What is an IND? Keith Wonnacott, Ph.D. Division of Cellular and Gene Therapies Office of Cellular, Tissue, and Gene Therapies Center for Biologics Evaluation and Research FDA

Basis for Regulation of INDs Statutes: THE LAW --- passed by Congress and signed by the President 42 USC 262 (United States Code) Regulations: details of the law --- written by the Agency and approved by the Executive Branch 21 CFR 312 (Code of Federal Regulations) Guidance: the Agency’s interpretation of the Regulations --- written and approved within the Agency 68 FR 49488 (Federal Register) As is true throughout the federal gov’t, the FDA’s regulatory authority is a three-tiered system. The Statutes are the the Law with a capital L. They are the bills written, debated, and passed by Congress and signed by the President. They tend to be conceptual in nature. For example, it is illegal to market drugs that are adulterated. The Regulations are the fleshed out details of the statutes. They are written by the relevant agency and approved by the Executive Branch. The Regulations give a clearer picture of what one must do to be in compliance with the law. For example, drugs must be manufactured in an appropriately controlled environment or they may be considered adulterated. The Regulations carry the weight of law. As such they MUST be obeyed by the Agency and the public, alike. Guidance Documents are somewhat different. These are the Agency’s interpretation of how the Regulations apply to specific types of products. For example, harvested pharmaceutical-plants should be stored in a manner that does not increase the level contaminants. If there is a justifiable reason to deviate from the recommendations in a guidance document, one can propose the alternative procedure to the Agency. This talk will focus first on the statutory history of INDs and then outline the current regulations for INDs Title Chapter Subchapter Part Subpart Section

The following is a very brief history of the statutory basis for INDs Drug and Biologics Law The following is a very brief history of the statutory basis for INDs

In the wild west days of pharmaceutical development there were no rules. Manufacturers could put anything they wanted into a bottle and make any claim they wished about what their substance could do. So, when did we start requiring that drugs be shown to be safe and effective?

Biologics Control Act 1901 13 children in St. Louis died of tetanus after receiving diphtheria antitoxin from a horse named Jim. 9 children die of tetanus from contaminated smallpox vaccine 1902 Biologics Control Act authorizes Hygienic Laboratory to issue regulations to ensure purity and safety of serums, vaccines, and similar products The first attempts to regulate were in response to a contamination of diphtheria toxin as you have already heard about. 1944 PHS Act incorporates provisions for biologics regulation. Outlines licensing requirements that are independent from pre-marketing requirements for drugs. 1973 Blood, blood products, and allergenics included in the PHS Act

Food and Drug Act 1905 Samuel Hopkins Adams published “The Great American Fraud,” a commentary on the patent medicine industry exposing cure-all claims for worthless and dangerous patent medicines. Upton Sinclair publishes “The Jungle” with shocking disclosures of insanitary conditions in meat-packing plants. 1906 Food and Drug Act prohibits interstate commerce in misbranded and adulterated foods, drinks, and drugs. We then moved on to prevent false advertising, but this was extremely difficult to enforce since the burden of proof was on us to show that the manufacturer INTENDED to defraud the purchaser.

Food, Drug, and Cosmetic Act 1937 Sulfanilimide elixir containing diethylene glycol kills 107 people Food, Drug, and Cosmetic Act required new drugs to be shown safe before marketing — starting a new system of drug regulation. It also authorized factory inspections and other provisions. Burden of safety shifted to manufacturer. So now manufacturers had to do investigational studies to prove safety before they could receive a license. But we still did not regulate these investigational studies.

Kefauver-Harris Amendments 1962 Thalidomide, a new sleeping pill, is found to have caused birth defects in thousands of babies born in western Europe. Over two million pills distributed in the United States for investigational studies. 1962 Kefauver-Harris Drug Amendments passed to ensure drug efficacy and greater drug safety. It required drug manufacturers to prove the effectiveness of their products before marketing them, gave FDA control over drug advertising, and allowed FDA to regulate investigational studies. Finally, in 1962 the law was amended to ensure that both safety and efficacy would be proven before licensure. In addition, the law was amended to give FDA over investigational studies. Interestingly, Thalidomide was approved in 1998 to treat the symptoms of leprosy and it is also being studied in a number of other indications.

Summary A new biologic, drug, or device may not be entered into interstate commerce unless: It is approved by the FDA as safe and effective (biological license application [BLA], new drug application [NDA], pre-market approval [PMA], or other marketing approval) OR … An IND is in effect (exempting the study from the premarketing approval requirements that are otherwise applicable)

OR… Just ditch the claim and call it a dietary supplement

Where do I find IND requirements? 21 CFR 312 Investigational New Drug Application

PART 312 – INVESTIGATIONAL NEW DRUG APPLICATIONS Subpart A – General provisions Subpart B – IND application Subpart C – Administrative action Subpart D – Responsibilities of sponsors and investigators Subpart E – Drugs intended to treat life-threatening and severely debilitating illnesses Subpart F – Miscellaneous Subpart G – Drugs for investigational use in laboratory research animals or in vitro tests 312.6 – package must be labeled for investigational use 312.10 - to my knowledge, a waiver has never been granted by CBER

PART 312 – INVESTIGATIONAL NEW DRUG APPLICATIONS Subpart A – General provisions Subpart B – IND application Subpart C – Administrative action Subpart D – Responsibilities of sponsors and investigators Subpart E – Drugs intended to treat life-threatening and severely debilitating illnesses Subpart F – Miscellaneous Subpart G – Drugs for investigational use in laboratory research animals or in vitro tests

When do I need an IND? Anytime you are doing a clinical investigation with a drug or biologic EXCEPT…

EXCEPT… If your study is: An in vitro diagnostics used to confirm the results of an approved test A study in animals A placebo study not otherwise requiring an IND (not involving a drug or biologic)

EXCEPT… If you are using an FDA approved product AND your study: Is not intended to support a labeling or advertising change Is administered so as not to increase the safety risk to the patients Has institutional review board (IRB) approval Follows the rules on charging for investigational drugs

What are the phases of an investigation? Sponsor Perspective Marketing Preclinical Phase 1 Phase 2 Phase 3 Phase 4 Proof of concept, safety, potential toxicity, dosing strategy Post marketing commitments to monitor safety and efficacy Evaluate safety and side effects Evaluate safety and explore efficacy and dose ranging Obtain efficacy and safety data for approval IND filing BLA filing

What are the phases of an investigation? Investigator Perspective Publication Preclinical Phase 1 Proof of concept Extend proof of concept to human IND filing

What are the phases of an investigation? FDA Perspective Marketing Preclinical Phase 1 Phase 2 Phase 3 Phase 4 IND review (30 days) BLA review (6/10 months) Pre-IND Meeting End of Phase 2 Meeting Pre-BLA Meeting Amendment Review CONSULTATION

How do I label an investigational drug? “Caution: New Drug – Limited by Federal law to investigational use.” No false or misleading claims No statement that the drug is safe or effective for the indication for which it is being investigated

Can I promote or charge for my investigational drug? No promoting drug as safe or effective No commercial distribution No charging without the consent of the FDA For clinical trials, FDA must give written consent after sponsor provides a full written explanation of why charging is necessary and not part of the normal cost of doing business 21 CFR 312.7(d)

PART 312 – INVESTIGATIONAL NEW DRUG APPLICATIONS Subpart A – General provisions Subpart B – IND application Subpart C – Administrative action Subpart D – Responsibilities of sponsors and investigators Subpart E – Drugs intended to treat life-threatening and severely debilitating illnesses Subpart F – Miscellaneous Subpart G – Drugs for investigational use in laboratory research animals or in vitro tests 312.6 – package must be labeled for investigational use 312.10 - to my knowledge, a waiver has never been granted by CBER

IND Checklist  Form FDA 1571 21 CFR 312.23(a)(1) Table of Contents 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) Chemistry, manufacturing, and control data 21 CFR 312.23(a)(7) Pharmacology and toxicology data 21 CFR 312.23(a)(8) Previous human experience 21 CFR 312.23(a)(9) Additional information 21 CFR 312.23(a)(10)

Just as a reminder, this is not a grant application Just as a reminder, this is not a grant application. Not only is the application form different—the content required is substantially different as well.

IND Checklist   Form FDA 1571 21 CFR 312.23(a)(1) Table of Contents 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) Chemistry, manufacturing, and control data 21 CFR 312.23(a)(7) Pharmacology and toxicology data 21 CFR 312.23(a)(8) Previous human experience 21 CFR 312.23(a)(9) Additional information 21 CFR 312.23(a)(10)

Introductory Statement/ General Investigational Plan Description of the drug Summary of previous human experience Overall plan for investigating the drug Next the submission should include an introductory statement and general investigational plan. This section should contain a description of the drug, a brief summary of previous human experience with the drug if applicable and a brief description of the plan for investigation of the drug for the following year.

IND Checklist   Form FDA 1571 21 CFR 312.23(a)(1) Table of Contents 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) Chemistry, manufacturing, and control data 21 CFR 312.23(a)(7) Pharmacology and toxicology data 21 CFR 312.23(a)(8) Previous human experience 21 CFR 312.23(a)(9) Additional information 21 CFR 312.23(a)(10)

Investigator’s Brochure An investigators brochure contains information and instructions for investigators so that they can properly perform the study. It is required if a commercial sponsor product is providing product to clinical investigators It is not required for sponsor-investigators performing a trial at one clinical site The next section is the Investigator’s Brochure. This is required if the product will be supplied to clinical investigators other than the sponsor. It should contain a description of the biologic, a summary of preclinical pharmacologic and toxicologic findings as well as the pharmacokinetic and biologic disposition of the product, a summary of safety and effectiveness in humans from prior studies if available and a description of possible risks and precautionary measures that should be taken.

IND Checklist   Form FDA 1571 21 CFR 312.23(a)(1) Table of Contents 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) Chemistry, manufacturing, and control data 21 CFR 312.23(a)(7) Pharmacology and toxicology data 21 CFR 312.23(a)(8) Previous human experience 21 CFR 312.23(a)(9) Additional information 21 CFR 312.23(a)(10)

Protocols Protocol for each planned study including: Statement of objectives and purpose of study Estimated enrollment Inclusion & exclusion criteria Dosing plan (dose, duration, route) Plan for patient monitoring Toxicity based stopping/dose adjustment rules Investigator data (Form FDA 1572) Next, a section containing a protocol for each planned study should be included. The protocol should contain a statement of the objectives and purpose of the study, it should specify the inclusion and exclusion criteria as well as the doses to be administered. A description of the clinical measurements to be used to monitor effects of the biologic should be provided as well as information on the qualifications of investigators participating in the study.

IND Checklist   Form FDA 1571 21 CFR 312.23(a)(1) Table of Contents 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)  Chemistry, manufacturing, and control data 21 CFR 312.23(a)(7) Pharmacology and toxicology data 21 CFR 312.23(a)(8) Previous human experience 21 CFR 312.23(a)(9) Additional information 21 CFR 312.23(a)(10)

Product Information (CMC) Physical, chemical, and/or biological characteristics Manufacturers Source and method of preparation Removal of toxic reagents Quality controls (e.g., identity, assay, purity, impurities profile) Description of testing and acceptable limits Sterility (aseptic processing or sterilization process, sterility and endotoxin testing, etc.) Linkage of pharmacological and/or toxicity batches to clinical trial batches Stability information

IND Checklist   Form FDA 1571 21 CFR 312.23(a)(1) Table of Contents 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) Chemistry, manufacturing, and control data 21 CFR 312.23(a)(7)  Pharmacology and toxicology data 21 CFR 312.23(a)(8) Previous human experience 21 CFR 312.23(a)(9) Additional information 21 CFR 312.23(a)(10)

Pharmacology and Toxicology Data Data for studies demonstrating Safety Efficacy Potential toxicities Optimal dosing Identification and qualifications of study evaluators Statement regarding where and how (GLP) studies were performed

IND Checklist   Form FDA 1571 21 CFR 312.23(a)(1) Table of Contents 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) Chemistry, manufacturing, and control data 21 CFR 312.23(a)(7) Pharmacology and toxicology data 21 CFR 312.23(a)(8)  Previous human experience 21 CFR 312.23(a)(9) Additional information 21 CFR 312.23(a)(10)

Previous Human Experience/ Additional Information Previous human experience is only required when it is relevant It should be presented as a summary report Additional information may be submitted if the sponsor feels it is necessary

How do I make changes to my IND? Send an amendment Amendment = Any document, from the sponsor, in support of their IND An amendment can be made at any time during the life of the IND

Types of Amendments Protocol Amendments Safety reports Annual reports New protocol, Protocol changes, New investigator Safety reports Serious and unexpected clinical adverse event or laboratory finding affecting safety SAE within 15 days, life-threatening within 7 days Annual reports A summary report on progress, findings, changes and future plans Must be submitted within 60 days of anniversary Information Amendments Everything else

Can I treat patients who don’t qualify for my study? YES, under… A treatment protocol or IND Allows access to investigational drugs Can be for a single patient who doesn’t qualify for existing protocol

A treatment protocol or IND is only allowed if: Serious or immediately life-threatening disease No comparable or alternative therapy Actively pursuing market approval Treatment use may begin 30 days after FDA receives protocol

PART 312 – INVESTIGATIONAL NEW DRUG APPLICATIONS Subpart A – General provisions Subpart B – IND application Subpart C – Administrative action Subpart D – Responsibilities of sponsors and investigators Subpart E – Drugs intended to treat life-threatening and severely debilitating illnesses Subpart F – Miscellaneous Subpart G – Drugs for investigational use in laboratory research animals or in vitro tests 312.6 – package must be labeled for investigational use 312.10 - to my knowledge, a waiver has never been granted by CBER

What is the objective of regulatory actions? 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(a)]

Administrative Status and Actions Exempt – Study does not have to be conducted under IND Pending – IND is in initial 30-day review period In Effect – Study may proceed Hold – FDA orders sponsor to delay or suspend a clinical investigation Partial Hold – A delay or suspension of part of the clinical investigation Inactivated – IND is subject to no activity, but may be reactivated Withdrawal – Sponsor requests to end IND, IND cannot be reactivated Terminated – FDA orders sponsor to end all clinical investigation, IND cannot be reactivated

PART 312 – INVESTIGATIONAL NEW DRUG APPLICATIONS Subpart A – General provisions Subpart B – IND application Subpart C – Administrative action Subpart D – Responsibilities of sponsors and investigators Subpart E – Drugs intended to treat life-threatening and severely debilitating illnesses Subpart F – Miscellaneous Subpart G – Drugs for investigational use in laboratory research animals or in vitro tests 312.6 – package must be labeled for investigational use 312.10 - to my knowledge, a waiver has never been granted by CBER

Responsibilities of Sponsors Select qualified investigators Provide investigators information needed to properly conduct the study (Investigator Brochure) Ensure proper study monitoring

Responsibilities of Sponsors Ensure the study is in accordance with the general investigational plan Maintain an effective IND Ensure that FDA and all participating investigators are promptly informed of significant new adverse effects or risks.

Responsibilities of Investigators FOLLOW THE PROTOCOL! Control of the drug Keep and retain accurate records Fill out appropriate reports Ensure IRB protocol review

Responsibilities of Institutional Review Boards [21 CFR 56] Review and approve all research studies involving humans within an institution Be composed of at least 5 diverse members at least one scientific member and one non-scientific member at least one member not otherwise affiliated with the institution Assure that: risks to subjects are minimized and reasonable selection of subjects is equitable informed consent will be sought and adequately documented

General Tips Educate yourself Communicate with the FDA Create reviewer-friendly submissions Start solving the problems early: plan ahead Keep good records

Remember that public perception affects all of us.

The End Any Questions?