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Report
Investigational New Drug (IND) Orientation
Responsibilities of IND
Sponsor-Investigators
MICHR IND/IDE Assistance Program (MIAP)
Responsibilities of IND Sponsor-Investigators
Definitions
• 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 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.
Responsibilities of IND Sponsor-Investigators
APPLICABLE REGULATIONS
 The Federal Food, Drug, and Cosmetic Act (FD&C
Act) gives the FDA authority to regulate drugs and biologics
 Code of Federal Regulations (CFR)
21 CFR Part 312: Investigational New Drugs
Contains procedures and requirements governing the use of
investigational new drugs
Applies to all clinical investigations of products that are
subject to section 505 of the FD&C Act
Website for INDs:
IND Regulations
Responsibilities of IND Sponsor-Investigators
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 §1271
Good Tissue Practices
Responsibilities of IND Sponsor-Investigators
Regulations
Investigational Application
21 CFR §312
21 CFR §812
21 CFR §809
IND Drugs and Biologics
IDE Devices
IVD In Vitro Diagnostics
Marketing Application
21 CFR §601
21 CFR §314
21 CFR §814
BLA Biologics
NDA Drugs
PMA Devices
Responsibilities of IND Sponsor-Investigators
Good Clinical Practice (GCP)
www.fda.gov/oc/gcp/
GCP is a standard for the design, conduct, performance,
monitoring, auditing, recording, analysis, and reporting of clinical
trials.
Not Law, but FDA has adopted GCP.
(follow them…)
Responsibilities of IND Sponsor-Investigators
FDA RESPONSIBILITIES OF IND INVESTIGATORS
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Conduct study in compliance with GCP, protocol, & applicable IND/IDE
regulations
Ensure informed consent of each subject is obtained (and retained)
Personally conduct or supervise the investigation
Protect the rights, safety, and welfare of participants
Ensure adequate medical care for the study participants
Obtain necessary approvals from IRB
Maintain and retain drug/device disposition and patient case history records
Provide written reports to the IRB, as required
Ensure changes are not implemented without prospective IRB/FDA approval
Promptly report serious adverse events to the sponsor, IRB, and FDA
Furnish Progress reports and Safety reports
Ensure all study team members are informed about their obligations noted above
Responsibilities of IND Sponsor-Investigators
FDA RESPONSIBILITIES OF IND SPONSOR-INVESTIGATORS
IN ADDITION TO THE INVESTIGATOR RESPONSIBILITIES,
SPONSOR-INVESTIGATORS ARE REQUIRED TO:
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Select qualified investigators at other
institutions for multi-site trials
Provide information to other
investigators and study staff to ensure
that the study is performed properly
Ensure proper monitoring of the study
Ensure the study is performed in
accordance with the general
investigational plan and protocol
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Submit necessary
amendments/supplements to FDA
Ensure that FDA and all participating
investigators are promptly informed of
significant new adverse effects or risks
Maintain adequate records
Maintain proper control of the study
drug/device
Responsibilities of IND Sponsor-Investigators
FDA Form 1571 (CFR 21 §312.23(a)(1)(i-ix))
• Contractual agreement between sponsor and FDA
• Contains name of person responsible for conduct and progress of
the study (Item 15)
• Contains name of person responsible for the review and evaluation
of information relevant to the safety of the drug (Item 16)
• Sponsor or sponsor’s authorized representative agrees to conduct
investigation in accordance with all applicable regulatory
requirements (Item 17)
FDA Form 1571
FDA Form 1571
Responsibilities of IND Sponsor-Investigators
IND Maintenance (IND Amendments)
IND Amendment (Documents submitted to an active IND)
The 4 major types are…
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Protocol Amendments (21 CFR §312.30)
Information Amendments (21 CFR § 312.31)
IND Safety Reports (21 CFR § 312.32)
IND Annual Reports (21 CFR § 312.33)
Responsibilities of IND Sponsor-Investigators
FDA Submissions - Responsibilities To FDA
Submission
Timing
Amendment - New protocol
After IRB approval
Amendment - Changed protocol
At time of change, usually after IRB approval
Amendment - New investigator
Within 30 days of being added
Amendment - Information
At time of occurrence
IND safety report (unexpected AE that is
serious and associated with the use of the
drug or lab tests that suggest significant risk)
Within 15 calendar days of receiving notification
Contact MIAP when you receive notification
IND safety report (unexpected fatal or life
threatening experience associated with the use
of the drug)
Within 7 calendar days of receiving notification
Contact MIAP when you receive 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
Responsibilities of IND Sponsor-Investigators
Amendments - New Protocol
• New study that is not covered by a protocol already contained in the
IND
• Must submit the new protocol to the FDA
• The new protocol can begin after both conditions have been
met:
– The protocol has been approved by the IRB
– The sponsor has submitted the protocol to the FDA for its review
• There is no need to wait for the 30 day review period at the
FDA unless we have specifically asked the FDA for advice on
the protocol content
• Contact MIAP early to discuss regulatory strategy
Responsibilities of IND Sponsor-Investigators
Amendments - Changes in a Protocol
• A sponsor shall submit a protocol amendment describing any
change in a Phase I protocol that significantly affects the safety of
subjects or any change in a Phase 2 or 3 protocol that significantly
affects the safety of subjects, the scope of the investigation, or the
scientific quality of the study
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Examples:
– Any increase in drug dosage or duration of exposure of any individual
subjects
– Any significant increase in the number of subjects under study
– Any significant change in the design of a protocol (the addition or
dropping of a control group)
– The addition of a new test, or procedure, that is intended to improve
monitoring for, or reduce the risk of, a side effect or adverse event; or
the dropping of a test intended to monitor safety
Responsibilities of IND Sponsor-Investigators
Amendments – Changes in a protocol (continued)
• A protocol change may be implemented provided the following
two conditions are met:
– The change has been approved by the IRB with responsibility for
review and approval of the study
– The sponsor has submitted the change to FDA for its review
• No need to wait 30 days unless we have specifically asked
for feedback
• Contact MIAP early in process to discuss regulatory strategy
– IRB Minor Amendment: URGENT REQUEST
• PLEASE contact MIAP immediately when starting this
process
Responsibilities of IND Sponsor-Investigators
Amendments – Changes in Protocol (continued)
• Documents required to submit to the FDA
– Summary of Changes Document for protocol
– Tracked changed version of protocol
– Clean version of protocol
– Tracked changed version of informed consent document
– Clean version of informed consent document
Responsibilities of IND Sponsor-Investigators
Amendments – New Investigator
• A sponsor shall submit a protocol amendment when a new
investigator is added to carry out a previously submitted protocol
• The sponsor shall notify FDA of the new investigator within 30 days
of the investigator being added
• Try to group new investigators/and or sites together
• Also includes new lab, new clinic
• Can submit together with a change in protocol or new protocol
submission
• Required paperwork
– Form 1572
– Investigator CV – signed and dated on first page
FDA Form 1572
FDA Form 1572
Responsibilities of IND Sponsor-Investigators
Amendments – Information
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New toxicology, chemistry, or other technical information
New Investigator’s Brochure
Submit at the time of change, but, to the extent feasible, not more than
every 30 days
Can submit with protocol amendment or new investigator amendment
Responsibilities of IND Sponsor-Investigators
IND Safety Report
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Unexpected fatal or life threatening suspected adverse reactions
– Must submit to the FDA within 7 calendar days of receiving the notification
– Complete MedWatch 3500 A
– Follow-up reports must be submitted as soon as possible
Unexpected serious suspected adverse reactions
– Must submit to the FDA within 15 calendar days of receiving the notification
– Complete MedWatch 3500A
Follow-up reports should be submitted within 15 days of receiving the first
notification (not required if 7 day report is complete)
If FDA requests any additional data or information, the sponsor must submit it to
the FDA as soon as possible, but no later than 15 calendar days after receiving
the request
Contact MIAP if the IRB (at any site) disagrees with the Sponsor-Investigator
assessment of attribution and causality
Safety Reporting Via MedWatch
How to report
Patient/
Subject
Product info
(drug, biologic, device, etc.)
Description of Event
or Problem
Relevant tests/labs
Reporter
Responsibilities of IND Sponsor-Investigators
Annual Report
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Due to the FDA within 60 calendar days of the IND Anniversary Date (date
IND was deemed “safe to proceed”)
MIAP will contact study coordinator and PI approximately 60 days before
the report is due to obtain required information
– Patient demographics
– Study information (number of patients enrolled, number of sites, etc.)
– Adverse events
– Any other new information
MIAP will complete the annual report template and send to study
coordinator and PI to review
MIAP will send final annual report to the FDA
Upload FDA annual report into eResearch application (ORIO)
Responsibilities of IND Sponsor-Investigators
Monitoring the Trial
• Clinical Trial Monitoring is required for clinical trials conducted
under an IND
• Clinical Trial Monitor examines quality of trial conduct:
– Perform on-site (if indicated, also off-site) evaluations of
trial-related activities
– Identify deviations in protocol conduct
– Review documents for Adverse Events
– Drug accountability – see also handout of IDS monitoring
• Extent and frequency of monitoring as appropriate:
– Length, complexity, subject enrollment and other aspects
of the trial
Responsibilities of IND Sponsor-Investigators
Monitoring the Trial: DSMB
• Additional measure of human subject protection
• Evaluates accumulating data from a clinical trial
• Generally, established by the sponsor
– Select members, should be independent
– Charter generally written by sponsor, may have consultation
by members
• Recommendations regarding the conduct and design of the trial
(safety and efficacy)
• Does not visit sites or substitute for clinical trial monitors
• Send DSMB reports to the IRB for review
Responsibilities of IND Sponsor-Investigators
Responsibilities of IND Sponsor-Investigators
The FDA Calls – now what?
• Make immediate internal notifications
– IRB
– Regulatory Affairs
– MIAP
• Review UMHS Policy 01-01-020 “External/Third Party Reviews
• IRBMED ORIO Reporting
– “As soon as possible after notification of the audit and prior to a
site visit by an external oversight entity (e.g. sponsor, FDA). For
FDA audits, you should also call the IRBMED Office
Responsibilities of IND Sponsor-Investigators
Most Common Violations Noted by the FDA
• Failure to follow the protocol
example: Required testing is incomplete
• Recordkeeping errors
• Informed consent problems/issues
Responsibilities of IND Sponsor-Investigators
Most Significant Violations noted by the FDA
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Enrollment of ineligible subjects
Violation of protocol affecting safety
Extensive data corrections and questionable changes
Inadequate oversight of study personnel
– Inappropriate delegation of authority
– Poor oversight of sites
• No Informed consent
• Failure to communicate with IRB
Responsibilities of IND Sponsor-Investigators
Responsibilities of IND Sponsor-Investigators
If you are doing something in eResearch then it
may need to be reported to the FDA! Contact
MIAP.
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Protocol deviations – dosing errors, safety reasons
Lapse in IRB Approval
Urgent Amendment request
Addition of new site
Adverse event
Responsibilities of IND Sponsor-Investigators
Add MIAP lead as a study team member in
eResearch
• Add as administrative staff
• Question 1.6 NO to edit right
• Question 1.7 YES to include this person on all correspondence
Responsibilities of IND Sponsor-Investigators
MIAP Established to Provide Comprehensive:
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Regulatory Expertise…
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Regulatory Support…
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Regulatory Education Services…
To Faculty Investigators and their Team Involved In FDA Regulated
Clinical Research At The University of Michigan
Responsibilities of IND Sponsor-Investigators
MIAP SERVICES OVERVIEW
• Agent/Device development strategy consultation
• IND/IDE consultation including determination of need for IND or IDE
• Pre-IND FDA meeting requests and support
• Protocol development
• IND/IDE application preparation and submission
• Clinical hold response preparation/submission
• Communication with the FDA, IRB and other regulatory bodies
• IND/IDE “maintenance” support
–Safety report submissions
–Protocol amendments to the FDA
–Annual reports to the FDA
• Clinical Trial Monitoring
–Investigators meetings
–Site initiation visits
–Interim site monitoring visits
–Study close out activities
Responsibilities of IND Sponsor-Investigators
MIAP Activities FY 2012
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Supported 31 active INDs (representing 34 active clinical study protocols)
and 2 IDEs
Submitted 21 new IND applications and 2 new IDE applications to the FDA
Submitted 5 single-patient (expanded access) INDs and 2 emergency use
IDEs to the FDA
Submitted over 110 IND/IDE life-cycle maintenance submissions to the FDA
Submitted 10 IND exemption requests to the FDA
Submitted 3 pre IND/IDE meeting packages to the FDA
Responsibilities of IND Sponsor-Investigators
MIAP is here to help with INDs and IDEs
MIAP contacts:
Kevin Weatherwax, BS, CCRC, CCRA
Manager, MICHR IND/IDE Assistance Program (MIAP)
Michigan Institute for Clinical and Health Research (MICHR)
University of Michigan Health System
NCRC Bldg # 400
2800 Plymouth Road
Ann Arbor, MI 48109-2800
Phone: 734-998-6275 Pager: 734-936-6266, #9912
Fax: 734-998-7318
Website: www.MICHR.umich.edu
[email protected]
Responsibilities of IND Sponsor-Investigators
MIAP contacts (cont’d):
MICHR/MIAP CLINICAL RESEARCH PROJECT MANAGERS:
Mona Moore, MS, RAC
Phone: 734-998-7818
[email protected]
Bill Reisdorph, MS, CQA, RAC
Phone: 734-998-8427
[email protected]
Jeanne Wright, RN, BSN, MT, CCRP, RAC
Phone: 734-998-7598
[email protected]
E. Mitchell Seymour, PhD, RAC
Phone: 734-998-6421
[email protected]
MIAP TEAM
Shared group e-mail for documents:
[email protected]
Responsibilities of IND Sponsor-Investigators
Office of Human Research Compliance Review (OHRCR)
Director
Ron Maio, D.O., M.S., Professor, Department of Emergency Medicine
[email protected]
734 647-0489
Research Compliance Associates
Terry VandenBosch, PhD, RN, CIP, CCRP
[email protected]
734 647-0457
Ted Hamilton, MS
[email protected]
734 647-1622
Responsibilities of IND Sponsor-Investigators
UMMS Regulatory Affairs
Ray Hutchinson, MD, MS, Associate Dean
734 615-1702
[email protected]
Pat Ward, MPA, Director
734-647-1954
[email protected]
Responsibilities of IND Sponsor-Investigators
Office of the General Counsel
Kara Morgenstern, JD, MPH, Assistant General Counsel
Phone: 734-763-6240
[email protected]
Institutional Review Board - IRBMED
Judith Birk, JD, IRBMED Director
Phone: 734-647-7615
Fax: 734-763-1234
[email protected]
Responsibilities of IND Sponsor-Investigators
Investigational Drug Service (IDS)
Helen Tamer, Pharm.D.
Clinical Pharmacist
Phone: 734-936-7469
Fax: 734-647-9302
[email protected]
Amy Skyles, Pharm. D.
Clinical Pharmacist
Phone: 734-936-8210
Fax: 734-936-7027
[email protected]
Drug shipment address:
University of Michigan Hospital
Department of Pharmacy Services-IDS
UH B2D400
1500 E. Medical Center Drive
Ann Arbor, MI 48109-0008
Attention: Investigational Drug Service
Responsibilities of IND Sponsor-Investigators
Labeling of Investigational Agents
21 CFR §312.6
• Immediate packaging of product
– “Caution: New Drug – Limited by Federal (or United
States) law to investigational use”
• The labels and labeling shall not
– Bear false and misleading statements
– Represent that the drug is safe and effective for
purposes being investigated
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Responsibilities of IND Sponsor-Investigators
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