# Presentation: 323885

## What Is An IND?

- Loris McVittie, PhD.
- OVRR/CBER/FDA

## Regulation

- The regulations in 21 CFR 312 cover procedures and requirements for Investigational New Drug Applications (INDs)
- These regulations define the roles and responsibilities of FDA reviewers, IND sponsors, and clinical investigators

## Definitions

_**Sponsor**_
- A sponsor is an individual, company, institution, or organization that takes responsibility for and initiates a clinical study (21 CFR 312.3(b), 312.50)

## Sponsor

- A sponsor is responsible for:
- Selecting qualified investigators
- Ensuring study monitoring
- Maintaining an effective IND, and
- Ensuring AE risk information is provided to the FDA and investigators

## Definitions

_**Investigator**_
- An investigator is an individual under whose immediate direction the study drug is administered or dispensed. If a team is involved, the leader is the investigator; other team members are sub-investigators
- 	(21 CFR 312(b), 312.60)

## Investigator

- An investigator is responsible for:
- Ensuring the study is conducted according to the plan
- Protecting the rights, safety and welfare of subjects, and
- Control of drug under investigation

## Definitions

_**Sponsor-Investigator**_
- A sponsor-investigator is an individual who both initiates and conducts a study and under whose immediate direction the study drug is administered or dispensed. This person must follow the requirements pertaining to a sponsor and those pertaining to an investigator
- 	(21 CFR 312(b))

- The primary concern during all phases of clinical study is the safety and rights of study subjects

## IND Requirements

- Even FDA-licensed products are subject to IND regulations if not used under conditions of licensure (“an experiment is any use of a drug except for the use of a marketed drug in the course of medical practice” 21 CFR 312.3(b))

## IND Requirements (cont’d)

- For a lawfully marketed product, no IND submission is required if three specific conditions apply (21 CFR 312.2)
- The study is not intended to support a new indication or labeling change
- The study does not intend to support a change in advertising
- The study does not involve a route, dosage or patient population, etc. that increases risk

## NOTE!

- The FDA may be aware of other studies that may affect evaluation of potential risk, and
- the FDA is subject to confidentiality requirements and by law can not share this specific information with others

## IND Content Requirements21 CFR 312.23

- Format pertains to all sponsors and sponsor-investigators and fosters efficient review
- Cover Sheet (and Form FDA 1571)
- Table of Contents
- Introductory Statement and General Investigational Plan
- Clinical Protocol
- Chemistry, Manufacturing and Control (CMC) Information
- Pharmacology and Toxicology Information
- Previous Human Experience
- Additional Information

## Introductory Content Elements

- Cover Sheet (Form FDA 1571)
- Table of Contents
- Introductory Statement (description of product, formulation, route, broad study objectives, relevant previous use, foreign experience)
- General Investigational Plan (rationale, indication, general approach, anticipated studies including number of subjects and possible risks)

## Investigator’s Brochure (IB)

- Sponsor must provide to all clinical investigators, not required for sponsor investigators (21 CFR 312.55). It must include:
- Brief product description
- Pharm/tox summaries
- Previous human experience
- Description of anticipated risk and any special monitoring needs
- Updates as appropriate

## Clinical Protocol

- The clinical protocol must contain the following elements:
- A statement of objectives
- Investigator, subinvestigator, site and IRB information
- Inclusion/Exclusion criteria
- Study size and design
- Dosage information
- Monitored parameters
- Clinical procedures and lab tests

## CMC Information

- Emphasis in Phase I is on identification and control of raw materials and new drug substance, including information on any placebo as well
- Even for Phase I, need enough information to assess safety
- Extent of expected information increases as drug development proceeds
- Throughout product development, good documentation of all manufacturing and testing steps is essential
- Deficiencies in CMC information can result in clinical hold

## Pharm/Tox Information

- Animal studies may be conducted to obtain proof of concept or tox information
- Studies should support proposed clinical dose and regimen
- Best to get CBER concurrence on pivotal tox protocols prior to initiation
- Need to submit complete study reports for tox studies, including summary and individual animal data

## Other IND Items

- Previous human experience needs to be included (if applicable)
- Additional information such as pre-IND meeting minutes or critical references should be included as well
- Serial numbering of pages of an IND is required (21 CFR 312.23(11)(e)) as this facilitates reference if the FDA has questions

## IND Protocol Amendments

- 21 CFR 312.30
- A new protocol
- Safety or design related changes to an existing protocol
- New investigator (notification is required within 30 days of being added)
- These should be submitted to the FDA prior to implementation
- IRB approval is needed prior to implementation

## IND Information Amendments

- 21 CFR 312.31
- Information amendments advise the FDA of:
- New tox, CMC or other technical information
- Notice of discontinuance of a clinical study

## Annual Reports

- 21 CFR 312.33
- To be submitted within 60 days of the anniversary of “in effect” date
- Include enrollment, demographic and conduct status information for each study
- Adverse event summaries (safety reports, deaths, dropouts)
- Drug action information
- Preclinical study status information

## Annual Reports (cont’d)

- CMC change information
- Revised/updated investigator brochure with revisions described
- Foreign marketing experience
- Outstanding business with the FDA

## Annual Reporting of Adverse Events

- RECOMMENDATIONS
- For solicited events – tabulate by study, study group and severity
- For unsolicited events use a line listing by study
- SAEs should be highlighted and discussed
- Include numerators and denominators
- Include cumulative cross-study, multi-year summaries
- Include all events regardless of attribution of relatedness to study drug

## Specific Responsibilities of Sponsors

- Selecting qualified investigators and monitors (21 CFR 312.53)
- Obtaining investigator information (signed Form FDA 1572 and CV)
- Controlling shipment of drug – only to participating investigators
- Obtaining clinical protocol information
- Obtaining financial disclosure information
- Providing each investigator an investigator brochure (21 CFR 312.55)
- Informing investigators of new safety observations (see 21 CFR 312.32 on IND safety reports)

## Specific Responsibilities of Sponsors

- Review ongoing investigations (21 CFR 312.56)
- Monitor study progress for compliance with protocol
- Dealing with noncompliant investigators
- Review and report to FDA safety and effectiveness data (annual reports and IND safety reports)
- Discontinuance of unsafe investigations and informing the FDA, IRBs and investigators of these actions

## Specific Responsibilities of Sponsors

- Maintenance of adequate records (21 CFR 312.57) including:
- Tracking of drug shipment and information
- Recording financial interest of investigators
- Keeping records for 2 years post approval or post last IND drug shipment
- Retention of reserve samples and standards for certain tests
- Providing FDA with records upon request (21 CFR 312.58)
- Proper disposition of unused investigational drug (21 CFR 312.59)

## Specific Responsibilities of Investigators

- Control administration of investigational drug (21 CFR 312.61)
- Provide qualification and study conduct information to sponsor
- Following the protocol (commitment to this required per Form FDA 1572)
- Maintenance of records (21 CFR 312.62) including:
- Drug disposition
- Case histories (CRFs, ICFs, medical records)
- Keeping records for 2 years post approval or post study discontinuation

## Specific Responsibilities of Investigators

- Reports to sponsor (21 CFR 312.64)
- Providing progress reports for IND annual report
- Promptly reporting safety concerns
- Provision of final report after study completion
- Providing financial disclosure information
- Assuring IRB review (21 CFR 312.66)
- Providing FDA with records upon request (21 CFR 312.68)