What is an IND

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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

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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 Agencys interpretation of the
  Regulations --- written and approved within the
  Agency
• 68 FR 49488 (Federal Register)

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Drug and Biologics Law

• The following is a very brief history of the
  statutory basis for INDs

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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

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
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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.

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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.

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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.

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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)

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OR
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Where do I find IND requirements?

• 21 CFR 312
• Investigational New Drug Application

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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

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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

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When do I need an IND?

• Anytime you are doing a clinical investigation
  with a drug or biologic
• EXCEPT

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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)

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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

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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
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What are the phases of an investigation?
Investigator Perspective
Publication
Preclinical
Phase 1
Extend proof of concept to human
Proof of concept
IND filing
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What are the phases of an investigation?
FDA Perspective
Marketing
Preclinical
Phase 1 Phase 2 Phase 3
Phase 4
BLA review (6/10 months)
IND review(30 days)
End of Phase 2 Meeting
Pre-IND Meeting
Pre-BLA Meeting
Amendment Review
CONSULTATION
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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

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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)

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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

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IND Checklist
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IND Checklist
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Introductory Statement/ General Investigational
Plan

• Description of the drug
• Summary of previous human experience
• Overall plan for investigating the drug

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IND Checklist
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Investigators 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

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IND Checklist
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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)

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IND Checklist
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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

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IND Checklist
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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

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IND Checklist
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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

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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

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Types of Amendments

• Protocol Amendments
• 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

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Can I treat patients who dont qualify for my
study?

• YES, under
• A treatment protocol or IND
• Allows access to investigational drugs
• Can be for a single patient who doesnt qualify
  for existing protocol

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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

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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

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What is the objective of regulatory actions?

• FDAs 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 drugs effectiveness
  and safety. 21 CFR 312.22(a)

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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

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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

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Responsibilities of Sponsors

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

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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.

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Responsibilities of Investigators

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

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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

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General Tips

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

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The End

• Any Questions?