The Rough Waters of the Regulatory Environment

Navigating the Rough Waters of the Regulatory Environment

Kevin WeatherwaxMICHR IND/IDE Investigator Assistance Program (MIAP)

September 24, 2014

Photo by Jean Guichard

The Regulatory Environment can seem like the Bay of Fundy…Constantly Changing

Rough Waters

Rough Waters

Early Opportunities: Pre-IND Meeting with FDA

Critical Path

Ongoing Regulatory Support

Early Opportunities: Pre-Sub (Pre-IDE) Meeting with FDA

Critical Path

Ongoing Regulatory Support

AGENDA

1.DEFINITIONS AND APPLICABLE REGULATIONS

2. INVESTIGATIONAL NEW DRUG (IND) PROCESS

3. INVESTIGATONAL DEVICE EXEMPTION (IDE) PROCESS

4. RESOURCES AVAILABLE

5. CASE EXAMPLES

Definitions Related to Drugs Investigational Drug is a new drug or biologic used in a clinical

investigation

Drug: articles used to treat, mitigate, cure, diagnose, or prevent a disease in man or other animals; and articles intended to affect the structure or any function of the body

IND application: An Investigational New Drug (IND) Application is a request for authorization to administer an investigational drug or biologic to humans or to administer a marketed (approved) drug for a new indication, dosage and/or patient population. An IND contains documentation submitted to the Food and Drug Administration (FDA) to allow for the conduct of a clinical study using an investigational drug

Definitions related to Devices

Investigational Device: An investigational device is a medical device that is the subject of a clinical study designed to evaluate the effectiveness and/or safety of the device.

Device: an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent or other similar or related article including any component part or accessory, which is recognized in the National Formulary, or U.S. Pharmacopoeia, or any supplement to them, intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment or prevention of a disease in man or other animals; and articles intended to affect the structure or any function of the body (not through chemical means)

IDE application: An Investigational Device Exemption (IDE) contains documentation submitted to the FDA to allow for the conduct of a clinical study using a significant risk device that is new or not approved for the proposed indication. An IDE covers the procedures for the conduct of clinical studies with medical devices including application, responsibilities of sponsors and investigators, labeling, records, and reports.

Definitions (continued)

• 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.

Great ideaSuccessful trial and publication

Key Regulations

APPLICABLE REGULATIONS

The Federal Food, Drug, and Cosmetic Act (FD&C Act) gives the FDA authority to regulate drugs and devices

Drugs/Biologics/Medical Devices

Code of Federal Regulations (CFR)

Regulations

RegulationsInvestigational Application

21 CFR §312 IND Drugs and Biologics21 CFR §812 IDE Devices21 CFR §809 IVD In Vitro Diagnostics

Marketing Application

21 CFR §601 Biologics License App. (BLA) Biologics21 CFR §314 New Drug Application (NDA) Drugs21 CFR §814 Premarket Approval (PMA) Devices21 CFR §814.102 (a)Humanitarian Use Device (HUD) Devices21 CFR §814.104(b)(1) Humanitarian Device Exemption (HDE)

Devices510(k) FD&C Act Premarket Notification (PMN) Devices

21 CFR §11 Electronic Records; Electronic Signatures

21 CFR §50 FDA (21 CFR) Protection of Human Subjects

21 CFR §54 Financial Disclosure by Clinical Investigators

21 CFR §56 Institutional Review Boards

21 CFR §58 Good Laboratory Practices

21 CFR §211, § 810 Good Manufacturing Practices

21 CFR § 820 Quality System Regulation

21 CFR §1271 Good Tissue Practices

Regulations

45 CFR Part 46 (DHHS) Protection of Human Subjects

If a Federally Funded Study…

Regulations

AGENDA

1. DEFINITIONS AND APPLICABLE REGULATIONS




5. CASE EXAMPLES

IND Applicability IND means an investigational new drug application; synonymous

with Notice of Claimed Investigational Exemption for a New Drug;

Investigational new drug means a new drug or biological drug that is used in a clinical investigation. It also includes a biological product that is used in vitro for diagnostic purposes.

NOTE: IND application refers to route and dose as well as new indication or new population!

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)

When is an IND Needed?

When is an IND NOT Needed?

IND Exemption Criteria

• Lawfully marketed in the US and :– Not intended to support a new indication;– Not intended to support a change in advertising;– Does not involve a factor that increases risk of use;– Conducted in compliance with IRB and Informed Consent

requirements;– Complies with the requirements for promotion and charging of

investigational drugs.

January 2004

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071717.pdf


October 2010http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM229175.pdf



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


What Information is Needed to Submit an IND? Final Protocol

(If oncology trial, the protocol should have PRC approval before submitting to the FDA)

Final Informed Consent Document (and other associated documents)

Draft Case Report Forms PI CV (signed and current) Investigator’s Brochure (for multi-center study) Labeling information (for approved drug) Letter of Authorization (LOA) to cross-reference a company’s

product (for off-label use) Relevant reference articles

Content Requirements per 21 CFR 312.23 Cover Sheet Table of Contents Introductory statement and General Investigational Plan Investigator Brochure (IB) Study Protocol and Informed Consent Chemistry, Manufacture, and Control Information (via LOA) Pharmacology and Toxicology Information (via LOA) Previous Human Experience (via LOA) Additional Information (draft CRFs, hard-copy reference articles)

Submission Timing

Amendment - New protocol After IRB approval

Amendment - Changed protocol At time of change

Amendment - New investigator Within 30 days of being added

Amendment - Information At time of occurrence

IND safety report (Serious and unexpected suspected adverse reaction, findings from other studies, findings from animal or in vitro testing, increased rate of occurrence of serious suspected adverse reactions)

Within 15 calendar days of receiving notification

IND safety report (Unexpected fatal or life-threatening suspected adverse reaction)

Within 7 calendar days of receiving notification

Annual report Within 60 days of anniversary of IND

Withdrawal of IND At time of withdrawal

Discontinuation of investigation Within 5 working days of discontinuance

Financial disclosure report At time of change

FDA Submissions - Responsibilities To FDA for an IND (312.32-IND safety reports)

Responsibilities

AGENDA1. DEFINITIONS AND APPLICABLE REGULATIONS




5. CASE EXAMPLES

Regulatory Controls

Pa t i ent

R i sk

Class IGeneral Controls

Class IIGeneral &

Special Controls

510(k)IDE (??)

Class IIIPMAIDE

Required

MEDICAL DEVICESFDA RISK BASED CLASSIFICATION SCHEME

January 2006

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

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

Who Decides Whether a Device is SR or NSR?

Sponsor/Investigator Make the initial risk determination Presents the IRB with information

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

IRBs Required 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 Available to help Final arbiter



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 Devices Non-significant risk 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.

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

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)

Requirements for an IDE Application (for SR devices) Name and address of the sponsor Complete report of prior investigations of the device Investigational Plan, including monitoring procedures Description of the methods, facilities, and controls used for the manufacture,

processing, packing, storage of the device Investigational agreement Investigator names, institutions, and CVs IRB information Amount being charged for the device and explanation why the sale does not

constitute commercialization Labels Informed Consent Additional information

Submission Timing Supplement- New protocol After IRB approval

Supplement- Changed protocol At time of change

Supplement - New investigator Within 30 days of being added

Supplement - Information At time of occurrence

Unanticipated Adverse Device Effects Within 10 working days of receiving notification

Recalls and Device Disposition Within 30 days

Progress/Annual report At regular intervals (at least yearly)

Withdrawal of IRB or FDA approval Within 5 working days of receipt of notice

Completion or Termination of investigation – Final Report

Within 30 days

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/InvestigationalDeviceExemptionIDE/ucm046717.htm

FDA Submissions - Responsibilities To FDA for an IDE (812.150)

Responsibilities

AGENDA




4.RESOURCES AVAILABLE

5. CASE EXAMPLES

Photo by Rebel Sessions/Nic Bothma

MIAP is here to Help!

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.

Resources

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

Services

Challenges and Solutions for Early Sponsor-Investigator Support

Seymour, Wright, Reisdorph, Moore, Weatherwax; Experimental Biology 2012

Challenges

Sponsor-investigators often provide clinical protocols and study-related materials with information gaps that affect an IND or IDE submission.

Solutions

• Review the medical literature• Review FDA Guidance documents• Research similar products and their regulatory paths• Perform due diligence on the nonclinical and clinical studies/data that

support the IND or IDE

Gap Analysis

Challenges/Solutions

Challenges

FDA submissions require a unique format and clear writing with attention to principles of Good Clinical Practice. This effort begins with a well-written clinical study protocol.

Solutions

• Transform research proposals into clinical protocols• Transform clinical protocols into IND/IDE submissions• Assist with informed consent documents and case report forms• Assist with IRB submissions

Regulatory Writing


Challenges

Sponsor-investigators have limited experience interacting with industry regulatory professionals. Industry may not cooperate with individual sponsor-investigators or place undue burden upon them causing unnecessary project delays.

Solutions

• Assist with obtaining Letters of Authorization, Right of Reference, and Investigator Brochures

• Assist with industry cooperation and communication• Assist with industry-requested safety reporting

Industry Interaction


Challenges

Sponsor-investigators have limited experience interacting with FDA, limited knowledge of FDA requirements, and limited resources to address these gaps. Solutions

• Conduct IND/IDE submissions and maintenance• Prepare and submit FDA meeting packets • Attend FDA meetings• Respond to FDA inquiries and requests• Assist with study/site monitoring and audit preparation

FDA Interaction


AGENDA





5.CASE EXAMPLES

“A Phase I In-Vivo Esophageal Protocol for Detection of Neoplasia in the Digestive Tract”

Develop the use of fluorescence-labeled peptides that affinity bind to pre-cancerous mucosa (dysplastic Barrett’s Esophagus) in the digestive tract for use as an imaging agent to guide endoscopic biopsy or endoscopic mucosal resection

Specific aims:

1) To evaluate the safety of topically administered fluorescence-labeled peptides to the surface of esophageal mucosa.

2) To validate binding of the fluorescence-labeled peptide to esophageal neoplasia.

Investigational study agent: fluorescent-labeled peptide composed of a 7-amino acid chain attached to a substituted fluorescein derivative. The compound was manufactured under current Good Manufacturing Practices (GMP).

Case Example

“A Phase I In-Vivo Colon Protocol for Detection of Neoplasia in the Digestive Tract”

Develop the use of fluorescence-labeled peptides that affinity bind to pre-cancerous mucosa in the digestive tract for use as an imaging agent to aid in the early detection of colon cancer.

Specific Aims:

1) To evaluate the safety of topically administered fluorescence-labeled peptides to the surface of intra-colonic mucosa.

2) To validate binding of the fluorescence-labeled peptide to intra-colonic neoplasia.

Investigational Study Agent: fluorescence-labeled peptide composed of a 7-amino acid chain attached to a substituted fluorescein derivative. The compound was manufactured under current Good Manufacturing Practices (GMP).

Case Example

7. FDA

1. Sponsor initiates

study

2. GMP synthesis compound21CFR 58

3. Analytical validation of dose

range

4. Pharmacology & Toxicology

6. Chemistry, manufacturing,

control

5. Clinical protocols

IND#110,444IND#116,907

NTR Standards & Compliance Research Core provides guidance for preparation of Investigation of New Drug (IND) application to FDA to perform Phase 1 clinical study

fluorescence

biopsychannel

white light

air/water

lightguide

lightguide

NTR industrial partners provide novel imaging instruments compatible with molecular probes to accelerate translation into the clinic

Bill Reisdorph, MIAP

Jin Ito, Olympus Medical

Network for Translational Research National Cancer Institute

2009 2010 2011 2012 2013

Meetings

with Industry Partner

IND support requested

Study Team

Planning

Qualificaton of GLP vendors

MILESTONESDetection of Neoplasia in the Digestive Tract

CMC docs received from GMP manufacturer

Esophageal

IND Submitted

11/2010

FDA

Approval 12/2010

Esophegeal Phase I Study Enrollment Begins 2/2011

Esophageal Phase Ib Study Protocol submitted 5/2012

Colon IND Submitted

11/2012

FDA

Approval 12/2012

Timeline

Colon

Phase I Study Enrollment Begins 2/2013

Esophageal Phase I Study Enrollment completed 2/2013

Colon

Phase I Study Enrollment Completed 8/2013

Esophageal Phase Ib Study Enrollment completed 9/2013

MIAP Team

Kevin WeatherwaxManager, MIAP

[email protected]

Mona MooreMIAP Team Member

[email protected]

Jeanne WrightMIAP Lead

[email protected]

Bill ReisdorphMIAP Team [email protected]

E. Mitchell Seymour, PhDMIAP Team Member

[email protected]

Photo by ©Desra Pickers

mailto:[email protected]





Parting thought……Ed would not be able to do it without his team

Photo by ©Veikka Gustafsson

QUESTIONS/COMMENTS