Good Review Practice:
`Clinical Review of Investigational New Drug
`Applications
`
`This document has been prepared by the Office of New Drugs in the Center for Drug
`Evaluation and Research at the Food and Drug Administration.
`
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`Table of Contents
`
`3.2
`
`INTRODUCTION ...................................................................................1
`GENERAL CONSIDERATIONS ...............................................................2
`2.1
`Pre-IND Meeting/IND Original Submission ..........................2
`2.2
`Phase 1 Clinical Trial Protocol ...............................................4
`2.3
`End-of-Phase 2/Phase 3 Planning ...........................................5
`2.4
`Controlled Clinical Trial Protocol Review (including
`Special Protocol Assessments) ...............................................8
`Fast Track or Breakthrough Designation..............................11
`2.5
`IND Safety Reports (21 CFR 312.32(c)) ..............................12
`2.6
`DOSING AND CLINICAL PHARMACOLOGY.........................................13
`3.1
`Phase 1 Tolerability Trials....................................................13
`3.1.1 Choosing a Starting Dose for Phase 1 .......................................... 13
`3.1.2 Dose-Escalation and Maximum Dose and Duration in Phase 1 ... 15
`3.1.3 Toxicity-Induced Modifications in Enrollment or Dosing (Safety
`Rules) ............................................................................................ 17
`Pharmacokinetic and Pharmacodynamic Trials....................17
`3.2.1 Effect of Intrinsic and Extrinsic Factors on PK and PD ............... 18
`3.2.2 Classic PK Clinical Trials (Frequent Sampling)........................... 19
`3.2.3 Population PK Clinical Trials ....................................................... 19
`3.2.4 Bioavailability and Bioequivalence Trials.................................... 19
`3.2.5 Drug-Drug Interactions................................................................. 20
`Choice of Dosing Interval.....................................................21
`3.3
`ASSESSING DOSE-RESPONSE..............................................................22
`4.1
`Fixed-Dose Clinical Trials....................................................24
`4.2
`Titration Clinical Trials.........................................................25
`4.3
`Crossover Dose-Response Trials ..........................................26
`CONTROLS, TRUTH STANDARDS, AND COMPLIANCE ........................26
`5.1
`Types of Controls..................................................................26
`5.1.1 Placebo Control............................................................................. 27
`5.1.2 No-Treatment Control................................................................... 28
`5.1.3 Dose-Comparison Control ............................................................ 28
`5.1.4 Active-Treatment Control............................................................. 29
`5.1.5 External (Historical) Control ........................................................ 31
`Trial Design Features............................................................32
`5.2.1 Randomized Withdrawal Trials .................................................... 32
`5.2.2 Adaptive Designs.......................................................................... 33
`5.2.3 Enrichment.................................................................................... 33
`5.2.4 Crossover and Multiple Treatment Trials..................................... 34
`5.2.5 Trials in Nonresponders or Intolerants ......................................... 34
`Truth Standards.....................................................................34
`5.3
`Assessing Treatment Compliance.........................................35
`5.4
`Background Care and Standard of Care................................35
`5.5
`RANDOMIZATION AND BLINDING......................................................36
`
`5.2
`
`1.
`2.
`
`3.
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`4.
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`5.
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`6.
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`6.1
`
`6.2
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`Randomization ......................................................................36
`6.1.1 Fixed-Randomization Schemes .................................................... 37
`6.1.1.1 Blocked randomization
`37
`6.1.1.2 Stratified randomization
`38
`6.1.2 Adaptive-Randomization Schemes............................................... 39
`6.1.3 Allocation Ratio............................................................................ 39
`6.1.4 Review of Randomization............................................................. 40
`Blinding.................................................................................40
`6.2.1 Optimizing and Maintaining the Blinding .................................... 41
`6.2.1.1 Character of the placebo and trial drug
`41
`6.2.1.2 Unblinding drug effects
`41
`6.2.1.3 Dealing with imperfect blinding
`42
`6.2.1.4 Assessing unblinding
`42
`6.2.1.5 Blinded evaluators or evaluation committees42
`PATIENT POPULATIONS, SPECIAL POPULATIONS..............................43
`7.1
`Trial Population ....................................................................43
`7.1.1 Homogeneity vs. Heterogeneity; Individualization of Treatment 44
`7.1.2 Factors Influencing the Nature of the Trial Population ................ 44
`Special Populations, Demographic Subgroups.....................45
`7.2.1 Subgroup Analyses vs. Special Population Trials ........................ 46
`7.2.2 Pediatric Populations .................................................................... 46
`7.2.2.1 Timing of studies in pediatric populations
`49
`7.2.2.2 Types of studies in pediatric populations
`51
`7.2.3 Women.......................................................................................... 52
`7.2.3.1 PK issues regarding women
`53
`7.2.3.2 Interactions with oral contraceptives
`53
`7.2.3.3 Studying pregnant women
`54
`7.2.4 Elderly Subjects ............................................................................ 54
`7.2.5 Racial Groups................................................................................ 55
`7.2.6 Other Subpopulations of Interest: Genetic, Proteomic, and
`Concomitant Illness ...................................................................... 56
`Patient Population Size .........................................................57
`7.3.1 Sample Size in Phase 1 Clinical Trials ......................................... 57
`7.3.2 Sample Size in Phase 2 and Phase 3 Clinical Trials ..................... 57
`7.3.3 Total Population Exposure............................................................ 59
`STATISTICAL ANALYSIS PLANS .........................................................60
`8.1
`Planned Analyses..................................................................60
`8.1.1 Adequacy of the Statistical Analysis Plan .................................... 61
`8.1.2 Reviewing Changes to the Statistical Analysis Plan..................... 63
`8.1.3
`Interim Analysis Plans .................................................................. 64
`8.1.3.1 Confidentiality of interim data
`64
`8.1.3.2 Stopping rules for an early finding of efficacy
`or toxicity
`65
`8.1.3.3 Risks of early stopping for efficacy
`66
`8.1.3.4 Unplanned interim analyses
`66
`8.1.3.5 Reviewer’s role during the trial
`67
`
`7.2
`
`7.3
`
`7.
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`8.3
`
`8.2
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`Intent-to-Treat Analysis................................................................ 67
`8.1.4
`Endpoints ..............................................................................68
`8.2.1 Primary Endpoints ........................................................................ 69
`8.2.1.1 Composite endpoints
`72
`8.2.2 Secondary Endpoints .................................................................... 73
`8.2.2.1 Descriptive analyses
`74
`8.2.3 Surrogate Endpoints...................................................................... 74
`8.2.4 Patient-Reported Outcome Measures ........................................... 76
`Discussions With the Sponsor ..............................................77
`8.3.1 Target Product Profile................................................................... 77
`8.3.2 Continuous Involvement............................................................... 77
`GOOD CLINICAL PRACTICES .............................................................78
`9.1
`The Institutional Review Board............................................79
`9.2
`Informed Consent..................................................................80
`9.2.1 Consent in Pediatric or Other Vulnerable Populations................. 81
`9.2.2 Waiver of Informed Consent ........................................................ 82
`Investigator’s Brochure.........................................................82
`9.3
`Investigator Qualifications and Responsibilities ..................83
`9.4
`Trial Monitoring and Auditing..............................................83
`9.5
`ADVERSE DRUG EXPERIENCES AND REPORTS...................................84
`10.1 Safety Monitoring .................................................................84
`10.2 Reporting Requirements for Sponsors..................................86
`10.3
`IND Safety Reports — Written Reports ...............................87
`10.3.1 Definition: Adverse Event ........................................................... 88
`10.3.2 Definition: Adverse Reaction ...................................................... 88
`10.3.3 Definition: Suspected Adverse Reaction ..................................... 89
`10.3.4 Definition: Unexpected................................................................ 89
`10.3.5 Definition: Serious....................................................................... 89
`10.3.6 Definition: Life-Threatening........................................................ 90
`10.4 Assessment of Adverse Drug Reports ..................................90
`10.5 Actions After Reviewing Adverse Drug Reports .................91
`10.6 Annual Reports .....................................................................92
`10.7 Other Safety Data..................................................................93
`EXPEDITED DRUG DEVELOPMENT PROGRAMS .................................93
`11.1 Serious or Life-Threatening Condition.................................94
`11.2 Available Therapy.................................................................95
`11.3 Demonstrating the Potential to Address Unmet Medical
`Need ......................................................................................96
`11.4 Qualifying Criteria for Expedited Drug Development
`Designations..........................................................................97
`11.4.1 Fast Track
`............................................................................... 97
`11.4.2 Breakthrough Therapy .................................................................. 98
`11.5 Features of Expedited Drug Development Designations....100
`11.5.1 Features of Fast Track................................................................. 100
`11.5.2 Features of Breakthrough............................................................ 100
`REFERENCES 101
`
`9.
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`10.
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`11.
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`13.
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`GLOSSARY OF ACRONYMS ..............................................................107
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`Good Review Practice:
`Clinical Review of Investigational New Drug Applications
`
`INTRODUCTION
`1.
`This good review practice (GRP) document was prepared to assist FDA clinical review
`staff in reviewing clinical submissions to an investigational new drug application (IND)
`from the pre-IND phase to the time of the pre-new drug application/biologics license
`application meeting.1 Although the primary focus is on the clinical review of INDs for
`new molecular entities, many of the principles can be applied to all INDs and to new drug
`applications/biologics license applications (NDAs/BLAs) and their supplements.
`
`This document identifies and describes issues that should be prospectively considered
`during IND development to facilitate development of a complete, high-quality database
`that could be submitted in an NDA/BLA. It also identifies important areas that may
`warrant additional consideration and discussion.2
`
`The extent and type of clinical review and communication with the sponsor for each
`submission to the IND will vary, depending upon the drug’s novelty, FDA familiarity
`with other drugs in the same class, potential safety concerns, the stage of development,
`and the disease the drug is intended to diagnose, treat, or prevent. Because CDER has
`limited resources, CDER review staff will prioritize submission review based on: (1)
`relative importance to patient safety; and (2) the context of the sponsor’s development
`plan.
`
`The term review refers to the formal process of review and what should be considered,
`not to the reviewer’s report documenting that review. The written report will reflect
`many of the considerations discussed in this document, but the length of the document is
`not necessarily reflective of the thoroughness of the review.
`
`This GRP document is organized as follows:
`
`(cid:120) Section 2, General Considerations: Organized by major stages of drug
`development; lists questions for reviewers to consider
`
`(cid:120) Sections 3 to 11: Presents detailed discussions of critical aspects of overall
`development and trial design; expands on components of section 2
`
`1 An investigational drug is defined as any drug or biologic that is used in a study or clinical trial. For the
`purposes of this document, all references to drugs include both human drugs and therapeutic biological
`products regulated by CDER unless otherwise specified.
`
`2 The Federal Food, Drug, and Cosmetic Act (FD&C Act), the regulations, and finalized guidances take
`priority over this document.
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`(cid:120) Sections 12 to 13: Glossary and references to other relevant documents
`
`Hypertext links are provided for ease of navigation and cross-reference throughout this
`document.
`
`GENERAL CONSIDERATIONS
`2.
`The following links contain lists of questions to help the reviewer during various stages
`of drug development to ensure review completeness and consistency. The lists can be
`particularly helpful when a sponsor has not raised critical issues for discussion and for
`reminding reviewers of the most important issues that they should communicate to
`sponsors. They are arranged by major stages in drug development.
`
`Select the appropriate quicklink for the submission type:
`
`(cid:120) Section 2.1
`
`Pre-IND Meeting/IND Original Submission
`
`(cid:120) Section 2.2
`
`Phase 1 Clinical Trial Protocol
`
`(cid:120) Section 2.3
`
`End-of-Phase 2/Phase 3 Planning
`
`(cid:120) Section 2.4
`
`Controlled Clinical Trial Protocol Review (including Special
`Protocol Assessments)
`
`(cid:120) Section 2.5
`
`Fast Track or Breakthrough Designation
`
`(cid:120) Section 2.6
`
`IND Safety Reports (21 CFR 312.32(c))
`
`2.1 Pre-IND Meeting/IND Original Submission
`When reviewing an original IND submission or planning for a pre-IND meeting, the FDA
`review team’s primary concern is the safety of the subjects who will receive the drug
`during the proposed clinical trial. A secondary consideration is evaluation of the initial
`drug development plan and the role of the proposed study or clinical trial in that plan.
`The following list includes questions that should be considered during the pre-IND/IND
`period.
`
`Are the purity, potency, stability, and sterility (if applicable) of the drug adequate to
`support the proposed development phase? This item is the primary responsibility of
`the review chemists/product quality reviewers and microbiology review staff with
`whom this should be discussed.3
`
`3 See the guidance for industry IND Meetings for Human Drugs and Biologics; Chemistry, Manufacturing,
`and Controls Information.
`(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM0705
`68.pdf)
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`Do animal studies provide sufficient safety support for the starting dose and schedule
`in the proposed or planned clinical trials? This item is the primary responsibility of
`the pharmacology and toxicology review staff with whom this should be discussed.
`Choice or relevance of animal species and model used as a basis for dose
`selection? (See section 3.1.1, Choosing a Starting Dose for Phase 1.)
`Identification of potential target organs of toxicity and potential means for
`monitoring those toxicities?
`Is the plan for human pharmacokinetic (PK) and pharmacodynamic (PD) trials
`sufficient and does it appropriately reflect nonclinical findings? This item is the
`primary responsibility of the clinical pharmacology review staff with whom this
`should be discussed.
`Duration, dose, schedule, and route of exposure? (See section 3.1.1, Choosing
`a Starting Dose for Phase 1; and section 3.1.2, Dose-Escalation and Maximum
`Dose and Duration in Phase 1.)
`PK and PD assessments? (See section 3.2, Pharmacokinetic and
`Pharmacodynamic Trials.)
`Identification of dose-response? (See section 3.1.2, Dose-Escalation and
`Maximum Dose and Duration in Phase 1.)
`Safety in special populations to be studied (e.g., neonates, pregnant women,
`renal and hepatic impaired patients)? (See section 7.2, Special Populations,
`Demographic Subgroups.)
`Clinical/regulatory issues
`Is the overall drug development plan described in detail and appropriate? If
`so, are the indications sought clear? (See section 8.3.1, Target Product
`Profile.)
`Are the phase 1 clinical trial protocols appropriately designed to ensure safety
`and meet objectives, including criteria for dose escalation (e.g., schema,
`number of subjects per dose level, observation period, and number of subjects
`exposed before dose escalation)? (See section 7.3.1, Sample Size in Phase 1
`Clinical Trials.)
`Does the overall drug development plan include consideration of or plans to
`study appropriate pediatric populations? (See section 7.2.2, Pediatric
`Populations.)
`Is the drug being developed under the animal efficacy rule (21 CFR part 314,
`subpart I, Approval of New Drugs When Human Efficacy Studies Are Not
`Ethical or Feasible, or 21 CFR part 601, subpart H, Approval of Biological
`Products When Human Efficacy Studies Are Not Ethical or Feasible)?
`CDER’s Office of Counter-Terrorism and Emergency Coordination should be
`consulted regarding any protocol or meeting regarding animal models.
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`For indications with a history of high trial failure rate and/or for submissions
`with poor dose selection processes, has the sponsor considered requesting an
`end-of-phase 2A (EOP2A) meeting?4
`
`2.2 Phase 1 Clinical Trial Protocol
`Are the purity, potency, stability, and sterility (if applicable) of the drug adequate to
`support phase 1? This item is the primary responsibility of the review
`chemists/product quality reviewers and microbiology review staff with whom this
`should be discussed.5
`Is subject selection appropriate? Are healthy volunteers acceptable, given drug
`toxicity or mechanism of action?
`Is the proposed starting dose appropriate with an acceptable safety margin? Are
`nonclinical data properly taken into account? (See section 3.1.1, Choosing a Starting
`Dose for Phase 1.)
`Is the dose escalation scheme appropriate? Are nonclinical data and concerns
`addressed? (See section 3.1.2, Dose-Escalation and Maximum Dose and Duration in
`Phase 1; section 3.3, Choice of Dosing Interval; and section 4, Assessing Dose-
`Response.)
`Is the amount of information available (e.g., duration of observation, laboratory, and
`clinical observations) and the plan to consider additional accrued data before each
`escalation appropriate? (See section 3.1.2, Dose-Escalation and Maximum Dose and
`Duration in Phase 1; section 3.3, Choice of Dosing Interval; and section 4, Assessing
`Dose-Response.)
`Is the number of subjects treated at each dose appropriate, and is there an appropriate
`duration of observation before treating the next subject in each cohort and before
`subsequent dose escalation? (See section 3.1.2, Dose-Escalation and Maximum Dose
`and Duration in Phase 1; section 3.3, Choice of Dosing Interval; and section 4,
`Assessing Dose-Response.)
`Is the size of each dose increment appropriate? (See section 3.1.2, Dose-Escalation
`and Maximum Dose and Duration in Phase 1.)
`Is the monitoring scheme for toxicity and pharmacologic activity appropriate? Is the
`case report form (CRF) adequate, if applicable? (See section 10.1, Safety
`Monitoring.)
`
`4 See the guidance for industry End-of-Phase 2A Meetings.
`(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079690
`.pdf)
`
`5 See the guidance for industry Content and Format of Investigational New Drug Applications (INDs) for
`Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived Products.
`(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM0715
`97.pdf)
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`For multicenter trials, is the plan adequate for sharing safety data among clinical
`investigators as well as with the sponsor?
`Are the rules for stopping the administration of the investigational drug, stopping
`enrollment, and stopping dose escalation clear and appropriate? (See section 3.1.3,
`Toxicity-Induced Modifications in Enrollment or Dosing (Safety Rules).)
`Are PK and PD data appropriately collected? Are immunogenicity data for biologics
`appropriately collected? (See section 3, Dosing and Clinical Pharmacology.)
`Does the consent form (when submitted or requested by the FDA for review) contain
`all the necessary elements and is it inaccurate or misleading? (See section 9.2,
`Informed Consent.)
`Is the investigator’s brochure complete, not misleading, and up to date? (An
`investigator’s brochure is not required for single center trials.) (See section 9.3,
`Investigator’s Brochure.)
`If the investigator has a particular interest in the success of the trial, such as financial
`(development of a patent or stake in a drug as an employee of clinical research
`organization, or being paid with stock options) or intellectual (evaluation of pet
`theory), what arrangements have been made for involvement, accompaniment, and
`assessment by a disinterested party?
`For new phase 1 trials submitted to an IND, were data from previously conducted
`trials adequately taken into account when designing the new trial, including the
`choice of dose and dose-escalation schema?
`Is the product being developed under the animal efficacy rule, 21 CFR 314.600
`(subpart I, Approval of New Drugs When Human Efficacy Studies Are Not Ethical or
`Feasible) or 21 CFR 601.90 (subpart H, Approval of Biological Products When
`Human Efficacy Studies Are Not Ethical or Feasible)?6 CDER’s Office of Counter-
`Terrorism and Emergency Coordination should be consulted regarding any protocol
`or meeting regarding animal models.
`
`2.3 End-of-Phase 2/Phase 3 Planning
`Before initiation of phase 3 trials, both development to date and planned development
`should be reviewed to ensure that the development program will address the relevant
`regulatory requirements and issues. This review is typically done at an end-of-phase 2
`(EOP2) meeting with the sponsor.
`
`For drugs developed under the animal efficacy rule, human trials before approval are
`required to assess safety and PK/PD. The PK/PD results are used to extrapolate animal
`findings to humans to select an appropriate dose. These trials will be conducted in
`healthy human volunteers, and the sample size will depend upon factors such as whether
`
`6 See the draft guidance for industry Animal Models — Essential Elements to Address Efficacy Under the
`Animal Rule.
`(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm078923
`.pdf)
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`the product is a new molecular entity (versus an approved drug seeking a new indication
`where human efficacy trials are not feasible or ethical), or if the indication is for
`treatment versus prophylaxis. Confirmatory efficacy trials, for ethical reasons, may only
`be conducted after approval in a setting when the approval medical countermeasure is
`required.
`
`A review of an EOP2 meeting package (or other meeting of similar intent) should take
`into account the following.
`
`Are the purity, potency, stability, and sterility (if applicable) of the drug adequate to
`support phase 2 and/or phase 3? This item is the primary responsibility of the review
`chemists/product quality reviewers and microbiology review staff with whom this
`should be discussed.7
`Are sufficient data available to plan a phase 3 program?
`Are the assessments of general safety and safety in specific subpopulations pertinent
`to the planned use? (See section 7, Patient Populations, Special Populations.)
`Is the target population well defined and appropriate? (See section 7.1, Trial
`Population.) Does the sponsor include an assessment of prior therapy in the target
`population for use in selecting patients, stratifying patients, or other purposes?
`Are the proposed endpoints well defined and appropriate? (See section 8.2,
`Endpoints.)
`Is the choice of dosing regimen, including dose and dose interval, appropriate? (See
`section 3, Dosing and Clinical Pharmacology.)
`Are there appropriate choices of control and for diagnostic tests, truth standards?
`(See section 5, Controls, Truth Standards, and Compliance)8
`Has the use of concomitant therapies been sufficiently addressed? (See section 5.5,
`Background Care and Standard of Care.)
`Will the total planned population exposure (e.g., subject numbers, duration of dosing,
`exposures at relevant dose levels) be adequate to assess safety? (See section 7,
`Patient Populations, Special Populations.)9
`Will the planned development, together with ongoing and completed trials, provide
`adequate data regarding drug effects in a broad population including subpopulations
`
`7 See the guidance for industry INDs for Phase 2 and Phase 3 Studies Chemistry, Manufacturing, and
`Controls Information.
`(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070567
`.pdf)
`
`8 See the ICH guidance for industry E10 Choice of Control Group and Related Issues in Clinical Trials.
`(http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm129460.pdf)
`
`9 See the ICH guidance for industry E1A The Extent of Population Exposure to Assess Clinical Safety: For
`Drugs Intended for Long-Term Treatment of Non-Life-Threatening Conditions.
`(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073083
`.pdf)
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`of interest (see section 7.2, Special Populations, Demographic Subgroups),
`particularly including those defined by:
`Sex? (See section 7.2.3, Women.)
`Race? (See section 7.2.5, Racial Groups.)
`Age (various pediatric groups and geriatric groups)? (See section 7.2.2, Pediatric
`Populations; and section 7.2.4, Elderly Subjects.)
`Body weight/body surface area?
`Genetic difference in metabolism, risk factors? (See section 7.2.6, Other
`Subpopulations of Interest: Genetic, Proteomic, and Concomitant Illness.)
`Disease severity?
`Patients with single or multiple concomitant illnesses? (See section 7.2.6, Other
`Subpopulations of Interest: Genetic, Proteomic, and Concomitant Illness.)
`Immunodeficiency (where appropriate)?
`Pregnancy (if there is reason to expect use in pregnancy)? (See section 7.2.3.3,
`Studying pregnant women.)
`Concomitant medications? (See section 3.2.5, Drug-Drug Interactions.)
`Renal/hepatic/excretory organ impairment? (See section 3.2.1, Effect of Intrinsic
`and Extrinsic Factors on PK and PD.)
`Are there exclusions for demographic factors (e.g., older than 75 years of age) or
`concomitant illness that are not needed but will decrease the breadth of the population
`studied? (See section 7.2.4, Elderly Subjects; and section 7.2.6, Other
`Subpopulations of Interest: Genetic, Proteomic, and Concomitant Illness.)
`Will there be adequate assessment of drug-drug interactions of likely importance?
`(See section 3.2.5, Drug-Drug Interactions.)
`Will there be adequate assessment of a broad enough range of doses to provide
`informative labeling regarding dosing? (See section 4, Assessing Dose-Response.)10
`Are the submitted clinical trial protocols adequately designed and powered (i.e.,
`adequate sample size) to meet their stated objectives and provide the basis for
`evaluating the safety and effectiveness of the drug?
`Has the sponsor submitted an initial pediatric study plan (PSP), including a request
`for waiver or deferral if needed, and been informed of the requirement under the Food
`and Drug Administration Safety and Innovation Act of 2012 (FDASIA) to do so no
`later than 60 days after the EOP2 meeting?
`
`10 See the ICH guidance for industry E4 Dose-Response Information to Support Drug Registration.
`(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073115
`.pdf)
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`Will there be adequate assessments of specific potential safety problems (e.g., QT
`prolongation, hepatotoxicity, immunogenicity) either suggested by nonclinical data or
`always needed?11
`Have any diagnostic tests necessary for use of the drug been validated (e.g., to
`identify patients based on genomic characteristics) and is there a plan to ensure
`availability of the test if the drug is marketed?
`
`2.4 Controlled Clinical Trial Protocol Review (including Special Protocol
`Assessments)
`Is there a statement describing the trial hypothesis and trial type (e.g., superiority,
`noninferiority)?
`Is the choice of control (placebo or active), and trial design (e.g., withdrawal,
`crossover) appropriate and well supported? (See section 5.1, Types of Controls, and
`the ICH guidance for industry E10 Choice of Control Group and Related Issues in
`Clinical Trials.12)
`If there is a placebo-controlled trial, is there also an active control to assess assay
`sensitivity, if appropriate?
`If an active-controlled noninferiority trial, is the noninferiority margin described and
`supported? (See section 5.1.4, Active-Treatment Control.)
`If this is a randomized fixed-dose dose-response trial, are the doses reasonable, based
`on phase 2 experience? Is the dosage spread sufficient? If a titration design is used,
`is there any plan for additional dose finding? (See section 4, Assessing Dose-
`Response.)
`Is the choice of primary endpoints clear and acceptable? (See section 8.2.1, Primary
`Endpoints.)
`If the endpoint is a surrogate, is the surrogate adequately supported? (See section
`8.2.3, Surrogate Endpoints.)
`Are the methods used to assess the endpoints well validated and appropriate? (See
`section 8.2.1, Primary Endpoints.)
`
`11 See the ICH guidance for industry E2A Clinical Safety Data Management: Definitions and Standards for
`Expedited Reporting
`(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073087
`.pdf), the ICH guidance for industry E14 Clinical Evaluation of QT/QTc Interval Prolongation and
`Proarrhythmic Potential for Non-Antiarrhythmic Drugs
`(http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm129357.pdf), and the guidance for
`industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation.
`(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM1740
`90.pdf)
`
`12 http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm129460.pdf
`
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`Are the secondary endpoints clearly and appropriately defined and is there a plan for
`their analysis (e.g., shared, alpha, step-down)? (See section 8.2.2, Secondary
`Endpoints.)
`Are the endpoints assessed at the appropriate time points? (See section 8.2.1, Primary
`Endpoints.)
`Are subject inclusion and exclusion criteria appropriate? (See section 7.1, Trial
`Population.)
`Is there a screening period for eligibility for enrollment and is it well described?
`Are the