Food and Drug AdministrationCenter for Biologics Evaluation and Research

The Office of Cellular, Tissue, and Gene Therapies Web Seminar Series

presents:

The Office of Cellular, Tissue, and Gene Therapies Web Seminar Series

presents:

IND Basics in OCTGT

Patrick Riggins, Ph.D.

Branch Chief

Regulatory Management Staff

Overview

• Regulatory Framework

• What is an IND?

• Who can hold an IND?

• What should an IND contain?

• How is an IND reviewed?

• Are there different types of INDs?

• Where can I get more information?

FDA Mission Statement

The FDA is responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation’s food supply, cosmetics, and products that emit radiation.

The FDA is also responsible for advancing the public health by helping to speed innovations that make medicines and foods more effective, safer, and more affordable; and helping the public get the accurate, science-based information they need to use medicines and foods to improve their health

Regulatory Framework

• Federal regulatory authority is a 3-tiered system• Statutes (Laws)

– Passed by Congress and signed into law by the President• Food, Drug & Cosmetic Act, Public Health Service Act

• Regulations (full force of Law)– Promulgated by the Agency

• IND Regulations 21 CFR 312• IRB and Consent Regulations 21 CFR 50 and 56• Good Laboratory Practice 21 CFR 58• Human Cells, Tissues, and Cellular and Tissue Based Products

21 CFR 1271

• Guidance Documents (Not legally binding)– Provides Agency’s current thinking on specific issues

FDA Regulation of Clinical Research

• FDA regulates clinical research in the US that involves drugs, biological products, and medical devices regardless of funding source

• Clinical investigations with an unapproved drug must be conducted under an IND

What is an IND?

• Investigational New Drug Application– A formal submission with defined structure and

content– Provides an exemption from restrictions on

interstate commerce of shipment of an unapproved new drug

• 21 USC 355

– 21 CFR 312 outlines requirements• § 312.23 IND Content and Format• § 312.42 Clinical Holds• § 312.50 – 312.69 Responsibilities of Sponsors /

Investigators

Who Can Apply for an IND?

• IND applicant is called: “Sponsor”– Person/Organization who takes responsibility for

and initiates a clinical investigation

• IND Sponsor may be a company, institution, or individual

• Investigator conducts the clinical study• Sponsor-Investigator both initiates and

conducts the clinical investigation– Must be an individual

Responsibilities of IND Sponsors

– 21 CFR 312.50-312.59

• Select qualified investigators• Providing Investigators with needed information• Ensure study conducted in accordance with

Investigational Plan• Ensure investigation is properly monitored• Promptly report adverse events and new risks to

FDA and all investigators• Maintain adequate records

Responsibilities of Investigators

– 21 CFR 312.60-312.69

• Perform investigation consistent with protocols

• Ensure safety and welfare of subjects under care

• Obtain IRB approval for investigations

• Promptly report any adverse events to Sponsor

• Maintain adequate records

Life Cycle of an IND

• IND is a “living document”

• Sponsor updates over time to include protocol amendments, study data, safety reports, manufacturing changes, preclinical reports, annual reports…

• What is the basic process of an IND?

IND Submission Process

• Step 1: Pre-IND teleconference with OCTGT– Highly recommended for new products– See the Webinar pertaining to meetings

• Step 2: Submission of complete IND package– All forms, all sections

• Step 3: IND Review– FDA will notify Sponsor within 30 calendar days of receipt

of the IND whether the study may proceed or is placed on clinical hold

• Studies may not begin until 30 day review is complete or FDA notifies Sponsor studies may proceed

Elements of an IND Application

• Form FDA 1571 21 CFR 312.23(a)(1)• Table of Contents 21 CFR 312.23(a)(2)• Introductory statement and general

investigational plan 21 CFR 312.23(a)(3)• Investigator’s Brochure 21 CFR 312.23(a)(5)• Protocols 21 CFR 312.23(a)(6)• Product/CMC information 21 CFR 312.23(a)(7)• Pharmacology/Toxicology information 21 CFR 312.23(a)(8)• Previous human experience 21 CFR 312.23(a)(9)• Additional Information 21 CFR 312.23(a)(10)

Form FDA-1571

• Cover sheet containing information about the Sponsor and submission components

• Required for original submission• Recommended but not required for

amendments

– Available at: http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/default.htm

Chemistry, Manufacturing and Controls

• CMC = Product Manufacturing and Testing Info

• Details of product manufacturing

• Product safety and quality testing

• Product stability and shelf life

• Container, label, and tracking information

• Can cross reference prior INDs or Master Files

Letter of Cross-Reference

• Gives Sponsor benefit of information previously submitted to the Agency in another file while maintaining confidentiality of the data

• INDs on clinical hold, inactive, or withdrawn cannot be cross-referenced

Preclinical Information

• Scientific basis for conducting the clinical study

• Data from animal or in vitro studies to establish an initial safe dose in humans

• Proof of concept animal models, if appropriate

• Toxicology studies in relevant animal model

• Complete study reports to be submitted

Clinical Information

• Protocols– Starting dose and dose escalation schemes– Route of administration– Dosing schedules– Definition of patient population

• Detailed entry and exclusion criteria– Safety monitoring plans

• Study stopping rules• 21 CFR 312.32

– Statement of the desired endpoints and objectives– Statement of the phase of the investigation

• Form FDA 1572

Phases of Investigation– 21 CFR 312.21

• Phase 1– Designed to predominantly evaluate safety– Limited number of subjects

• Phase 2– Preliminary efficacy studies and dose ranging

• Phase 3– Confirmatory efficacy studies intended to

provided statistical evidence of effectiveness– Much larger number of subjects

• Primary concern in all phases is SAFETY

Form FDA-1572

• Sponsor is required to obtain a signed 1572 from each investigator (§ 312.53(c)) and

• Submission of the name and qualifications of each investigator to the IND is required (§ 312.23(a)(iii)(b)

• However, submission of Form 1572 is not required• But for ease of submission, many Sponsors choose

to submit the 1572

– Available at:

http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/default.htm

Investigator’s Brochure

• Not required of Sponsor-Investigators• Brief description of the product• Summary of pharmacological and toxicological

effects of the product in animals and if known in humans

• Summary of pharmacokinetics, if known• Summary of any safety information from prior

clinical studies• Description of anticipated risks based on prior

human experience with this or related products

• Plans for pediatric assessment (§ 312.23(10)(iii))

• Form FDA 3674 - Certification of Compliance with Requirements of ClinicalTrials.gov Data Bank

(42 USC 282(j))– MUST be included with EVERY submission to the IND

http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/default.htm

• Must submit 3 copies of any submission to the IND– 21 CFR 312.23(d)

Additional Information

IND Status

• Pending – within the initial 30 day review period• Active – Study may proceed• Hold – An order issued by FDA to delay a proposed

clinical investigation or suspend an ongoing investigation– 21 CFR 312.42

• Partial Hold – A delay or suspension of part of the clinical work under an IND– e.g. IND with 2 protocols where 1 can proceed and 1 is on

clinical hold

Grounds for Clinical Hold Phase 1 Study

• Subjects are or would be exposed to an unreasonable and significant risk

• Insufficient information to assess risk to subjects

• Clinical investigators are not qualified

• Investigator’s Brochure is misleading, erroneous, or materially incomplete

Additional Grounds for Clinical Hold Phase 2/3 Study

• Each of the reasons identified for phase 1 studies

• The plan or protocol is clearly deficient in design to meet its stated objectives

• Additional reasons for clinical hold can be found in 21 CFR 312.42

• FDA’s primary objectives in reviewing an IND are, in all phases of the investigation, to assure the safety and rights of subjects

• And in phase 2 and 3 to help assure that the quality of the scientific evaluation of drugs is adequate to permit an evaluation of the drug’s effectiveness and safety– 21 CFR 312.22

Objective of FDA Review

IND Review Process

• A Team Approach to IND Review– Regulatory Project Manager

– Product/CMC reviewer

– Pharmacology/Toxicology reviewer

– Clinical Reviewer

– Statistical Reviewer

– Consults as needed• e.g. from CDRH for review of a device component

• Within 30 days the file is Active or On Hold– Outstanding Hold and Non-hold issues conveyed by

phone/email and a detailed letter may be issued

– All hold issues must be satisfactorily resolved in order to proceed

Using email to Communicate

• OCTGT strongly encourages the use of secure email. For detailed instructions on setting up a secure email account, please send an email requesting these instructions to:CBEROCTGTRMS@fda.hhs.gov

• To permit the use of non-secure email, a Sponsor should include a statement in the cover letter of the IND that states the use of non-secure email is authorized and lists the names and emails of those with whom OCTGT may communicate via email

Using email (cont’d)

• OCTGT will only use email in place of telephone calls, to relay regulatory issues, and to request information.

• Documents will not be sent over email and amendments may not be submitted over email.

IND Review Process (cont’d)

• Emphasis of review is on data to support:– Product safety and characterization– Manufacturing and quality control issues– Scientific rationale

• Sound scientific principles– Preclinical studies– Product development– Clinical protocol

How Do I make changes to an IND?

• Send an amendment to the file– Submit three copies– Inclusion of Form 1571 is recommended

• An amendment can be made at any time

• No specific 30 day review period

• Two requirements necessary– Submission to the IND and IRB approval

Types of Amendments

• Protocol Amendments (§ 312.30)– New Protocol, change in protocol, new investigator

• IND Safety Reports (§ 312.32)– Serious and unexpected clinical adverse event or laboratory

finding affecting safety– Fatal or life threatening within 7 days, 15 days for others

• Annual Reports (§ 312.33)– Must be submitted within 60 days of the anniversary of

when IND went into effect– See the regulation for content and format

• Information Amendments (§ 312.31)– All other changes

Are There Different Types of INDs?

• 21 CFR 312 Subpart I – Expanded Access to Investigational Drugs for Treatment Use– § 312.310 Individual patients, including for emergency use– § 312.315 Intermediate-size patient populations– § 312.320 Treatment IND or treatment protocol

• General Requirements § 312.305– Serious or immediately life- threatening with no alternative– Favorable risk-benefit– Use of the investigational drug will not interfere with

investigations to support a marketing application– Appropriate IRB Approval

Expanded Access SubmissionSingle Patient

• 21 CFR 312.3101. Submission plainly marked “EXPANDED ACCESSS

SUBMISSION”

2. Form FDA-1571

3. Rationale for the proposed treatment including why the investigational drug is preferable to alternatives

4. Patient description including medical history and prior treatments

5. Administration method including dose and duration and relevant concomitant medications

6. Description of the facility of manufacture of the drug (or letter of cross-reference)

Expanded Access SubmissionSingle Patient (cont’d)

• 21 CFR 312.310 (cont’d)7. CMC information (or letter of cross-reference)

8. Pharmacology/Toxicology information adequate to conclude that the use of the drug is reasonably safe as proposed (or letter of cross-reference)

9. Description of the clinical procedures laboratory tests, or other monitoring necessary to evaluate the effects of the drug and minimize risks

10. Plan for safety reporting

Expanded Access - Single Patient Emergency Situation

• In the case where an investigator wishes to use an investigational product in a single patient but it is an emergency situation

• An initial formal submission is not necessarily required. Rather the information can initially be submitted by phone, fax, or email

• Must meet § 312.305 and 312.310 and the formal submission must be within 15 working days of the authorization to use the product

Treatment IND or ProtocolWide Use

• 21 CFR 312.320

– Must meet the requirements of § 312.305(a) and 312.305(b)– Drug must be investigated in a controlled clinical trial under

IND to support marketing application for the expanded access use, or

– All clinical trials of the drug are completed, and– A marketing application is being actively pursued for the

expanded access use with due diligence– Sufficient evidence exists generally from phase 3 trials for

the proposed expanded access use

What Have We Learned?

• A basic understanding of the form and content of an IND submission to OCTGT

• An introduction to the regulatory basis of the requirements of an IND

• Information on the required forms: 1571, 1572, 3674• The basics of different types of INDs including single

patient and emergency submissions

• This then leads to a rather important question…

How Do I Submit to OCTGT?

FDA/CBER

Attn: Office of Cellular, Tissue, and Gene Therapies

Document Control Center/HFM-99/Suite 200N

1401 Rockville Pike

Rockville, MD 20852

Fax: 301-827-9796

Phone: 301-827-5102

Email: CBEROCTGTRMS@fda.hhs.gov

Further Resources

• Information about the general processes of OCTGT:– http://www.fda.gov/BiologicsBloodVaccines/

GuidanceComplianceRegulatoryInformation/OtherRecommendationsforManufacturers/ucm094338.htm

• Website regarding CBER IND/IDE process:– http://www.fda.gov/BiologicsBloodVaccines/

DevelopmentApprovalProcess/InvestigationalNewDrugINDorDeviceExemptionIDEProcess/default.htm

• Accompanying Web Seminar Series from OCTGT

Contact Information

• If the webinar series and referenced websites leave you with unanswered questions

CBEROCTGTRMS@fda.hhs.gov or

patrick.riggins@fda.hhs.gov

301-827-5366

THANK YOU