Patrick Riggins, Ph.D. Branch Chief Regulatory Management Staff Food and Drug Administration Center for Biologics Evaluation and Research 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 C B E R

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 Form FDA 1572 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

Additional Information 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)

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

Objective of FDA Review 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

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 Submission Single Patient 21 CFR 312.310 Submission plainly marked “EXPANDED ACCESSS SUBMISSION” Form FDA-1571 Rationale for the proposed treatment including why the investigational drug is preferable to alternatives Patient description including medical history and prior treatments Administration method including dose and duration and relevant concomitant medications Description of the facility of manufacture of the drug (or letter of cross-reference)

Expanded Access Submission Single Patient (cont’d) 21 CFR 312.310 (cont’d) CMC information (or letter of cross-reference) Pharmacology/Toxicology information adequate to conclude that the use of the drug is reasonably safe as proposed (or letter of cross-reference) Description of the clinical procedures laboratory tests, or other monitoring necessary to evaluate the effects of the drug and minimize risks 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 Protocol Wide 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