LINKS TO 21 CFR PART 312--INVESTIGATIONAL NEW DRUG APPLICATION
312.1(a) Requirements for use of investigational new
drugs
312.1(b) References are to Title 21
312.2(a) All clinical investigations of covered products
312.2(b) Exemptions
312.2(b)(1) Study of marketed
drug not intended to support changes in labeling or advertising
312.2(b)(2) Study of in vitro
diagnostic products that meet certain requirements
312.2(b)(3) Drug intended for in
vitro tests or in laboratory animals
312.2(b)(4) IND not accepted for
exempt studies
312.2(b)(5) Study using placebo
not requiring an IND is exempt
312.2(b)(6) Planned emergency
research with consent waiver is not exempt
312.2(c) Bioavailability studies
312.2(d) Off-label use for treatment
312.2(e) FDA will provide guidance and advice on
exemptions
312.3 Definitions and interpretations.
312.3(a) Definitions from section 201
apply
312.3(b) These definitions also apply
Contract research organization
312.6 Labeling of an investigational new drug.
312.6(a) Immediate package shall be labeled
312.6(b) No false statements
312.7 Promotion and charging for investigational drugs.
312.7(a) No promotion of investigational new drug
312.7(b) No commercial distribution or marketing
312.7(c) Investigation not to be unduly prolonged
312.7(d) Charging for investigational
drugs
312.7(d)(1) Not allowed in
clinical investigations without prior written approval
312.7(d)(2) May charge for
treatment use under certain conditions
312.7(d)(3) Noncommercialization
of investigational drug
312.7(d)(4) Withdrawal of authorization to charge
312.10(a) Request to waive requirements must
include:
312.10(a)(1) Explanation
312.10(a)(2) Description of
alternate
312.10(a)(3) Other information
312.10(b) FDA may grant waiver if risk is
not significant and:
312.10(b)(1) Not required for
evaluation
312.10(b)(2) Alternative is
sufficient
312.10(b)(3) Submission otherwise justifies a waiver
Subpart B--Investigational New Drug Application (IND)
312.20 Requirement for an IND.
312.20(a) IND required for clinical
investigation
312.20(b) Requirements must be met before investigation begins
312.20(c) Separate IND when emergency consent waiver is used
312.21 Phases of an investigation.
312.21(a) Phase 1 includes
312.21(a)(1) Initial
introduction of drug into humans to study pharmacokinetics, pharmacological effects and side effects
312.21(a)(2) Studies of drug
metabolism
312.21(b) Phase 2: controlled studies to
evaluate effectiveness
312.21(c) Phase 3: expanded controlled and uncontrolled trials
312.22 General principles of the IND submission.
312.22(a) FDA objectives in each phase
312.22(b) Information required depends on
various factors
312.22(c) Focus of IND
312.22(d) Standard format for IND will be followed
312.23 IND content and format.
312.23(a) The IND will include:
312.23(a)(1) Cover Sheet
(FDA-1571)
312.23(a)(2) Table of Contents
312.23(a)(3) Introductory
statement and general investigational plan
312.23(a)(4) [Reserved]
312.23(a)(5) Investigator's
brochure
312.23(a)(6) Protocols
312.23(a)(7) Chemistry,
manufacturing, and control information
312.23(a)(8) Pharmacology and
toxicology information
312.23(a)(9) Previous human
experience with the investigational drug
312.23(a)(10) Additional
information
312.23(a)(11) Other relevant
information may be requested
312.23(b) Information previously submitted.
312.23(c) Material in a foreign language
312.23(d) Number of copies to be submitted
312.23(e) Numbering of IND submissions
312.23(f) Identification of exception from
informed consent
312.30(a) New protocol may be added if
312.30(a)(1) It has been
submitted to FDA
312.30(a)(2) It has been
approved by an IRB
312.30(b) Changes in a protocol
312.30(b)(1) When an amendment
must be submitted
312.30(b)(2) Conditions for
making protocol change
312.30(c) New investigator
312.30(d) Content and format of a protocol
amendment
312.30(d)(1) Description(s) of
change(s)
312.30(d)(2) Reference to
supporting information
312.30(d)(3) Request for FDA
comment
312.30(e) When to submit
312.31 Information amendments.
312.31(a) An information
amendment may include
312.31(a)(1) New
technical information
312.31(a)(2) Report
of discontinuation
312.31(b) Content and
format:
312.31(b)(1) Nature
and purpose of amendment
312.31(b)(2) Data
312.31(b)(3) Request
for comment
312.31(c) When submitted
312.32(a) Definitions
Associated with the use of the drug
Life-threatening adverse drug
experience
Serious adverse drug experience
Unexpected adverse drug experience
312.32(b) Review of safety information
312.32(c) IND safety reports
312.32(c)(1) Written reports
312.32(c)(2) Telephone and
facsimile transmission
312.32(c)(3) FDA may require
a different reporting format or frequency
312.32(c)(4) Safety reports
only from clinical study
312.32(d) Followup
312.32(d)(1) Sponsor will
investigate
312.32(d)(2) Followup
information will be submitted
312.32(d)(3) Report after
determination
312.32(d)(4) Results of
investigation to be reported
312.32(e) Disclaimer
312.33 Annual reports will include:
312.33(a) Individual study information,
including:
312.33(a)(1) Study
description
312.33(a)(2) Subject
information
312.33(a)(3) Available
results
312.33(b) Summary information
312.33(b)(1) Summary
of adverse experiences
312.33(b)(2) Summary
of safety reports
312.33(b)(3) List
of deaths
312.33(b)(4) Withdrawals
due to adverse experiences
312.33(b)(5) Information
gained about drug’s actions
312.33(b)(6) Preclinical
studies
312.33(b)(7) Manufacturing
or microbiologcal changes
312.33(c) Investigational plan
312.34 Treatment use of an investigational new drug.
312.34(a) Treatment use of drugs in Phase 3
or Phase 2
312.34(b) Criteria
312.34(b)(1) Conditions for
use
312.34(b)(2) For serious
disease, may be denied if evidence is insufficient
312.34(b)(3) For immediately
life-threatening disease, may be denied under certain circumstances
312.34(c) Safeguards
312.34(d) Clinical hold
312.35 Submissions for treatment use.
312.35(a) Treatment protocol submitted by
IND sponsor
312.35(a)(1) Contents of
treatment protocol
312.35(a)(2) Supporting
information
312.35(a)(3) Practitioner to
be considered an investigator
312.35(b) Treatment IND submitted by
investigator
312.35(b)(1) Conditions and
elements of application
312.35(b)(2) Practitioner is sponsor-investigator
312.36 Emergency use of an investigational new drug.
312.38(a) Sponsor may withdraw IND
312.38(b) Actions upon withdrawal
312.38(c) Actions if withdrawal is for
safety reason
Subpart C--Administrative Actions
312.40 General requirements for use of an investigational new drug in a clinical investigation.
312.40(a) Drug may be used if:
312.40(a)(1) IND conditions
are met
312.40(a)(2) Each investigator
complies with requirements
312.40(b) IND goes into effect:
312.40(b)(1) Thirty days after
receipt
312.40(b)(2) Or with earlier
notification
312.40(c) Sponsor may ship:
312.40(c)(1) Thirty days
after receipt
312.40(c)(2) Or with earlier
notification
312.40(d) IND must be in effect before use
of drug
312.41 Comment and advice on an IND.
312.41(a) FDA may communicate with sponsor
312.41(b) FDA will provide advice upon
request
312.41(c) Communications are advisory
312.42 Clinical holds
and requests for modification.
312.42(a) Description of clinical hold
312.42(b) Grounds for imposition
312.42(b)(1) Risks to human
subjects, unqualified investigator, inaccurate investigator brochure, insufficient
information
312.42(b)(2) Conditions for
clinical hold of Phase 2 or 3 study
312.42(b)(3) Clinical hold of
a treatment IND
312.42(b)(4) Clinical hold of any
study that is not designed to be adequate and well-controlled
312.42(b)(5) Clinical hold of
any investigation involving an exception from informed consent (planned
emergency research)
312.42(b)(6) Clinical hold of
any investigation involving an exception from informed consent (exemption under
combat conditions)
312.42(c) Discussion of deficiency
312.42(d) Imposition of clinical hold
312.42(e) Resumption of clinical
investigations
312.42(f) Appeal
312.42(g) Conversion to inactive status
312.44(a) Procedures under which FDA may
terminate an IND
312.44(b) Grounds for termination
312.44(b)(1) Conditions for
Phase 1 termination
312.44(b)(2) Phase 2 or 3
termination
312.44(b)(3) Other conditions
for termination
312.44(c) Opportunity for sponsor response
312.44(c)(1) Notification
within 30 days
312.44(c)(2) Sponsor response
312.44(c)(3) FDA will provide
reasons for nonacceptance
312.44(d) Immediate termination of IND
312.45(a) Conditions for inactive status
312.45(b) Notification and disposal of drug
stocks
312.45(c) Reports and disclosure
312.45(d) Procedure to resume:
312.45(d)(1) Thirty days after
receipt
312.45(d)(2) Or earlier FDA
notification
312.45(e) Inactive IND may be terminated after 5 years
312.47(a) Meetings between sponsor and FDA
312.47(b) ``End-of-Phase 2'' meetings and
``pre-NDA'' meetings
312.47(b)(1) Procedure for
end-of-Phase 2 meetings
312.47(b)(2) Procedure for``pre-NDA'' and ``pre-BLA'' meetings
312.48(a) General
312.48(b) Administrative and procedural
issues
312.48(c) Scientific and medical disputes
312.48(c)(1) Procedure for
meetings
312.48(c)(2) ``End-of-Phase
2'' and ``pre-NDA'' meetings may also be used
312.48(c)(3) Outside consultants may be used
Subpart D--Responsibilities of Sponsors and Investigators
312.50 General responsibilities of sponsors.
312.52 Transfer of obligations to a contract research organization.
312.52 (a) Sponsor may transfer responsibility,
described in writing
312.52 (b) Contract research organization shall comply with all sponsor requirements
312.53 Selecting investigators and monitors.
312.53(a) Selecting investigators
312.53(b) Control of drug
312.53(c) Information to be obtained from
the investigator
312.53(c)(1) Form FDA-1572
312.53(c)(2) Curriculum vitae
312.53(c)(3) Clinical
protocol to be used
312.53(c)(4) Financial
disclosure information
312.53(d) Selecting monitors
312.54 Emergency research under Sec. 50.24 of this chapter.
312.54(a) Sponsor shall monitor and report
public disclosures to FDA
312.54(b) IRB disapprovals will be reported
312.55 Informing investigators.
312.55(a) Investigator brochure will be
distributed to investigators
312.55(b) Sponsor will keep investigators
informed
312.56 Review of ongoing investigations.
312.56(a) Sponsor shall monitor the progress
312.56(b) Sponsor will insure compliance by investigators
312.56(c) Sponsor will review evidence for safety and effectiveness
312.56(d) Sponsor’s responsibility when drug is determined to present unreasonable risk
312.57 Recordkeeping and record retention.
312.57(a) A sponsor shall maintain adequate
records
312.57(b) A sponsor shall maintain records
of financial interests of investigators
312.57(c) Length of time records are to be
kept
312.57(d) Sponsor shall retain reserve samples of test article
312.58 Inspection of sponsor's records and reports.
312.58(a) FDA inspection
312.58(b) Controlled substances
312.59 Disposition of unused supply of investigational drug.
312.60 General responsibilities of investigators.
312.61 Control of the investigational drug.
312.62 Investigator recordkeeping and record retention.
312.62(a) Disposition of drug
312.62(b) Case histories
312.62(c) Record retention
312.64(a) Progress reports
312.64(b) Safety reports
312.64(c) Final report
312.64(d) Financial disclosure reports
312.66 Assurance of IRB review.
312.68 Inspection of investigator's records and reports.
312.69 Handling of controlled substances.
312.70 Disqualification of a clinical investigator.
312.70(a) Procedure for notifying
investigator, response and hearing
312.70(b) Commissioner will notify if
investigator is not entitled to receive investigational drugs
312.70(c) Data will be examined for
reliability
312.70(d) Commissioner may act on IND
312.70(e) Commissioner may withdraw approval
312.70(f) Investigator may be reinstated
Subpart E--Drugs Intended to Treat Life-threatening and Severely-debilitating Illnesses
312.81(a) ``Life-threatening'' means:
312.81(a)(1) Likelihood of
death is high
312.81(a)(2) Diseases with
potentially fatal outcomes, with survival end point
312.81(b) Definition of ``severely
debilitating''
312.81(c) Sponsors should consult with FDA
312.82(a) Pre-investigational new drug (IND)
meetings
312.82(b) End-of-phase 1 meetings
312.84(a) FDA will consider risk/benefit
balance
312.84(b) FDA will seek outside consultation
312.84(c) FDA will notify about
deficiencies
312.84(d) Marketing applications subject to
part 314 or part 600
312.86 Focused FDA regulatory research.
312.87 Active monitoring of conduct and evaluation of clinical trials.
312.88 Safeguards for patient safety.
312.110 Import and export requirements.
312.110(a) Investigational new drug may be
imported if
312.110(a)(1) Consignee is the
IND sponsor in US, or
312.110(a)(2) Consignee is an
investigator for the IND, or
312.110(a)(3) Consignee is the
domestic agent of a foreign sponsor
312.110(b) Investigational new drug may be
exported if
312.110(b)(1) IND is in effect
and drug is received by investigators
312.110(b)(2) FDA authorizes
shipment of the drug
312.110(b)(3) Applies only drug
is to be used for clinical investigation
312.110(b)(4) Does not apply to
the export of new drugs authorized for export under other sections
312.120 Foreign clinical studies not conducted under an IND.
312.120(a) Criteria for acceptance by FDA of
foreign clinical studies not conducted under an IND
312.120(b) Data submissions to include:
312.120(b)(1) Investigator's
qualifications
312.120(b)(2) Description of
research facilities
312.120(b)(3) Summary of the
protocol and results of the study
312.120(b)(4) Description of the
drug substance
312.120(b)(5) Information that
the study is adequate and well controlled
312.120(c) Ethical principles
312.120(c)(1) Conducted in
accordance with the ``Declaration of Helsinki'' or equivalent laws
312.120(c)(2) Explanation
of how the research conformed to these
ethical principles
312.120(c)(3) Documentation of
reviewing committee
312.120(c)(4) Declaration of
Helsinki
II.
Medical Research Combined with Professional Care (Clinical Research)