The IND Process

1
The IND Process

• David A. Lepay, M.D., Ph.D.
• Senior Advisor for Clinical Science
• Office of the Commissioner, US FDA
• Johns Hopkins Program
• December 10, 2001

2
FDAs Mission

• FDA has a broad public protection mission
• Ensure the safe use of regulated products that
  are themselves safe and efficacious
• Underlying this mission is FDA decision-making on
  product applications and labeling
• Based on complete and accurate information from
  well-designed, ethically-conducted, and
  well-monitored clinical research

3
FDAs Mission in Clinical Research

• Ensure Implementation of Good Clinical Practice
  Standards
• Embodied in FDA regulation and guidance since the
  1960s and 70s
• International Standard (ICH E6) since 1996
• Enforced through FDAs review process and in its
  program of on-site inspections
• U.S. Clinical Investigator inspections from 1962
• Ethics Committee (IRB) inspections from 1978
• International CI inspections from 1980

4
GCP is Comprehensive

• International ethical and scientific quality
  standard for designing, conducting, recording,
  and reporting trials that involve the
  participation of human subjects
• GCP embraces trial objectives, trial design,
  study oversight, data collection and quality
  assurance, study analysis, as well as human
  subject protection in studies that support
  product applications

5
Good Clinical Practice

• GCP is most fundamentally a System of Shared
  Responsibilities
• Clinical Investigators
• Institutions/Institutional Review Boards
• Industry (Sponsors/Monitors)
• Government Regulators

6
FDAs Authority to Regulate

• Federal Food Drug and Cosmetic Act
• Requires that an FDA approved marketing or
  research permit be obtained before certain
  commodities (such as human drugs, medical
  devices, veterinary drugs, food additives, etc.)
  may move across state lines

7
Pharmaceuticals may move across state lines
during two stages of human use

• Research prior to approval
• Requires research permit e.g, Investigational
  New Drug Exemption (IND)
• Marketing after approval
• Requires marketing permit e.g., New Drug
  Application (NDA)

8
What is an IND/IDE ?

• An exemption from the law which otherwise
  requires that a drug (biologic, device) be
  approved before it can be transported across
  state lines
• The standard for approval is evidence of safety
  and efficacy
• The IND exemption is granted for purposes of
  clinical investigation (research)

9
Importance of the IND

• Affirms a body of knowledge about the
  manufacturing, pharmacology, and toxicology of
  the drug to support its use in human testing
• Requires that the clinical investigation(s) be
  performed in accordance with Good Clinical
  Practice (GCP)
• Provides an additional level of protection
  through FDA oversight

10
The FDC Act Defines Drug Very Broadly

• Any of
• Article recognized in the U.S. Pharmacopeia,
  official Homeopathic Pharmacopeia of the US, or
  official National Formulary, or any supplement
• Article intended for use in the diagnosis, cure,
  mitigation, treatment, or prevention of disease
  in man or other animals

11
The FDC Act Defines Drug Very Broadly

• Any of
• Article (other than food) intended to affect the
  structure or any function of the body of man or
  other animals
• Article intended for use as a component of any
  article specified in clauses above
• Section 201(g) of the FDC Act

12
Clinical Investigation is also Defined Broadly

• Any experiment in which a drug is administered or
  dispensed to, or used involving, one or more
  human subjects. For the purposes of this part,
  an experiment is any use of a drug except for the
  use of a marketed drug in the course of medical
  practice
• 21 CFR 312.3

13
So When Is an IND Required ?

• In general An IND is required when an
  unapproved drug (or biologic) is used in a
  clinical investigation

14
What About Approved Products

• No IND is needed when an approved product is used
  in the course of medical practice (even for an
  indication different from the approved
  indication)
• But an IND may be required when an approved
  products is used in a clinical investigation

15
What About Approved Products

• An IND is needed if
• The clinical investigation is intended to be
  reported to FDA as a well-controlled study in
  support of a new indication or a significant
  change in the labeling of the drug
• The clinical investigation is intended to support
  a significant change in advertising for the
  product

16
What About Approved Products

• With the above caveats, clinical investigation of
  an approved product may be exempt from IND
  requirements if
• The investigation does not involve a route of
  administration or dosage level or use in a
  patient population or other factor that
  significantly increases risks AND
• The investigation is conducted in accordance with
  IRB and informed consent requirements

17
What About Approved Products

• FDA has generally allowed the IRB to assess
  whether risk of an approved product is increased
  for a given protocol
• But FDA retains final authority for such
  determinations

18
What About Approved Products

• It is also important to note that shelf chemicals
  which bear the same name as an approved product
  are not considered as lawfully marketed
  equivalents of the approved product
• Approval is specific to dose, formulation, and
  applicant

19
Need for an IND/IDEWho to Contact with Questions

• Drugs (CDER)
• Drug Information Branch [phone]
• Biological Products (CBER)
• [phone]
• Medical Devices (CDRH)
• IDE Staff [phone]
• Food Safety (CFSAN) [phone]

20
Related Information

• GCP Regulations
• IND/IDE Regulations 21 CFR Part 312/812
• IRB Regulations 21 CFR Part 56
• Informed Consent Regs 21 CFR Part 50
• All are accessible at
• www.fda.gov/oc/gcp

21
Related Information

• IND Forms
• Available on-line through
• www.fda.gov/cder/regulatory/applications/

22
IND What is Required -1-

• General Investigation Plan
• Investigators Brochure
• Protocol(s) Later protocols submitted as
  amendments
• Chemistry, manufacturing and control information
• Animal pharmacology and toxicology information

23
IND What is Required -2-

• Previous human experience
• Additional information
• Dependence and abuse potential
• Plans for pediatric studies
• Amount of information required in each section
  depends on novelty of the drug, extent studied,
  and known or suspected safety concerns

24
The FDA Form 1572

• IND sponsors are required to obtain a signed FDA
  Form 1572 from each clinical investigator,
  containing
• Name and address of CI
• Name and code number of any protocol(s)
• Name and address of research facility and any
  clinical labs
• Name and address of responsible IRB
• Names of subinvestigators
• Signed commitment by the investigator

25
Clinical Investigator Responsibilities

• Personally conduct or supervise investigations
• Ensure all persons assisting in conduct of
  studies are informed of their obligations
• Ensure informed consent (21 CFR 50) and IRB
  review, approval , and reporting (21 CFR 56)
  requirements are met

(Form FDA 1572 9. Commitments)
26
Clinical Investigator Responsibilities

• Conduct studies according to relevant, current
  protocol
• Make changes in a protocol only after notifying
  the sponsor
• Maintain adequate and accurate records
• Make records available for inspection
• Agree to comply with all other requirements in 21
  CFR 312

(Form FDA 1572 9. Commitments)
27
Review of IND Application

• FDA also has responsibilities under GCP
• The focus of FDAs IND Review is on safety for
  human research subjects and ensuring that the
  studies will produce useful information to assess
  safety and efficacy of the test product

28
Reviews are Conducted by Teams of Specialists

• Medical Officer
• Consumer Safety Officer/Project Manager
• Statistician
• Chemist
• Pharmacologist
• Human Biopharmaceutics
• (Microbiologist)

29
Review of IND Application

• Review team has 30 days to review
• Focus of review is always on safety/ human
  subject protection
• No News Good News

30
IND Application If Problems..

• Clinical Hold
• Legal order to delay or stop the study in the
  U.S.
• Subjects may not be given the investigational
  drug
• May be imposed if
• Exposure of subjects to unreasonable risk
  (includes manufacturing problems)
• Investigator brochure is misleading, erroneous,
  or materially incomplete
• Investigator is not qualified

31
Drug Development Under an IND

• Review Team Monitors
• New Protocols (IND amendments)
• Safety reports
• Annual reports
• Additional chemistry, animal toxicology,
  microbiology data
• Review team is available to consult/meet with
  sponsors advise on protocol design, advise on
  drug development plan

32
IND and Non-US Studies

• Studies performed outside of the U.S. may be
  conducted with or without IND
• With an IND
• Test article can be exported from the U.S.
• Study must conform to U.S. IND regulations
  (including U.S. IRB and informed consent rules)

33
IND and Non-US Studies

• Studies performed outside of the U.S. may be
  conducted with or without IND
• Without an IND
• May be acceptable for FDA review in support of a
  marketing application
• Export of the test article from the U.S. must
  conform to FDA regulations

34
Export of an Investigational Drug

• Mechanisms (21 CFR 312.110)
• FDA authorization of a written request from the
  person that seeks to export
• Adequate information investigational purposes
  only can be legally used in the importing
  country for investigation specifies
  quantity/frequency of shipment
• FDA authorization of a formal request from the
  government of the receiving country

35
Export of an Investigational Drug

• 1996 law also allows drug export for
  investigational use without prior FDA approval if
  intended for use in one of 25 countries
• Australia Canada Israel Japan, New Zealand
  Switzerland European Union Member States (15),
  Iceland, Norway, and Liechtenstein

36
IND Content/SubmissionWho to Contact with
Questions

• Center for Drugs ODE I
• Cardio-Renal (110)
• 301-594-5300
• Neuropharm (120)
• 301-594-2850
• Oncology (150)
• 301-594-2473

• Center for Drugs ODE II
• Anesthetic, Critical Care Addiction (170)
• 301-827-7410
• Metabolic/Endocrine (510)
• 301-827-6430
• Pulmonary (570)
• 301-827-1050

37
IND Content/SubmissionWho to Contact with
Questions

• Center for Drugs ODE III
• Medical Imaging Radiopharm (160)
• 301-827-7510
• GI Coagulation (180)
• 301-827-7310
• Repro/Urologic (580)
• 301-827-4260

• Center for Drugs ODE IV
• Anti-Infective (520)
• 301-827-2120
• Antiviral (530)
• 301-827-2330
• Special Pathogens Immunologic (590)
• 301-827-2336

38
IND Content/SubmissionWho to Contact with
Questions

• Center for Drugs ODE V
• Derm/Dental (540)
• 301-827-2021
• Anti-Inflammatory, Analgesic Ophthalmic (550)
• 301-827-2040
• Over-the-Counter (OTC) (560)
• 301-827-2222

39
IND Content/SubmissionWho to Contact with
Questions

• Center for Biologics (CBER)
• Office of Vaccines Research and Review
• [phone]
• Office of Blood Research and Review
• [phone]
• Office of Therapeutics Research and Review
• [phone]

40
Office of Generic DrugsWho to Contact with
Questions

• OGD Regulatory Support Branch
• [phone]

41
IDE Content/SubmissionWho to Contact with
Questions

• Center for Devices and Radiological Health (CDRH)
• General, Restorative, and Neurological Devices
  [phone]
• Clinical Laboratory Devices [phone]
• Cardiovascular and Respiratory Devices (301)
  443-8320

42
IDE Content/SubmissionWho to Contact with
Questions

• Center for Devices and Radiological Health (CDRH)
• Ophthalmic and ENT Devices [phone]
• Reproductive, Abdominal, and Radiological
  Devices [phone]
• Dental, Infection Control, and General Hospital
  Devices [phone]

43
Sponsor Responsibilities

• Selecting Qualified Investigators
• Providing investigators with information they
  need to conduct an investigation properly.
• Ensuring proper monitoring of the
  investigation(s)
• Conduct per protocol
• Ethical considerations
• Control of investigational product(s)
• Safety reporting

44
Sponsor Responsibilities

• Review Ongoing Investigations
• A sponsor who discovers that an investigator is
  not complying with the signed 1572, general
  investigation plan, or regulations shall promptly
  either
• secure compliance or
• end the investigators participation in the
  investigation (discontinue shipment and require
  return/disposal of drug notify FDA).

45
Sponsor-Investigators

• FDA regulations allow an individual to be both
  study sponsor and clinical investigator
• The Dilemma
• Many sponsor-investigators believe that the lack
  of external monitoring and oversight means that
  they can perform to a lower standard

46
Sponsor-Investigators

• The Dilemma -2-
• Where a sponsor and an investigator are the same,
  the number of GCP control points is reduced from
  four to three
• A sponsor-investigator therefore needs to be more
  (not less) informed of responsibilities and more
  attentive to standards of study conduct and
  subject protection

47
Subject Education

• Subject Education is an often neglected facet of
  GCP yet, an educated, fully informed, and
  inquiring subject may be the best resource for
  ensuring ethical and quality performance in a
  clinical trial
• The IRB and institution should pay particular
  attention to informing subjects where to go with
  questions or complaints

48
Reporting to FDA

• Sponsors are required to report serious
  non-compliance
• But anyone can report complaints in FDA-regulated
  clinical trials to FDA
• FDAs GCP website (www.fda.gov/oc/gcp) highlights
  where to report complaints in clinical trials

49
New At FDA

• FDA has recently established a new Office for
  Good Clinical Practice to coordinate GCP across
  FDA and beyond...

50
OGCP Structure

• Small Office
• Strategically located
• Office of the Commissioner and its Office of
  Science Coordination and Communication
• Key Positions
• David A. Lepay, MD PhD Senior Advisor for
  Clinical Science and Director
• Stan W. Woollen Associate Director for
  Bioresearch Monitoring
• Bonnie Lee Associate Director for Human Subject
  Protection Policy

51
OGCP Functions

• Centralized (Commissioners Office) Role in
• GCP Policy
• Bioresearch Monitoring of Clinical Trials
• GCP Initiatives
• International GCP (harmonization) activities
• GCP Education and Outreach

52
OGCP and Quality Assurance

• OGCP will reflect FDAs Commitment to Quality
  Assurance
• Internally
• Coordinating QA for the Agencys clinical
  Bioresearch Monitoring Program of on-site
  inspections
• Externally
• Coordinating Agency GCP policy and initiatives to
  enhance the quality of clinical research

53
Clinical Trial QA What We Should Strive For

• Building quality in upfront
• Assuring quality throughout
• Developing capacity for continuous quality
  improvement now and in the future

54
Working Together Plentiful Opportunities

• Well-designed, well-conducted clinical trials are
  not easy
• If you dont want to do it right, you should
  not be conducting clinical trials
• The best systems can only emerge from the
  broadest possible participation

55
Working Together Plentiful Opportunities

• Quality assurance and quality improvement are
  integral to development of the best systems !