CENTER FOR DRUG EVALUATION AND
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`APPLICATION NUMBER:
`APPLICA TION NUMBER:
`22-334
`22-334
`
`SUMMARY REVIEW
`SUMMARY REVIEW
`
`

`

`Summary Review for Regulatory Action
`
`Date
`From
`Sub.iect
`NDAlLA#
`Supplement #
`Applicant Name
`Date of Submission
`PDUFA Goal Date
`Proprietary Name /
`Established (USAN) Name
`Dosa2e Forms / Stren~th
`Proposed Indication(s)
`
`(electronic stamp)
`Robert L. Justice, M.D., M.S.
`Division Director Summary Review/CDTL Review
`22-334
`
`Novartis Pharmaceuticals Corporation
`June 30, 2008
`March 30, 2008
`Afinitor/everolimus
`
`Tablets/ 5 mg and 10 mg
`
`AFINITORCI is indicated for the treatment of
`
`patients
`
`with advanced renal cell carcinoma after failure of
`treatment with sunitinib or sorafenib.
`ActionlRecommended Action for Approval
`NME:
`
`Material Reviewed/Consulted
`OND Action Package, including:
`Medical Officer Review
`Statistical Review
`Pharmacology Toxicology Review
`CMC Review/OBP Review
`Microbiology Review
`Clinical Pharmacology Review
`DDMAC
`DSI
`CDTLReview
`OSEIDMEPA
`OSEIDDRE
`OSEIDRISK
`Other- IRT Review
`OND-Offce of New Drugs
`Drug Marketing, Advertising and Communication
`DDMAC=Division of
`OSE= Offce of Surveilance and Epidemiology
`DMEPA=Division of Medication Error Prevention and Analysis
`DSI=Division of Scientific Investigations
`DDRE= Division of Drug Risk Evaluation
`DRISK=Division of Risk Management
`CDTL=Cross-Discipline Team Leader
`
`X
`X
`X
`X
`X
`X
`X
`X
`N/A
`X
`N/A
`X
`X
`
`

`

`Signatory Authority Review
`
`1. Introduction
`
`treatment of
`
`patients with advanced renal cell carcinoma after failure of
`
`This new drug application seeks approval of AFINITOR(ß (everolimus) tablets for the
`treatment with
`sunitinib or sorafenib. This review wil summarize the safety and efficacy data and the
`conclusions and recommendations of each review discipline. This review wil also serve as
`the Cross-Discipline Team Leader Review.
`
`2. Background
`
`The application was received on6/30/08 and was designated a priority review. However, the
`major amendments.
`
`review clock was extended to 3/30/09 because of
`
`the submission of
`
`The mechanism of action of Afinitor is described in the following excerpt from the agreed-
`upon package insert.
`
`threonine kinase, downstream of
`
`Everolimus is an inhibitor ofmTOR (mammalian target ofrapamycin), a serine-
`the PI3KJAKT pathway. The mTOR pathway is
`dysregulated in several human cancers. Everolimus binds to an intracellular protein,
`FKBP-12, resulting in an inhibitory complex formation and inhibition ofmTOR kinase
`activity. Everolimus reduced the activity ofS6 ribosomal protein kinase (S6Kl) and
`eukaryotic elongation factor 4E-binding protein (4E-BP), downstream effectors of
`mTOR, involved in protein synthesis. In addition, everolimus inhibited the expression
`vascular
`endothelial growth factor (VEGF). Inhibition ofmTOR by everolimus has been shown
`to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo
`studies.
`
`of
`
`hypoxia-inducible factor (e.g., HIF-l) and reduced the expression of
`
`3. CMC/Device
`
`The Chemistry Review ofthe drug substance made the following recommendation and
`conclusion on approvability.
`
`2
`
`

`

`Sufficient information is provided in this Ne\v Dmg Applicatioii, as amended, to
`ensure tile identity, strength, quality, and purity of the dmg substance, everolimus.
`The dnig substance manufactui;ng facilities have acceptable cGMP status. From
`controls perspective, applications makng \1' 4\
`reference to everolimus drug substance CMC in NDA _ can be approved. \: rJ
`The adequacy of drug product CMC is being evaluated under separate NDA
`reviews.
`
`the chemistry, manufacturing and
`
`The Chemistry Review of
`
`the drug product made the following recommendations.
`
`A. Recommendation and Conclusion on Approvabilty:
`
`The application is recommended for an approval action for chemistry, manufacnirîiig and controls (CIVC) under
`seetion 505 of the Act.
`
`B. RecOlnmendatioii on Phase 4 (Post-ì\larketing) Commitments, Agreements,and/or Risk
`Management Steps, if Apployable
`
`In order to achieve proper dose reductions the following post marketig commitment was agreed to by Novars in
`their submission dated 03-Mar-2009:
`
`Develop and propose a 2.5 mg dosing form (tablet) to allow for proper dose reductíons when everolimus needs to be
`co-admiiistered with moderate CYP3A4 inibitors. The 2.5 mg dose fomishould be suffciently distinguishable
`controls (CMC) informatiou for the 2.5 mg
`from the 5 mg and the 10 mg tablets. Ful chemitr, manufcturig and
`dosage fonn including the batch data and stabíHty data, labels, updated labeling; updated environmental assessent
`approval supplen1ent.
`section is reuired in a prior
`Protocol submission Date: 45 days frm date of action.
`Submission Date: 6 months afier FDA agreement to submtted protocol
`
`The ONDQA Division Director's Memo stated that "ONDQA recommends approval (AP) of
`the 5 mg and 10 mg tablet strengths as provided in the original submission and as provided in
`the twelve amendments cited herein."
`
`Comment: I concur with the conclusions reached by the chemistry reviewers regarding the
`acceptability of the manufacturing of the drug product and drug substance and with the
`proposed post-marketing commitment. Manufacturing site inspections were acceptable.
`Stability testing supports an expiry of24 months. There are no outstanding issues.
`
`4. Nonclinical Pharmacology/Toxicology
`
`The Pharmacology/Toxicology Review and Evaluation made the following recommendations.
`
`3
`
`

`

`A. Recommendation onapprovability
`There are no phauuacology/toxicology issues which preclude approval of everolimus
`(Afìnitor'~) for the requested indication.
`
`B. Rec01mnendation for nonc1inical studies
`
`No additionaJ.llon-c1inical studies are required for the
`
`proposed indication.
`
`C. Recommendations 011
`
`labeling
`labeling have been provided within team meetings and
`comuui1Ìcated to the sponsor.
`
`Recommendations on
`
`The Pharmacology Acting Team Leader Memorandum concurred that the pharmacology and
`toxicology data support the approval of Afinitor and noted that "There are no outstanding non-
`clinical issues related to the approval of Afinitor for the proposed indication."
`
`The Associate Director for Pharmacology Memorandum concurred with the reviewers'
`conclusions that Afinitor may be approved and that no additional pharmacology or toxicology
`studies are necessary for the proposed indication.
`
`Comment: I concur with the conclusions reached by the pharmacology/toxicology reviewers
`that there are no outstanding pharmacology/toxicology issues that preclude approvaL.
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`The Clinical Pharmacology Review provided the following executive summary and
`recommendations.
`
`Everolimus is an ìnbitor of the human kiase mammalian target of rapamydn (mTOR). The
`CUlTent submission is the original1\TDA for everolimus for the treatment of advanced renal cell
`carcÙloma (RCC). Everolimus has also been evaluated imder b(4)
`indications.
`To support the effcacy Ùl advanced renal cell carcinoma, the sponsor conducted one
`randomized, controlled phase 3 study. Patients in the phase 3 study were randomized to receive
`best supportive care plus placebo or 10 mg of everolimus daily. Progression free survival \-vas
`the primary endpoint and the median PFS for the everolimus treatment ann ranged from 3.71 to
`5.52 months coiiared to 1.87 months for patients receiving placebo.
`Everolius is a CYP3A4 substrate. ~'fuitipie drg-dnig interaction studies were conducted
`under the 1\TDAs for the transplant indications. Based on the results from the drug-drug
`
`interaction studies with ketoconaole, erythromycin and verapaniil no dose adjustments
`
`wil be
`provide-d Ùl the label sÙlce the increasesÙl everolimus exposures can not be adjusted by lowering
`the dose to 5 mg QD. For strong CYP3A4 inducers, a dose increase to 20 mg \vould compensate
`for the decrease in everolimus exposme. For strong CYP3A4 inhibitors because ofthe
`significant Ùlcrease Ùl exposure labeling instruction co-admistrtion is not recommended.
`CUlTelltly, for moderate CY3A4 inibitors generic 'use \\lith caution' statements wil be
`proposed iiiti the sponsor can develop a 2.5 mg dose for market.
`
`4
`
`

`

`A study in patients with nonnal hepatic function and patients with moderate hepatic impaiiment
`supported the labeling recommendation of a 50% dose reduction for patients \\'Ìth moderate
`hepatic impairment. Patients v.'Ìth severe hepatic impai11ient have not been studied and that
`everolimus should not be used iii ths patient population.
`the thorough QT study suggested that everolimus has a low potential to
`prolong the QT interval. IR T proposed labeliiig has been added to the package insert.
`1.1 RECOMl'HENDATIONS
`
`The IRT review of
`
`The Offce of Clinical PhainiacologylDivision of Clinical Phaimacology 5 has reviewed the
`inoimation contained in 1''DA 22-334. Th 1\TJA is considered acceptable from a clical
`phamiacology perspective.
`Post Marketing Requirements
`1. A study in patients Vvitli severe hepatic impamnent
`2. Make available a 2.5 mg fonmilation.
`Labeling Recommendations
`Please refer to Section 3 - Detailed Labelig Recommendations
`
`Comment: I concur with the conclusions reached by the clinical
`pharmacology/biopharmaceutics reviewer that there are no outstanding clinical
`pharmacology issues that preclude approval. I also concur with the recommended post-
`for a study in patients with severe hepatic impairment. The availability
`of a 2.5 mgformulation wil be a postmarketing commitment.
`
`marketing requirement
`
`6. Clinical Microbiology
`
`The Product Quality Microbiology Review recommended approvaL.
`
`7. Clinical/Statistical-Efficacy
`
`A single randomized trial was submitted in support of
`
`the application. A summary ofthe
`study design and results is provided in the following excerpt from the agreed-upon package
`insert.
`
`An international, multicenter, randomized, double-blind trial comparing AFINITOR 10
`mg daily and placebo, both in conjunction with best supportive care, was conducted in
`patients with metastatic renal cell carcinoma whose disease had progressed despite
`prior treatment with sunitinib, sorafenib, or both sequentially. Prior therapy with
`bevacizumab, interleukin 2, or interferon-a was also permitted. Randomization was
`stratified according to prognostic score! and prior anticancer therapy.
`
`5
`
`

`

`Progression-free survival (PFS), documented using RECIST (Response Evaluation
`Criteria in Solid Tumors) was assessed via a blinded, independent, central radiologic
`review. After documented radiological progression, patients could be unblinded by the
`investigator: those randomized to placebo were then able to receive open-label
`AFINITOR 10 mg daily.
`
`In total, 416 patients were randomized 2:1 to receive AFINITOR (n=277) or placebo
`(n=139). Demographics were well balanced between the two arms (median age 61
`years; 77% male, 88% Caucasian, 74% received prior sunitinib or sorafenib, and 26%
`received both sequentially).
`
`AFINITOR was superior to placebo for progression-free survival (see Table 3 and
`Figure 1). The treatment effect was similar across prognostic scores and prior sorafenib
`patients
`
`and/or sunitinib. The overall survival (OS) results were not mature and 32% of
`
`had died by the time of cut-off.
`
`Median Progression-free Survival
`(95% CI)
`Objective Response Rate
`, Log-rank test stratified by prognostic score.
`bNot applicable.
`
`Table3
`
`Effcacy Results by Central Radiologic Review
`AFINITOR Placebo Hazard Ratio
`N=277 N=139 (95%CI)
`4.9 months 1.9 months 0.33
`2% 0% nla b
`(4.0 to 5.5) (1.8 to 1.9) (0.25 to 0.43)
`
`p-value
`
`-cO.OOOI
`
`nla b
`
`Figure 1 Kaplan-Meier Progression-free Survival Curves
`
`100%
`
`80%
`
`= 0.33
`Hazard Ratio
`95 % Ci fO.25, 0.43)
`
`Logrank p value = ..0.0001
`
`Kaplan-Meier medians
`Afinitof: 4.9 months
`Placebo: 1.9 months
`
`v II Censoring times
`-- Afínitof (N =277)
`-----'V----- Placebo (N =139)
`
`~ê
`
`60%
`
`£~ ~
`
` 40%
`
`20%
`
`0%
`
`o
`
`2
`
`4
`
`6
`
`8
`
`10
`
`12
`
`14
`
`Time (months)
`
`The Clinical Review recommended approval of everolimus for the proposed indication with
`the following phase 4 commitments.
`
`6
`
`

`

`1. Develop and propose a 2.5 mg dosing form (tablet) to allow for proper dose
`reductions when everolimus needs to be co-administered with moderate CYP3A4
`inhibitors. The 2.5 mg dose form should be sufficiently distinguishable from the 5 mg
`and the 10 mg tablets.
`
`2. Conduct a trial in patients with severe hepatic impairment (Child Pugh Class C).
`This study need not be conducted in patients with cancer and a single dose evaluation
`wil be appropriate. The protocol should be submitted prior to initiation for review and
`concurrence.
`
`3. Submit the final, per-protocol overall survival analysis of
`
`study C2240, which was
`to be conducted at time of2 years after randomization ofthe last patient.
`
`The Statistical Review and Evaluation provided the following conclusions and
`recommendations.
`
`were previously
`
`care (BSe) and placebo plus BSC in patients "vith advanced renal
`
`The applicant has submitted resiùts from one phase il, randomized, double-blind, comparative
`clincal trial (Study C2240) comparng Aftol (everolimus or RAOOl) plus best supportive
`cell carcinoma (RCe) who
`trated "ijtIi sunitinib, sorafei:b or both sequentially. The study showed benefit
`of RAOOl over placebo in tenus of progression-free survival (PFS) as detenined by
`independent radiologic review in this patient population based on the data frm a planned interi
`analysis. However, the overa survival, a secondary endpoint, was not improved with RAOOl
`with approximately 32% overal deaths, but a trend íàvoring RAOOl "vas observed. R...DOOI
`also did not show statistically significant superiority over placebo in terms of overall response
`rate (another secondary endpoint) as determined by independent radiologic review. The d."1ta and
`statistical resiùts provide adequate evidence to suppoit the claims about PFS proposed in tIie
`NDA.
`
`The Statistical Team Leader's Memo provided the following conclusion.
`
`Tils Team Leader concurs with the recommendations and conclusions ofthe sttistical
`reviewer (Dr. Somesh Chattopadhyay) ofthis application. The study showed benefit of
`Ri\DOOl over placebo in ters of progression-free survival (PFS) as determined by
`independent radiologic revie,,, in tils patient poulation based on the data from a planned
`interim analysis. However, the overall survival, a secondar endpoint, was not improved
`with RAOOl with applOximately 32% overall death, but a trnd favoring RAOOl was
`obseived. RAom also did not sho"\v statistically signficant supeiiority over placebo in
`tenus of overall response rate (another secondary endpoint) as determined by
`independent radiologic review. The data and statistical results provide adequate evidenc.e
`to suppoii the claims about PFS proposed in the NDA.
`
`7
`
`

`

`Comment: I concur that a clinically and statistically signifcant improvement in PFS has been
`demonstrated in this trial. Although only a single randomized trial was submitted, the PFS
`
`findings are robust.
`
`8. Safety
`
`The safety profie of everolimus is provided in the following summary from the agreed-upon
`package insert.
`
`The data described below reflect exposure to AFINITOR (n=274) and placebo (n=137)
`in a randomized, controlled trial in patients with metastatic renal cell carcinoma who
`received prior treatment with sunitinib and/or sorafenib. The median age of patients
`was 61 years (range 27-85),88% were Caucasian, and 78% were male. The median
`blinded study treatment was 141 days (range 19-451) for patients receiving
`AFINITOR and 60 days (range 21-295) for those receiving placebo.
`
`duration of
`
`The most common adverse reactions (incidence 2:30%) were stomatitis, infections,
`asthenia, fatigue, cough, and diarrhea. The most common grade 3/4 adverse reactions
`(incidence 2:3%) were infections, dyspnea, fatigue, stomatitis, dehydration,
`pneumonitis, abdominal pain, and asthenia. The most common laboratory
`abnormalities (incidence 2:50%) were anemia, hypercholesterolemia,
`hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most
`common grade 3/4 laboratory abnormalities (incidence 2:3%) were lymphopenia,
`hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths due to
`acute respiratory failure (0.7%), infection (0.7%) and acute renal failure (0.4%) were
`treatment-
`
`observed on the AFINITOR arm but none on the placebo arm. The rates of
`
`emergent adverse events (irrespective of causality) resulting in permanent
`discontinuation were 14% and 3% for the AFINITOR and placebo treatment groups,
`respectively. The most common adverse reactions (irrespective of causality) leading to
`treatment discontinuation were pneumonitis and dyspnea. Infections, stomatitis, and
`pneumonitis were the most common reasons for treatment delay or dose reduction. The
`most common medical interventions required during AFINITOR treatment were for
`infections, anemia, and stomatitis.
`
`Table 53 from the Clinical Review compares the incidence of adverse reactions reported with
`an incidence of2:10% for patients receiving AFINITOR 10 mg daily versus placebo.
`
`Table 1: Adverse reaction that occurred in the everolimus arm )0 10% by selected broader terms search
`(Feb 28, 2008 cut-off)
`
`An adverse reaction
`Gastrointestinal disorders
`Stomatitis'
`Diarrhea
`Nausea
`
`Placebo N=137 (%)
`
`All
`97
`
`44
`30
`26
`
`Gr4
`13
`
`.:1
`0
`0
`
`All
`93
`
`8
`7
`19
`
`4
`
`1
`
`1
`
`Gr4
`5
`
`0
`0
`0
`
`0
`0
`0
`
`8
`
`

`

`2
`7
`
`3
`5
`~1
`~1
`1
`
`~1
`6
`0
`4
`
`1
`~1
`~1
`
`1
`
`~1
`0
`
`I
`
`0
`3
`
`~1
`0
`0
`0
`0
`
`0
`i
`0
`0
`
`0
`0
`0
`
`0
`
`~1
`0
`
`0
`
`30
`24
`18
`14
`
`29
`14
`13
`
`25
`
`19
`10
`
`10
`
`Vomiting
`20
`Infections and infestationsb
`I 37
`General disorders and administration site conditions
`Asthenia
`33
`Fatigue
`31
`Edema peripheral
`25
`Pyrexia
`20
`Mucosal inflammation
`19
`Respiratorv, thoracic and mediastinal disorders
`Cough
`Dyspnea
`Epistaxis
`PneumonitisC
`Skin and subcutaneous tissue disorders
`Rash
`Pruritus
`Dry skin
`Metabolism and nutrition disorders
`Anorexia
`Nervous system disorders
`Headache
`Dysgeusia
`Musculoskeletal and connective tissue disorders
`Pain in extremity
`1
`141
`treatment (davS)
`Median duration of
`. .
`. .
`a Stomatitis (including aphthous stomatitis), and mouth and tongue ulceration.
`b Includes all preferred terms within the 'infections and infestations' system organ class including pneumonia,
`aspergillosis, candidiasis, and sepsis.
`lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary
`c Includes pneumonitis, interstitial
`toxicity, and alveolitis.
`Source: Study C2240 study report and safety update
`
`12
`18
`
`23
`27
`8
`9
`
`1
`
`16
`15
`0
`0
`
`7
`7
`5
`
`14
`
`9
`2
`
`7
`
`0
`
`1
`
`4
`3
`~1
`0
`0
`
`0
`3
`0
`0
`
`0
`0
`0
`
`~1
`
`~1
`0
`
`0
`60
`
`I
`
`0
`0
`
`0
`~1
`0
`0
`0
`
`0
`0
`0
`0
`
`0
`0
`0
`
`0
`
`0
`0
`
`0
`
`Key laboratory abnormalities are summarized in Table 2 from the package insert.
`
`Table
`
`2
`
`Key Laboratory Abnormalities Reported at a Higher rate in the AFINITOR Arm than the Placebo Arm
`
`Laboratory Parameter
`
`AFINITOR 10 mg/day
`N=274
`
`3
`
`4
`
`Placebo
`N=137
`
`Hematology.
`Hemoglobin decreased
`Lymphocytes decreased
`Platelets decreased
`Neutrophils decreased
`Clinical Chemistry
`
`Cholesterol increased
`Triglycerides increased
`Glucose increased
`
`Creatinine increased
`
`Phosphate decreased
`Aspartate transaminase (AST) increased
`Alanine transaminase (ALT) increased
`
`All grades
`%
`
`Grade
`%
`
`Grade
`%
`
`All grades
`%
`
`Grade
`%
`
`92
`
`51
`23
`
`14
`
`77
`73
`57
`50
`37
`25
`
`21
`
`12
`)6
`
`)
`
`0
`
`4
`.:)
`)5
`
`)
`6
`.:)
`
`i
`
`2
`
`0
`.:)
`
`0
`0
`
`.:1
`
`0
`0
`
`.:1
`
`0
`
`79
`28
`2
`4
`
`35
`34
`25
`34
`
`8
`
`7
`4
`
`5
`
`5
`0
`0
`
`0
`
`0
`
`)
`
`0
`
`0
`
`0
`
`0
`
`3
`
`Grade
`
`4
`
`0/0
`
`.:1
`
`0
`.:)
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`0
`0
`
`9
`
`

`

`Bilirubin increased
`
`3
`
`-cl
`
`-cl
`
`2
`
`o
`
`o
`
`CTCAE Version 3.0
`" Includes reports of anemia, leukopenia, lymphopenia, neutropenia, pancytopenia, thrombocytopenia.
`
`Comment: The safety database is adequate for this indication. Major safety concerns include
`non-infectious pneumonitis, infections, oral ulcerations, renal dysfunction, hyperglycemia,
`hyperlipidemia, myelosuppression, drug-drug interactions with strong or moderate CYP3A4
`inhibitors or with strong CYP 3A 4 inducers, use in patients with impaired hepatic function, use
`of live vaccines, and use in pregnancy. These are all addressed in the Warnings and
`Precautions section of the package insert.
`
`9. Advisory Committee Meeting
`This application was not taken to a meeting ofthe Oncologic Drugs Advisory Committee
`(ODAC) because the application is based on a trial demonstrating a clinically and statistically
`significant improvement in progression-free survival with an acceptable benefit/risk ratio.
`Progression-free survival has previously been used as the basis for approval of drugs for the
`treatment of advanced renal cell carcinoma and the safety profieis similar to that of other
`drugs approved for this indication.
`
`10. Pediatrics
`
`The PeRC concurred with a waiver ofthe pediatric study requirement for this application
`because necessary studies are impossible or highly impracticable since this disease does not
`occur in the pediatric population.
`
`11. Other Relevant Regulatory Issues
`
`There are no other unresolved relevant regulatory issues.
`
`12. Labeling
`Includes:
`· Proprietary name: DMEP A concurred with the proprietary name.
`· Physician labeling: Agreement was reached on the physician labeling.
`· Carton and immediate container labels: Agreement was reached on the final carton and
`blister labels.
`· Patient labeling/Medication guide: Agreement was reached on patient labeling.
`
`13. Decision/Action/Risk Benefit Assessment
`
`· Regulatory Action: Approval is recommended.
`· Risk Benefit Assessment: The risk benefit assessment is acceptable for this patient
`population. The improvement in PFS is clinically significant, the toxicity profie is similar
`
`10
`
`

`

`to that of other agents approved for the treatment of advanced renal cell cancer, and there
`are no other therapies of proven benefit in patients with failure of prior treatment with
`sunitinib or sorafenib.
`· Recommendation for Postmarketing Risk Management Activities: Routine postmarketing
`surveilance with special emphasis on non-infectious pneumonitis, infections, and renal
`dysfunction.
`· Recommendation for other Postmarketing Requirements and Commitments:
`
`Trial A2303 evaluated everolimus in patients with moderate hepatic impairment (Child
`Pugh Class B) and due to increases in everolimus exposure, a dose reduction is needed in
`these patients. No exposure data are available for patients with severe hepatic impairment
`and current labeling recommends that Afinitor(ß (everolimus) should not be used in these
`patients. Because of an unexpected serious risk of increased drug exposure when Afinitor(ß
`(everolimus) is administered to patients with severe hepatic impairment, the following
`postmarketing clinical trial wil be required:
`
`1. Conduct a trial in patients with severe hepatic impairment (Child Pugh Class C). This
`trial need not be conducted in patients with cancer and a single dose evaluation wil be
`appropriate. The protocol should be submitted prior to initiation for review and
`concurrence.
`
`Final Protocol Submission:
`Trial Start Date:
`Final Report Submission:
`
`May 14,2009
`October 14,2009
`April 14,2011
`
`The following are the agreed-upon postmarketing study commitments:
`
`2. Submit the final, per-protocol overall survival analysis of protocol C2240 which was to
`the last patient.
`
`be conducted 2 years after randomization of
`
`Protocol Submission: July 27,2006
`Trial Start Date: December 6, 2006
`Final Report Submission: June 2010
`
`3. Develop a 2.5 mg dosage form (tablet) to allow for proper dose reductions when
`Afinitor(ß (everolimus) is co-administered with moderate CYP3A4 inhibitors. The 2.5
`mg dosage form should be sufficiently distinguishable from the 5 mg and 10 mg
`tablets. Full chemistry, manufacturing and controls (CMC) information for the 2.5 mg
`dosage form including batch and stability data, updated labeling, and an updated
`environmental assessment should be submitted as a prior approval supplement.
`
`Protocol Submission Date:
`Final Report Submission:
`
`May 14,2009
`January 14,2010
`
`11
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`/s/
`Robert Justice
`3 /27 / 2 009 07: 08 : 3 0 PM
`MEDICAL OFFICER
`
`