IND Process and General
Responsibilities under IND
August 27, 2010
Kate Marusina, PhD, MBA
Pav Aujla, MS, CCRP, RAC
Primo N. Lara, Jr. MD
A Translational Innovation Forum
Agenda
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Definition of Drug and other helpful definitions
 21
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CFR 312
What is Regulatory Sponsor?
Overview of IND process
General Responsibilities under IND
Agenda
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University of California Davis Cancer Center –
Clinical Trials Support Unit (CTSU)
Best Practices for:
IND Exemptions: Consultative Process
 Protocol Development
 Protocol Initiation Meeting
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Post Study on http://www.clinicaltrials.gov
Key Compliance Documents
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Good Laboratory Practices (GLPs) for non-clinical
studies
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21 CFR 58
Good Manufacturing Practices
 21
CFR 210, 211
 Comprehensive regulations to assure the identity,
strength and purity
Key Compliance Documents
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Good Clinical Practices (GCPs)
 Protection
of Human Subjects 21 CFR 50
 Financial Disclosure of Investigators 21 CFR 54
 Institutional Review Boards 21 CFR 56
 Sponsor, Monitor and Investigator Obligations 21 CFR
312, Subpart D
21 CFR 312 contains IND information
What is a New Drug?
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“ Any drug (or biologic) that is not generally
recognized as safe and effective for use under the
conditions prescribed, recommended or suggested
in the labeling thereof”
- Section 201 FD&C Act
What is a New Drug?
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FD&C Act prohibits shipment of any drug across the
state lines without an approved NDA
Investigational New Drug (IND) Application
provides an exemption to allow shipment of the
drug for clinical testing
Some Useful Definitions
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New Molecular entity
A
pharmacologically active moiety which is not been
studied or used clinically in man or is not approved for
such use
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Drug Substance (API)
 Pharmacologically
active
 Subsequently formulated with excipients to produce the
drug product
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Drug Product
 Finished
product in certain dosage form (capsule, tablet,
injection)
Types of IND applications
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Commercial
Research (non-commercial), also called an Investigator
IND.
Submitted by a physician who both initiates and conducts an
investigation, and under whose immediate direction the
investigational drug is administered or dispensed.
 Goal is to study:
 an unapproved drug
 an approved product for a new indication or in a new
patient population
 dietary supplements – may be considered drugs
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What is “Regulatory Sponsor”?
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New Full Committee Clinical Application Form
Financial Sponsor:
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Private Co, Foundation, Feds, individual donations, PI’s Ed fund,
Department
Regulatory Sponsor
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Who prepared the protocol
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Is the study exempt?
If the study is initiated by a UC Davis Principal Investigator and the
study is NOT exempt:
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I understand that I am a regulatory sponsor and investigator on this
study, assuming responsibility for all regulatory requirements specified
in 21 CFR 312 (Investigational New Drug Application) and/or 21 CFR
812 (Investigational Device Exemption).
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FDA Form 1572 is attached (required for regulatory sponsorinvestigators)
Types of IND applications
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Expanded Access
Emergency Use IND
 “Compassionate Use”
 experimental drug in an emergency situation that does
not allow time for submission of a “regular” IND.
 Also used for patients who do not meet the criteria of an
existing study protocol, or if an approved study protocol
does not exist
 Treatment IND: promising experimental drugs for serious
or immediately life-threatening conditions while FDA
review is ongoing
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Emergency IND (Compassionate Use)
21 CFR 312.36
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FDA = no formal compassionate use policy
 Patient
does not meet existing protocol eligibility
 Life-threatening situation
 Company agrees to ship the drug
 Exempt from prior IRB review and approval
 IRB notified within 5 days
 Verbal approval by the FDA by phone
 Written
 Informed
follow-up
Consent required
 Company required to follow up
Treatment IND
21 CFR 312.34 and .35
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Facilitate availability of drugs to critically ill patients, even
if the drug is not yet approved
Available to patients not enrolled in controlled trials
No comparable or satisfactory treatments
The drug is currently in a controlled clinical trial under an
IND in Phase III (for immediately life-threatening diseases in phase II)
PI can submit separate treatment IND, providing that the
drug manufacturer agreed to provide the drug and to
authorize incorporation-by-reference of the technical
information required for treatment IND.
Group C Treatment IND
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Agreement between FDA and National Cancer
Institute (NCI)
Group C classification system allows access to
certain cancer drugs
Group C drugs: generally Phase III - have shown
reproducible anti-tumor activity
Provided only to properly trained physicians who
have registered themselves with NCI
Group C drugs are provided free of charge
See Handout
Treatment IND (cont.)
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Letter of Authorization provided by Sponsor/Drug
Manufacturer
Authorize incorporation-by-reference of the technical
information required for treatment IND
See Example
When is an IND Required?
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Applies to all clinical investigations of products that are subject
to section 505 of the Federal Food, Drug, and Cosmetic Act or
to the licensing provisions of the Public Health Service Act (58
Stat. 632, as amended (42 U.S.C. 201 et seq .)).
 New molecular entity
 Lawfully marketed drug/biologics for a new indication, new
formulation or in a new combination (with exceptions)
 Investigation compound (under IND from a company)
See decision tree
IND Exemptions for lawfully marketed
drugs
21 CFR 312.2(b)(1)
 Not intended to be reported to FDA as a wellcontrolled study in support of a new indication
 Not
intended to support a significant change in the
advertising/labeling for the product
 Does
not involve a route of administration or dosage
level or use in a patient population or other factor
that significantly increases the risks (or decreases the
acceptability of the risks) of the drug product
IND Exemptions for lawfully marketed
drugs
21 CFR 312.2(b)(1)
(continued)
 Conducted
in compliance with the requirements for
institutional review
 As per part 56 and requirements for informed
consent in part 50
 Conducted
in compliance with requirements of Sec.
312.7 (i.e., not promoting or charging for
investigational drugs )
IND Exemption Review Process: The
UCD Cancer Center
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Investigator reviews requirements for exemption per 21
CFR 312.2(b)(1)
Guidance for Industry IND Exemptions for Studies of Lawfully
Marketed Drugs or Biological Products for the Treatment of
Cancer
Clinical Trials Navigator (or designee) confirms that each
requirement for exemption is addressed
Exemption items reviewed with study team at Site
Initiation Visit
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Consensus obtained
Memorandum on UCD letterhead [Investigator and CoInvestigator sign off]
See Examples
Overview of IND Process for
academics
FDA will respond
with the date
FDA will send
meeting minutes and
recommendations
30 days
14 days
60 days
Request
pre-IND mtg
Pre-IND mtg
Pre-IND
materials due
4 weeks prior
Prepare and
submit IND
Overview of IND Process for
academics
IND effective date
1 year date
60 days
30 days
Prepare and
submit IND
Annual Report Due
Protocol Amendments
Information Amendments
IND Safety Reports
Withdrawal of IND/ Inactive Status
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21 CFR 312.38
Sponsor may withdraw IND
at any time w/o prejudice
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Notify FDA of the reasons
End clinical investigations
All drug stock disposed of or
returned to the drug
manufacturer
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21 CFR 312.45
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On clinical hold for > 1 year
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No subjects enrolled for >2 years
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FDA will notify the sponsor – needs
response within 30 days
To reopen – sponsor must submit a
protocol amendment – wait for 30
days
Terminated after 5 years in inactive
status
Termination by the FDA
21 CFR 312.44
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FDA proposes termination giving opportunity to respond
Clinical investigations are being conducted in a manner
substantially different than that described in the
protocols submitted in the IND.
Drug is being promoted or distributed for commercial
purposes not justified by the requirements of the
investigation or permitted by §312.7.
Termination by the FDA (continued)
21 CFR 312.44
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IND, or any amendment or report to the IND, contains an
untrue statement of a material fact or omits material
information required by this part.
!Sponsor fails promptly to investigate and inform the
FDA and all investigators of serious and unexpected
adverse experiences
!Sponsor fails to submit an accurate annual report
General Responsibilities under IND
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21 CFR 312 Subpart D
Collect Investigator CVs
Ensure Investigators have current protocol version
Aware of any adverse events associated with the drug
Control of drug under investigation
FDA Form 1572 – ensure investigation is conducted
according to signed Statement of the Investigator
IRB approvals – Informed Consent for each subject
Protect RIGHTS, SAFETY, and WELFARE of subject
Cancer Center: Clinical Trials Support
Unit (CTSU)
12 Clinical Research Coordinators
 3 Oncology Clinical Nurses
 5 Regulatory Coordinators
 2 Database Administrators
 Clinical Trials Navigator
 Clinical Trials search website
http://ccresources.ucdmc.ucdavis.edu/csr/
content/clinicaltrialspublicsearch.csr
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Protocol Development
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Cancer Therapy Evaluation Program (CTEP) – National
Program for Cancer Research
Suggested Templates [Phase I, II, III]
http://ctep.cancer.gov/protocolDevelopment/templates_appli
cations.htm#policiesAndGuidelines
See Handout – Detailed Table of Contents
Protocol Development –Table of
Contents
SCHEMA
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1. OBJECTIVES
2. BACKGROUND
3. PATIENT SELECTION
4. REGISTRATION PROCEDURES
5. TREATMENT PLAN
6. DOSING DELAYS/DOSE MODIFICATIONS
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS
8. PHARMACEUTICAL INFORMATION
9. CORRELATIVE/SPECIAL STUDIES
10.STUDY CALENDAR
11.MEASUREMENT OF EFFECT
12.DATA REPORTING / REGULATORY CONSIDERATIONS
13.STATISTICAL CONSIDERATIONS
REFERENCES
INFORMED CONSENT TEMPLATE
APPENDICES
Protocol Initiation Meeting aka “Site
Initiation Visit”
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Subjects may not be enrolled onto a new study until a protocol
initiation meeting has taken place
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Completion of the Study Initiation Checklist and the Site Signature
and Responsibility Log
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The completed checklist and log filed in the study regulatory files

As study personnel change, the Regulatory Coordinator will update
the Site Signature and Responsibility Log to reflect these personnel
changes
Protocol Initiation Meeting aka “Site Initiation
Visit”

Members of the research team attend a study-specific
initiation meeting within four weeks of study activation or
before enrolling the first subject.
 [Clinical Research Coordinator (CRC), Regulatory
Coordinator, study nurse, Principal Investigator (PI)],
attendees from the Investigational Drug Service and the
Cancer Center Pharmacy, and other interested parties

If the PI is unavailable, he/she may appoint another study
investigator to attend on his/her behalf.
Protocol Initiation Meeting
aka “Site Initiation Visit”

At a minimum, study-specific initiation meetings will include a review
of:
 research team member responsibilities
 eligibility criteria
 treatment schedule
 pretreatment procedures
 AE reporting requirements
 pending revisions/modification/amendments
 study agents to be ordered
 study-specific supplies to be ordered
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The completed Study Initiation Checklist and the signed Site Signature
and Responsibility Log will serve as documentation that the initiation
meeting occurred.
Investigator-Initiated Study-Specific
Meetings
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For investigator-initiated studies, the PI and the CRC meet monthly,
at a minimum, to discuss the status of the study.
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If study involves dose escalation, the dose limiting toxicity (DLT) status of
the current cohort of subjects is discussed.
Based on these subjects, the PI will decide whether or not to escalate the
dose level.
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The CRC assigned to the study creates minutes for all studyrelated meetings with the PI.
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If study involves dose escalation, the CRC assigned to the study
will complete the Dose Escalation Minutes form.
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This is filed in the study’s regulatory file, and one copy will be submitted
to the Phase I Committee coordinator.
Post Study on
http://www.ClinicalTrials.gov
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Must register study within 21 days of 1st patient
enrollment
Using Protocol Registration System (PRS)
http://prsinfo.ClinicalTrials.gov – set up
organization account
Denise Owensby – PRS Administrator – for account
set up
Can modify study information
See Handout
The end
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Thank you for your attention.
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Questions? Clarification?