1. 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

2. 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 (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

4. 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

5. 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?

6. Biologics Control Act
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

7. Food and Drug Act
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.

8. 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.

9. 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.

10. 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)

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

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

13. 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
to my knowledge, a waiver has never been granted by CBER

14. 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

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

16. 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)

17. 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

18. What are the phases of an investigation?
Sponsor Perspective
Marketing
Preclinical
Phase Phase 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

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

20. What are the phases of an investigation?
FDA Perspective
Marketing
Preclinical
Phase Phase 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

21. 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

22. 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)

23. 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
to my knowledge, a waiver has never been granted by CBER

24. IND Checklist  Form FDA 1571 21 CFR 312.23(a)(1) Table of Contents
Introductory statement and general investigational plan
21 CFR (a)(3)
Investigator’s brochure
21 CFR (a)(5)
Protocols
21 CFR (a)(6)
Chemistry, manufacturing, and control data
21 CFR (a)(7)
Pharmacology and toxicology data
21 CFR (a)(8)
Previous human experience
21 CFR (a)(9)
Additional information
21 CFR (a)(10)

26. 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.

27. IND Checklist   Form FDA 1571 21 CFR 312.23(a)(1) Table of Contents
Introductory statement and general investigational plan
21 CFR (a)(3)
Investigator’s brochure
21 CFR (a)(5)
Protocols
21 CFR (a)(6)
Chemistry, manufacturing, and control data
21 CFR (a)(7)
Pharmacology and toxicology data
21 CFR (a)(8)
Previous human experience
21 CFR (a)(9)
Additional information
21 CFR (a)(10)

28. 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.

29. IND Checklist   Form FDA 1571 21 CFR 312.23(a)(1) Table of Contents
Introductory statement and general investigational plan
21 CFR (a)(3) 
Investigator’s brochure
21 CFR (a)(5)
Protocols
21 CFR (a)(6)
Chemistry, manufacturing, and control data
21 CFR (a)(7)
Pharmacology and toxicology data
21 CFR (a)(8)
Previous human experience
21 CFR (a)(9)
Additional information
21 CFR (a)(10)

30. 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.

31. IND Checklist   Form FDA 1571 21 CFR 312.23(a)(1) Table of Contents
Introductory statement and general investigational plan
21 CFR (a)(3)
Investigator’s brochure
21 CFR (a)(5) 
Protocols
21 CFR (a)(6)
Chemistry, manufacturing, and control data
21 CFR (a)(7)
Pharmacology and toxicology data
21 CFR (a)(8)
Previous human experience
21 CFR (a)(9)
Additional information
21 CFR (a)(10)

32. 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.

33. IND Checklist   Form FDA 1571 21 CFR 312.23(a)(1) Table of Contents
Introductory statement and general investigational plan
21 CFR (a)(3)
Investigator’s brochure
21 CFR (a)(5)
Protocols
21 CFR (a)(6) 
Chemistry, manufacturing, and control data
21 CFR (a)(7)
Pharmacology and toxicology data
21 CFR (a)(8)
Previous human experience
21 CFR (a)(9)
Additional information
21 CFR (a)(10)

34. 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

35. IND Checklist   Form FDA 1571 21 CFR 312.23(a)(1) Table of Contents
Introductory statement and general investigational plan
21 CFR (a)(3)
Investigator’s brochure
21 CFR (a)(5)
Protocols
21 CFR (a)(6)
Chemistry, manufacturing, and control data
21 CFR (a)(7) 
Pharmacology and toxicology data
21 CFR (a)(8)
Previous human experience
21 CFR (a)(9)
Additional information
21 CFR (a)(10)

36. 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

37. IND Checklist   Form FDA 1571 21 CFR 312.23(a)(1) Table of Contents
Introductory statement and general investigational plan
21 CFR (a)(3)
Investigator’s brochure
21 CFR (a)(5)
Protocols
21 CFR (a)(6)
Chemistry, manufacturing, and control data
21 CFR (a)(7)
Pharmacology and toxicology data
21 CFR (a)(8) 
Previous human experience
21 CFR (a)(9)
Additional information
21 CFR (a)(10)

38. 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

39. 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

40. 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

41. 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

42. 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

43. 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
to my knowledge, a waiver has never been granted by CBER

44. 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 (a)]

45. 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

46. 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
to my knowledge, a waiver has never been granted by CBER

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

48. 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.

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

50. 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

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

52. Remember that public perception affects all of us.

53. The End
Any Questions?