CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`
`
`APPLICATION NUMBER:
`202788Orig1s000
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`
`MEDICAL REVIEW(S)
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`

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`CLINICAL REVIEW
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`Application Type NDA
`Application Number(s) 202-788
`Priority or Standard Standard
`
`Submit Date(s) 04 March 2011
`Received Date(s) 04 March 2011
`PDUFA Goal Date 04 January 2012
`Division / Office DAAAP/ODE2
`
`Reviewer Name(s) Luke Yip, MD
`Review Completion Date 15 December 2011
`
`Established Name Fentanyl sublingual spray
`(Proposed) Trade Name
`Therapeutic Class Opioid analgesic
`Applicant
`Insys Therapeutics, Inc
`
`Formulation(s) Sublingual spray solution
`Dosing Regimen PRN, not to exceed 4 doses
`per 24 hours and not more
`frequent than 4 hours apart
`Indication(s) Breakthrough cancer pain
`Intended Population(s) Adult cancer patients receiving
`around the clock opioids with
`breakthrough pain
`
`
`Reference ID: 3059426
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`

`

`Template Version: March 6, 2009
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`
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`Reference ID: 3059426
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`

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`Clinical Review
`{Insert Reviewer Name}
`{Insert Application Type and Number}
`{Insert Product Trade and Generic Name}
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`
`Table of Contents
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`2
`
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ......................................... 9
`1.1 Recommendation on Regulatory Action ............................................................. 9
`1.2 Risk Benefit Assessment.................................................................................. 10
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies . 10
`1.4 Recommendations for Postmarket Requirements and Commitments .............. 10
`INTRODUCTION AND REGULATORY BACKGROUND ...................................... 10
`2.1 Product Information .......................................................................................... 10
`2.2 Tables of Currently Available Treatments for Proposed Indications ................. 11
`2.3 Availability of Proposed Active Ingredient in the United States ........................ 11
`2.4
`Important Safety Issues With Consideration to Related Drugs......................... 12
`2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 12
`2.6 Other Relevant Background Information .......................................................... 14
`3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 14
`3.1 Submission Quality and Integrity ...................................................................... 14
`3.2 Compliance with Good Clinical Practices ......................................................... 15
`3.3 Financial Disclosures........................................................................................ 15
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ......................................................................................................... 15
`4.1 Chemistry Manufacturing and Controls ............................................................ 15
`4.2 Clinical Microbiology......................................................................................... 20
`4.3 Preclinical Pharmacology/Toxicology ............................................................... 20
`4.4 Clinical Pharmacology...................................................................................... 21
`4.4.1 Mechanism of Action.................................................................................. 21
`4.4.2 Pharmacodynamics.................................................................................... 21
`4.4.3 Pharmacokinetics....................................................................................... 21
`5 SOURCES OF CLINICAL DATA............................................................................ 28
`5.1 Tables of Studies/Clinical Trials ....................................................................... 28
`5.2 Review Strategy ............................................................................................... 29
`5.3 Discussion of Individual Studies/Clinical Trials................................................. 30
`6 REVIEW OF EFFICACY......................................................................................... 30
`Efficacy Summary...................................................................................................... 30
`6.1
`Indication .......................................................................................................... 30
`6.1.1 Methods ..................................................................................................... 30
`6.1.2 Demographics............................................................................................ 49
`6.1.3 Subject Disposition..................................................................................... 50
`6.1.4 Analysis of Primary Endpoint(s) ................................................................. 60
`6.1.5 Analysis of Secondary Endpoints(s) .......................................................... 64
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`6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .... 73
`6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects................. 73
`6.1.10 Additional Efficacy Issues/Analyses........................................................... 73
`7 REVIEW OF SAFETY............................................................................................. 74
`Safety Summary ........................................................................................................ 74
`7.1 Methods............................................................................................................ 74
`7.1.1 Studies/Clinical Trials Used to Evaluate Safety ......................................... 74
`7.1.2 Categorization of Adverse Events.............................................................. 79
`7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare
`Incidence.................................................................................................... 79
`7.2 Adequacy of Safety Assessments .................................................................... 79
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of
`Target Populations..................................................................................... 79
`7.2.2 Explorations for Dose Response................................................................ 81
`7.2.3 Special Animal and/or In Vitro Testing ....................................................... 81
`7.2.4 Routine Clinical Testing ............................................................................. 81
`7.2.5 Metabolic, Clearance, and Interaction Workup .......................................... 81
`7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class .. 81
`7.3 Major Safety Results ........................................................................................ 82
`7.3.1 Deaths........................................................................................................ 82
`7.3.2 Nonfatal Serious Adverse Events .............................................................. 86
`7.3.3 Dropouts and/or Discontinuations .............................................................. 92
`7.3.4 Significant Adverse Events ........................................................................ 99
`7.3.5 Submission Specific Primary Safety Concerns .......................................... 99
`7.4 Supportive Safety Results .............................................................................. 101
`7.4.1 Common Adverse Events ........................................................................ 101
`7.4.2 Laboratory Findings ................................................................................. 111
`7.4.3 Vital Signs ................................................................................................ 111
`7.4.4 Electrocardiograms (ECGs) ..................................................................... 111
`7.4.5 Special Safety Studies/Clinical Trials....................................................... 111
`7.4.6
`Immunogenicity........................................................................................ 111
`7.5 Other Safety Explorations............................................................................... 112
`7.5.1 Dose Dependency for Adverse Events .................................................... 112
`7.5.2 Time Dependency for Adverse Events..................................................... 112
`7.5.3 Drug-Demographic Interactions ............................................................... 112
`7.5.4 Drug-Disease Interactions........................................................................ 113
`7.5.5 Drug-Drug Interactions............................................................................. 113
`7.6 Additional Safety Evaluations ......................................................................... 113
`7.6.1 Human Carcinogenicity............................................................................ 113
`7.6.2 Human Reproduction and Pregnancy Data.............................................. 113
`7.6.3 Pediatrics and Assessment of Effects on Growth .................................... 113
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound.................... 114
`7.7 Additional Submissions / Safety Issues.......................................................... 114
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`Clinical Review
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`8 POSTMARKET EXPERIENCE............................................................................. 115
`
`9 APPENDICES ...................................................................................................... 116
`9.1 Literature Review/References ........................................................................ 116
`9.2 Labeling Recommendations ........................................................................... 116
`9.3 Advisory Committee Meeting.......................................................................... 116
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`Reference ID: 3059426
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`Clinical Review
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`
`Table of Tables
`
`Table 1: Currently marketed fentanyl containing products ............................................ 11
`Table 2: Recovery of fentanyl from unit dose spray device........................................... 19
`Table 3: FSS pharmacokinetics over dose range 100 mcg to 800 mcg ........................ 22
`Table 4: FSS pharmacokinetics over dose range 100 mcg to 800 mcg ........................ 23
`Table 5: Bioavailability of fentanyl after FSS and Actiq administration.......................... 24
`Table 6: Bioavailability of fentanyl after FSS 400 mcg (Treatment A) and Actiq 400 mcg
`(Treatment B) administration ......................................................................... 24
`Table 7: Effect of temperature and pH on FSS pharmacokinetics................................. 25
`Table 8: Fentanyl pharmacokinetics in patients without and with mucositis.................. 27
`Table 9: Summary of Clinical Studies Supporting Findings of Efficacy and Safety ....... 28
`Table 10: Protocol Amendments ................................................................................... 30
`Table 11: Schedule of Study Events ............................................................................. 33
`Table 12: Summary of patient demographics................................................................ 49
`Table 13: Reason for discontinuation............................................................................ 53
`Table 14: Reason for discontinuation (revised) ............................................................. 56
`Table 15: Summary of randomized patients by FSS dose group .................................. 57
`Table 16: Summary of protocol deviations/violations .................................................... 59
`Table 17: SPID30 “evaluable” population (N=92).......................................................... 60
`Table 18: Summary analysis of SPID30 by mITT and actual ITT population ................ 61
`Table 19: SPID30 “evaluable” population (N=92) subgroup analysis............................ 62
`Table 20: Sensitivity analysis summary of SPID30 ....................................................... 63
`Table 21: Mean SPID by time point “evaluable” population (N=92)............................... 64
`Table 22: Mean Total Pain Relief1 by time point “evaluable” population (N=92)........... 65
`Table 23: Mean Patient Global Evaluation of study medication by treatment................ 66
`Table 24: Mean PID1 by Treatment and time point “evaluable” population (N=92)....... 67
`Table 25: TSQM safety population – Baseline and change from baseline .................... 69
`Table 26: Satisfaction with FSS .................................................................................... 69
`Table 27: Incidence of rescue (supplemental) medication use...................................... 71
`Table 28: Bivariate distribution of BTCP episodes treated with FSS or placebo requiring
`rescue medication.......................................................................................... 72
`Table 29: Hazard analysis of time to rescue medication usage .................................... 72
`Table 30: Clinical studies .............................................................................................. 74
`Table 31: Patient disposition – titration period............................................................... 77
`Table 32: Patient disposition – maintenance period...................................................... 77
`Table 33: Duration of FSS exposure by dose in cancer patients – multiple-dose FSS
`studies (INS-05-001 and INS-006-007).......................................................... 79
`Table 34: Demographics of the cancer patients from the multiple-dose FSS studies
`(INS-05-001 and INS-006-007)...................................................................... 80
`Table 35: SAEs during open-label and double-blind periods......................................... 87
`Table 36: Incidence of SAEs during titration and maintenance periods ........................ 89
`Table 37: Incidence of SAEs by multiple-dose during titration period ........................... 89
`Table 38: Incidence of SAEs by multiple-dose during maintenance period................... 90
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`Table 39: Incidence of AEs leading to study drug discontinuation – titration period...... 95
`Table 40: Incidence of AEs leading to study drug discontinuation – maintenance period
`....................................................................................................................... 96
`Table 41: Incidence of adverse events – open-label, dose-titration period.................. 102
`Table 42: Incidence of adverse events >3% of patients – open-label period, dose-
`titration period .............................................................................................. 105
`Table 43: Adverse events associated with FSS use and mode of administration – open-
`label period .................................................................................................. 106
`Table 44: Incidence of adverse events – double-blind placebo-controlled cross over
`period........................................................................................................... 106
`Table 45: Incidence of adverse events >3% of patients – double-blind placebo-
`controlled cross over period......................................................................... 108
`Table 46: Adverse events associated with FSS use and mode of administration –
`double-blind period ...................................................................................... 109
`Table 47: Incidence of most common adverse events occurring in ≥5% of patients ... 110
`
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`Reference ID: 3059426
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`7
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`Clinical Review
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`
`Table of Figures
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`Figure 1: FSS unit dose system .................................................................................... 15
`Figure 2: Disposal of a used FSS unit........................................................................... 16
`Figure 3: Use of disposal HDPE bottle.......................................................................... 17
`Figure 4: Mean fentanyl concentration-time profiles...................................................... 21
`Figure 5: Mean fentanyl concentration-time profiles after FSS 100 mcg (A), 200 mcg
`(B), 400 mcg (C), 600 mcg (D), and 800 mcg (E) .......................................... 23
`Figure 6: Fentanyl concentration – patients without mucositis ...................................... 26
`Figure 7: Fentanyl concentration – patients with mucositis ........................................... 26
`Figure 8: Study flow chart.............................................................................................. 42
`Figure 9: Patient disposition .......................................................................................... 51
`Figure 10: SPID (mean ± SE) after FSS and placebo “evaluable” population (N=92) ... 65
`Figure 11: Total Pain Relief Scores (mean ± SE) after FSS and placebo “evaluable”
`population (N=92) .......................................................................................... 66
`Figure 12: PI Score (mean ± SE) after FSS and placebo “evaluable” population (N=92)
`....................................................................................................................... 67
`Figure 13: Pain Relief Scores (mean ± SE) after FSS and placebo “evaluable”
`population (N=92) .......................................................................................... 68
`Figure 14: Patient disposition INS-06-007..................................................................... 75
`Figure 15: Multiple-dose FSS studies – basis for FSS safety assessment.................... 78
`
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`Reference ID: 3059426
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`Clinical Review
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`
`1 Recommendations/Risk Benefit Assessment
`
`
`1.1 Recommendation on Regulatory Action
`
`I recommend that fentanyl sublingual spray (FSS) be approved for the indication: “the
`management of breakthrough pain in cancer patients, 18 years of age and older, who
`are already receiving and who are tolerant to opioid therapy for their underlying
`persistent cancer pain.”
`
`Evidence of efficacy was provided by a single adequate and well-controlled efficacy
`study in cancer patients with breakthrough pain. The evaluation of safety was based on
`a safety database of approximately 350 cancer patients with breakthrough pain,
`primarily those enrolled in a multiple-dose Phase 3 open-label trial.
`
`As a 505(b)(2) application, these findings also rest, in part, on the Agency’s previous
`findings of safety and efficacy for Actiq (oral transmucosal fentanyl citrate) which was
`approved for the same indication in 1998.
`
`There are limitations to the safety data submitted by the Applicant, as follows:
`
`
`1. Since FSS was being dosed in patients taking around-the-clock opioids for
`background pain, and the adverse event profile is expected to be similar for all
`opioids, the determination of causality of adverse events was difficult.
`
`2. The patients enrolled in all trials were extremely ill and were receiving additional
`therapeutic agents for their underlying conditions that may have been associated
`with significant toxicities. This made it difficult to adequately assess and assign
`causality of the adverse events.
`
`
`
`
`
`3. Because of the cross-over design of the double-blind study period of the efficacy
`trial, the relationship of the time of the dose of study drug to the time of adverse
`event was not generally available. This information was also not available for the
`open-label period of the study.
`
`
`Despite these limitations, a thorough review of the safety data did not reveal any
`unexpected adverse events that could be attributed to the study drug. FSS appears to
`be associated with typical opioid-related adverse events, and the vast majority of
`serious adverse events and deaths appeared to be attributable to the patients’
`underlying disease, treatments, or complications of treatment. A relatively small
`proportion of patients had administration site reactions (oral adverse events) that could
`be attributed to FSS use.
`
`Reference ID: 3059426
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`Clinical Review
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`
`FSS will be the sixth oral transmucosal fentanyl product approved for the treatment of
`breakthrough cancer pain, joining Actiq, Fentora, Onsolis, Abstral, and Lazanda. All six
`product lines have some overlapping strengths. FSS is not bioequivalent to Actiq. These
`products are not interchangeable on a microgram by microgram basis. As has become
`evident with Fentora and Actiq, medication errors with associated adverse events have
`already occurred. It is important that this risk, along with the risks of overdose, abuse,
`misuse, and addiction, be mitigated by appropriate strategies.
`
`1.2 Risk Benefit Assessment
`
`Based on the efficacy and safety data presented by the Applicant from their Phase 3
`clinical development program, as well as the known chemistry, pharmacology and
`toxicology profiles of this and other transmucosal fentanyl products, the benefits of FSS
`outweigh the risks for the intended use.
`
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation
`Strategies
`
`As a fentanyl-containing product for breakthrough cancer pain, FSS is subject to a Risk
`Evaluation and Mitigation Strategies (REMS) program.
`
`1.4 Recommendations for Postmarket Requirements and Commitments
`
`The Applicant requested a deferral of the Pediatric Assessment required under PREA
`(Section 7.6.3). As described in this section, the Applicant will need to fulfill the
`requirements of PREA.
`
`2 Introduction and Regulatory Background
`
`2.1 Product Information
`
`The proposed indication for FSS, an opioid analgesic, is the management of
`breakthrough pain in cancer patients, 18 years of age and older, who are already
`receiving and who are tolerant to opioid therapy for their underlying persistent cancer
`pain.
`
`FSS is an opioid analgesic intended for oral sublingual administration. FSS is
`formulated as a clear, colorless solution that is available in six unit dosage strengths:
`100 mcg (1 mg/mL), 200 mcg (2 mg/mL), 400 mcg (4 mg/mL), 600 mcg (6 mg/mL), or
`800 mcg (8 mg/mL) fentanyl solution.
`
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`Reference ID: 3059426
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`Clinical Review
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`The proposed trade name, which has been found acceptable by Division of Medical
`Errors and Technical Support (DMETS), is SUBSYS, and the established name is
`fentanyl sublingual spray. This product is a new dosage form of fentanyl, an opioid first
`approved in 1968 for the intravenous treatment of pain.
`
`2.2 Tables of Currently Available Treatments for Proposed Indications
`
`Historically, the treatment of BTCP in cancer patients has consisted of treatment of the
`pain episode with a short-acting, immediate-release oral opioid (or opioid/non-opioid
`combination product) consisting of approximately 15% of the patient’s total baseline
`opioid dose. Typically, morphine, oxycodone, or hydromorphone have been used in this
`setting. However none of the immediate release oral opioids are approved for this
`indication.
`
`There are currently five products (i.e., Actiq, Fentora, Onsolis, Abstral, and Lazanda)
`approved for BTCP in opioid-tolerant cancer patients.
`
`2.3 Availability of Proposed Active Ingredient in the United States
`
`There are currently eight approved drug products (not including generic forms) in the
`United States containing the fentanyl moiety. Table 1 summarizes the important aspects
`of regulatory and post-marketing experience with these products. The overall adverse
`event profiles for all of the products are similar, and are typical of opioid effects (e.g.,
`sedation, constipation, and respiratory depression). Table 1 also illustrates safety
`concerns that have occurred in addition to the expected events.
`
`Table 1: Currently marketed fentanyl containing products
`Trade Name
`Major Labeling
`(Established Name)
`Changes
`Sublimaze®
`None
`(fentanyl injection)
`Duragesic®
`(fentanyl transdermal
`system)
`
`Pre- and Postmarketing
`Safety Concerns
`
`None
`
`• Leaking patches resulting in 2
`recalls (2004 and 2008)
`• Lack of adhesion
`• Overdose, misuse and abuse
`• Use in opioid naïve patients
`
`• Dental caries
`• Accidental pediatric exposures
`• Off-label use in opioid naïve patients
`• Abuse, misuse, overdose
`
`Never marketed due to safety issues
`regarding the device component
`
`• RiskMAP
`• Medguide
`• Use of overlay
`• Increased
`warnings regarding
`use in opioid naïve
`patients
`• RiskMAP
`• Medguide
`• Warnings
`regarding dental
`caries
`None
`
`NDA #
`16-619
`
`Approval Date
`February 19, 1968
`
`19-813
`
`August 7, 1990
`
`20-747
`
`November 4, 1998
`
`21-338
`
`May 22, 2006
`
`Actiq®
`(oral transmucosal
`fentanyl citrate)
`
`IONSYS®
`(fentanyl
`iontophoretic
`transdermal system)
`Fentora®
`
`21-947
`
`September 25, 2006
`
`• Increased
`
`• Off label use in opioid naïve patients
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`Reference ID: 3059426
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`Clinical Review
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`
`(fentanyl buccal
`tablet)
`
`Onsolis®
`(fentanyl bioerodible
`mucoadhesive
`system)
`
`22-266
`
`July 16, 2009
`
`Abstral®
`(fentanyl sublingual
`tablet)
`
`22-510
`
`January 7, 2010
`
`Lazanda®
`(fentanyl nasal
`spray)
`
`22-569
`
`June 30, 2011
`
`
`
`• Improper dosing stemming from fact
`that this product is not bioequivalent
`to Actiq and therefore doses are not
`interchangeable
`
`• Off label use in opioid naïve patients
`• Improper dosing stemming from fact
`that this product is not bioequivalent
`to Actiq and therefore doses are not
`interchangeable
`
`• Off label use in opioid naïve patients
`• Improper dosing stemming from fact
`that this product is not bioequivalent
`to Actiq and therefore doses are not
`interchangeable
`
`• Off label use in opioid naïve patients
`• Improper dosing stemming from fact
`that this product is not bioequivalent
`to Actiq and therefore doses are not
`interchangeable
`
`warnings regarding
`mis-prescribing to
`opioid naïve
`patients and
`improper dosing
`• RiskMAP was part
`of original approval
`• Increased
`warnings regarding
`mis-prescribing to
`opioid naïve
`patients and
`improper dosing
`• REMS was part of
`original approval
`• Increased
`warnings regarding
`mis-prescribing to
`opioid naïve
`patients and
`improper dosing
`• REMS was part of
`original approval
`• Increased
`warnings regarding
`mis-prescribing to
`opioid naïve
`patients and
`improper dosing
`• REMS was part of
`original approval
`
`2.4 Important Safety Issues With Consideration to Related Drugs
`
`All opioids have well established adverse event profiles that include sedation, nausea,
`vomiting, pruritus, hypotension and constipation. The most serious adverse reactions
`associated with all opioids include respiratory depression (potentially leading to apnea
`or respiratory arrest), circulatory depression, hypotension, and shock. Other recognized
`risks associated with this class of drugs include abuse and addiction.
`
`2.5 Summary of Presubmission Regulatory Activity Related to Submission
`
`FSS has been developed under IND 72,411.
`
`Pre-IND meeting (25 August 2005)
`The advice provided by the Division is summarized below:
`• One adequate and well-controlled clinical trial would be sufficient to demonstrate
`efficacy of this sublingual drug delivery system.
`• Evidence supporting proper dosing would be required for the claim of
`management of breakthrough cancer pain.
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`•
`
`“Taste Masking” will be necessary to ensure blinding between drug product and
`placebo.
`• A safety database of at least 300 patients who used the to-be-marketed
`formulation and delivery device should be submitted at the time of NDA
`submission; 150 patients should be treated for 3 months and a significant
`proportion of the patients should be treated at the highest-to-be-marketed dose.
`• The product should be tested under clinical conditions that may potentially alter
`the absorption of the product, i.e., stomatitis or drug/drug interactions with other
`co-incident oral preparations.
`• Dosing guidelines for special populations (e.g., hepatic impairment and drug-drug
`interactions) should be developed.
`• Conduct a single dose cross-over relative bioavailability with Actiq as the RLD,
`single dose PK: 200 vs. 400 vs. 600 vs. 800 mg (a single actuation (100 mL)
`from 2, 4, 6 and 8 mg/mL strengths).
`• Contemplate how the PK of this drug might be altered with the consumption of
`alkaline or acidic beverages.
`
`
`End-of-Phase 2 meeting (17 December 2007)
`The advice provided by the Division is summarized below:
`• A safety database of 300 patients is reasonable. This number should not include
`normal subjects who have received the investigational product during
`pharmacokinetic studies. Out of this total number of patients, 150 should have
`been treated for a minimum of 3 months with investigational product that is
`reasonably representative of the proposed to-be-marketed doses.
`
`•
`• Provide PK data of the drug product from 8-10 patients with mild
`stomatitis/mucositis in order to assess if membrane changes would lead to any
`changes in systemic absorption of the drug.
`• Only clinically relevant information assessed with appropriate statistical methods
`will be included in the label. Secondary outcomes reflecting a variation of the
`primary outcome results will not be included in the product labeling.
`• The term “opioid-treated” was not acceptable and the Sponsor should use the
`language of “opioid-tolerant.”
`
`
`
`
`Pre-NDA meeting (17 August 2010)
`The advice provided by the Division is summarized below:
`• Not required to conduct specific studies in patients with renal or hepatic
`insufficiency with your product.
`• Three pharmacokinetic studies in healthy volunteers, one pharmacokinetic study
`in patients with or without mucositis, an efficacy and safety study in 130 patients,
`and a 3-month safety study in ≥150 patients will be sufficient to form the basis of
`a determination of product safety and efficacy barring any unanticipated safety
`
`Reference ID: 3059426
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`(b) (4)
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`Clinical Review
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`{Insert Reviewer Name}
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`signals and presuming the results of your adequate and well controlled trial are
`confirmed.
`
`. With respect to the pharmacokinetic study in patients with or without mucositis,
`include cancer patients with oral mucositis of grades 1, 2, 3, and 4. Alternatively,
`you may study cancer patients with grade 4 oral mucositis, and if there is no
`change in the PK in this group, patients with lower grade mucositis need not be
`studied.
`
`0 For the primary efficacy endpoint, a graphical representation of the data may be
`included in the label.
`(m4)
`
`0 For secondary efficacy endpoints, only clinically relevant information (assessed
`with appropriate outcome measures and analyzed with appropriate statistical
`methods) will be included in the label.
`
`(”(4)
`
`o A Risk Evaluation and Mitigation Strategy (REMS) is required, and at a minimum
`will consist of Medication Guide, Elements to Assure Safe Use, Implementation
`System, Timetable for Submission of Assessments, address proper disposal of
`residual fentanyl product in the device, prescribing to opioid-tolerant patients
`only, appropriate dosing of these fentanyl products, and sur