A Translational Innovation Forum

IND Process and General IND Process and General Responsibilities under Responsibilities under INDIND

August 27, 2010August 27, 2010

Kate Marusina, PhD, MBAKate Marusina, PhD, MBAPav Aujla, MS, CCRP, RACPav Aujla, MS, CCRP, RACPrimo N. Lara, Jr. MDPrimo N. Lara, Jr. MD

A Translational Innovation Forum

Agenda

Definition of Drug and other helpful definitions 21 CFR 312

What is Regulatory Sponsor? Overview of IND process General Responsibilities under IND

Agenda

University of California Davis Cancer Center – Clinical Trials Support Unit (CTSU) Best Practices for: IND Exemptions: Consultative Process Protocol Development Protocol Initiation Meeting Post Study on http://www.clinicaltrials.gov

Key Compliance Documents

Good Laboratory Practices (GLPs) for non-clinical studies 21 CFR 58

Good Manufacturing Practices 21 CFR 210, 211 Comprehensive regulations to assure the

identity, strength and purity

Key Compliance Documents

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?

“ 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?

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

New Molecular entity A pharmacologically active moiety which is

not been studied or used clinically in man or is not approved for such use

Drug Substance (API) Pharmacologically active Subsequently formulated with excipients to

produce the drug product Drug Product

Finished product in certain dosage form (capsule, tablet, injection)

Types of IND applications

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

What is “Regulatory Sponsor”? New Full Committee Clinical Application Form Financial Sponsor:

Private Co, Foundation, Feds, individual donations, PI’s Ed fund, Department

Regulatory Sponsor Who prepared the protocol Is the study exempt?

If the study is initiated by a UC Davis Principal Investigator and the study is NOT exempt:

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).

FDA Form 1572 is attached (required for regulatory sponsor-investigators)

Types of IND applications

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

Emergency IND (Compassionate Use) 21 CFR 312.36

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 follow-up Informed Consent required Company required to follow up

Treatment IND 21 CFR 312.34 and .35

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

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.)

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?

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 well-

controlled 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 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 Consensus obtained

Memorandum on UCD letterhead [Investigator and Co-Investigator sign off]

See Examples

Overview of IND Process for academics

Request pre-IND mtg

FDA will respond with the date

60 days

14 days

Pre-IND mtg

FDA will send meeting minutes and recommendations

30 days

Prepare and submit IND

Pre-IND materials due4 weeks prior

Overview of IND Process for academics

IND effective date

30 days

Annual Report Due

1 year date

Prepare and submit IND

60 days

Protocol AmendmentsInformation AmendmentsIND Safety Reports

Withdrawal of IND/ Inactive Status

21 CFR 312.38 Sponsor may

withdraw IND at any time w/o prejudice Notify FDA of the

reasons End clinical

investigations All drug stock disposed

of or returned to the drug manufacturer

21 CFR 312.45 On clinical hold for > 1 year No subjects enrolled for >2

years 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 FDA21 CFR 312.44

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

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 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 websitehttp://ccresources.ucdmc.ucdavis.edu/csr/content/clinicaltrialspublicsearch.csr

Protocol Development

Cancer Therapy Evaluation Program (CTEP) – National Program for Cancer Research

Suggested Templates [Phase I, II, III]

http://ctep.cancer.gov/protocolDevelopment/templates_applications.htm#policiesAndGuidelines

See Handout – Detailed Table of Contents

Protocol Development –Table of Contents

SCHEMA 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”

Subjects may not be enrolled onto a new study until a protocol initiation meeting has taken place

Completion of the Study Initiation Checklist and the Site Signature and Responsibility Log

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

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.


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

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

For investigator-initiated studies, the PI and the CRC meet monthly, at a minimum, to discuss the status of the study.

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.

The CRC assigned to the study creates minutes for all study-related meetings with the PI.

If study involves dose escalation, the CRC assigned to the study will complete the Dose Escalation Minutes form.

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 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

Thank you for your attention.

Questions? Clarification?