Investigational New Drug Application21 CFR Part 312

A Review for OCRA US RAC Study GroupSeptember 2005

Ginger Clasby, MSPromedica Internationalgclasby@promedica-intl.com714-799-1617 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