Investigational New Drug Application 21 CFR Part 312 A Review for OCRA US RAC Study Group September...
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Transcript of Investigational New Drug Application 21 CFR Part 312 A Review for OCRA US RAC Study Group September...
Investigational New Drug Application21 CFR Part 312
A Review for OCRA US RAC Study GroupSeptember 2005
Ginger Clasby, MSPromedica [email protected] x 25
IND ApplicationAbout the Regulation
• Provides procedures for use of investigational new drugs
• Exempts products from premarketing approval requirements:
– Registration, listing, interstate distribution
– Labeling
– GMPs
• Applies to most studies to determine drug safety & effectiveness
When IND Application is Not RequiredClinical Study Situations
• Drug legally marketed for indicated use
– Study not intended to support new indication or significant labeling change
– Study not intended to support significant change in advertising
– Study doesn’t involve change in route of admin, dosage, or use that significantly increases patient risks
• IVD biological for confirmatory diagnostic procedure
• Intended for tests of in vitro or lab research animals
• Placebo products
“Treatment” INDWhen Used
• Drug intended to treat or diagnose serious or life-threatening condition
• No satisfactory alternative available
• Controlled clinical trials in progress under IND
– Or when trials completed & FDA review of request to market is pending
• Sponsor actively pursuing device marketing approval with FDA
“Emergency Use” INDWhen Used
• Need FDA authorization to use experimental drug in an emergency situation that does not allow time for submission of an IND in accordance with 21 CFR Part 312
• May be used for patients ineligible per existing study protocol(s), or if approved study protocol does not exist
IND ApplicationProduct Labeling Requirements
• Immediate package must be labeled:
– “Caution: New Drug – Limited by Federal (or United States) law to investigational use”
• No false or misleading statements
• No representation that drug is safe or effective for indicated use
IND ApplicationPromotion & Charging for Investigational Drugs
• No representation that drug is safe or effective for indicated use
• No commercial distribution or test marketing
• No prolongation of study
• Prior written approval from FDA required to “charge” for drug, unless being used under “treatment” IND
IND ApplicationClinical Study Phases
• Phase 1 – first time in human
– Small number of healthy volunteers
– Closely monitored – focus on safety
• Phase 2 – controlled studies to evaluate effectiveness
– Small number of subjects with condition to be treated
– Closely monitored – focus on efficacy (& safety)
• Phase 3 – expanded controlled & uncontrolled studies
– Large number of subjects with condition to be treated
– Focus on efficacy (& safety)
IND Application ContentsAdministrative Details
• Sponsor responsibility
• Submit original & 2 copies of application
• FDA notifies Sponsor in writing of date application is received
• IND in effect 30 days after FDA receipt of application, unless FDA notifies Sponsor otherwise
IND Review/ApprovalFDA’s Considerations
• Subject safety & welfare
• Rendered 30 days of FDA receipt
– Only disapproval or early approval is rendered in writing
• Clinical hold may be ordered if:
– Sponsor fails to comply with applicable regulations
– Sponsor is non-responsive to requests for add’l info
– Subject risks outweigh benefits
– Unreasonable to proceed due to inadequacy of investigational plan, manufacturing or monitoring
Clinical HoldsTo Delay/Suspend A Study
• Phase I clinical holds
– Subject safety concerns
• Phase II & III clinical holds
– Concerns about safety or efficacy
• Treatment IND clinical holds
– Alternative treatment drug now commercially available
– Sponsor not diligently pursuing marketing approval
– Administrative oversights by Sponsor
IND Application ContentsAn Overview
• Cover sheet/application form (Form FDA-1571)
• Table of contents
• Introductory statement
• General investigational plan
• Investigator brochure
• Protocol(s)
• Chemistry, manufacturing & control info
IND Application ContentsAn Overview
• Pharmacology & toxicology info
• Previous human experience with drug
• Add’l info as required:
– Drug dependence/abuse potential
– Radioactive drugs
– Pediatric studies
• Add’l info as requested by FDA
IND Application ContentsApplication Form - FDA 1571
• Required for initial IND & all subsequent submissions
• Provides basic info about Sponsor & submission contents
• Must be signed & dated
– Obligates Sponsor to comply with laws & regs
IND Application ContentsIntroductory Statement
• Drug name, structure, pharmacological class, development history, foreign testing
IND Application ContentsGeneral Investigational Plan
• Summary of studies anticipated in first year
• Study rationale
IND Application ContentsInvestigator Brochure
• Package insert
• Early versions contain more pre-clinical data
• Later versions more heavily weighted with clinical data
IND Application ContentsProtocol(s)
• Must include at least the initial protocol
• Phase I – protocol outline:
– No. subjects planned
– Eligibility requirements
– Dosing
– Safety assessments
• Phase II & III – detailed protocols
IND Application ContentsChemistry, Manufacturing & Controls
• Manufacturing process
• Raw materials & finished product testing
• May refer to drug master file or previous application
IND Application ContentsPharmacology & Toxicology
• Non-clinical study summaries of pharmacological & toxicological effects
IND Application ContentsPrevious Human Experience
• Foreign trials
• Data from other INDs, NDAs
IND Application ContentsAdditional Info
• Other relevant info
• Minutes of FDA meetings
• Copies of referenced materials
• Address issues re: possible drug abuse, dependence, radioactivity, etc.
IND AmendmentsNecessary When:
• New protocol introduced
• Changes made to protocol that may affect:
– Scientific soundness of study
– Rights, safety or welfare of study subjects
• Addition of new study investigators (FDA Form 1572)
• New/revised information not related to protocol
– New pharmacology, toxicology, chemistry, clinical info
– Discontinuance of a study
IND Safety Reports FDA Form 3500A
• Any unexpected, serious adverse experience associated with drug use – 15 calendar days
• Any finding from animal studies suggesting significant risk for human subjects – 15 calendar days
• Any unexpected fatal or life-threatening experience associated with drug use – 7 calendar days
IND Annual ReportsWhen Required
• Due within 60 days of IND anniversary
• Individual study information
• Summary information for all studies, including:– Summary of safety results & significant changes in product
manufacturing, pre-clinical study status
– General investigational plan for upcoming year
– Any Investigator Brochure revisions
– Significant Ph I protocol modifications
– Significant foreign marketing developments during prior year
– Log of outstanding business
IND Review/ApprovalFDA Meetings
• Pre-IND Submission
– Facilitates planning for IND
• End of Phase II
– Facilitates planning for later studies
• Pre-NDA or Pre-BLA
– Facilitates preparation & review of NDA or BLA
Sponsors & InvestigatorsResponsibilities
• Similar to 21 CFR 812
IRBResponsibilities
• As identified in 21 CFR 50, 56
IND RegulationReference Documents & Links (www.fda.gov/cder)
• CDER Guidance: IND Application Process (interactive session)
http://www.fda.gov/cder/regulatory/applications/ind_page_1.htm
IND RegulationReference Documents & Links (www.fda.gov/cder)
• FDA Guidance for Financial Disclosure by Clinical Investigators
• FDA Guidance for IRBs & Clinical Investigators
• FDA Guidance for Monitoring Clinical Investigations
• FDA/ORA Compliance Program Guidance for Bioresearch Monitoring of Clinical Investigations