The Rough Waters of the Regulatory Environment

Kevin Weatherwax
MICHR 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

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 idea
Successful
trial and
publication
Key Regulations

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
Investigational Application
21 CFR §312 IND Drugs and Biologics
21 CFR §812 IDE Devices
21 CFR §809 IVD In Vitro Diagnostics
Marketing Application
21 CFR §601 Biologics License App. (BLA) Biologics
21 CFR §314 New Drug Application (NDA) Drugs
21 CFR §814 Premarket Approval (PMA) Devices
21 CFR §814.102 (a) Humanitarian Use Device (HUD) Devices
21 CFR §814.104(b)(1) Humanitarian Device Exemption (HDE) Devices
510(k) FD&C Act Premarket Notification (PMN) Devices

Regulations
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

If a Federally Funded Study…
Regulations
45 CFR Part 46 (DHHS) Protection of Human Subjects

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!

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)

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 2010
http://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)

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

Regulatory Controls
P
a
t
i
e
n
t
R
i
s
k
Class I
General
Controls
Class II
General &
Special
Controls
510(k)
IDE (??)
Class III
PMA
IDE
Required
MEDICAL DEVICES
FDA RISK BASED CLASSIFICATION SCHEME

January 2006
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

Responsibilities
FDA Submissions - Responsibilities To FDA for an IDE (812.150)
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
Within 30 days
– Final Report
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/In
vestigationalDeviceExemptionIDE/ucm046717.htm

AGENDA
4.RESOURCES AVAILABLE
5. CASE EXAMPLES

MIAP is here to Help!
Photo by Rebel Sessions/Nic Bothma

Resources
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.

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
Services
 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

Challenges and Solutions for Early
Sponsor-Investigator Support
Seymour, Wright, Reisdorph, Moore, Weatherwax; Experimental Biology 2012

Challenges
Gap Analysis
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
Challenges/Solutions

Challenges
Regulatory Writing
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

Challenges
Industry Interaction
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

Challenges
FDA Interaction
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

AGENDA
5.CASE EXAMPLES

Case Example
“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).

1. Sponsor
initiates
study
7. FDA
2. GMP synthesis
compound
21CFR 58
3. Analytical
validation of dose
range
4. Pharmacology &
Toxicology
6. Chemistry,
manufacturing,
control
5. Clinical
protocols
IND#110,444
IND#116,907
NTR industrial partners
provide novel imaging
instruments compatible
with molecular probes
to accelerate translation
into the clinic
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
white
light
biopsy
channel
light
guide
air/
water
light
guide
Bill Reisdorph, MIAP
Jin Ito, Olympus Medical
Network for Translational Research
National Cancer Institute

Meetings
with Industry
Partner
IND support
requested
Esophegeal
Phase I Study
Enrollment
Begins 2/2011
Esophageal
IND Submitted
11/2010
Colon IND
Submitted
11/2012
Colon
Phase I Study
Enrollment
Completed 8/2013
2009 2010 2011 2012 2013
Qualificaton
of GLP
vendors
Study Team
Planning
MILESTONES
Detection of Neoplasia in the Digestive Tract
FDA
Approval
12/2010
CMC docs
received from
GMP
manufacturer
FDA
Approval
12/2012
Esophageal
Phase Ib Study
Protocol
submitted
5/2012
Timeline
Colon
Phase I Study
Enrollment
Begins 2/2013
Esophageal
Phase I Study
Enrollment
completed
2/2013
Esophageal
Phase Ib Study
Enrollment
completed
9/2013

MIAP Team
Kevin Weatherwax
Manager, MIAP
kweath@umich.edu
Mona Moore
MIAP Team Member
monamoor@umich.edu
Jeanne Wright
MIAP Lead
jeanburn@umich.edu
Bill Reisdorph
MIAP Team Member
reisdorp@umich.edu
E. Mitchell Seymour, PhD
MIAP Team Member
seymoure@umich.edu
Photo by ©Desra Pickers

The Rough Waters of the Regulatory Environment

The Rough Waters of the Regulatory Environment

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