which was later converted to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST
`v1.1). Of 360 patients with GEP-NETs, the ORR rate was 45% and Complete Response (CR) was 3%.
`
`5 Risk Assessment
`The safety data are based on pooled data from NETTER-1 and ERASMUS studiese. In the NETTER-1 trial,
`Lutathera was administered with an amino acid solution and octreotide LAR in 111 patients with
`advanced, progressive midgut neuroendocrine tumors. Safety data was obtained in an additional 833
`patients (22 patients in non-randomized pharmacokinetic sub-study from NETTER-1 and 811 patients
`with advanced somatostain receptor positive tumors, including midgut neuroendocrine tuors from
`ERASMUS). The main analysis was conducted on 811 Dutch patients with different somatostatin
`receptor positive tumor types.
`
`In the NETTER-1 trial, deaths were reported in 5% of patients in the Lutathera arm compared to 8% in
`the control arm.
`
`
`e Section 505-1 (a) of the FD&C Act: FDAAA factor (E): The seriousness of any known or potential adverse events
`that may be related to the drug and the background incidence of such events in the population likely to use the
`drug.
`
`
`
`Reference ID: 4193058
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`

`The critical organs for radiation toxicity with Lutathera are kidney and bone marrow, which may occur
`many months or years following the treatment. Monitoring the kidney and bone marrow function are
`required and adapt the treatment protocol if necessary (dose, infusion interval, and number of
`infusions) before each aministration and during the treatment.
`
`If approved, labeling will include the following risks in the Warnings and Precautions section, as well as
`recommended dose modifications to manage toxicities in labeling section 2.3 and 2.4:
`
`• Myelosuppression: In NETTER-1, myelosuppression occurred more frequently in patients
`receiving Lutathera with octretide LAR compared to patients receiving octreiotide LAR alone –
`(all grades and grade 3 or 4): anemia: 81% and 0%; thrombocytopenia: 53% and 1%;
`neutropenia:26% and 3%.
`
`• Secondary Myelodysplastic Syndrome and Leukemia: In NETTER-1 study, with a median follow-
`up time of 24 months, myelodysplastic syndrome (MDS) was reported in 2.7% of patients
`receiving Lutathera with octreotide LAR compared no patients receving octreotide LAR alone. In
`ERASMUS study, the median time to the development was 28 months (9 to 41 months) for MDS
`and 55 months (32 to 155 months) for acute leukemia.
`
`• Renal toxicity: In the ERASMUS study, less than 1% of patients developed renal failure 3 to 36
`months following Lutathera. Two of these patients had underlying renal impairment or risks
`factors for renal failure (diabetes or hypertension) and required dialysis. The proposed label
`includes recommendations for the administration of amino acid solution before, during, and
`after Lutathera to decrease the reabsorption of Lutethera through the promimal tubules
`todecrease the radiation dose to the kidneys.
`
`• Risk of hepatic toxicity: In the ERASMUS study, severe abdominal and epigastric pain were
`reported in less then 1% of patients; it developed hours to days following Lutathera
`administration. Two patients (<1%) were reported to have tumor hemorrhage, edema or
`necrosis with one patient experiencing intrahepatic congestion and cholestasis. Radiation
`exposure to the liver may be increased in patients with hepatic tumors.
`
`• Neuroendocrine hormonal crises, manifesting with flushing, diarrhea, bronchospasm, and
`hypotension, occurred in 1% of patients in the ERASMUS study and typically occurred during or
`within 24 hours following the initial Lutathera dose. Two (<1%) patients were reported to have
`hypercalcemia.
`
`• Embryo-fetal toxicity: all radiopharmaceuticals, including Lutathera, have the potential to cause
`fetal harm.
`
`• Risks of male infertility: in a subset of 35 men from ERASMUS, decreased inhibin-B and
`increased FSH were observed 3 months following Lutathera. The recommended cumulative dose
`of 29.6 GBq of Lutathera results in a radiation absorbed dose to the testis within the range
`where temporary or permanent infertility can be expected following external beam
`radiotherapy. Consider cryopreservation of sperm in male patients.
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`Reference ID: 4193058
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`

`

`6 Expected Postmarket Use
`Lutathera therapy is limited to inpatient settings, and is prepared and administered by nuclear medicine
`physicians and staff with appropriate radiation training. Like other radionuclide drugs, Lutathera will not
`be marketed to the general population.
`
`7 Risk Management Activities Proposed by the Applicant
`
`The Applicant did not propose any risk management activities for Lutathera beyond routine
`pharmacovigilance and labeling. The applicant did propose
`
`.
`
`8 Discussion of Need for a REMS
`When evaluating factors of whether a REMS is necessary to ensure that the benefits outweigh the risks
`of Lutathera, DRISK considers patient population size, seriousness of disease, expected benefit of the
`drug, the expected duration of treatment, and the seriousness of known or potential adverse reactions.
`
`The prevalence rate of neuroendocrine tumors in the United States during 2004 is estimated to be 3.4
`per 100,000 persons and with a living population of 103,312. Adjusting for an annual 4% increase in
`incidence, the living population in the US for 2015 is estimated to be about 159,000.
`
`GEP-NETs patients with early stage disease are often asymptomatic or present with poorly defined
`symptoms. At the time of confirmed diagnosis, a significant percertage of GEP-NET patients have hepatic
`metastasis. Delayed diagnosis is typical (5-7 years) in patients with non-functioning GEP-NETs, resulting
`in greater morbidity, increased probability of metastatic disease, and increaded mortality.
`
`In the case of inoperable disease, neither chemotherapy nor external beam radiation therapy are
`considered effective. There are few treatment options with significant efficacy for patients with
`advanced disease. Most of the products approved in the targeted indication have limited application
`because they are only approved for use in sub-populations of GEP-NET patients. There is a clear unmet
`need for an effective therapeutic option in this population.
`
`Based on the efficacy and safety information currently available, the clinical reviewers recommend
`approval of Lutathera. The NETTER-1 study and ERASMUS study both demonstrated the efficacy of
`Lutathea. The main serious risks are due to radiation exposure. The critical organs for radiation toxicity
`with Lutathera are kidney and bone marrow. Section 2.3 “Premedication and concomitant medications”
`in the proposed label provides detailed instructions to give amino acid solution before, during, and after
`Lutathera to decrease the reabsorption of Lutethera through the promimal tubules to decrease the
`radiation dose to the kidneys; section 2.4 “Dose Modifications” of the proposed label communicates
`how to decrease/withhold/discontinue Lutathera for myelosuppression. The risks of renal toxicity,
`myelosuppression, secondary MDS, neuroendocrine crises, embryo-fetal toxicity, and risk of male
`infertility will be described in the Warnings and Precautions section of the label. The labeling review is
`still ongoing at this time. If approved, the risks of radiation exposure will in
`
`Warnings and Precautions to communicate minimizing the risks of radiation exposure consistent with
`
`Reference ID: 4193058
`
`
`9
`
`(b) (4)
`
`(b) (4)
`
`

`

`institutional good radiation safety practices. In addition, radiopharmaceuticals should be used by or
`under the control of physicians who are qualified by specific training and experience in the safe use and
`handling of radionuclides and whose experience and training have been approved by the appropriate
`governmental agency authorized to license the use of radiopharmaceuticals.
`
`9 Conclusion & Recommendations
`Based on the clinical review, the benefit-risk profile is favorable, therefore a REMS is not necessary for
`Lutathera to ensure its benefits outweigh its risks. At the time of this review, evaluation of safety
`information and labeling was ongoing. Please notify DRISK if new safety information becomes available
`that changes the benefit-risk profile; this recommendation can be reevaluated.
`
`10 Appendices
`
`10.1 REFERENCES
`
`1 Klimstra DS, Yang z, Pathylogy, classification, and grading of neuroendocrine tumors arising in the digestive
`system, UpToDate, accessed October 16, 2017
`
` 2
`
` Strosberg, JR, Staging, treatment, and posttreatment surveillance of nonmetastatic, well-differentiated
`gastrointestinal tract neuroendocrine (carcinoid) tumors, UpToDate, accessed October 16, 2017.
`
` 3
`
` Chan JA, Kulke M, Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: System
`therapy options to control tumor growth and symptoms of hormone hypersecretion, UpToDate, accessed October
`16, 2017
`
` 4
`
` Advanced Accelerator Applications. Clinical Overview for Lutathera, July 2017.
`
` 5
`
` Sandostatin LAR (octreotide) Prescring Information, dated July 2016.
`
` 6
`
` Afinitor (everolimus) Prescribing Information, dated September 2017.
`
` 7
`
` Sutent (sunitinib) Prescribing Information, dated November 2017.
`
` 8
`
` Somatuline Depot (lanreotide) Prescribing Information, dated September 2017.
`
`Reference ID: 4193058
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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/
`----------------------------------------------------
`
`MEI-YEAN T CHEN
`12/08/2017
`
`CYNTHIA L LACIVITA
`12/10/2017
`Concur
`
`Reference ID: 4193058
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`Deferral of Risk Evaluation and Mitigation Strategies (REMS) Review
`
`Date:
`
`November 21, 2016
`
`Mei-Yean Chen, Pharm.D.
`Reviewer(s):
`Division of Risk Management (DRISK)
`
`Naomi Redd, Pharm.D., DRISK
`Team Leader:
`
`
`Cynthia Lacivita, Pharm.D., DRISK
`Division Director:
`
`
`Lutathera (177Lu-DOTA0-Tyr3-Octreotate)
`Drug Name(s):
`Radioisotope Agent
`Therapeutic Class:
`7.4 GBq (200 mCi) intravenously for 4 doses
`Dosage and Route:
`Application Type/Number: NDA 208700
`Applicant/sponsor:
`Advanced Accelerator Applications USA, Inc. (AAA)
`OSE RCM #:
`2016-809
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4016569
`
`1
`
`

`

`This document is to defer Division of Risk Management (DRISK) evaluation of the need
`for a risk evaluation and mitigation strategh (REMS) for Lutathera (Lutathera (177Lu-
`DOTA0-Tyr3-Octreotate), NDA 208700.
`
` 505(b)(1) application for Lutathera was received by the Division of Oncolgoy Products
`2 (DOP2) from Advanced Accelerator Applications USA, Inc. (AAA) on April 28, 2016,
`with the proposed indication for the treatment of patients with
`
` somatostatin receptor positive, gastroenteropancreatic neuroendocrine
`tumors (GEP-NETs), including foregut, midgut and hindgut neuroendocrine tomors or
`carcinoid tumors.
`During a teleconference October 21, 2016 with AAA, DOP2 communicated that due to
`AAA’s deficiencies in meeting FDA requirements for electronic datasets, DOP2 plans to
`issue a Complete Response (CR) letter. DOP2 also communicated that AAA could
`choose to withdraw their application, request a Type A meeting for follow up and
`clarification regarding requirements for a new application submission.
`An evaluation of the need for REMS for Lutathera will be undertaken by DRISK after
`AAA resubmits the NDA for review. Please send DRISK a new consult request at such
`time. This memo serves to close the existing consult request to DRISK for Lutathera
`under NDA 208700.
`
`
` A
`
`
`
`Reference ID: 4016569
`
`2
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MEI-YEAN T CHEN
`11/20/2016
`
`CYNTHIA L LACIVITA
`11/20/2016
`Concur
`
`Reference ID: 4016569
`
`