educate • fund • connect • support

MIAP – Introduction to INDs and IDEs

E Mitchell Seymour, PhD RACResearch Faculty

Regulatory Project Manager

educate • fund • connect • support

MICHR is here to enable & enhance clinical & translational research. We do this by being a catalytic partner who educates, funds, connects, and supports research teams at U-M.

educate • fund • connect • support

Why

Created in 2006, awarded a $55M CTSA grant from the NIH in 2007, and renewed in May 2012,

MICHR is part of a consortium of CTSA institutions working together to

accelerate discoveries toward better health.

MICHR serves the entire U-M campus.

• Michigan Clinical Research Unit• IND/IDE Regulatory Assistance• Biostatistical Design & Analysis• Study Monitoring• Database Development• Study & Data Management

Mentoring• Clinical Trials Office• Clinical Research Informatics Tools

MICHR Research Support Services

educate • fund • connect • support

“MICHR IND/IDE INVESTIGATOR ASSISTANCE PROGRAM”

MIAP 

Regulatory assistance with IND/IDE application submission & support

What is the definition of a drug? “Articles intended for use in the diagnosis, cure,

mitigation, treatment, or prevention of disease…” and

“Articles (other than food) intended to affect the structure or any function of the body of man or other animals”

What constitutes a drug? Exogenous compounds (small and large molecule, organic

and inorganic) Endogenous compounds Live organisms Cosmetics Food (when used/applied in a certain way…)

Dietary supplements Conventional foods

Applicable RegulationsThe Federal Food, Drug, and Cosmetic Act (FD&C Act) gives

the FDA authority to regulate drugs and devices

Drugs/Biologics

Code of Federal Regulations (CFR)

21 CFR Part 312: Investigational New Drugs (IND)

Devices

Code of Federal Regulations (CFR)

21 CFR Part 812: Investigational Device Exemptions (IDE)

Academic Research – “Investigator” vs. “Sponsor-Investigator”

Sponsor is an individual, company, academic institution, or other organization that takes responsibility for and initiates a clinical investigation. The sponsor is not the “funding organization” by FDA definitions.

Investigator is an individual under whose immediate direction a drug/device is administered or dispensed.

Sponsor-Investigator is an individual who both initiates and conducts an investigation. The requirements/responsibilities under this part include both those applicable to an investigator and a sponsor. Sponsor-Investigators must also conclude or close investigations.

When is an IND Needed??

Sponsor-Investigator intends to conduct a clinical study with an investigational drug

Sponsor-Investigator intends to conduct a study with an approved drug, but… In a new indication/population Dosage form OR Dosage range that is not covered in the current package insert (off

label)

Changed Risk of Product and/or to Population Route of Administration

Drug approved for oral administration is going to be given intravenously

Dose Increases in dose, frequency, or duration of administration can

increase risk Decrease in dose can also increase risk

Patient Population Adult to children Moving from very ill population to a less ill population

IND Exemption Criteria The drug product is lawfully marketed in the United States. The investigation is not intended to be reported to FDA as a well-controlled

study in support of a new indication and there is no intent to support any other significant change in the labeling of the drug.

In the case of a prescription drug, the investigation is not intended to support a significant change in the advertising for the drug.

The investigation does not involve a route of administration, dose, patient population, or other factor that significantly increases the risk (or decreases the acceptability of the risk) associated with the use of the drug product.

The investigation is conducted in compliance with the requirements for review by an IRB and with the requirements for informed consent.

The investigation is not intended to promote or commercialize the drug product.

January 2004

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/

Guidances/UCM071717.pdf

October 2010

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM229175.pdf

What Information is Submitted in an IND Application? Clinical Protocol Draft Informed Consent Document Draft Case Report Forms PI CV (signed and current, dated) Investigator Brochure (for investigational study drug, also for multi-

site studies with an approved drug) Labeling information (for approved drug) Letter of Authorization (LOA) to Cross-reference the approved drug Relevant reference articles

IND Application Content Requirements per 21 CFR 312.2

Cover Sheet (FDA Form 1571) Table of Contents Introductory statement and General Investigational Plan Investigator Brochure* (provided by the company or by investigator) Study Protocol and Informed Consent Chemistry, Manufacture, and Control Information (can be via LOA, IB) Pharmacology and Toxicology Information (can be via LOA, IB) Previous Human Experience (can be via LOA, IB) Additional Information (draft Case Report Forms, pertinent professional

guidances, manuscripts)

Written by or provided by the investigative team!

* Not required for Sponsor-Investigator INDs for single-site studies

IND MaintenanceIND Amendments

Protocol Amendments New protocol Changes in protocol New investigator

Information Amendments New toxicology, chemistry, or other technical information New Investigator’s Brochure

IND Safety Reports Unexpected fatal or life threatening suspected adverse reactions – 7 calendar days Unexpected serious suspected adverse reactions – 15 calendar days

IND Annual Reports Submitted to FDA within 60 calendar days of the IND Anniversary Date

Expanded Access to Investigational Drugs

Types of Expanded Access

Single-patient - Emergency Use

Single-patient - Non-emergency Use

Intermediate-size patient populations

Treatment IND or treatment protocol

Devices

The first regulatory hurdle… “Significant Risk”, or “Non-significant Risk”?

January 2006

http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126418.pdf

Who Decides Whether a Device is SR or NSR? Sponsor-Investigator - makes the initial risk determination - presents the IRB with this information

IRBsRequired to determine whether the device study involves a SR or NSR device.

For an investigational device that is considered to be non-significant risk, the IRB can approve the “IDE”.

FDA Is available to help, and is the final arbiter!

What is the sponsor’s responsibility to the IRB for NSR device studies?Provide reviewing IRB(s) with an explanation of why the device is not a SR

- Description of device- Reports of prior investigations- Proposed investigational plan- Subject selection criteria

Inform IRB if FDA determined the study to be NSR

A Significant Risk device is an investigational device that:

(1) is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject;

(2) is for use in supporting or sustaining human life and represents a potential for serious risk to the health, safety, or welfare of a subject;

(3) is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease or otherwise preventing impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a subject; or

(4) otherwise presents a potential for serious risk to a subject.

Non-significant Risk (NSR) Devices NSR devices are devices that do not pose a potential for serious risk to

the human subjects. A NSR device study requires only IRB approval prior to initiation of a

clinical study. Sponsors of studies involving NSR devices are not required to submit an IDE application to FDA for approval. Submissions for NSR device investigations are made directly to the IRB of each participating institution.

If the IRB disagrees and determines that the device poses a SR, the sponsor must report this finding to FDA within five working days [§812.150(b)(9)].

FDA considers an investigation of a NSR device to have an approved IDE when IRB concurs with the NSR determination and approves the study.

What are the Requirements for NSR Device Studies?

Abbreviated requirements per 21CFR 812.2(b) Labeling IRB approval informed consent monitoring record keeping reports prohibition against promotion.

• NSR studies are considered to have an approved IDE therefore no IDE to FDA• Sponsors and IRBs do not have to advise FDA of NSR device studies• IRBs must make a SR or NSR determination for every NSR study (21 CFR 812.66)

IDE Exempt if:

Used in accordance with indications/labeling

Non-invasive diagnostic

Consumer preference testing

Solely for veterinary use

Research on or with lab animals

IDE Application Content Requirements per 21 CFR 312.2

(1) The name and address of the sponsor.

(2) A complete report of prior investigations of the device and a complete investigational plan (Protocol)

(3) A description of the methods, facilities, and controls used for the manufacture, processing, packing, storage, and, where appropriate, installation of the device

(4) An example of the agreements to be entered into by all investigators to comply with investigator obligations under this part, and a list of the names and addresses of all investigators who have signed the agreement.

(5) A certification that all investigators who will participate in the investigation have signed the agreement, that the list of investigators includes all the investigators participating in the investigation, and that no investigators will be added to the investigation until they have signed the agreement.

(6) A list of the name, address, and chairperson of each IRB that has been or will be asked to review the investigation and a certification of the action concerning the investigation taken by each such IRB.

(7) The name and address of any institution at which a part of the investigation may be conducted

(8) If the device is to be sold, the amount to be charged and an explanation of why sale does not constitute commercialization of the device.

(9) An environmental assessment (if applicable) or claim of exemption therefrom

(10) Copies of all labeling for the device.

(11) Copies of all forms and informational materials to be provided to subjects to obtain informed consent.

(12) Any other relevant information FDA requests for review of the application.

Written by or provided by the investigative team!

MICHR IND/IDE Investigator Assistance Program (MIAP)Provides Comprehensive:

Regulatory Expertise…

Regulatory Support…

Regulatory Education…

…to Investigators and their Team involved in FDA-regulated research.

Providing valuable support services for research studies

MIAP Team

Kevin WeatherwaxManager, MIAP

kweath@umich.edu

Mona MooreMIAP Team Member

monamoor@umich.edu

Jeanne WrightMIAP Lead

jeanburn@umich.edu

Bill ReisdorphMIAP Team Memberreisdorp@umich.edu

E. Mitchell Seymour, PhDMIAP Team Member

seymoure@umich.edu

MICHRMIAP@med.umich.edu

MIAP Team

• Various certifications from the Regulatory Affairs Professional Society, the Association of Clinical Research Professionals, the Society of Clinical Research Associates, the National Association of IRB Managers, and the American Society for Quality.

• Varied backgrounds in academia and industry with expertise in life sciences, chemistry (drug discovery R&D), nursing, Human Subjects Research Protection, Good Clinical Practice, Good Laboratory Practice, Good Manufacturing practice, quality assurance, and clinical trialoperations.

• Mean year professional experience = 26.3 Research (clinical + preclinical) = 15.2Regulatory Affairs = 10.5

MIAP SERVICES OVERVIEW Agent/Device

development/regulatory strategy consultation

IND/IDE consultation including determination of need for IND or IDE

Pre-IND/IDE FDA meeting requests and support

Protocol/Informed Consent review

IND/IDE application preparation and submission to FDA

Clinical hold/conditional approval response preparation/submission

Communication with the FDA, IRB and other regulatory bodies

IND/IDE “maintenance” support

– Safety report submissions

– Protocol amendments

– Annual reports

– Investigator Amendments

– Informational Amendments

Contact us!

MICHRMIAP@med.umich.edu

https://www.michr.umich.edu/services/regulatorysupport/miap

Want this slide deck? seymoure@med.umich.edu