CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`208630Orig1s000
`
`CLINICAL REVIEW(S)
`
`
`
`
`
`
`
`
`

`

`Clinical Review
`Betsy Ballard, MD
`NDA 208630
`Gleolan (5-aminolevulinic acid)
`
`CLINICAL REVIEW
`
`Application Type NDA
`Application Number(s) 208630
`Priority or Standard Fast Type Designation
`Submit Date(s) 12/6/2016
`Received Date(s) 12/6/2016
`PDUFA Goal Date 6/6/2017
`Division/Office DMIP/OND IV
`Reviewer Name(s) Betsy Ballard, MD
`Review Completion Date 5/15/2017
`Established Name Gliolan (5-Aminolevulinic Acid)
`(Proposed) Trade Name Gleolan
`Applicant NX Development Corp
`Formulation(s) Oral powder
`Dosing Regimen 20mg/kg given a single time 3-4 hours prior to surgery
`Applicant Proposed
`An imaging agent to facilitate the real time detection and
`Indication(s)/Population(s)
`visualization of malignant tissue during glioma surgery.
`Recommendation on
`Approval
`Regulatory Action
`Recommended
`Indication(s)/Population(s)
`(if applicable)
`
`An imagining agent indicated as an adjunct to other neurosurgical
`tools, to visualize WHO grades III and IV gliomas intra-operatively
`during glioma surgery.
`
`(This is the reviewer’s proposed statement and may differ from
`the indication that will be approved)
`
`Review Team Clinical Reviewer: BALLARD, BETSY
`Statistician: MUCCI, ANTHONY
`Clinical Pharmacology: JOHN, CHRISTY S.
`Non-Clinical Reviewer: HONCHEL, RONALD
`Product Quality Reviewer: AMARTEY, JOHN K.
`Product Quality Reviewer: HABER, MARTIN T.
`Product Quality Microbiology Reviewer: PFEILER, ERIKA A.
`CDRH Consultants: OGDEN, NEIL and CHEN, COLIN KEJING
`(DSD/GSDB I)
`Regulatory Project Manager: SKARUPA, LISA M
`
`CDER Clinical Review Template 2015 Edition
`Version date: November 5, 2015 for initial rollout (NME/original BLA reviews)
`Reference ID: 4106167
`
`1
`
`

`

`Clinical Review
`Betsy Ballard, MD
`NDA 208630
`Gleolan (5-aminolevulinic acid)
`
`Table of Contents
`
`Glossary ..........................................................................................................................................8
`
`1
`
`2
`
`3
`
`4
`
`Executive Summary...............................................................................................................10
`1.1.
`Product Introduction......................................................................................................10
`1.2.
`Conclusions on the Substantial Evidence of Effectiveness.............................................10
`1.3.
`Benefit-Risk Assessment ................................................................................................10
`
`Therapeutic Context..............................................................................................................16
`2.1. Analysis of Condition......................................................................................................16
`2.2. Analysis of Current Treatment Options .........................................................................17
`
`Regulatory Background .........................................................................................................19
`3.1. U.S. Regulatory Actions and Marketing History.............................................................19
`3.2.
`Summary of Presubmission/Submission Regulatory Activity ........................................19
`3.3.
`Foreign Regulatory Actions and Marketing History .......................................................21
`
`Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on
`Efficacy and Safety ................................................................................................................21
`4.1. Office of Scientific Investigations (OSI) ..........................................................................21
`The results of the OSI data confirmation were not available at the time of this review..........21
`4.2.
`Product Quality ..............................................................................................................21
`4.3.
`Clinical Microbiology......................................................................................................21
`4.4. Nonclinical Pharmacology/Toxicology ...........................................................................21
`4.5.
`Clinical Pharmacology ....................................................................................................22
`4.5.1. Mechanism of Action..............................................................................................22
`4.5.2. Pharmacodynamics.................................................................................................23
`4.5.3. Pharmacokinetics....................................................................................................23
`4.6. Devices and Companion Diagnostic Issues ....................................................................23
`4.7.
`Consumer Study Reviews...............................................................................................24
`
`5
`
`Sources of Clinical Data and Review Strategy .......................................................................24
`5.1.
`Table of Clinical Studies .................................................................................................24
`5.2.
`Review Strategy .............................................................................................................27
`
`CDER Clinical Review Template 2015 Edition
`Version date: November 5, 2015 for initial rollout (NME/original BLA reviews)
`Reference ID: 4106167
`
`2
`
`

`

`Clinical Review
`Betsy Ballard, MD
`NDA 208630
`Gleolan (5-aminolevulinic acid)
`
`6
`
`7
`
`8
`
`Review of Relevant Individual Trials Used to Support Efficacy .............................................28
`6.1.
`Fluorescence-guided resection of malignant gliomas with 5-Aminolevulinic acid (5-ALA)
`vs. conventional resection........................................................................................................28
`6.1.1. Study Design ...........................................................................................................28
`6.1.2. Study Results ..........................................................................................................32
`Clinical Phase II Trial of 5-Aminolevulinic Acid Hydrochloride (5-ALA, 5-ALS) for
`6.2.
`Fluorescence-guided Resection of Malignant Gliomas (ALS-28) ..............................................43
`6.2.1. Study Design ...........................................................................................................43
`6.2.2. Study Results ..........................................................................................................47
`Clinical Phase II Trial of MC 506/1 (5-Aminolevulinic Acid hydrochloride, 5-ALA, 5-ALS)
`6.3.
`for Fluorescence-Guided Resection of Malignant Gliomas in Progression Therapy (ALS-30) ..50
`6.3.1. Study Design ...........................................................................................................50
`6.3.2. Study Results ..........................................................................................................52
`
`Integrated Review of Effectiveness.......................................................................................56
`7.1. Assessment of Efficacy Across Trials..............................................................................56
`7.1.1. Primary Endpoints ..................................................................................................56
`7.1.2. Subpopulations.......................................................................................................60
`7.1.3. Dose and Dose-Response .......................................................................................60
`7.1.4. Onset, Duration, and Durability of Efficacy Effects.................................................60
`7.2. Additional Efficacy Considerations.................................................................................60
`7.2.1. Considerations on Benefit in the Postmarket Setting.............................................60
`7.2.2. Other Relevant Benefits..........................................................................................60
`Integrated Assessment of Effectiveness ........................................................................61
`
`7.3.
`
`Review of Safety....................................................................................................................62
`8.1.
`Safety Review Approach ................................................................................................63
`8.2.
`Review of the Safety Database ......................................................................................63
`8.2.1. Overall Exposure.....................................................................................................63
`8.2.2. Relevant characteristics of the safety population: .................................................63
`8.2.3. Adequacy of the safety database: ..........................................................................63
`8.3. Adequacy of Applicant’s Clinical Safety Assessments....................................................64
`8.3.1. Issues Regarding Data Integrity and Submission Quality........................................64
`
`CDER Clinical Review Template 2015 Edition
`Version date: November 5, 2015 for initial rollout (NME/original BLA reviews)
`Reference ID: 4106167
`
`3
`
`

`

`Clinical Review
`Betsy Ballard, MD
`NDA 208630
`Gleolan (5-aminolevulinic acid)
`
`8.4.
`
`8.3.2. Categorization of Adverse Events...........................................................................64
`8.3.3. Routine Clinical Tests..............................................................................................64
`Safety Results.................................................................................................................65
`8.4.1. Deaths.....................................................................................................................65
`8.4.2. Serious Adverse Events...........................................................................................66
`8.4.3. Dropouts and/or Discontinuations Due to Adverse Effects....................................66
`8.4.4. Significant Adverse Events......................................................................................66
`8.4.5. Treatment Emergent Adverse Events and Adverse Reactions ...............................67
`8.4.6. Laboratory Findings ................................................................................................67
`8.4.7. Vital Signs................................................................................................................68
`8.4.8. Electrocardiograms (ECGs) .....................................................................................68
`8.4.9. QT ...........................................................................................................................69
`The applicant also stated that the post-marketing world-wide data base was queried
`and there were no cardiac events associated with QT prolongation. ..............................70
`8.4.10.
`Immunogenicity...............................................................................................70
`8.5. Analysis of Submission-Specific Safety Issues ................................................................70
`8.5.1. Neurologic Events...................................................................................................70
`8.5.2. Photosensitivity ......................................................................................................71
`Safety Analyses by Demographic Subgroups .................................................................72
`8.6.
`Specific Safety Studies/Clinical Trials .............................................................................72
`8.7.
`8.8. Additional Safety Explorations.......................................................................................72
`8.8.1. Human Carcinogenicity or Tumor Development ....................................................72
`8.8.2. Human Reproduction and Pregnancy.....................................................................72
`8.8.3. Pediatrics and Assessment of Effects on Growth ...................................................72
`8.8.4. Overdose, Drug Abuse Potential, Withdrawal, and Rebound.................................72
`Safety in the Postmarket Setting ...................................................................................72
`8.9.1. Safety Concerns Identified Through Postmarket Experience .................................72
`8.9.2. Expectations on Safety in the Postmarket Setting..................................................72
`8.10.
`Additional Safety Issues From Other Disciplines ........................................................73
`8.11.
`Integrated Assessment of Safety................................................................................73
`
`8.9.
`
`9
`
`Advisory Committee Meeting and Other External Consultations .........................................73
`
`CDER Clinical Review Template 2015 Edition
`Version date: November 5, 2015 for initial rollout (NME/original BLA reviews)
`Reference ID: 4106167
`
`4
`
`

`

`Clinical Review
`Betsy Ballard, MD
`NDA 208630
`Gleolan (5-aminolevulinic acid)
`
`10 Labeling Recommendations ..................................................................................................73
`10.1.
`Prescribing Information..............................................................................................73
`10.2.
`Patient Labeling..........................................................................................................74
`10.3.
`Nonprescription Labeling ...........................................................................................74
`
`11 Risk Evaluation and Mitigation Strategies (REMS) ................................................................74
`11.1.
`Safety Issue(s) that Warrant Consideration of a REMS ..............................................74
`11.2.
`Conditions of Use to Address Safety Issue(s) .............................................................74
`11.3.
`Recommendations on REMS ......................................................................................74
`
`Given the favorable safety profile of this drug in the given population, there are no additional
`risk management strategies required beyond the recommended labeling. Therefore, the
`subsequent subsections are not applicable for this review and have been omitted............75
`
`12 Postmarketing Requirements and Commitments.................................................................75
`
`13 Appendices............................................................................................................................75
`13.1.
`References..................................................................................................................75
`13.2.
`Financial Disclosure ....................................................................................................75
`
`CDER Clinical Review Template 2015 Edition
`Version date: November 5, 2015 for initial rollout (NME/original BLA reviews)
`Reference ID: 4106167
`
`5
`
`

`

`Clinical Review
`Betsy Ballard, MD
`NDA 208630
`Gleolan (5-aminolevulinic acid)
`
`No table of figures entries found.
`
`Table of Tables
`
`CDER Clinical Review Template 2015 Edition
`Version date: November 5, 2015 for initial rollout (NME/original BLA reviews)
`Reference ID: 4106167
`
`6
`
`

`

`Clinical Review
`Betsy Ballard, MD
`NDA 208630
`Gleolan (5-aminolevulinic acid)
`
`No table of figures entries found.
`
`Table of Figures
`
`CDER Clinical Review Template 2015 Edition
`Version date: November 5, 2015 for initial rollout (NME/original BLA reviews)
`Reference ID: 4106167
`
`7
`
`

`

`Clinical Review
`Betsy Ballard, MD
`NDA 208630
`Gleolan (5-aminolevulinic acid)
`
`Glossary
`
`5-ALA 5-aminolevulinic acid
`AC
`advisory committee
`AE
`adverse event
`ALT alanine aminotransferase
`BBB blood brain barrier
`BRF
`Benefit Risk Framework
`CDER
`Center for Drug Evaluation and Research
`CDRH
`Center for Devices and Radiological Health
`CDTL
`Cross-Discipline Team Leader
`CFR
`Code of Federal Regulations
`CMC
`chemistry, manufacturing, and controls
`CRF
`case report form
`CSR
`clinical study report
`DMC
`data monitoring committee
`EANO European Association of Neuro-Oncology
`ECG
`electrocardiogram
`eCTD
`electronic common technical document
`EU European Union
`FAS Full analysis set
`FDA
`Food and Drug Administration
`FDAAA
`Food and Drug Administration Amendments Act of 2007
`FDASIA
`Food and Drug Administration Safety and Innovation Act
`FN False Negative
`FNR-FL False Negative Rate-Fluorescent
`GCP
`good clinical practice
`GGT
`gamma-glutamyl transferase
`GRMP
`good review management practice
`ICH
`International Conference on Harmonization
`iMRI Intra-operative MRI
`IND
`Investigational New Drug
`ISE
`integrated summary of effectiveness
`ISS
`integrated summary of safety
`ITT
`intent to treat
`LFT’s liver function tests
`MedDRA
`Medical Dictionary for Regulatory Activities
`mITT
`modified intent to treat
`
`CDER Clinical Review Template 2015 Edition
`Version date: November 5, 2015 for initial rollout (NME/original BLA reviews)
`Reference ID: 4106167
`
`8
`
`

`

`Clinical Review
`Betsy Ballard, MD
`NDA 208630
`Gleolan (5-aminolevulinic acid)
`
`National Cancer Institute-Common Terminology Criteria for Adverse Event
`NCI-CTCAE
`new drug application
`NDA
`new molecular entity
`NME
`negative predictive value
`NPV
`Office of Computational Science
`OCS
`Office of Pharmaceutical Quality
`OPQ
`Office of Surveillance and Epidemiology
`OSE
`Office of Scientific Investigation
`OSI
`Periodic Benefit-Risk Evaluation Report
`PBRER
`pharmacodynamics
`PD
`prescribing information
`PI
`pharmacokinetics
`PK
`postmarketing commitment
`PMC
`postmarketing requirement
`PMR
`per protocol
`PP
`patient package insert
`PPI
`PpIX protoporphyrin IX
`PPV positive predictive value
`PREA
`Pediatric Research Equity Act
`PRO
`patient reported outcome
`PSUR
`Periodic Safety Update report
`REMS
`risk evaluation and mitigation strategy
`SAE
`serious adverse event
`SAP
`statistical analysis plan
`SGE
`special government employee
`SOC
`standard of care
`TEAE
`treatment emergent adverse event
`
`CDER Clinical Review Template 2015 Edition
`Version date: November 5, 2015 for initial rollout (NME/original BLA reviews)
`Reference ID: 4106167
`
`9
`
`

`

`Clinical Review
`Betsy Ballard, MD
`NDA 208630
`Gleolan (5-aminolevulinic acid)
`
`1 Executive Summary
`
`1.1.
`
`Product Introduction
`
`The applicant has proposed the use of Gleolan (5-ALA) as an imaging agent to facilitate the real
`time detection and visualization of malignant tissue during glioma surgery. The recommended
`dose is a single oral dose of 5-ALA at 20mg/kg given 3 hours prior to surgery. It is not considered
`an NME, as 5-ALA in other forms, has been approved for several indications.
`
`1.2.
`
`Conclusions on the Substantial Evidence of Effectiveness
`
`The application contains sufficient evidence based upon the totality of the data within the
`submitted completed clinical trials and literature to support its safe use to visualize malignant
`tissue during glioma surgery. It is important to note that only high-grade anaplastic tumors
`(WHO III and IV) exhibit fluorescence and were the only WHO grade studied. In comparison to
`existing technology, it is not hampered by changes in tumor location due to brain shift during
`surgery and it does not require interruption of the surgical procedure to acquire images (such
`as with iMRI). When strong fluorescence is seen, it is correlated with the presence of solid
`tumor. Due to the infiltrative nature of the disease, the converse is not true; in the absence of
`fluorescence, tissue may also be positive for malignant cells.
`
`1.3.
`
`Benefit-Risk Assessment
`
`CDER Clinical Review Template 2015 Edition
`Version date: November 5, 2015 for initial rollout (NME/original BLA reviews)
`Reference ID: 4106167
`
`10
`
`

`

`Clinical Review
`Betsy Ballard, MD
`NDA 208630
`Gleolan (5-aminolevulinic acid)
`
`Benefit-Risk Summary and Assessment
`
`5-ALA HCl is a chemical substance developed to identify malignant brain tissue during surgery to aid in removal of tumor (“surgical tool”),
`where possible, to achieve maximal safe resection. 5-ALA HCl was granted orphan drug designation.
`
`Gliomas are a lethal brain tumor which are highly vascular, infiltrative (difficult to observe tumor-normal brain interface), with tumor
`heterogeneity (low and high-grade elements and satellite lesions within normal brain tissue. The tumor dissemination can cross midlines but is
`limited to CNS without distant metastases. The ability to identify tumor during surgery is critical to improve the extent of resection and the
`prognosis for patients with these tumors. Current neurosurgical tools available, such as neuronavigation and iMRI, have their limitations of
`use. Current treatments have not really improved overall survival for these patients.
`
`The submitted evidence describes the benefit of the product in terms of its strong positive predicative value. There is a solid correlation
`between fluorescent areas and presence of tumor; however the converse is not true. The absence of fluorescence does not necessarily
`correlate to absence of tumor. The product works best at identifying the more anaplastic lesions, WHO Grades III and IV, but less so in WHO
`Grades I or II or other brain lesions that have radiologic findings similar to gliomas on MRI.
`
`The randomized study showed an increase in the extent of resection using 5-ALA compared to the standard conventional surgical procedure
`and although the studies presented demonstrate a trend upwards in neurologic deficits in the treated arm these returned to baseline within
`the first post-operative month. The more recent literature has shown that the rate of neurologic deficit is similar to conventional surgery.
`
`It is expected that the product will be able to facilitate disease visualization intra-operatively in conjunction with other neuro-monitoring
`methods without additional safety concerns.
`
`Dimension
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
`CDER Clinical Review Template 2015 Edition
`Version date: November 5, 2015 for initial rollout (NME/original BLA reviews)
`Reference ID: 4106167
`
`11
`
`

`

`Clinical Review
`Betsy Ballard, MD
`NDA 208630
`Gleolan (5-aminolevulinic acid)
`
`Dimension
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
`•
`
`• Gliomas are tumors that arise from glial or precursor cells and include
`astrocytoma, glioblastoma, oligodendroglioma, ependymoma, mixed
`glioma, malignant glioma, not otherwise specified (NOS), and a few rare
`histologies. They are infiltrative in nature and cross midline structures
`often appearing beyond the image seen on MRI making tumor-free
`margins during resection unrealistic.
`The incidence of the disease is 5 to 10 cases per 100,000 persons per year
`and more than 14,000 new cases of GBM are diagnosed in the United
`States each year.
`• The most important prognostic factors for glioblastoma are extent of
`tumor resection, age at diagnosis, and Karnofsky performance
`status.
`• Even with current treatments, survival has not been greatly improved
`with only small increments (months) of gain.
`• Recurrence is common in patients with GBM. Greater than 85% of all
`recurrences are within 2.5cm of the surgical margins; therefore the
`initial resection is critical. Only 20% of these patients are
`candidates for additional debulking surgery
`Primary treatment is surgical resection to the maximal safe resection
`possible followed by concurrent chemotherapy and post-operative
`radiation with temozolmide chemotherapy continuing after completion of
`radiation therapy. Electric field based loco-regional, antimitotic treatment
`modality is another post-operative treatment modality.
` Intra-operative tools for assessment of tumor include the following, all of
`which have limitations:
`o Neuronavigation with registration to pre-operative MRI or
`
`•
`
`•
`
`This is a lethal disease with a median survival
`of 15 months. The 5-year survival in the US is
`<5%. Current treatments have not really
`improved overall survival for these patients.
`The ability to identify tumor is critical to
`improve the extent of resection which in turn
`should improve the prognosis for these
`patients.
`
`Surgical treatment is complicated by the
`diffusely infiltrating nature of the malignant
`gliomas, the need to avoid damage to eloquent
`cortical areas during surgery, and the problem
`of removing healthy tissue taken as tumor.
`It is inherently difficult to define residual
`tumor during surgery. 5-ALA can identify areas
`of tumor at the margin and in anaplastic foci
`
`Analysis of
`Condition
`
`Current
`Treatment
`Options
`
`CDER Clinical Review Template 2015 Edition
`Version date: November 5, 2015 for initial rollout (NME/original BLA reviews)
`Reference ID: 4106167
`
`12
`
`

`

`Clinical Review
`Betsy Ballard, MD
`NDA 208630
`Gleolan (5-aminolevulinic acid)
`
`Dimension
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
`PET imaging
`o Intra-operative MRI (iMRI)
`o Intra-operative ultrasonography
`o Sensory-motor mapping/awake craniotomy
`• For recurrent disease the options include:
`o Second surgical procedure with or without the use of
`carmustine wafer implantation (Gliadel Wafers)
`o A radiation boost to area of recurrence
`o Salvage chemotherapy, usually bevacizumab or other
`investigational therapies
`o TTFields (tumor treating fields), an electric field based loco-
`regional, antimitotic treatment modality
`• Use of 5-ALA during glioma surgery allowed for a greater extent of
`resection (64% 5-ALA vs. 38% white light)
`• The presence of fluorescence correlates well with presence of tumor.
`The PPV was 96-98% in all the studies reviewed
`• The ability to see borders offers an opportunity for selective sampling
`of the invading cells which appear to be different from the center of
`the tumor
`• For patients with non-operable tumors, stereotactic or open biopsy is
`performed for tissue diagnosis, so the high PPV would let surgeon
`identify the most malignant area within the tumor where the
`likelihood of obtaining an adequate tissue sample is higher, thus
`reducing the number of passes needed, reducing the risk of
`sampling error and possible under-grading.
`• For patients with low-grade gliomas, in whom the risk of malignant
`
`Benefit
`
`within more “benign” tumors. As an adjunct to
`good surgical judgement and use of
`appropriate neurosurgical tools, it is a method
`to allow the surgeon information regarding the
`presence of tumor cells in areas of ambiguity.
`
`The use of 5-ALA to delineate the tumor is
`useful to improve the rate of complete
`resections and prognosis for patients, and
`obtain adequate tissue for more precise
`neuropathological grading for subsequent
`treatment.
`
`CDER Clinical Review Template 2015 Edition
`Version date: November 5, 2015 for initial rollout (NME/original BLA reviews)
`Reference ID: 4106167
`
`13
`
`

`

`Clinical Review
`Betsy Ballard, MD
`NDA 208630
`Gleolan (5-aminolevulinic acid)
`
`Dimension
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
`transformation exist, may identify anaplastic foci within the low-
`grade mass reducing the risk of under-grading and undertreating
`these patients.
`• There were no serious drug related adverse reactions seen in the
`randomized trial or in the European safety update 2015.
`• Non-serious adverse drug-related reactions the were seen included
`photosensitivity in 2 patients, transient elevation of liver function
`tests, hypotension, pyrexia
`• Post-market data (2015) showed an exposure of >58,000 patients to
`the drug without any unexpected adverse events and no actions
`were taken for a safety signal.
`• There was a trend toward risk of greater neurologic harm resulting
`from the surgical procedure in the 5-ALA arm
`• Although 5-ALA is correlated with tumor when the tissue fluoresces,
`(PPV near 100%), there is also a high rate of tumor in non-fluorescent
`areas leading to false negatives (80%).
`• 10% of patients who received the study drug were not included in the
`efficacy analysis because their histopathology was not WHO Grade III
`or IV. For these patients, the pathology was not known at the
`enrollment phase as pre-operative stereotactic biopsy was not done
`and enrollment was based on MRI findings.
`
`Risk
`
`Although there seems to be an increase in
`neurologic symptoms in the immediate post-
`operative period, these findings improve with
`time and persistent new neurologic deficits are
`no greater than conventional surgery.
`Neurological deterioration after surgery occurs
`in 13-26% of all patients with 30-60%
`experiencing post-op seizures. Patients also
`exhibit fluctuation of neurologic symptoms
`throughout the course of the disease. With the
`use of newer technologies to monitor patients
`during surgery, injury to critical areas can be
`avoided. Although there was a risk of greater
`morbidity from more aggressive surgery this
`may be countered by surgery being more
`
`CDER Clinical Review Template 2015 Edition
`Version date: November 5, 2015 for initial rollout (NME/original BLA reviews)
`Reference ID: 4106167
`
`14
`
`

`

`Clinical Review
`Betsy Ballard, MD
`NDA 208630
`Gleolan (5-aminolevulinic acid)
`
`Dimension
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
`Risk
`Management
`
`• No risk management issues were identified for the drug.
`• There are technical aspects to fluorescent-guided surgery that may
`require additional training.
`
`accurate.
`
`Patients without a tissue diagnosis of WHO
`Grade III or IV pre-operatively may receive 5-
`ALA, and 5-ALA is not taken up in lower grade
`tumors or metastatic disease. These patients
`will still require surgical resection for their
`tumor. The drug appears to be safe even in
`this population.
`The drug has a favorable safety profile for its
`indicated use and patient population.
`Education of neurosurgeons via labeling to the
`limitations of the 5-ALA.
`
`CDER Clinical Review Template 2015 Edition
`Version date: November 5, 2015 for initial rollout (NME/original BLA reviews)
`Reference ID: 4106167
`
`15
`
`

`

`Clinical Review
`Betsy Ballard, MD
`NDA 208630
`Gleolan (5-aminolevulinic acid)
`
`2 Therapeutic Context
`
`2.1.
`
`Analysis of Condition
`
`Gliomas are primary brain tumors arising from neuroglial stem cells. They have been classified
`on the basis of the cell of origin and assigned WHO grading I-IV based on the degree of
`anaplastic change and malignant potential. In 2016 the WHO reclassified diffusely infiltrative
`gliomas on the basis of their natural histories and response to treatment/outcomes. The
`resulting system now has three classes: (IDH)-mutant, 1p/19q co(cid:3)deleted tumors with mostly
`oligodendroglial morphology that are associated with the best prognosis, IDH-mutant, 1p/19q
`non(cid:3)co(cid:3)deleted tumors with mostly astrocytic histology that are associated with intermediate
`outcome; and IDH wild-type, mostly higher WHO grade (III or IV) tumors that are associated
`with poor prognosis.
`
` GBM’s are microscopically different from lower grade tumors due to their highly vascular
`proliferation with areas of necrosis and their infiltrative nature (difficult to observe tumor
`normal brain interface) with tumor heterogeneity (low-grade elements and satellite lesions).
`Glioblastoma cells infiltrate significant distances across white matter away from
`radiographically and clinically evident primary masses making it difficult to determine the
`extent of tumor present.
`
`Gliomas account for about 30% of all brain tumors and the 80% of malignant tumors in adults.
`There is an incidence of gliomas of 6.6 per 100,000 people of which about half were
`glioblastomas. The incidence of gliomas in general increases with age, with the most
`pronounced increase in glioblastoma incidence (per 100,000 people) ranging from 0.15 in
`children and 0.41 in young adults to 13.1 in those aged 65–75 years and 15.0 in individuals
`between 75 and 84 years of age. Many environmental factors have been studied (i.e. cell
`phone use) but only exposure to ionizing radiation at a therapeutic dose has been identified as
`a causative factor. Gliomas have been associated with certain familial syndromes such as
`Neurofibromatosis types 1 and 2, Li-Fraumeni syndrome and Turcot’s syndrome.
`
`There is a high morbidity and mortality associated with the disease. Population based studies
`GBM show a median survival of 42% at 6 mos and 18% at 1 year. 3-5% of patients will survive 3
`years. I