**CODE OF FEDERAL REGULATIONS**

**Title 21\--Food and Drugs**

**CHAPTER I\--FOOD AND DRUG ADMINISTRATION,**

**DEPARTMENT OF HEALTH AND HUMAN SERVICES**

# **PART 312\--INVESTIGATIONAL NEW DRUG APPLICATION**

Table of Contents

312.1 Scope.

> 312.2 Applicability.
>
> 312.3 Definitions and interpretations.
>
> 312.6 Labeling of an investigational new drug.
>
> 312.7 Promotion and charging for investigational drugs.
>
> 312.10 Waivers.
>
> 312.20 Requirement for an IND.
>
> 312.21 Phases of an investigation.
>
> 312.22 General principles of the IND submission.
>
> 312.23 IND content and format.
>
> 312.30 Protocol amendments.
>
> 312.31 Information amendments.
>
> 312.32 IND safety reports.
>
> 312.33 Annual reports.
>
> 312.34 Treatment use of an investigational new drug.
>
> 312.35 Submissions for treatment use.
>
> 312.36 Emergency use of an investigational new drug.
>
> 312.38 Withdrawal of an IND.

312.40 General requirements for use of an investigational new drug in a
clinical investigation.

312.41 Comment and advice on an IND.

312.42 Clinical holds and requests for modification.

312.44 Termination.

312.45 Inactive status.

> 312.47 Meetings.
>
> 312.48 Dispute resolution.
>
> 312.50 General responsibilities of sponsors.
>
> 312.52 Transfer of obligations to a contract research organization.
>
> 312.53 Selecting investigators and monitors.
>
> 312.54 Emergency research under 50.24 of this chapter
>
> 312.55 Informing investigators.
>
> 312.56 Review of ongoing investigations.
>
> 312.57 Recordkeeping and record retention.
>
> 312.58 Inspection of sponsor\'s records and reports.
>
> 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.
>
> 312.64 Investigator 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.
>
> 312.80 Purpose.
>
> 312.81 Scope.
>
> 312.82 Early consultation.
>
> 312.83 Treatment protocols.
>
> 312.84 Risk-benefit analysis in review of marketing applications for
> drugs to treat life-threatening and severely-debilitating illnesses.
>
> 312.85 Phase 4 studies.
>
> 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.
>
> 312.120 Foreign clinical studies not conducted under an IND
>
> 312.130 Availability for public disclosure of data and information in
> an IND.
>
> 312.140 Address for correspondence.
>
> 312.145 Guidelines.
>
> 312.160 Drugs for investigational use in laboratory research animals
> or in vitro tests.

**Subpart A\--General Provisions**

**Sec. 312.1 Scope.**

\(a\) This part contains procedures and requirements governing the use
of investigational new drugs, including procedures and requirements for
the submission to, and review by, the Food and Drug Administration of
investigational new drug applications (IND\'s). An investigational new
drug for which an IND is in effect in accordance with this part is
exempt from the premarketing approval requirements that are otherwise
applicable and may be shipped lawfully for the purpose of conducting
clinical investigations of that drug.

\(b\) References in this part to regulations in the Code of Federal

Regulations are to chapter I of title 21, unless otherwise noted.

**Sec. 312.2** **Applicability.**

\(a\) Applicability. Except as provided in this section, this part
applies to all clinical investigations of products that are subject to
section 505 of the Federal Food, Drug, and Cosmetic Act or to the
licensing provisions of the Public Health Service Act (58 Stat. 632, as
amended (42 U.S.C. 201 et seq.)).

\(b\) Exemptions. (1) The clinical investigation of a drug product that
is lawfully marketed in the United States is exempt from the
requirements of this part if all the following apply:

\(i\) The investigation is not intended to be reported to FDA as a
well-controlled study in support of a new indication for use nor
intended to be used to support any other significant change in the
labeling for the drug;

\(ii\) If the drug that is undergoing investigation is lawfully marketed
as a prescription drug product, the investigation is not intended to
support a significant change in the advertising for the product;

\(iii\) The investigation does not involve a route of administration or
dosage level or use in a patient population or other factor that
significantly increases the risks (or decreases the acceptability of the
risks) associated with the use of the drug product;

\(iv\) The investigation is conducted in compliance with the
requirements for institutional review set forth in part 56 and with the
requirements for informed consent set forth in part 50; and

\(v\) The investigation is conducted in compliance with the requirements
of Sec. 312.7.

(**2**)(i) A clinical investigation involving an in vitro diagnostic
biological product listed in paragraph (b)(**2**)(ii) of this section is
exempt from the requirements of this part if (a) it is intended to be
used in a diagnostic procedure that confirms the diagnosis made by
another, medically established, diagnostic product or procedure and (b)
it is shipped in compliance with Sec. 312.160.

\(ii\) In accordance with paragraph (b)(**2**)(i) of this section, the
following products are exempt from the requirements of this part: (a)
blood grouping serum; (b) reagent red blood cells; and (c) anti-human
globulin.

\(3\) A drug intended solely for tests in vitro or in laboratory
research animals is exempt from the requirements of this part if shipped
in accordance with Sec. 312.160.

\(4\) FDA will not accept an application for an investigation that is
exempt under the provisions of paragraph (b)(1) of this section.

\(5\) A clinical investigation involving use of a placebo is exempt from
the requirements of this part if the investigation does not otherwise
require submission of an IND.

\(6\) A clinical investigation involving an exception from informed
consent under Sec. 50.24 of this chapter is not exempt from the
requirements of this part.

\(c\) Bioavailability studies. The applicability of this part to in vivo
bioavailability studies in humans is subject to the provisions of Sec.
320.31.

\(d\) Unlabeled indication. This part does not apply to the use in the
practice of medicine for an unlabeled indication of a new drug product
approved under part 314 or of a licensed biological product.

\(e\) Guidance. FDA may, on its own initiative, issue guidance on the
applicability of this part to particular investigational uses of drugs.
On request, FDA will advise on the applicability of this part to a
planned clinical investigation.

**Sec. 312.3 Definitions and interpretations.**

\(a\) The definitions and interpretations of terms contained in section
201 of the Act apply to those terms when used in this part:

\(b\) The following definitions of terms also apply to this part:

Act means the Federal Food, Drug, and Cosmetic Act (secs. 201-902,

52 Stat. 1040 et seq., as amended (21 U.S.C. 301-392)).

Clinical investigation means 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.

Contract research organization means a person that assumes, as an
independent contractor with the sponsor, one or more of the obligations
of a sponsor, e.g., design of a protocol, selection or monitoring of
investigations, evaluation of reports, and preparation of materials to
be submitted to the Food and Drug Administration.

FDA means the Food and Drug Administration.

IND means an investigational new drug application. For purposes of this
part, \`\`IND\'\' is synonymous with \`\`Notice of Claimed
Investigational Exemption for a New Drug.\'\'

Investigational new drug means a new drug or biological drug that is
used in a clinical investigation. The term also includes a biological
product that is used in vitro for diagnostic purposes. The terms
\`\`investigational drug\'\' and \`\`investigational new drug\'\' are
deemed to be synonymous for purposes of this part.

Investigator means an individual who actually conducts a clinical
investigation (i.e., under whose immediate direction the drug is
administered or dispensed to a subject). In the event an investigation
is conducted by a team of individuals, the investigator is the
responsible leader of the team. \`\`Subinvestigator\'\' includes any
other individual member of that team.

Marketing application means an application for a new drug submitted
under section 505(b) of the Act or a product license application for a
biological product submitted under the Public Health Service Act.

Sponsor means a person who takes responsibility for and initiates a
clinical investigation. The sponsor may be an individual or
pharmaceutical company, governmental agency, academic institution,
private organization, or other organization. The sponsor does not
actually conduct the investigation unless the sponsor is a
sponsor-investigator. A person other than an individual that uses one or
more of its own employees to conduct an investigation that it has
initiated is a sponsor, not a sponsor-investigator, and the employees
are investigators.

Sponsor-Investigator means an individual who both initiates and conducts
an investigation, and under whose immediate direction the
investigational drug is administered or dispensed. The term does not
include any person other than an individual. The requirements applicable
to a sponsor-investigator under this part include both those applicable
to an investigator and a sponsor.

Subject means a human who participates in an investigation, either as a
recipient of the investigational new drug or as a control. A subject may
be a healthy human or a patient with a disease.

**Sec. 312.6 Labeling of an investigational new drug.**

\(a\) The immediate package of an investigational new drug intended for
human use shall bear a label with the statement \`\`Caution: New
Drug\--Limited by Federal (or United States) law to investigational
use.\'\'

\(b\) The label or labeling of an investigational new drug shall not
bear any statement that is false or misleading in any particular and
shall not represent that the investigational new drug is safe or
effective for the purposes for which it is being investigated.

**Sec. 312.7 Promotion and charging for investigational drugs.**

\(a\) Promotion of an investigational new drug. A sponsor or
investigator, or any person acting on behalf of a sponsor or
investigator, shall not represent in a promotional context that an
investigational new drug is safe or effective for the purposes for which
it is under investigation or otherwise promote the drug. This provision
is not intended to restrict the full exchange of scientific information
concerning the drug, including dissemination of scientific findings in
scientific or lay media. Rather, its intent is to restrict promotional
claims of safety or effectiveness of the drug for a use for which it is
under investigation and to preclude commercialization of the drug before
it is approved for commercial distribution.

\(b\) Commercial distribution of an investigational new drug. A sponsor
or investigator shall not commercially distribute or test market an
investigational new drug.

\(c\) Prolonging an investigation. A sponsor shall not unduly prolong an
investigation after finding that the results of the investigation appear
to establish sufficient data to support a marketing application.

\(d\) Charging for and commercialization of investigational drugs\--(1)
Clinical trials under an IND. Charging for an investigational drug in a
clinical trial under an IND is not permitted without the prior written
approval of FDA. In requesting such approval, the sponsor shall provide
a full written explanation of why charging is necessary in order for the
sponsor to undertake or continue the clinical trial, e.g., why
distribution of the drug to test subjects should not be considered part
of the normal cost of doing business.

\(2\) Treatment protocol or treatment IND. A sponsor or investigator may
charge for an investigational drug for a treatment use under a treatment
protocol or treatment IND provided: (i) There is adequate enrollment in
the ongoing clinical investigations under the authorized IND; (ii)
charging does not constitute commercial marketing of a new drug for
which a marketing application has not been approved; (iii) the drug is
not being commercially promoted or advertised; and (iv) the sponsor of
the drug is actively pursuing marketing approval with due diligence. FDA
must be notified in writing in advance of commencing any such charges,
in an information amendment submitted under Sec. 312.31. Authorization
for charging goes into effect automatically 30 days after receipt by FDA
of the information amendment, unless the sponsor is notified to the
contrary.

\(3\) Noncommercialization of investigational drug. Under this section,
the sponsor may not commercialize an investigational drug by charging a
price larger than that necessary to recover costs of manufacture,
research, development, and handling of the investigational drug.

\(4\) Withdrawal of authorization. Authorization to charge for an
investigational drug under this section may be withdrawn by FDA if the
agency finds that the conditions underlying the authorization are no
longer satisfied.

**Sec. 312.10** **Waivers.**

\(a\) A sponsor may request FDA to waive applicable requirement under
this part. A waiver request may be submitted either in an IND or in an
information amendment to an IND. In an emergency, a request may be made
by telephone or other rapid communication means. A waiver request is
required to contain at least one of the following:

\(1\) An explanation why the sponsor\'s compliance with the requirement
is unnecessary or cannot be achieved;

\(2\) A description of an alternative submission or course of action
that satisfies the purpose of the requirement; or

\(3\) Other information justifying a waiver.

\(b\) FDA may grant a waiver if it finds that the sponsor\'s
noncompliance would not pose a significant and unreasonable risk to
human subjects of the investigation and that one of the following is
met:

\(1\) The sponsor\'s compliance with the requirement is unnecessary for
the agency to evaluate the application, or compliance cannot be
achieved;

\(2\) The sponsor\'s proposed alternative satisfies the requirement; or

\(3\) The applicant\'s submission otherwise justifies a waiver.

**Subpart B\--Investigational New Drug Application (IND)**

**Sec. 312.20 Requirement for an IND.**

\(a\) A sponsor shall submit an IND to FDA if the sponsor intends to
conduct a clinical investigation with an investigational new drug that
is subject to Sec. 312.2(a).

\(b\) A sponsor shall not begin a clinical investigation subject to Sec.
312.2(a) until the investigation is subject to an IND which is in effect
in accordance with Sec. 312.40.

\(c\) A sponsor shall submit a separate IND for any clinical
investigation involving an exception from informed consent under Sec.
50.24 of this chapter. Such a clinical investigation is not permitted to
proceed without the prior written authorization from FDA. FDA shall
provide a written determination 30 days after FDA receives the IND or
earlier.

**Sec. 312.21 Phases of an investigation.**

An IND may be submitted for one or more phases of an investigation. The
clinical investigation of a previously untested drug is generally
divided into three phases. Although in general the phases are conducted
sequentially, they may overlap. These three phases of an investigation
are a follows:

\(a\) Phase 1. (1) Phase 1 includes the initial introduction of an
investigational new drug into humans. Phase 1 studies are typically
closely monitored and may be conducted in patients or normal volunteer
subjects. These studies are designed to determine the metabolism and
pharmacologic actions of the drug in humans, the side effects associated
with increasing doses, and, if possible, to gain early evidence on
effectiveness. During Phase 1, sufficient information about the drug\'s
pharmacokinetics and pharmacological effects should be obtained to
permit the design of well-controlled, scientifically valid, Phase 2
studies. The total number of subjects and patients included in Phase 1
studies varies with the drug, but is generally in the range of 20 to 80.

\(2\) Phase 1 studies also include studies of drug metabolism,
structure-activity relationships, and mechanism of action in humans, as
well as studies in which investigational drugs are used as research
tools to explore biological phenomena or disease processes.

\(b\) Phase 2. Phase 2 includes the controlled clinical studies
conducted to evaluate the effectiveness of the drug for a particular
indication or indications in patients with the disease or condition
under study and to determine the common short-term side effects and
risks associated with the drug. Phase 2 studies are typically well
controlled, closely monitored, and conducted in a relatively small
number of patients, usually involving no more than several hundred
subjects.

\(c\) Phase 3. Phase 3 studies are expanded controlled and uncontrolled
trials. They are performed after preliminary evidence suggesting
effectiveness of the drug has been obtained, and are intended to gather
the additional information about effectiveness and safety that is needed
to evaluate the overall benefit-risk relationship of the drug and to
provide an adequate basis for physician labeling. Phase 3 studies
usually include from several hundred to several thousand subjects.

**Sec. 312.22** **General principles of the IND submission.**

\(a\) 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. Therefore, although FDA\'s review of Phase 1
submissions will focus on assessing the safety of Phase 1
investigations, FDA\'s review of Phases 2 and 3 submissions will also
include an assessment of the scientific quality of the clinical
investigations and the likelihood that the investigations will yield
data capable of meeting statutory standards for marketing approval.

\(b\) The amount of information on a particular drug that must be
submitted in an IND to assure the accomplishment of the objectives
described in paragraph (a) of this section depends upon such factors as
the novelty of the drug, the extent to which it has been studied
previously, the known or suspected risks, and the developmental phase of
the drug.

\(c\) The central focus of the initial IND submission should be on the
general investigational plan and the protocols for specific human
studies. Subsequent amendments to the IND that contain new or revised
protocols should build logically on previous submissions and should be
supported by additional information, including the results of animal
toxicology studies or other human studies as appropriate. Annual reports
to the IND should serve as the focus for reporting the status of studies
being conducted under the IND and should update the general
investigational plan for the coming year.

\(d\) The IND format set forth in Sec. 312.23 should be followed
routinely by sponsors in the interest of fostering an efficient review
of applications. Sponsors are expected to exercise considerable
discretion, however, regarding the content of information submitted in
each section, depending upon the kind of drug being studied and the
nature of the available information. Section 312.23 outlines the
information needed for a commercially sponsored IND for a new molecular
entity. A sponsor-investigator who uses, as a research tool, an
investigational new drug that is already subject to a manufacturer\'s
IND or marketing application should follow the same general format, but
ordinarily may, if authorized by the manufacturer, refer to the
manufacturer\'s IND or marketing application in providing the technical
information supporting the proposed clinical investigation. A
sponsor-investigator who uses an investigational drug not subject to a
manufacturer\'s IND or marketing application is ordinarily required to
submit all technical information supporting the IND, unless such
information may be referenced from the scientific literature.

**Sec. 312.23 IND content and format.**

\(a\) A sponsor who intends to conduct a clinical investigation subject
to this part shall submit an \`\`Investigational New Drug
Application\'\' (IND) including, in the following order:

\(1\) Cover sheet (Form FDA-1571). A cover sheet for the application
containing the following:

\(i\) The name, address, and telephone number of the sponsor, the date
of the application, and the name of the investigational new drug.

\(ii\) Identification of the phase or phases of the clinical
investigation to be conducted.

\(iii\) A commitment not to begin clinical investigations until an IND
covering the investigations is in effect.

\(iv\) A commitment that an Institutional Review Board (IRB) that
complies with the requirements set forth in part 56 will be responsible
for the initial and continuing review and approval of each of the
studies in the proposed clinical investigation and that the investigator
will report to the IRB proposed changes in the research activity in
accordance with the requirements of part 56.

\(v\) A commitment to conduct the investigation in accordance with all
other applicable regulatory requirements.

\(vi\) The name and title of the person responsible for monitoring the
conduct and progress of the clinical investigations.

\(vii\) The name(s) and title(s) of the person(s) responsible under Sec.
312.32 for review and evaluation of information relevant to the safety
of the drug.

\(viii\) If a sponsor has transferred any obligations for the conduct of
any clinical study to a contract research organization, a statement
containing the name and address of the contract research organization,
identification of the clinical study, and a listing of the obligations
transferred. If all obligations governing the conduct of the study have
been transferred, a general statement of this transfer\--in lieu of a
listing of the specific obligations transferred\--may be submitted.

\(ix\) The signature of the sponsor or the sponsor\'s authorized
representative. If the person signing the application does not reside or
have a place of business within the United States, the IND is required
to contain the name and address of, and be countersigned by, an
attorney, agent, or other authorized official who resides or maintains a
place of business within the United States.

\(2\) A table of contents.

\(3\) Introductory statement and general investigational plan. (i) A
brief introductory statement giving the name of the drug and all active
ingredients, the drug\'s pharmacological class, the structural formula
of the drug (if known), the formulation of the dosage form(s) to be
used, the route of administration, and the broad objectives and planned
duration of the proposed clinical investigation(s).

\(ii\) A brief summary of previous human experience with the drug, with
reference to other IND\'s if pertinent, and to investigational or
marketing experience in other countries that may be relevant to the
safety of the proposed clinical investigation(s).

\(iii\) If the drug has been withdrawn from investigation or marketing
in any country for any reason related to safety or effectiveness,
identification of the country(ies) where the drug was withdrawn and the
reasons for the withdrawal.

\(iv\) A brief description of the overall plan for investigating the
drug product for the following year. The plan should include the
following: (a) The rationale for the drug or the research study; (b) the
indication(s) to be studied; (c) the general approach to be followed in
evaluating the drug; (d) the kinds of clinical trials to be conducted in
the first year following the submission (if plans are not developed for
the entire year, the sponsor should so indicate); (e) the estimated
number of patients to be given the drug in those studies; and (f) any
risks of particular severity or seriousness anticipated on the basis of
the toxicological data in animals or prior studies in humans with the
drug or related drugs.

\(4\) \[Reserved\]

\(5\) Investigator\'s brochure. If required under Sec. 312.55, a copy of
the investigator\'s brochure, containing the following information:

\(i\) A brief description of the drug substance and the formulation,
including the structural formula, if known.

\(ii\) A summary of the pharmacological and toxicological effects of the
drug in animals and, to the extent known, in humans.

\(iii\) A summary of the pharmacokinetics and biological disposition of
the drug in animals and, if known, in humans.

\(iv\) A summary of information relating to safety and effectiveness in
humans obtained from prior clinical studies. (Reprints of published
articles on such studies may be appended when useful.)

\(v\) A description of possible risks and side effects to be anticipated
on the basis of prior experience with the drug under investigation or
with related drugs, and of precautions or special monitoring to be done
as part of the investigational use of the drug.

\(6\) Protocols. (i) A protocol for each planned study. (Protocols for
studies not submitted initially in the IND should be submitted in
accordance with Sec. 312.30(a).) In general, protocols for Phase 1
studies may be less detailed and more flexible than protocols for Phase
2 and 3 studies. Phase 1 protocols should be directed primarily at
providing an outline of the investigation\--an estimate of the number of
patients to be involved, a description of safety exclusions, and a
description of the dosing plan including duration, dose, or method to be
used in determining dose\--and should specify in detail only those
elements of the study that are critical to safety, such as necessary
monitoring of vital signs and blood chemistries. Modifications of the
experimental design of Phase 1 studies that do not affect critical
safety assessments are required to be reported to FDA only in the annual
report.

\(ii\) In Phases 2 and 3, detailed protocols describing all aspects of
the study should be submitted. A protocol for a Phase 2 or 3
investigation should be designed in such a way that, if the sponsor
anticipates that some deviation from the study design may become
necessary as the investigation progresses, alternatives or contingencies
to provide for such deviation are built into the protocols at the
outset. For example, a protocol for a controlled short-term study might
include a plan for an early crossover of nonresponders to an alternative
therapy.

\(iii\) A protocol is required to contain the following, with the
specific elements and detail of the protocol reflecting the above
distinctions depending on the phase of study:

\(a\) A statement of the objectives and purpose of the study.

\(b\) The name and address and a statement of the qualifications
(curriculumvitae or other statement of qualifications) of each
investigator, and the name of each subinvestigator (e.g., research
fellow, resident) working under the supervision of the investigator; the
name and address of the research facilities to be used; and the name and
address of each reviewing Institutional Review Board.

\(c\) The criteria for patient selection and for exclusion of patients
and an estimate of the number of patients to be studied.

\(d\) A description of the design of the study, including the kind of
control group to be used, if any, and a description of methods to be
used to minimize bias on the part of subjects, investigators, and
analysts.

\(e\) The method for determining the dose(s) to be administered, the
planned maximum dosage, and the duration of individual patient exposure
to the drug.

\(f\) A description of the observations and measurements to be made to
fulfill the objectives of the study.

\(g\) A description of clinical procedures, laboratory tests, or other
measures to be taken to monitor the effects of the drug in human
subjects and to minimize risk.

\(7\) Chemistry, manufacturing, and control information. (i) As
appropriate for the particular investigations covered by the IND, a
section describing the composition, manufacture, and control of the drug
substance and the drug product. Although in each phase of the
investigation sufficient information is required to be submitted to
assure the proper identification, quality, purity, and strength of the
investigational drug, the amount of information needed to make that
assurance will vary with the phase of the investigation, the proposed
duration of the investigation, the dosage form, and the amount of
information otherwise available. FDA recognizes that modifications to
the method of preparation of the new drug substance and dosage form and
changes in the dosage form itself are likely as the investigation
progresses. Therefore, the emphasis in an initial Phase 1 submission
should generally be placed on the identification and control of the raw
materials and the new drug substance. Final specifications for the drug
substance and drug product are not expected until the end of the
investigational process.

\(ii\) It should be emphasized that the amount of information to be
submitted depends upon the scope of the proposed clinical investigation.
For example, although stability data are required in all phases of the
IND to demonstrate that the new drug substance and drug product are
within acceptable chemical and physical limits for the planned duration
of the proposed clinical investigation, if very short-term tests are
proposed, the supporting stability data can be correspondingly limited.

\(iii\) As drug development proceeds and as the scale or production is
changed from the pilot-scale production appropriate for the limited
initial clinical investigations to the larger-scale production needed
for expanded clinical trials, the sponsor should submit information
amendments to supplement the initial information submitted on the
chemistry, manufacturing, and control processes with information
appropriate to the expanded scope of the investigation.

\(iv\) Reflecting the distinctions described in this paragraph (a)(7),
and based on the phase(s) to be studied, the submission is required to
contain the following:

\(a\) Drug substance. A description of the drug substance, including its
physical, chemical, or biological characteristics; the name and address
of its manufacturer; the general method of preparation of the drug
substance; the acceptable limits and analytical methods used to assure
the identity, strength, quality, and purity of the drug substance; and
information sufficient to support stability of the drug substance during
the toxicological studies and the planned clinical studies. Reference to
the current edition of the United States Pharmacopeia\--National
Formulary may satisfy relevant requirements in this paragraph.

\(b\) Drug product. A list of all components, which may include
reasonable alternatives for inactive compounds, used in the manufacture
of the investigational drug product, including both those components
intended to appear in the drug product and those which may not appear
but which are used in the manufacturing process, and, where applicable,
the quantitative composition of the investigational drug product,
including any reasonable variations that may be expected during the
investigational stage; the name and address of the drug product
manufacturer; a brief general description of the manufacturing and
packaging procedure as appropriate for the product; the acceptable
limits and analytical methods used to assure the identity, strength,
quality, and purity of the drug product; and information sufficient to
assure the product\'s stability during the planned clinical studies.
Reference to the current edition of the United States
Pharmacopeia\--National Formulary may satisfy certain requirements in
this paragraph.

\(c\) A brief general description of the composition, manufacture, and
control of any placebo used in a controlled clinical trial.

\(d\) Labeling. A copy of all labels and labeling to be provided to each
investigator.

\(e\) Environmental analysis requirements. A claim for categorical
exclusion under Sec. 25.30 or 25.31 or an environmental assessment under
Sec. 25.40.

\(8\) Pharmacology and toxicology information. Adequate information
about pharmacological and toxicological studies of the drug involving
laboratory animals or in vitro, on the basis of which the sponsor has
concluded that it is reasonably safe to conduct the proposed clinical

investigations. The kind, duration, and scope of animal and other tests
required varies with the duration and nature of the proposed clinical
investigations. Guidelines are available from FDA that describe ways in
which these requirements may be met. Such information is required to
include the identification and qualifications of the individuals who
evaluated the results of such studies and concluded that it is
reasonably safe to begin the proposed investigations and a statement of
where the investigations were conducted and where the records are
available for inspection. As drug development proceeds, the sponsor is
required to submit informational amendments, as appropriate, with
additional information pertinent to safety.

\(i\) Pharmacology and drug disposition. A section describing the
pharmacological effects and mechanism(s) of action of the drug in
animals, and information on the absorption, distribution, metabolism,
and excretion of the drug, if known.

\(ii\) Toxicology. (a) An integrated summary of the toxicological
effects of the drug in animals and in vitro. Depending on the nature of
the drug and the phase of the investigation, the description is to
include the results of acute, subacute, and chronic toxicity tests;
tests of the drug\'s effects on reproduction and the developing fetus;
any special toxicity test related to the drug\'s particular mode of
administration or conditions of use (e.g., inhalation, dermal, or ocular

toxicology); and any in vitro studies intended to evaluate drug
toxicity.

\(b\) For each toxicology study that is intended primarily to support
the safety of the proposed clinical investigation, a full tabulation of
data suitable for detailed review.

\(iii\) For each nonclinical laboratory study subject to the good
laboratory practice regulations under part 58, a statement that the
study was conducted in compliance with the good laboratory practice
regulations in part 58, or, if the study was not conducted in compliance
with those regulations, a brief statement of the reason for the
noncompliance.

\(9\) Previous human experience with the investigational drug. A summary
of previous human experience known to the applicant, if any, with the
investigational drug. The information is required to include the
following:

\(i\) If the investigational drug has been investigated or marketed
previously, either in the United States or other countries, detailed
information about such experience that is relevant to the safety of the
proposed investigation or to the investigation\'s rationale. If the drug
has been the subject of controlled trials, detailed information on such
trials that is relevant to an assessment of the drug\'s effectiveness
for the proposed investigational use(s) should also be provided. Any
published material that is relevant to the safety of the proposed
investigation or to an assessment of the drug\'s effectiveness for its
proposed investigational use should be provided in full. Published
material that is less directly relevant may be supplied by a
bibliography.

\(ii\) If the drug is a combination of drugs previously investigated or
marketed, the information required under paragraph (a)(9)(i) of this
section should be provided for each active drug component. However, if
any component in such combination is subject to an approved marketing
application or is otherwise lawfully marketed in the United States, the
sponsor is not required to submit published material concerning that
active drug component unless such material relates directly to the
proposed investigational use (including publications relevant to
component-component interaction).

\(iii\) If the drug has been marketed outside the United States, a list
of the countries in which the drug has been marketed and a list of the
countries in which the drug has been withdrawn from marketing for
reasons potentially related to safety or effectiveness.

\(10\) Additional information. In certain applications, as described
below, information on special topics may be needed. Such information
shall be submitted in this section as follows:

\(i\) Drug dependence and abuse potential. If the drug is a psychotropic
substance or otherwise has abuse potential, a section describing
relevant clinical studies and experience and studies in test animals.

\(ii\) Radioactive drugs. If the drug is a radioactive drug, sufficient
data from animal or human studies to allow a reasonable calculation of
radiation-absorbed dose to the whole body and critical organs upon
administration to a human subject. Phase 1 studies of radioactive drugs
must include studies which will obtain sufficient data for dosimetry
calculations.

\(iii\) Pediatric studies. Plans for assessing pediatric safety and
effectiveness.

\(iv\) Other information. A brief statement of any other information
that would aid evaluation of the proposed clinical investigations with
respect to their safety or their design and potential as controlled
clinical trials to support marketing of the drug.

\(11\) Relevant information. If requested by FDA, any other relevant
information needed for review of the application.

\(b\) Information previously submitted. The sponsor ordinarily is not
required to resubmit information previously submitted, but may
incorporate the information by reference. A reference to information
submitted previously must identify the file by name, reference number,
volume, and page number where the information can be found. A reference
to information submitted to the agency by a person other than the
sponsor is required to contain a written statement that authorizes the
reference and that is signed by the person who submitted the
information.

\(c\) Material in a foreign language. The sponsor shall submit an
accurate and complete English translation of each part of the IND that
is not in English. The sponsor shall also submit a copy of each original
literature publication for which an English translation is submitted.

\(d\) Number of copies. The sponsor shall submit an original and two
copies of all submissions to the IND file, including the original
submission and all amendments and reports.

\(e\) Numbering of IND submissions. Each submission relating to an IND
is required to be numbered serially using a single, three-digit serial
number. The initial IND is required to be numbered 000; each subsequent
submission (e.g., amendment, report, or correspondence) is required to
be numbered chronologically in sequence.

\(f\) Identification of exception from informed consent. If the
investigation involves an exception from informed consent under Sec.
50.24 of this chapter, the sponsor shall prominently identify on the
cover sheet that the investigation is subject to the requirements in
Sec. 50.24 of this chapter.

**Sec. 312.30 Protocol amendments.**

Once an IND is in effect, a sponsor shall amend it as needed to ensure
that the clinical investigations are conducted according to protocols
included in the application. This section sets forth the provisions
under which new protocols may be submitted and changes in previously
submitted protocols may be made. Whenever a sponsor intends to conduct a
clinical investigation with an exception from informed consent for
emergency research as set forth in Sec. 50.24 of this chapter, the
sponsor shall submit a separate IND for such investigation.

\(a\) New protocol. Whenever a sponsor intends to conduct a study that
is not covered by a protocol already contained in the IND, the sponsor
shall submit to FDA a protocol amendment containing the protocol for the
study. Such study may begin provided two conditions are met: (1) The
sponsor has submitted the protocol to FDA for its review; and (2) the
protocol has been approved by the Institutional Review Board (IRB) with
responsibility for review and approval of the study in accordance with
the requirements of part 56. The sponsor may comply with these two
conditions in either order.

\(b\) Changes in a protocol. (1) A sponsor shall submit a protocol
amendment describing any change in a Phase 1 protocol that significantly
affects the safety of subjects or any change in a Phase 2 or 3 protocol
that significantly affects the safety of subjects, the scope of the
investigation, or the scientific quality of the study. Examples of
changes requiring an amendment under this paragraph include:

\(i\) Any increase in drug dosage or duration of exposure of individual
subjects to the drug beyond that in the current protocol, or any
significant increase in the number of subjects under study.

\(ii\) Any significant change in the design of a protocol (such as the
addition or dropping of a control group).

\(iii\) The addition of a new test or procedure that is intended to
improve monitoring for, or reduce the risk of, a side effect or adverse
event; or the dropping of a test intended to monitor safety.

(2)(i) A protocol change under paragraph (b)(1) of this section may be
made provided two conditions are met:

\(a\) The sponsor has submitted the change to FDA for its review; and

\(b\) The change has been approved by the IRB with responsibility for

review and approval of the study. The sponsor may comply with these two
conditions in either order.

\(ii\) Notwithstanding paragraph (b)(2)(i) of this section, a protocol
change intended to eliminate an apparent immediate hazard to subjects
may be implemented immediately provided FDA is subsequently notified by
protocol amendment and the reviewing IRB is notified in accordance with
Sec. 56.104(c).

\(c\) New investigator. A sponsor shall submit a protocol amendment when
a new investigator is added to carry out a previously submitted
protocol, except that a protocol amendment is not required when a
licensed practitioner is added in the case of a treatment protocol under
Sec. 312.34. Once the investigator is added to the study, the
investigational drug may be shipped to the investigator and the
investigator may begin participating in the study. The sponsor shall
notify FDA of the new investigator within **30** days of the
investigator being added.

\(d\) Content and format. A protocol amendment is required to be
prominently identified as such (i.e., \`\`Protocol Amendment: New
Protocol\'\', \`\`Protocol Amendment: Change in Protocol\'\', or
\`\`Protocol Amendment: New Investigator\'\'), and to contain the
following:

(1)(i) In the case of a new protocol, a copy of the new protocol and a
brief description of the most clinically significant differences between
it and previous protocols.

\(ii\) In the case of a change in protocol, a brief description of the
change and reference (date and number) to the submission that contained
the protocol.

\(iii\) In the case of a new investigator, the investigator\'s name, the
qualifications to conduct the investigation, reference to the

previously submitted protocol, and all additional information about the
investigator\'s study as is required under Sec. 312.23(a)(6)(iii)(b).

\(2\) Reference, if necessary, to specific technical information in the
IND or in a concurrently submitted information amendment to the IND that
the sponsor relies on to support any clinically significant change in
the new or amended protocol. If the reference is made to supporting
information already in the IND, the sponsor shall identify by name,
reference number, volume, and page number the location of the
information.

\(3\) If the sponsor desires FDA to comment on the submission, a request
for such comment and the specific questions FDA\'s response should
address.

\(e\) When submitted. A sponsor shall submit a protocol amendment for a
new protocol or a change in protocol before its implementation. Protocol
amendments to add a new investigator or to provide additional
information about investigators may be grouped and submitted at
**30**-day intervals. When several submissions of new protocols or
protocol changes are anticipated during a short period, the sponsor is
encouraged, to the extent feasible, to include these all in a single
submission.

**Sec. 312.31 Information amendments.**

\(a\) Requirement for information amendment. A sponsor shall report in
an information amendment essential information on the IND that is not
within the scope of a protocol amendment, IND safety reports, or annual
report. Examples of information requiring an information amendment
include:

\(1\) New toxicology, chemistry, or other technical information; or

\(2\) A report regarding the discontinuance of a clinical investigation.

\(b\) Content and format of an information amendment. An information
amendment is required to bear prominent identification of its contents
(e.g., \`\`Information Amendment: Chemistry, Manufacturing, and
Control\'\', \`\`Information Amendment: Pharmacology-Toxicology\'\',
\`\`Information Amendment: Clinical\'\'), and to contain the following:

\(1\) A statement of the nature and purpose of the amendment.

\(2\) An organized submission of the data in a format appropriate for
scientific review.

\(3\) If the sponsor desires FDA to comment on an information amendment,
a request for such comment.

\(c\) When submitted. Information amendments to the IND should be
submitted as necessary but, to the extent feasible, not more than every
30 days.

**Sec. 312.32 IND safety reports.**

\(a\) Definitions. The following definitions of terms apply to this
section:- Associated with the use of the drug. There is a reasonable
possibility that the experience may have been caused by the drug.

Disability. A substantial disruption of a person\'s ability to conduct
normal life functions.

Life-threatening adverse drug experience. Any adverse drug experience
that places the patient or subject, in the view of the investigator, at
immediate risk of death from the reaction as it occurred, i.e., it does
not include a reaction that, had it occurred in a more severe form,
might have caused death.

Serious adverse drug experience: Any adverse drug experience occurring
at any dose that results in any of the following outcomes: Death, a
life-threatening adverse drug experience, inpatient hospitalization or
prolongation of existing hospitalization, a persistent or significant
disability/incapacity, or a congenital anomaly/birth defect. Important
medical events that may not result in death, be life-threatening, or
require hospitalization may be considered a serious adverse drug
experience when, based upon appropriate medical judgment, they may
jeopardize the patient or subject and may require medical or surgical
intervention to prevent one of the outcomes listed in this definition.
Examples of such medical events include allergic bronchospasm requiring
intensive treatment in an emergency room or at home, blood dyscrasias or
convulsions that do not result in inpatient hospitalization, or the
development of drug dependency or drug abuse.

Unexpected adverse drug experience: Any adverse drug experience, the
specificity or severity of which is not consistent with the current
investigator brochure; or, if an investigator brochure is not required
or available, the specificity or severity of which is not consistent
with the risk information described in the general investigational plan
or elsewhere in the current application, as amended. For example, under
this definition, hepatic necrosis would be unexpected (by virtue of
greater severity) if the investigator brochure only referred to elevated
hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and
cerebral vasculitis would be unexpected (by virtue of greater
specificity) if the investigator brochure only listed cerebral vascular
accidents. \`\`Unexpected,\'\' as used in this definition, refers to an
adverse drug experience that has not been previously observed (e.g.,
included in the investigator brochure) rather than from the perspective
of such experience not being anticipated from the pharmacological
properties of the pharmaceutical product.

\(b\) Review of safety information. The sponsor shall promptly review
all information relevant to the safety of the drug obtained or otherwise
received by the sponsor from any source, foreign or domestic, including
information derived from any clinical or epidemiological investigations,
animal investigations, commercial marketing experience, reports in the
scientific literature, and unpublished scientific papers, as well as
reports from foreign regulatory authorities that have not already been
previously reported to the agency by the sponsor.

\(c\) IND safety reports. (1) Written reports\--(i) The sponsor shall
notify FDA and all participating investigators in a written IND safety
report of:

\(A\) Any adverse experience associated with the use of the drug that is
both serious and unexpected; or

\(B\) Any finding from tests in laboratory animals that suggests a
significant risk for human subjects including reports of mutagenicity,
teratogenicity, or carcinogenicity. Each notification shall be made as
soon as possible and in no event later than 15 calendar days after the
sponsor\'s initial receipt of the information. Each written notification
may be submitted on FDA Form 3500A or in a narrative format (foreign
events may be submitted either on an FDA Form 3500A or, if preferred, on
a CIOMS I form; reports from animal or epidemiological studies shall be
submitted in a narrative format) and shall bear prominent identification
of its contents, i.e., \`\`IND Safety Report.\'\' Each written
notification to FDA shall be transmitted to the FDA new drug review
division in the Center for Drug Evaluation and Research or the product
review division in the Center for Biologics Evaluation and Research that
has responsibility for review of the IND. If FDA determines that
additional data are needed, the agency may require further data to be
submitted.

\(ii\) In each written IND safety report, the sponsor shall identify all
safety reports previously filed with the IND concerning a similar
adverse experience, and shall analyze the significance of the adverse
experience in light of the previouos, similar reports.

\(2\) Telephone and facsimile transmission safety reports. The sponsor
shall also notify FDA by telephone or by facsimile transmission of any
unexpected fatal or life-threatening experience associated with the use
of the drug as soon as possible but in no event later than 7 calendar
days after the sponsor\'s initial receipt of the information. Each
telephone call or facsimile transmission to FDA shall be transmitted to
the FDA new drug review division in the Center for Drug Evaluation and
Research or the product review division in the Center for Biologics
Evaluation and Research that has responsibility for review of the IND.

\(3\) Reporting format or frequency. FDA may request a sponsor to submit
IND safety reports in a format or at a frequency different than that
required under this paragraph. The sponsor may also propose and adopt a
different reporting format or frequency if the change is agreed to in
advance by the director of the new drug review division in the Center
for Drug Evaluation and Research or the director of the products review
division in the Center for Biologics Evaluation and Research which is
responsible for review of the IND.

\(4\) A sponsor of a clinical study of a marketed drug is not required
to make a safety report for any adverse experience associated with use
of the drug that is not from the clinical study itself.

\(d\) Followup. (1) The sponsor shall promptly investigate all safety
information received by it.

\(2\) Followup information to a safety report shall be submitted as soon
as the relevant information is available.

\(3\) If the results of a sponsor\'s investigation show that an adverse
drug experience not initially determined to be reportable under
paragraph (c) of this section is so reportable, the sponsor shall report
such experience in a written safety report as soon as possible, but in
no event later than 15 calendar days after the determination is made.

\(4\) Results of a sponsor\'s investigation of other safety information
shall be submitted, as appropriate, in an information amendment or
annual report.

\(e\) Disclaimer. A safety report or other information submitted by a
sponsor under this part (and any release by FDA of that report or
information) does not necessarily reflect a conclusion by the sponsor or
FDA that the report or information constitutes an admission that the
drug caused or contributed to an adverse experience. A sponsor need not
admit, and may deny, that the report or information submitted by the
sponsor constitutes an admission that the drug caused or contributed to
an adverse experience.

**Sec. 312.33 Annual reports.**

A sponsor shall within 60 days of the anniversary date that the IND went
into effect, submit a brief report of the progress of the investigation
that includes:

\(a\) Individual study information. A brief summary of the status of
each study in progress and each study completed during the previous
year. The summary is required to include the following information for
each study:

\(1\) The title of the study (with any appropriate study identifiers
such as protocol number), its purpose, a brief statement identifying the
patient population, and a statement as to whether the study is
completed.

\(2\) The total number of subjects initially planned for inclusion in
the study; the number entered into the study to date, tabulated by age
group, gender, and race; the number whose participation in the study was
completed as planned; and the number who dropped out of the study for
any reason.

\(3\) If the study has been completed, or if interim results are known,
a brief description of any available study results.

\(b\) Summary information. Information obtained during the previous
year\'s clinical and nonclinical investigations, including:

\(1\) A narrative or tabular summary showing the most frequent and most
serious adverse experiences by body system.

\(2\) A summary of all IND safety reports submitted during the past
year.

\(3\) A list of subjects who died during participation in the
investigation, with the cause of death for each subject.

\(4\) A list of subjects who dropped out during the course of the
investigation in association with any adverse experience, whether or not
thought to be drug related.

\(5\) A brief description of what, if anything, was obtained that is
pertinent to an understanding of the drug\'s actions, including, for
example, information about dose response, information from controlled
trails, and information about bioavailability.

\(6\) A list of the preclinical studies (including animal studies)
completed or in progress during the past year and a summary of the major
preclinical findings.

\(7\) A summary of any significant manufacturing or microbiological
changes made during the past year.

\(c\) A description of the general investigational plan for the coming
year to replace that submitted 1 year earlier. The general
investigational plan shall contain the information required under Sec.
312.23(a)(3)(iv).

\(d\) If the investigator brochure has been revised, a description of
the revision and a copy of the new brochure.

\(e\) A description of any significant Phase 1 protocol modifications
made during the previous year and not previously reported to the IND in
a protocol amendment.

\(f\) A brief summary of significant foreign marketing developments with
the drug during the past year, such as approval of marketing in any
country or withdrawal or suspension from marketing in any country.

\(g\) If desired by the sponsor, a log of any outstanding business with
respect to the IND for which the sponsor requests or expects a reply,
comment, or meeting.

**Sec. 312.34** **Treatment use of an investigational new drug.**

\(a\) General. A drug that is not approved for marketing may be under
clinical investigation for a serious or immediately life-threatening
disease condition in patients for whom no comparable or satisfactory
alternative drug or other therapy is available. During the clinical
investigation of the drug, it may be appropriate to use the drug in the
treatment of patients not in the clinical trials, in accordance with a
treatment protocol or treatment IND. The purpose of this section is to
facilitate the availability of promising new drugs to desperately ill
patients as early in the drug development process as possible, before
general marketing begins, and to obtain additional data on the drug\'s
safety and effectiveness. In the case of a serious disease, a drug
ordinarily may be made available for treatment use under this section
during Phase 3 investigations or after all clinical trials have been
completed; however, in appropriate circumstances, a drug may be made
available for treatment use during Phase 2. In the case of an
immediately life-threatening disease, a drug may be made available for
treatment use under this section earlier than Phase 3, but ordinarily
not earlier than Phase 2. For purposes of this section, the
\`\`treatment use\'\' of a drug includes the use of a drug for
diagnostic purposes. If a protocol for an investigational drug meets the
criteria of this section, the protocol is to be submitted as a treatment
protocol under the provisions of this section.

\(b\) Criteria. (1) FDA shall permit an investigational drug to be used
for a treatment use under a treatment protocol or treatment IND if:

\(i\) The drug is intended to treat a serious or immediately
life-threatening disease;

\(ii\) There is no comparable or satisfactory alternative drug or other
therapy available to treat that stage of the disease in the intended
patient population;

\(iii\) The drug is under investigation in a controlled clinical trial
under an IND in effect for the trial, or all clinical trials have been
completed; and

\(iv\) The sponsor of the controlled clinical trial is actively pursuing
marketing approval of the investigational drug with due diligence.

\(2\) Serious disease. For a drug intended to treat a serious disease,
the Commissioner may deny a request for treatment use under a treatment
protocol or treatment IND if there is insufficient evidence of safety
and effectiveness to support such use.

\(3\) Immediately life-threatening disease. (i) For a drug intended to
treat an immediately life-threatening disease, the Commissioner may deny
a request for treatment use of an investigational drug under a treatment
protocol or treatment IND if the available scientific evidence, taken as
a whole, fails to provide a reasonable basis for concluding that the
drug:

\(A\) May be effective for its intended use in its intended patient
population; or

\(B\) Would not expose the patients to whom the drug is to be
administered to an unreasonable and significant additional risk of
illness or injury.

\(ii\) For the purpose of this section, an \`\`immediately
life-threatening\'\' disease means a stage of a disease in which there
is a reasonable likelihood that death will occur within a matter of
months or in which premature death is likely without early treatment.

\(c\) Safeguards. Treatment use of an investigational drug is
conditioned on the sponsor and investigators complying with the
safeguards of the IND process, including the regulations governing
informed consent (21 CFR part 50) and institutional review boards (21
CFR part 56) and the applicable provisions of part 312, including
distribution of the drug through qualified experts, maintenance of
adequate manufacturing facilities, and submission of IND safety reports.

\(d\) Clinical hold. FDA may place on clinical hold a proposed or
ongoing treatment protocol or treatment IND in accordance with Sec.
312.42.

**Sec. 312.35 Submissions for treatment use.**

\(a\) Treatment protocol submitted by IND sponsor. Any sponsor of a
clinical investigation of a drug who intends to sponsor a treatment use
for the drug shall submit to FDA a treatment protocol under Sec. 312.34
if the sponsor believes the criteria of Sec. 312.34 are satisfied. If a
protocol is not submitted under Sec. 312.34, but FDA believes that the
protocol should have been submitted under this section, FDA may deem the
protocol to be submitted under Sec. 312.34. A treatment use under a
treatment protocol may begin 30 days after FDA receives the protocol or
on earlier notification by FDA that the treatment use described in the
protocol may begin.

\(1\) A treatment protocol is required to contain the following:

\(i\) The intended use of the drug.

\(ii\) An explanation of the rationale for use of the drug, including,
as appropriate, either a list of what available regimens ordinarily
should be tried before using the investigational drug or an explanation
of why the use of the investigational drug is preferable to the use of
available marketed treatments.

\(iii\) A brief description of the criteria for patient selection.

\(iv\) The method of administration of the drug and the dosages.

\(v\) A description of clinical procedures, laboratory tests, or other
measures to monitor the effects of the drug and to minimize risk.

\(2\) A treatment protocol is to be supported by the following:

\(i\) Informational brochure for supplying to each treating physician.

\(ii\) The technical information that is relevant to safety and
effectiveness of the drug for the intended treatment purpose.
Information contained in the sponsor\'s IND may be incorporated by

reference.

\(iii\) A commitment by the sponsor to assure compliance of all
participating investigators with the informed consent requirements of 21
CFR part 50.

\(3\) A licensed practitioner who receives an investigational drug for
treatment use under a treatment protocol is an \`\`investigator\'\'
under the protocol and is responsible for meeting all applicable
investigator responsibilities under this part and 21 CFR parts 50 and
56.

\(b\) Treatment IND submitted by licensed practitioner. (1) If a
licensed medical practitioner wants to obtain an investigational drug
subject to a controlled clinical trial for a treatment use, the
practitioner should first attempt to obtain the drug from the sponsor of
the controlled trial under a treatment protocol. If the sponsor of the
controlled clinical investigation of the drug will not establish a
treatment protocol for the drug under paragraph (a) of this section, the
licensed medical practitioner may seek to obtain the drug from the
sponsor and submit a treatment IND to FDA requesting authorization to
use the investigational drug for treatment use. A treatment use under a
treatment IND may begin 30 days after FDA receives the IND or on earlier
notification by FDA that the treatment use under the IND may begin. A
treatment IND is required to contain the following:

\(i\) A cover sheet (Form FDA 1571) meeting Sec. 312.23(g)(1).

\(ii\) Information (when not provided by the sponsor) on the drug\'s
chemistry, manufacturing, and controls, and prior clinical and
nonclinical experience with the drug submitted in accordance with Sec.
312.23. A sponsor of a clinical investigation subject to an IND who
supplies an investigational drug to a licensed medical practitioner for
purposes of a separate treatment clinical investigation shall be deemed
to authorize the incorporation-by-reference of the technical information
contained in the sponsor\'s IND into the medical practitioner\'s
treatment IND.

\(iii\) A statement of the steps taken by the practitioner to obtain the
drug under a treatment protocol from the drug sponsor.

\(iv\) A treatment protocol containing the same information listed in
paragraph (a)(1) of this section.

\(v\) A statement of the practitioner\'s qualifications to use the
investigational drug for the intended treatment use.

\(vi\) The practitioner\'s statement of familiarity with information on
the drug\'s safety and effectiveness derived from previous clinical and
nonclinical experience with the drug.

\(vii\) Agreement to report to FDA safety information in accordance with
Sec. 312.32.

\(2\) A licensed practitioner who submits a treatment IND under this
section is the sponsor-investigator for such IND and is responsible for
meeting all applicable sponsor and investigator responsibilities under
this part and 21 CFR parts 50 and 56.

**Sec. 312.36 Emergency use of an investigational new drug.**

Need for an investigational drug may arise in an emergency situation
that does not allow time for submission of an IND in accordance with
Sec. 312.23 or Sec. 312.34. In such a case, FDA may authorize shipment
of the drug for a specified use in advance of submission of an IND. A
request for such authorization may be transmitted to FDA by telephone or
other rapid communication means. For investigational biological drugs,
the request should be directed to the Division of Biological
Investigational New Drugs (HFB-230), Center for Biologics Evaluation and
Research, 8800 Rockville Pike, Bethesda, MD 20892, 301-443-4864. For all
other investigational drugs, the request for authorization should be
directed to the Document Management and Reporting Branch (HFD-53),
Center for Drug Evaluation and Research, 5600 Fishers Lane, Rockville,
MD 20857, 301-443-4320. After normal working hours, eastern standard
time, the request should be directed to the FDA Division of Emergency
and Epidemiological Operations, 202-857-8400. Except in extraordinary
circumstances, such authorization will be conditioned on the sponsor
making an appropriate IND submission as soon as practicable after
receiving the authorization.

**Sec. 312.38** **Withdrawal of an IND.**

\(a\) At any time a sponsor may withdraw an effective IND without
prejudice.

\(b\) If an IND is withdrawn, FDA shall be so notified, all clinical
investigations conducted under the IND shall be ended, all current
investigators notified, and all stocks of the drug returned to the
sponsor or otherwise disposed of at the request of the sponsor in
accordance with Sec. 312.59.

\(c\) If an IND is withdrawn because of a safety reason, the sponsor
shall promptly so inform FDA, all participating investigators, and all
reviewing Institutional Review Boards, together with the reasons for
such withdrawal.

**Sec. 312.40** **General requirements for use of an investigational new
drug in a clinical investigation.**

\(a\) An investigational new drug may be used in a clinical
investigation if the following conditions are met:

\(1\) The sponsor of the investigation submits an IND for the drug to
FDA; the IND is in effect under paragraph (b) of this section; and the
sponsor complies with all applicable requirements in this part and parts
50 and 56 with respect to the conduct of the clinical investigations;
and

\(2\) Each participating investigator conducts his or her investigation
in compliance with the requirements of this part and parts 50 and 56.

\(b\) An IND goes into effect:

\(1\) Thirty days after FDA receives the IND, unless FDA notifies the
sponsor that the investigations described in the IND are subject to a
clinical hold under Sec. 312.42; or

\(2\) On earlier notification by FDA that the clinical investigations in
the IND may begin. FDA will notify the sponsor in writing of the date it
receives the IND.

\(c\) A sponsor may ship an investigational new drug to investigators
named in the IND:

\(1\) Thirty days after FDA receives the IND; or

\(2\) On earlier FDA authorization to ship the drug.

\(d\) An investigator may not administer an investigational new drug to
human subjects until the IND goes into effect under paragraph (b) of
this section.

**Sec. 312.41** **Comment and advice on an IND.**

\(a\) FDA may at any time during the course of the investigation
communicate with the sponsor orally or in writing about deficiencies in
the IND or about FDA\'s need for more data or information.

\(b\) On the sponsor\'s request, FDA will provide advice on specific
matters relating to an IND. Examples of such advice may include advice
on the adequacy of technical data to support an investigational plan, on
the design of a clinical trial, and on whether proposed investigations
are likely to produce the data and information that is needed to meet
requirements for a marketing application.

\(c\) Unless the communication is accompanied by a clinical hold order
under Sec. 312.42, FDA communications with a sponsor under this section
are solely advisory and do not require any modification in the planned
or ongoing clinical investigations or response to the agency.

**Subpart C\--Administrative Actions**

**Sec. 312.42 Clinical holds and requests for modification.**

\(a\) General. A clinical hold is an order issued by FDA to the sponsor
to delay a proposed clinical investigation or to suspend an ongoing
investigation. The clinical hold order may apply to one or more of the
investigations covered by an IND. When a proposed study is placed on
clinical hold, subjects may not be given the investigational drug. When
an ongoing study is placed on clinical hold, no new subjects may be
recruited to the study and placed on the investigational drug; patients
already in the study should be taken off therapy involving the
investigational drug unless specifically permitted by FDA in the
interest of patient safety.

\(b\) Grounds for imposition of clinical hold\--(1) Clinical hold of a
Phase 1 study under an IND. FDA may place a proposed or ongoing Phase 1
investigation on clinical hold if it finds that:

\(i\) Human subjects are or would be exposed to an unreasonable and
significant risk of illness or injury;

\(ii\) The clinical investigators named in the IND are not qualified by
reason of their scientific training and experience to conduct the
investigation described in the IND;

\(iii\) The investigator brochure is misleading, erroneous, or
materially incomplete; or

\(iv\) The IND does not contain sufficient information required under
Sec. 312.23 to assess the risks to subjects of the proposed studies.

\(2\) Clinical hold of a Phase 2 or 3 study under an IND. FDA may place
a proposed or ongoing Phase 2 or 3 investigation on clinical hold if it
finds that:

\(i\) Any of the conditions in paragraph (b)(1)(i) through (iv) of this
section apply; or

\(ii\) The plan or protocol for the investigation is clearly deficient
in design to meet its stated objectives.

\(3\) Clinical hold of a treatment IND or treatment protocol.

\(i\) Proposed use. FDA may place a proposed treatment IND or treatment
protocol on clinical hold if it is determined that:

\(A\) The pertinent criteria in Sec. 312.34(b) for permitting the
treatment use to begin are not satisfied; or

\(B\) The treatment protocol or treatment IND does not contain the
information required under Sec. 312.35 (a) or (b) to make the specified
determination under Sec. 312.34(b).

\(ii\) Ongoing use. FDA may place an ongoing treatment protocol or
treatment IND on clinical hold if it is determined that:

\(A\) There becomes available a comparable or satisfactory alternative
drug or other therapy to treat that stage of the disease in the intended
patient population for which the investigational drug is being used;

\(B\) The investigational drug is not under investigation in a
controlled clinical trial under an IND in effect for the trial and not
all controlled clinical trials necessary to support a marketing
application have been completed, or a clinical study under the IND has
been placed on clinical hold:

\(C\) The sponsor of the controlled clinical trial is not pursuing
marketing approval with due diligence;

\(D\) If the treatment IND or treatment protocol is intended for a
serious disease, there is insufficient evidence of safety and
effectiveness to support such use; or

\(E\) If the treatment protocol or treatment IND was based on an
immediately life-threatening disease, the available scientific evidence,
taken as a whole, fails to provide a reasonable basis for concluding
that the drug:

\(1\) May be effective for its intended use in its intended population;
or

\(2\) Would not expose the patients to whom the drug is to be
administered to an unreasonable and significant additional risk of
illness or injury.

\(iii\) FDA may place a proposed or ongoing treatment IND or treatment
protocol on clinical hold if it finds that any of the conditions in
paragraph (b)(4)(i) through (b)(4)(viii) of this section apply.

\(4\) Clinical hold of any study that is not designed to be adequate and
well-controlled. FDA may place a proposed or ongoing investigation that
is not designed to be adequate and well-controlled on clinical hold if
it finds that:

\(i\) Any of the conditions in paragraph (b)(1) or (b)(2) of this
section apply; or

\(ii\) There is reasonable evidence the investigation that is not
designed to be adequate and well-controlled is impeding enrollment in,
or otherwise interfering with the conduct or completion of, a study that
is designed to be an adequate and well-controlled investigation of the
same or another investigational drug; or

\(iii\) Insufficient quantities of the investigational drug exist to
adequately conduct both the investigation that is not designed to be
adequate and well-controlled and the investigations that are designed to
be adequate and well-controlled; or

\(iv\) The drug has been studied in one or more adequate and
well-controlled investigations that strongly suggest lack of
effectiveness; or

\(v\) Another drug under investigation or approved for the same
indication and available to the same patient population has demonstrated
a better potential benefit/risk balance; or

\(vi\) The drug has received marketing approval for the same indication
in the same patient population; or

\(vii\) The sponsor of the study that is designed to be an adequate and
well-controlled investigation is not actively pursuing marketing
approval of the investigational drug with due diligence; or

\(viii\) The Commissioner determines that it would not be in the public
interest for the study to be conducted or continued. FDA ordinarily
intends that clinical holds under paragraphs (b)(4)(ii), (b)(4)(iii) and
(b)(4)(v) of this section would only apply to additional enrollment in
nonconcurrently controlled trials rather than eliminating continued
access to individuals already receiving the investigational drug.

\(5\) Clinical hold of any investigation involving an exception from
informed consent under Sec. 50.24 of this chapter. FDA may place a
proposed or ongoing investigation involving an exception from informed
consent under Sec. 50.24 of this chapter on clinical hold if it is
determined that:

\(i\) Any of the conditions in paragraphs (b)(1) or (b)(2) of this

section apply; or

\(ii\) The pertinent criteria in Sec. 50.24 of this chapter for such an
investigation to begin or continue are not submitted or not satisfied.

\(6\) Clinical hold of any investigation involving an exception from
informed consent under Sec. 50.23(d) of this chapter. FDA may place a
proposed or ongoing investigation involving an exception from informed
consent under Sec. 50.23(d) of this chapter on clinical hold if it is
determined that:

\(i\) Any of the conditions in paragraphs (b)(1) or (b)(2) of this
section apply; or

\(ii\) A determination by the President to waive the prior consent
requirement for the administration of an investigational new drug has
not been made.

\(c\) Discussion of deficiency. Whenever FDA concludes that a deficiency
exists in a clinical investigation that may be grounds for the
imposition of clinical hold FDA will, unless patients are exposed to
immediate and serious risk, attempt to discuss and satisfactorily
resolve the matter with the sponsor before issuing the clinical hold
order.

\(d\) Imposition of clinical hold. The clinical hold order may be made
by telephone or other means of rapid communication or in writing. The
clinical hold order will identify the studies under the IND to which the
hold applies, and will briefly explain the basis for the action. The
clinical hold order will be made by or on behalf of the Division
Director with responsibility for review of the IND. As soon as possible,
and no more than 30 days after imposition of the clinical hold, the
Division Director will provide the sponsor a written explanation of the
basis for the hold.

\(e\) Resumption of clinical investigations. An investigation may only
resume after FDA (usually the Division Director, or the Director\'s
designee, with responsibility for review of the IND) has notified the
sponsor that the investigation may proceed. Resumption of the affected
investigation(s) will be authorized when the sponsor corrects the
deficiency(ies) previously cited or otherwise satisfies the agency that
the investigation(s) can proceed. FDA may notify a sponsor of its
determination regarding the clinical hold by telephone or other means of
rapid communication. If a sponsor of an IND that has been placed on
clinical hold requests in writing that the clinical hold be removed and
submits a complete response to the issue(s) identified in the clinical
hold order, FDA shall respond in writing to the sponsor within
30-calendar days of receipt of the request and the complete response.
FDA\'s response will either remove or maintain the clinical hold, and
will state the reasons for such determination. Notwithstanding the
30-calendar day response time, a sponsor may not proceed with a clinical
trial on which a clinical hold has been imposed until the sponsor has
been notified by FDA that the hold has been lifted.

\(f\) Appeal. If the sponsor disagrees with the reasons cited for the
clinical hold, the sponsor may request reconsideration of the decision
in accordance with Sec. 312.48.

\(g\) Conversion of IND on clinical hold to inactive status. If all
investigations covered by an IND remain on clinical hold for 1 year or
more, the IND may be placed on inactive status by FDA under Sec. 312.45.

**Sec. 312.44 Termination.**

\(a\) General. This section describes the procedures under which FDA may
terminate an IND. If an IND is terminated, the sponsor shall end all
clinical investigations conducted under the IND and recall or otherwise
provide for the disposition of all unused supplies of the drug. A
termination action may be based on deficiencies in the IND or in the
conduct of an investigation under an IND. Except as provided in
paragraph (d) of this section, a termination shall be preceded by a
proposal to terminate by FDA and an opportunity for the sponsor to
respond. FDA will, in general, only initiate an action under this
section after first attempting to resolve differences informally or,
when appropriate, through the clinical hold procedures described in Sec.
312.42.

\(b\) Grounds for termination\--(1) Phase 1. FDA may propose to
terminate an IND during Phase 1 if it finds that:

\(i\) Human subjects would be exposed to an unreasonable and significant
risk of illness or unjury.

\(ii\) The IND does not contain sufficient information required under
Sec. 312.23 to assess the safety to subjects of the clinical
investigations.

\(iii\) The methods, facilities, and controls used for the
manufacturing, processing, and packing of the investigational drug are
inadequate to establish and maintain appropriate standards of identity,
strength, quality, and purity as needed for subject safety.

\(iv\) The clinical investigations are being conducted in a manner
substantially different than that described in the protocols submitted
in the IND.

\(v\) The drug is being promoted or distributed for commercial purposes
not justified by the requirements of the investigation or permitted by
Sec. 312.7.

\(vi\) The IND, or any amendment or report to the IND, contains an
untrue statement of a material fact or omits material information
required by this part.

\(vii\) The sponsor fails promptly to investigate and inform the Food
and Drug Administration and all investigators of serious and unexpected
adverse experiences in accordance with Sec. 312.32 or fails to make any
other report required under this part.

\(viii\) The sponsor fails to submit an accurate annual report of the
investigations in accordance with Sec. 312.33.

\(ix\) The sponsor fails to comply with any other applicable requirement
of this part, part 50, or part 56.

\(x\) The IND has remained on inactive status for 5 years or more.

\(xi\) The sponsor fails to delay a proposed investigation under the IND
or to suspend an ongoing investigation that has been placed on clinical
hold under Sec. 312.42(b)(4).

\(2\) Phase 2 or 3. FDA may propose to terminate an IND during Phase 2
or Phase 3 if FDA finds that:

\(i\) Any of the conditions in paragraphs (b)(1)(i) through (b)(1)(xi)
of this section apply; or

\(ii\) The investigational plan or protocol(s) is not reasonable as a
bona fide scientific plan to determine whether or not the drug is safe
and effective for use; or

\(iii\) There is convincing evidence that the drug is not effective for
the purpose for which it is being investigated.

\(3\) FDA may propose to terminate a treatment IND if it finds that:

\(i\) Any of the conditions in paragraphs (b)(1)(i) through (x) of

this section apply; or

\(ii\) Any of the conditions in Sec. 312.42(b)(3) apply.

\(c\) Opportunity for sponsor response. (1) If FDA proposes to terminate
an IND, FDA will notify the sponsor in writing, and invite correction or
explanation within a period of 30 days.

\(2\) On such notification, the sponsor may provide a written
explanation or correction or may request a conference with FDA to
provide the requested explanation or correction. If the sponsor does not
respond to the notification within the allocated time, the IND shall be
terminated.

\(3\) If the sponsor responds but FDA does not accept the explanation or
correction submitted, FDA shall inform the sponsor in writing of the
reason for the nonacceptance and provide the sponsor with an opportunity
for a regulatory hearing before FDA under part 16 on the question of
whether the IND should be terminated. The sponsor\'s request for a
regulatory hearing must be made within 10 days of the sponsor\'s receipt
of FDA\'s notification of nonacceptance.

\(d\) Immediate termination of IND. Notwithstanding paragraphs (a)
through (c) of this section, if at any time FDA concludes that
continuation of the investigation presents an immediate and substantial
danger to the health of individuals, the agency shall immediately, by
written notice to the sponsor from the Director of the Center for Drug
Evaluation and Research or the Director of the Center for Biologics
Evaluation and Research, terminate the IND. An IND so terminated is
subject to reinstatement by the Director on the basis of additional
submissions that eliminate such danger. If an IND is terminated under
this paragraph, the agency will afford the sponsor an opportunity for a
regulatory hearing under part 16 on the question of whether the IND
should be reinstated.

**Sec. 312.47** **Meetings.**

\(a\) General. Meetings between a sponsor and the agency are frequently
useful in resolving questions and issues raised during the course of a
clinical investigation. FDA encourages such meetings to the extent that
they aid in the evaluation of the drug and in the solution of scientific
problems concerning the drug, to the extent that FDA\'s resources
permit. The general principle underlying the conduct of such meetings is
that there should be free, full, and open communication about any
scientific or medical question that may arise during the clinical
investigation. These meetings shall be conducted and documented in
accordance with part 10.

\(b\) \`\`End-of-Phase 2\'\' meetings and meetings held before
submission of a marketing application. At specific times during the drug
investigation process, meetings between FDA and a sponsor can be
especially helpful in minimizing wasteful expenditures of time and money
and thus in speeding the drug development and evaluation process. In
particular, FDA has found that meetings at the end of Phase 2 of an
investigation (end-of-Phase 2 meetings) are of considerable assistance
in planning later studies and that meetings held near completion of
Phase 3 and before submission of a marketing application
(\`\`pre-NDA\'\' meetings) are helpful in developing methods of
presentation and submission of data in the marketing application that
facilitate review and allow timely FDA response.

\(1\) End-of-Phase 2 meetings\--(i) Purpose. The purpose of an
end-of-phase 2 meeting is to determine the safety of proceeding to Phase
3, to evaluate the Phase 3 plan and protocols and the adequacy of
current studies and plans to assess pediatric safety and effectiveness,
and to identify any additional information necessary to support a
marketing application for the uses under investigation.

\(ii\) Eligibility for meeting. While the end-of-Phase 2 meeting is
designed primarily for IND\'s involving new molecular entities or major
new uses of marketed drugs, a sponsor of any IND may request and obtain
an end-of-Phase 2 meeting.

\(iii\) Timing. To be most useful to the sponsor, end-of-Phase 2
meetings should be held before major commitments of effort and resources
to specific Phase 3 tests are made. The scheduling of an end-of-Phase 2
meeting is not, however, intended to delay the transition of an
investigation from Phase 2 to Phase 3.

\(iv\) Advance information. At least 1 month in advance of an
end-of-Phase 2 meeting, the sponsor should submit background information
on the sponsor\'s plan for Phase 3, including summaries of the Phase 1
and 2 investigations, the specific protocols for Phase 3 clinical
studies, plans for any additional nonclinical studies, plans for
pediatric studies, including a time line for protocol finalization,
enrollment, completion, and data analysis, or information to support any
planned request for waiver or deferral of pediatric studies, and, if
available, tentative labeling for the drug. The recommended contents of
such a submission are described more fully in FDA Staff Manual Guide
4850.7 that is publicly available under FDA\'s public information
regulations in

part 20.

\(v\) Conduct of meeting. Arrangements for an end-of-Phase 2 meeting are
to be made with the division in FDA\'s Center for Drug Evaluation and
Research or the Center for Biologics Evaluation and Research which is
responsible for review of the IND. The meeting will be scheduled by FDA
at a time convenient to both FDA and the sponsor. Both the sponsor and
FDA may bring consultants to the meeting. The meeting should be directed
primarily at establishing agreement between FDA and the sponsor of the
overall plan for Phase 3 and the objectives and design of particular
studies. The adequacy of the technical information to support Phase 3
studies and/or a marketing application may also be discussed. FDA will
also provide its best judgment, at that time, of the pediatric studies
that will be required for the drug product and whether their submission
will be deferred until after approval. Agreements reached at the meeting
on these matters will be recorded in minutes of the conference that will
be taken by FDA in accordance with Sec. 10.65 and provided to the
sponsor. The minutes along with any other written material provided to
the sponsor will serve as a permanent record of any agreements reached.
Barring a significant scientific development that requires otherwise,
studies conducted in accordance with the agreement shall be presumed to
be sufficient in objective and design for the purpose of obtaining
marketing approval for the drug.

\(2\) \`\`Pre-NDA\'\' and \`\`pre-BLA\'\' meetings. FDA has found that
delays associated with the initial review of a marketing application may
be reduced by exchanges of information about a proposed marketing
application. The primary purpose of this kind of exchange is to uncover
any major unresolved problems, to identify those studies that the
sponsor is relying on as adequate and well-controlled to establish the
drug\'s effectiveness, to identify the status of ongoing or needed
studies adequate to assess pediatric safety and effectiveness, to
acquaint FDA reviewers with the general information to be submitted in
the marketing application (including technical information), to discuss
appropriate methods for statistical analysis of the data, and to discuss
the best approach to the presentation and formatting of data in the
marketing application. Arrangements for such a meeting are to be
initiated by the sponsor with the division responsible for review of the
IND. To permit FDA to provide the sponsor with the most useful advice on
preparing a marketing application, the sponsor should submit to FDA\'s
reviewing division at least 1 month in advance of the meeting the
following information:

\(i\) A brief summary of the clinical studies to be submitted in the
application.

\(ii\) A proposed format for organizing the submission, including
methods for presenting the data.

\(iii\) Information on the status of needed or ongoing pediatric
studies.

\(iv\) Any other information for discussion at the meeting.

Subpart C\--Administrative Actions

**Sec. 312.48** **Dispute resolution.**

\(a\) General. The Food and Drug Administration is committed to
resolving differences between sponsors and FDA reviewing divisions with
respect to requirements for IND\'s as quickly and amicably as possible
through the cooperative exchange of information and views.

\(b\) Administrative and procedural issues. When administrative or
procedural disputes arise, the sponsor should first attempt to resolve
the matter with the division in FDA\'s Center for Drug Evaluation and
Research or Center for Biologics Evaluation and Research which is
responsible for review of the IND, beginning with the consumer safety
officer assigned to the application. If the dispute is not resolved, the
sponsor may raise the matter with the person designated as ombudsman,
whose function shall be to investigate what has happened and to
facilitate a timely and equitable resolution. Appropriate issues to
raise with the ombudsman include resolving difficulties in scheduling
meetings and obtaining timely replies to inquiries. Further details on
this procedure are contained in FDA Staff Manual Guide 4820.7 that is
publicly available under FDA\'s public information regulations in part
20.

\(c\) Scientific and medical disputes. (1) When scientific or medical
disputes arise during the drug investigation process, sponsors should
discuss the matter directly with the responsible reviewing officials. If
necessary, sponsors may request a meeting with the appropriate reviewing
officials and management representatives in order to seek a resolution.
Requests for such meetings shall be directed to the director of the
division in FDA\'s Center for Drug Evaluation and Research or Center for
Biologics Evaluation and Research which is responsible for review of the
IND. FDA will make every attempt to grant requests for meetings that
involve important issues and that can be scheduled at mutually
convenient times.

\(2\) The \`\`end-of-Phase 2\'\' and \`\`pre-NDA\'\' meetings described
in Sec. 312.47(b) will also provide a timely forum for discussing and
resolving scientific and medical issues on which the sponsor disagrees
with the agency.

\(3\) In requesting a meeting designed to resolve a scientific or
medical dispute, applicants may suggest that FDA seek the advice of
outside experts, in which case FDA may, in its discretion, invite to the
meeting one or more of its advisory committee members or other
consultants, as designated by the agency. Applicants may rely on, and
may bring to any meeting, their own consultants. For major scientific
and medical policy issues not resolved by informal meetings, FDA may
refer the matter to one of its standing advisory committees for its
consideration and recommendations.

**Subpart D\--Responsibilities of Sponsors and Investigators**

**Sec. 312.50 General responsibilities of sponsors.**

Sponsors are responsible for selecting qualified investigators,
providing them with the information they need to conduct an
investigation properly, ensuring proper monitoring of the
investigation(s), ensuring that the investigation(s) is conducted in
accordance with the general investigational plan and protocols contained
in the IND, maintaining an effective IND with respect to the
investigations, and ensuring that FDA and all participating
investigators are promptly informed of significant new adverse effects
or risks with respect to the drug. Additional specific responsibilities
of sponsors are described elsewhere in this part.

**Sec. 312.52** **Transfer of obligations to a contract research
organization.**

\(a\) A sponsor may transfer responsibility for any or all of the
obligations set forth in this part to a contract research organization.
Any such transfer shall be described in writing. If not all obligations
are transferred, the writing is required to describe each of the
obligations being assumed by the contract research organization. If all
obligations are transferred, a general statement that all obligations
have been transferred is acceptable. Any obligation not covered by the
written description shall be deemed not to have been transferred.

\(b\) A contract research organization that assumes any obligation of a
sponsor shall comply with the specific regulations in this chapter
applicable to this obligation and shall be subject to the same
regulatory action as a sponsor for failure to comply with any obligation
assumed under these regulations. Thus, all references to \`\`sponsor\'\'
in this part apply to a contract research organization to the extent
that it assumes one or more obligations of the sponsor.

**Sec. 312.53 Selecting investigators and monitors.**

\(a\) Selecting investigators. A sponsor shall select only investigators
qualified by training and experience as appropriate experts to
investigate the drug.

\(b\) Control of drug. A sponsor shall ship investigational new drugs
only to investigators participating in the investigation.

\(c\) Obtaining information from the investigator. Before permitting an
investigator to begin participation in an investigation, the sponsor
shall obtain the following:

\(1\) A signed investigator statement (Form FDA-1572) containing:

\(i\) The name and address of the investigator;

\(ii\) The name and code number, if any, of the protocol(s) in the IND
identifying the study(ies) to be conducted by the investigator;

\(iii\) The name and address of any medical school, hospital, or other
research facility where the clinical investigation(s) will be conducted;

\(iv\) The name and address of any clinical laboratory facilities to be
used in the study;

\(v\) The name and address of the IRB that is responsible for review and
approval of the study(ies);

\(vi\) A commitment by the investigator that he or she:

\(a\) Will conduct the study(ies) in accordance with the relevant,
current protocol(s) and will only make changes in a protocol after
notifying the sponsor, except when necessary to protect the safety, the
rights, or welfare of subjects;

\(b\) Will comply with all requirements regarding the obligations of
clinical investigators and all other pertinent requirements in this
part;

\(c\) Will personally conduct or supervise the described
investigation(s);

\(d\) Will inform any potential subjects that the drugs are being used
for investigational purposes and will ensure that the requirements
relating to obtaining informed consent (21 CFR part 50) and
institutional review board review and approval (21 CFR part 56) are met;

\(e\) Will report to the sponsor adverse experiences that occur in the
course of the investigation(s) in accordance with Sec. 312.64;

\(f\) Has read and understands the information in the investigator\'s
brochure, including the potential risks and side effects of the drug;
and

\(g\) Will ensure that all associates, colleagues, and employees
assisting in the conduct of the study(ies) are informed about their
obligations in meeting the above commitments.

\(vii\) A commitment by the investigator that, for an investigation
subject to an institutional review requirement under part 56, an IRB
that complies with the requirements of that part will be responsible for
the initial and continuing review and approval of the clinical
investigation and that the investigator will promptly report to the IRB
all changes in the research activity and all unanticipated problems
involving risks to human subjects or others, and will not make any
changes in the research without IRB approval, except where necessary to
eliminate apparent immediate hazards to the human subjects. (viii) A
list of the names of the subinvestigators (e.g., research fellows,
residents) who will be assisting the investigator in the conduct of the
investigation(s).

\(2\) Curriculum vitae. A curriculum vitae or other statement of
qualifications of the investigator showing the education, training, and
experience that qualifies the investigator as an expert in the clinical
investigation of the drug for the use under investigation.

\(3\) Clinical protocol. (i) For Phase 1 investigations, a general
outline of the planned investigation including the estimated duration of
the study and the maximum number of subjects that will be involved.

\(ii\) For Phase 2 or 3 investigations, an outline of the study protocol
including an approximation of the number of subjects to be treated with
the drug and the number to be employed as controls, if any; the clinical
uses to be investigated; characteristics of subjects by age, sex, and
condition; the kind of clinical observations and laboratory tests to be
conducted; the estimated duration of the study; and copies or a
description of case report forms to be used.

\(4\) Financial disclosure information. Sufficient accurate financial
information to allow the sponsor to submit complete and accurate
certification or disclosure statements required under part 54 of this
chapter. The sponsor shall obtain a commitment from the clinical
investigator to promptly update this information if any relevant changes
occur during the course of the investigation and for 1 year following
the completion of the study.

\(d\) Selecting monitors. A sponsor shall select a monitor qualified by
training and experience to monitor the progress of the investigation.

**Sec. 312.54** **Emergency research under Sec. 50.24 of this chapter.**

\(a\) The sponsor shall monitor the progress of all investigations
involving an exception from informed consent under Sec. 50.24 of this
chapter. When the sponsor receives from the IRB information concerning
the public disclosures required by Sec. 50.24(a)(7)(ii) and (a)(7)(iii)
of this chapter, the sponsor promptly shall submit to the IND file and
to Docket Number 95S-0158 in the Dockets Management Branch (HFA-305),
Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville,
MD 20857, copies of the information that was disclosed, identified by
the IND number.

\(b\) The sponsor also shall monitor such investigations to identify
when an IRB determines that it cannot approve the research because it
does not meet the criteria in the exception in Sec. 50.24(a) of this
chapter or because of other relevant ethical concerns. The sponsor
promptly shall provide this information in writing to FDA, investigators
who are asked to participate in this or a substantially equivalent
clinical investigation, and other IRB\'s that are asked to review this
or a substantially equivalent investigation.

**Sec. 312.55** **Informing investigators.**

\(a\) Before the investigation begins, a sponsor (other than a
sponsor-investigator) shall give each participating clinical
investigator an investigator brochure containing the information
described in Sec. 312.23(a)(5).

\(b\) The sponsor shall, as the overall investigation proceeds, keep
each participating investigator informed of new observations discovered
by or reported to the sponsor on the drug, particularly with respect to
adverse effects and safe use. Such information may be distributed to
investigators by means of periodically revised investigator brochures,
reprints or published studies, reports or letters to clinical
investigators, or other appropriate means. Important safety information
is required to be relayed to investigators in accordance with Sec.
312.32.

**Sec. 312.56** **Review of ongoing investigations.**

\(a\) The sponsor shall monitor the progress of all clinical
investigations being conducted under its IND.

\(b\) A sponsor who discovers that an investigator is not complying with
the signed agreement (Form FDA-1572), the general investigational plan,
or the requirements of this part or other applicable parts shall
promptly either secure compliance or discontinue shipments of the

investigational new drug to the investigator and end the investigator\'s
participation in the investigation. If the investigator\'s participation
in the investigation is ended, the sponsor shall require that the
investigator dispose of or return the investigational drug in accordance
with the requirements of Sec. 312.59 and shall notify FDA.

\(c\) The sponsor shall review and evaluate the evidence relating to the
safety and effectiveness of the drug as it is obtained from the
investigator. The sponsors shall make such reports to FDA regarding
information relevant to the safety of the drug as are required under
Sec. 312.32. The sponsor shall make annual reports on the progress of
the investigation in accordance with Sec. 312.33.

\(d\) A sponsor who determines that its investigational drug presents an
unreasonable and significant risk to subjects shall discontinue those
investigations that present the risk, notify FDA, all institutional
review boards, and all investigators who have at any time participated
in the investigation of the discontinuance, assure the disposition of
all stocks of the drug outstanding as required by Sec. 312.59, and
furnish FDA with a full report of the sponsor\'s actions. The sponsor
shall discontinue the investigation as soon as possible, and in no event
later than 5 working days after making the determination that the
investigation should be discontinued. Upon request, FDA will confer with
a sponsor on the need to discontinue an investigation.

**Sec. 312.57** **Recordkeeping and record retention.**

\(a\) A sponsor shall maintain adequate records showing the receipt,
shipment, or other disposition of the investigational drug. These
records are required to include, as appropriate, the name of the
investigator to whom the drug is shipped, and the date, quantity, and
batch or code mark of each such shipment.

\(b\) A sponsor shall maintain complete and accurate records showing any
financial interest in Sec. 54.4(a)(3)(i), (a)(3)(ii), (a)(3)(iii), and
(a)(3)(iv) of this chapter paid to clinical investigators by the sponsor
of the covered study. A sponsor shall also maintain complete and
accurate records concerning all other financial interests of
investigators subject to part 54 of this chapter.

\(c\) A sponsor shall retain the records and reports required by this
part for 2 years after a marketing application is approved for the drug;
or, if an application is not approved for the drug, until 2 years after
shipment and delivery of the drug for investigational use is
discontinued and FDA has been so notified.

\(d\) A sponsor shall retain reserve samples of any test article and
reference standard identified in, and used in any of the bioequivalence
or bioavailability studies described in, Sec. 320.38 or Sec. 320.63 of
this chapter, and release the reserve samples to FDA upon request, in
accordance with, and for the period specified in Sec. 320.38.

**Sec. 312.58** **Inspection of sponsor\'s records and reports.**

\(a\) FDA inspection. A sponsor shall upon request from any properly
authorized officer or employee of the Food and Drug Administration, at
reasonable times, permit such officer or employee to have access to and
copy and verify any records and reports relating to a clinical
investigation conducted under this part. Upon written request by FDA,
the sponsor shall submit the records or reports (or copies of them) to
FDA. The sponsor shall discontinue shipments of the drug to any
investigator who has failed to maintain or make available records or
reports of the investigation as required by this part.

\(b\) Controlled substances. If an investigational new drug is a
substance listed in any schedule of the Controlled Substances Act (21
U.S.C. 801; 21 CFR part 1308), records concerning shipment, delivery,
receipt, and disposition of the drug, which are required to be kept
under this part or other applicable parts of this chapter shall, upon
the request of a properly authorized employee of the Drug Enforcement
Administration of the U.S. Department of Justice, be made available by
the investigator or sponsor to whom the request is made, for inspection
and copying. In addition, the sponsor shall assure that adequate
precautions are taken, including storage of the investigational drug in
a securely locked, substantially constructed cabinet, or other securely
locked, substantially constructed enclosure, access to which is limited,
to prevent theft or diversion of the substance into illegal channels of
distribution.

**Sec. 312.59** **Disposition of unused supply of investigational
drug.**

The sponsor shall assure the return of all unused supplies of the
investigational drug from each individual investigator whose
participation in the investigation is discontinued or terminated. The
sponsor may authorize alternative disposition of unused supplies of the
investigational drug provided this alternative disposition does not
expose humans to risks from the drug. The sponsor shall maintain written
records of any disposition of the drug in accordance with Sec. 312.57.

**Sec. 312.60** **General responsibilities of investigators.**

An investigator is responsible for ensuring that an investigation is
conducted according to the signed investigator statement, the
investigational plan, and applicable regulations; for protecting the
rights, safety, and welfare of subjects under the investigator\'s care;
and for the control of drugs under investigation. An investigator shall,
in accordance with the provisions of part 50 of this chapter, obtain the
informed consent of each human subject to whom the drug is administered,
except as provided in Secs. 50.23 or 50.24 of this chapter. Additional
specific responsibilities of clinical investigators are set forth in
this part and in parts 50 and 56 of this chapter.

**Sec. 312.61** **Control of the investigational drug.**

An investigator shall administer the drug only to subjects under the
investigator\'s personal supervision or under the supervision of a
subinvestigator responsible to the investigator. The investigator shall
not supply the investigational drug to any person not authorized under
this part to receive it.

**Sec. 312.62** **Investigator recordkeeping and record retention.**

\(a\) Disposition of drug. An investigator is required to maintain
adequate records of the disposition of the drug, including dates,
quantity, and use by subjects. If the investigation is terminated,
suspended, discontinued, or completed, the investigator shall return the
unused supplies of the drug to the sponsor, or otherwise provide for
disposition of the unused supplies of the drug under Sec. 312.59.

\(b\) Case histories. An investigator is required to prepare and
maintain adequate and accurate case histories that record all
observations and other data pertinent to the investigation on each
individual administered the investigational drug or employed as a
control in the investigation. Case histories include the case report
forms and supporting data including, for example, signed and dated
consent forms and medical records including, for example, progress notes
of the physician, the individual\'s hospital chart(s), and the nurses\'
notes. The case history for each individual shall document that informed
consent was obtained prior to participation in the study.

\(c\) Record retention. An investigator shall retain records required to
be maintained under this part for a period of 2 years following the date
a marketing application is approved for the drug for the indication for
which it is being investigated; or, if no application is to be filed or
if the application is not approved for such indication, until 2 years
after the investigation is discontinued and FDA is notified.

**Sec. 312.64** **Investigator reports.**

\(a\) Progress reports. The investigator shall furnish all reports to
the sponsor of the drug who is responsible for collecting and evaluating
the results obtained. The sponsor is required under Sec. 312.33 to
submit annual reports to FDA on the progress of the clinical
investigations.

\(b\) Safety reports. An investigator shall promptly report to the
sponsor any adverse effect that may reasonably be regarded as caused by,
or probably caused by, the drug. If the adverse effect is alarming, the
investigator shall report the adverse effect immediately.

\(c\) Final report. An investigator shall provide the sponsor with an
adequate report shortly after completion of the investigator\'s
participation in the investigation.

\(d\) Financial disclosure reports. The clinical investigator shall
provide the sponsor with sufficient accurate financial information to
allow an applicant to submit complete and accurate certification or
disclosure statements as required under part 54 of this chapter. The
clinical investigator shall promptly update this information if any
relevant changes occur during the course of the investigation and for 1
year following the completion of the study.

**Sec. 312.66 Assurance of IRB review.**

An investigator shall assure that an IRB that complies with the
requirements set forth in part 56 will be responsible for the initial
and continuing review and approval of the proposed clinical study. The
investigator shall also assure that he or she will promptly report to
the IRB all changes in the research activity and all unanticipated
problems involving risk to human subjects or others, and that he or she
will not make any changes in the research without IRB approval, except
where necessary to eliminate apparent immediate hazards to human
subjects.

**Sec. 312.68** **Inspection of investigator\'s records and reports.**

An investigator shall upon request from any properly authorized officer
or employee of FDA, at reasonable times, permit such officer or employee
to have access to, and copy and verify any records or reports made by
the investigator pursuant to Sec. 312.62. The investigator is not
required to divulge subject names unless the records of particular
individuals require a more detailed study of the cases, or unless there
is reason to believe that the records do not represent actual case
studies, or do not represent actual results obtained.

**Sec. 312.69** **Handling of controlled substances.**

If the investigational drug is subject to the Controlled Substances Act,
the investigator shall take adequate precautions, including storage of
the investigational drug in a securely locked, substantially constructed
cabinet, or other securely locked, substantially constructed enclosure,
access to which is limited, to prevent theft or diversion of the
substance into illegal channels of distribution.

**Sec. 312**.**70 Disqualification of a clinical investigator.**

\(a\) If FDA has information indicating that an investigator (including
a sponsor-investigator) has repeatedly or deliberately failed to comply
with the requirements of this part, part 50, or part 56 of this chapter,
or has submitted to FDA or to the sponsor false information in any
required report, the Center for Drug Evaluation and Research or the
Center for Biologics Evaluation and Research will furnish the
investigator written notice of the matter complained of and offer the
investigator an opportunity to explain the matter in writing, or, at the
option of the investigator, in an informal conference. If an explanation
is offered but not accepted by the Center for Drug Evaluation and
Research or the Center for Biologics Evaluation and Research, the
investigator will be given an opportunity for a regulatory hearing under
part 16 on the question of whether the investigator is entitled to
receive investigational new drugs.

\(b\) After evaluating all available information, including any
explanation presented by the investigator, if the Commissioner
determines that the investigator has repeatedly or deliberately failed
to comply with the requirements of this part, part 50, or part 56 of
this chapter, or has deliberately or repeatedly submitted false
information to FDA or to the sponsor in any required report, the
Commissioner will notify the investigator and the sponsor of any
investigation in which the investigator has been named as a participant
that the investigator is not entitled to receive investigational drugs.
The notification will provide a statement of basis for such

determination.

\(c\) Each IND and each approved application submitted under part 314
containing data reported by an investigator who has been determined to
be ineligible to receive investigational drugs will be examined to
determine whether the investigator has submitted unreliable data that
are essential to the continuation of the investigation or essential to
the approval of any marketing application.

\(d\) If the Commissioner determines, after the unreliable data
submitted by the investigator are eliminated from consideration, that
the data remaining are inadequate to support a conclusion that it is
reasonably safe to continue the investigation, the Commissioner will
notify the sponsor who shall have an opportunity for a regulatory
hearing under part 16. If a danger to the public health exists, however,
the Commissioner shall terminate the IND immediately and notify the
sponsor of the determination. In such case, the sponsor shall have an
opportunity for a regulatory hearing before FDA under part 16 on the
question of whether the IND should be reinstated.

\(e\) If the Commissioner determines, after the unreliable data
submitted by the investigator are eliminated from consideration, that
the continued approval of the drug product for which the data were
submitted cannot be justified, the Commissioner will proceed to withdraw
approval of the drug product in accordance with the applicable
provisions of the act.

\(f\) An investigator who has been determined to be ineligible to
receive investigational drugs may be reinstated as eligible when the
Commissioner determines that the investigator has presented adequate
assurances that the investigator will employ investigatioal drugs solely
in compliance with the provisions of this part and of parts 50 and 56.

**Subpart E\--Drugs Intended to Treat Life-threatening and Severely-
debilitating Illnesses**

**Sec. 312.80 Purpose.**

The purpose of this section is to establish procedures designed to
expedite the development, evaluation, and marketing of new therapies
intended to treat persons with life-threatening and
severely-debilitating illnesses, especially where no satisfactory
alternative therapy exists. As stated Sec. 314.105(c) of this chapter,
while the statutory standards of safety and effectiveness apply to all
drugs, the many kinds of drugs that are subject to them, and the wide
range of uses for those drugs, demand flexibility in applying the
standards. The Food and Drug Administration (FDA) has determined that it
is appropriate to exercise the broadest flexibility in applying the
statutory standards, while preserving appropriate guarantees for safety
and effectiveness. These procedures reflect the recognition that
physicians and patients are generally willing to accept greater risks or
side effects from products that treat life-threatening and
severely-debilitating illnesses, than they would accept from products
that treat less serious illnesses. These procedures also reflect the
recognition that the benefits of the drug need to be evaluated in light
of the severity of the disease being treated. The procedure outlined in
this section should be interpreted consistent with that purpose.

**Sec. 312.81 Scope.**

This section applies to new drug and biological products that are being
studied for their safety and effectiveness in treating life-threatening
or severely-debilitating diseases.

\(a\) For purposes of this section, the term \`\`life-threatening\'\'
means:

\(1\) Diseases or conditions where the likelihood of death is high
unless the course of the disease is interrupted; and

\(2\) Diseases or conditions with potentially fatal outcomes, where the
end point of clinical trial analysis is survival.

\(b\) For purposes of this section, the term \`\`severely
debilitating\'\' means diseases or conditions that cause major
irreversible morbidity.

\(c\) Sponsors are encouraged to consult with FDA on the applicability
of these procedures to specific products.

**Sec. 312.82 Early consultation.**

For products intended to treat life-threatening or severely-debilitating
illnesses, sponsors may request to meet with FDA-reviewing officials
early in the drug development process to review and reach agreement on
the design of necessary preclinical and clinical studies. Where
appropriate, FDA will invite to such meetings one or more outside expert
scientific consultants or advisory committee members. To the extent FDA
resources permit, agency reviewing officials will honor requests for
such meetings

\(a\) Pre-investigational new drug (IND) meetings. Prior to the
submission of the initial IND, the sponsor may request a meeting with
FDA-reviewing officials. The primary purpose of this meeting is to
review and reach agreement on the design of animal studies needed to
initiate human testing. The meeting may also provide an opportunity for
discussing the scope and design of phase 1 testing, plans for studying
the drug product in pediatric populations, and the best approach for
presentation and formatting of data in the IND.

\(b\) End-of-phase 1 meetings. When data from phase 1 clinical testing
are available, the sponsor may again request a meeting with
FDA-reviewing officials. The primary purpose of this meeting is to
review and reach agreement on the design of phase 2 controlled clinical
trials, with the goal that such testing will be adequate to provide
sufficient data on the drug\'s safety and effectiveness to support a
decision on its approvability for marketing, and to discuss the need
for, as well as the design and timing of, studies of the drug in
pediatric patients. For drugs for life-threatening diseases, FDA will
provide its best judgment, at that time, whether pediatric studies will
be required and whether their submission will be deferred until after
approval. The procedures outlined in Sec. 312.47(b)(1) with respect to
end-of-phase 2 conferences, including documentation of agreements
reached, would also be used for end-of-phase 1 meetings.

**Sec. 312.83** **Treatment protocols.**

If the preliminary analysis of phase 2 test results appears promising,
FDA may ask the sponsor to submit a treatment protocol to be reviewed
under the procedures and criteria listed in Secs. 312.34 and 312.35.
Such a treatment protocol, if requested and granted, would normally
remain in effect while the complete data necessary for a marketing
application are being assembled by the sponsor and reviewed by FDA
(unless grounds exist for clinical hold of ongoing protocols, as
provided in Sec. 312.42(b)(3)(ii)).

**Sec. 312**.**84 Risk-benefit analysis in review of marketing
applications for drugs to treat life-threatening and
severely-debilitating illnesses.**

\(a\) FDA\'s application of the statutory standards for marketing
approval shall recognize the need for a medical risk-benefit judgment in
making the final decision on approvability. As part of this evaluation,
consistent with the statement of purpose in Sec. 312.80, FDA will
consider whether the benefits of the drug outweigh the known and
potential risks of the drug and the need to answer remaining questions
about risks and benefits of the drug, taking into consideration the
severity of the disease and the absence of satisfactory alternative
therapy.

\(b\) In making decisions on whether to grant marketing approval for
products that have been the subject of an end-of-phase 1 meeting under
Sec. 312.82, FDA will usually seek the advice of outside expert
scientific consultants or advisory committees. Upon the filing of such a
marketing application under Sec. 314.101 or part 601 of this chapter,
FDA will notify the members of the relevant standing advisory committee
of the application\'s filing and its availability for review.

\(c\) If FDA concludes that the data presented are not sufficient for
marketing approval, FDA will issue (for a drug) a not approvable letter
pursuant to Sec. 314.120 of this chapter, or (for a biologic) a
deficiencies letter consistent with the biological product licensing
procedures. Such letter, in describing the deficiencies in the
application, will address why the results of the research design agreed
to under Sec. 312.82, or in subsequent meetings, have not provided
sufficient evidence for marketing approval. Such letter will also
describe any recommendations made by the advisory committee regarding
the application.

\(d\) Marketing applications submitted under the procedures contained in
this section will be subject to the requirements and procedures
contained in part 314 or part 600 of this chapter, as well as those in
this subpart.

**Sec. 312**.**85 Phase 4 studies.**

Concurrent with marketing approval, FDA may seek agreement from the
sponsor to conduct certain postmarketing (phase 4) studies to delineate
additional information about the drug\'s risks, benefits, and optimal
use. These studies could include, but would not be limited to, studying
different doses or schedules of administration than were used in phase 2
studies, use of the drug in other patient populations or other stages of
the disease, or use of the drug over a longer period of time.

**Sec. 312.86 Focused FDA regulatory research.**

At the discretion of the agency, FDA may undertake focused regulatory
research on critical rate-limiting aspects of the preclinical,
chemical/manufacturing, and clinical phases of drug development and
evaluation. When initiated, FDA will undertake such research efforts as
a means for meeting a public health need in facilitating the development
of therapies to treat life-threatening or severely debilitating
illnesses.

**Sec. 312.87** **Active monitoring of conduct and evaluation of
clinical trials.**

For drugs covered under this section, the Commissioner and other agency
officials will monitor the progress of the conduct and evaluation of
clinical trials and be involved in facilitating their appropriate
progress.

**Sec. 312.88** **Safeguards for patient safety.**

All of the safeguards incorporated within parts 50, 56, 312, 314, and
600 of this chapter designed to ensure the safety of clinical testing
and the safety of products following marketing approval apply to drugs
covered by this section. This includes the requirements for informed
consent (part 50 of this chapter) and institutional review boards (part
56 of this chapter). These safeguards further include the review of
animal studies prior to initial human testing (Sec. 312.23), and the
monitoring of adverse drug experiences through the requirements of IND
safety reports (Sec. 312.32), safety update reports during agency review
of a marketing application (Sec. 314.50 of this chapter), and
postmarketing adverse reaction reporting (Sec. 314.80 of this chapter).

**Subpart F\--Miscellaneous**

**Sec. 312.110** **Import and export requirements.**

\(a\) Imports. An investigational new drug offered for import into the
United States complies with the requirements of this part if it is
subject to an IND that is in effect for it under Sec. 312.40 and: (1)
The consignee in the United States is the sponsor of the IND; (2) the
consignee is a qualified investigator named in the IND; or (3) the
consignee is the domestic agent of a foreign sponsor, is responsible for
the control and distribution of the investigational drug, and the IND
identifies the consignee and describes what, if any, actions the
consignee will take with respect to the investigational drug.

\(b\) Exports. An investigational new drug intended for export from the
United States complies with the requirements of this part as follows:

\(1\) If an IND is in effect for the drug under Sec. 312.40 and each
person who receives the drug is an investigator named in the
application; or

\(2\) If FDA authorizes shipment of the drug for use in a clinical
investigation. Authorization may be obtained as follows:

\(i\) Through submission to the International Affairs Staff (HFY-50),
Associate Commissioner for Health Affairs, Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857, of a written request from the
person that seeks to export the drug. A request must provide adequate
information about the drug to satisfy FDA that the drug is appropriate
for the proposed investigational use in humans, that the drug will be
used for investigational purposes only, and that the drug may be legally
used by that consignee in the importing country for the proposed
investigational use. The request shall specify the quantity of the drug
to be shipped per shipment and the frequency of expected shipments. If
FDA authorizes exportation under this paragraph, the agency shall
concurrently notify the government of the importing country of such
authorization.

\(ii\) Through submission to the International Affairs Staff (HFY-50),
Associate Commissioner for Health Affairs, Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857, of a formal request from an
authorized official of the government of the country to which the drug
is proposed to be shipped. A request must specify that the foreign
government has adequate information about the drug and the proposed
investigational use, that the drug will be used for investigational
purposes only, and that the foreign government is satisfied that the
drug may legally be used by the intended consignee in that country. Such
a request shall specify the quantity of drug to be shipped per shipment
and the frequency of expected shipments.

\(iii\) Authorization to export an investigational drug under paragraph
(b)(2)(i) or (ii) of this section may be revoked by FDA if the agency
finds that the conditions underlying its authorization are not longer
met.

\(3\) This paragraph applies only where the drug is to be used for the
purpose of clinical investigation.

\(4\) This paragraph does not apply to the export of new drugs
(including biological products, antibiotic drugs, and insulin) approved
or authorized for export under section 802 of the act (21 U.S.C. 382) or
section 351(h)(1)(A) of thePublic Health Service Act (42 U.S.C.
262(h)(1)(A)).

**Sec. 312.120** **Foreign clinical studies not conducted under an
IND.**

\(a\) Introduction. This section describes the criteria for acceptance
by FDA of foreign clinical studies not conducted under an IND. In
general, FDA accepts such studies provided they are well designed, well
conducted, performed by qualified investigators, and conducted in
accordance with ethical principles acceptable to the world community.
Studies meeting these criteria may be utilized to support clinical
investigations in the United States and/or marketing approval. Marketing
approval of a new drug based solely on foreign clinical data is governed
by Sec. 314.106.

\(b\) Data submissions. A sponsor who wishes to rely on a foreign
clinical study to support an IND or to support an application for
marketing approval shall submit to FDA the following information:

\(1\) A description of the investigator\'s qualifications;

\(2\) A description of the research facilities;

\(3\) A detailed summary of the protocol and results of the study, and,
should FDA request, case records maintained by the investigator or
additional background data such as hospital or other institutional
records;

\(4\) A description of the drug substance and drug product used in the
study, including a description of components, formulation,
specifications, and bioavailability of the specific drug product used in
the clinical study, if available; and

\(5\) If the study is intended to support the effectiveness of a drug
product, information showing that the study is adequate and well
controlled under Sec. 314.126.

\(c\) Conformance with ethical principles. (1) Foreign clinical research
is required to have been conducted in accordance with the ethical
principles stated in the \`\`Declaration of Helsinki\'\' (see paragraph
(c)(4) of this section) or the laws and regulations of the country in
which the research was conducted, whichever represents the greater
protection of the individual.

\(2\) For each foreign clinical study submitted under this section, the
sponsor shall explain how the research conformed to the ethical
principles contained in the \`\`Declaration of Helsinki\'\' or the
foreign country\'s standards, whichever were used. If the foreign
country\'s standards were used, the sponsor shall explain in detail how
those standards differ from the \`\`Declaration of Helsinki\'\' and how
they offer greater protection.

\(3\) When the research has been approved by an independent review
committee, the sponsor shall submit to FDA documentation of such review
and approval, including the names and qualifications of the members of
the committee. In this regard, a \`\`review committee\'\' means a
committee composed of scientists and, where practicable, individuals who
are otherwise qualified (e.g., other health professionals or laymen).
The investigator may not vote on any aspect of the review of his or her
protocol by a review committee.

\(4\) The \`\`Declaration of Helsinki\'\' states as follows:

Recommendations Guiding Physicians in Biomedical Research Involving
Human Subjects

Introduction

It is the mission of the physician to safeguard the health of the
people. His or her knowledge and conscience are dedicated to the
fulfillment of this mission.

The Declaration of Geneva of the World Medical Association binds the
physician with the words, \`\`The health of my patient will be my first
consideration,\'\' and the International Code of Medical Ethics declares
that, \`\`A physician shall act only in the patient\'s interest when
providing medical care which might have the effect of weakening the
physical and mental condition of the patient.\'\'

The purpose of biomedical research involving human subjects must be to
improve diagnostic, therapeutic and prophylactic procedures and the
understanding of the aetiology and pathogenesis of disease.

In current medical practice most diagnostic, therapeutic or prophylactic
procedures involve hazards. This applies especially to biomedical
research.

Medical progress is based on research which ultimately must rest in part
on experimentation involving human subjects.

In the field of biomedical research a fundamental distinction must be
recognized between medical research in which the aim is essentially
diagnostic or therapeutic for a patient, and medical research, the
essential object of which is purely scientific and without implying
direct diagnostic or therapeutic value to the person subjected to the
research.

Special caution must be exercised in the conduct of research which may
affect the environment, and the welfare of animals used for research
must be respected.

Because it is essential that the results of laboratory experiments be
applied to human beings to further scientific knowledge and to help
suffering humanity, the World Medical Association has prepared the
following recommendations as a guide to every physician in biomedical
research involving human subjects. They should be kept under review in
the future. It must be stressed that the standards as drafted are only a
guide to physicians all over the world. Physicians are not relieved from
criminal, civil and ethical responsibilities under the laws of their own
countries.

I. Basic Principles

1\. Biomedical research involving human subjects must conform to
generally accepted scientific principles and should be based on
adequately performed laboratory and animal experimentation and on a
thorough knowledge of the scientific literature.

2\. The design and performance of each experimental procedure involving
human subjects should be clearly formulated in an experimental protocol
which should be transmitted for consideration, comment and guidance to a
specially appointed committee independent of the investigator and the
sponsor provided that this independent committee is in conformity with
the laws and regulations of the country in which the research experiment
is performed.

3\. Biomedical research involving human subjects should be conducted
only by scientifically qualified persons and under the supervision of a
clinically competent medical person. The responsibility for the human
subject must always rest with a medically qualified person and never
rest on the subject of the research, even though the subject has given
his or her consent.

4\. Biomedical research involving human subjects cannot legitimately be
carried out unless the importance of the objective is in proportion to
the inherent risk to the subject.

5\. Every biomedical research project involving human subjects should be
preceded by careful assessment of predictable risks in comparison with
foreseeable benefits to the subject or to others. Concern for the
interests of the subject must always prevail over the interests of
science and society.

6\. The right of the research subject to safeguard his or her integrity
must always be respected. Every precaution should be taken to respect
the privacy of the subject and to minimize the impact of the study on
the subject\'s physical and mental integrity and on the personality of
the subject.

7\. Physicians should abstain from engaging in research projects
involving human subjects unless they are satisfied that the hazards
involved are believed to be predictable. Physicians should cease any
investigation if the hazards are found to outweigh the potential
benefits.

8\. In publication of the results of his or her research, the physician
is obliged to preserve the accuracy of the results. Reports of
experimentation not in accordance with the principles laid down in this
Declaration should not be accepted for publication.

9\. In any research on human beings, each potential subject must be
adequately informed of the aims, methods, anticipated benefits and
potential hazards of the study and the discomfort it may entail. He or
she should be informed that he or she is at liberty to abstain from
participation in the study and that he or she is free to withdraw his or
her consent to participation at any time. The physician should then
obtain the subject\'s freely-given informed consent, preferably in
writing.

10\. When obtaining informed consent for the research project the
physician should be particularly cautious if the subject is in a
dependent relationship to him or her or may consent under duress. In
that case the informed consent should be obtained by a physician who is
not engaged in the investigation and who is completely independent of
this official relationship.

11\. In case of legal incompetence, informed consent should be obtained
from the legal guardian in accordance with national legislation. Where
physical or mental incapacity makes it impossible to obtain informed
consent, or when the subject is a minor, permission from the responsible
relative replaces that of the subject in accordance with national
legislation.

Whenever the minor child is in fact able to give a consent, the minor\'s
consent must be obtained in addition to the consent of the minor\'s
legal guardian.

12\. The research protocol should always contain a statement of the
ethical considerations involved and should indicate that the principles
enunciated in the present Declaration are complied with.

II\. Medical Research Combined with Professional Care (Clinical
Research)

1\. In the treatment of the sick person, the physician must be free to
use a new diagnostic and therapeutic measure, if in his or her judgment
it offers hope of saving life, reestablishing health or alleviating
suffering.

2\. The potential benefits, hazards and discomfort of a new method
should be weighed against the advantages of the best current diagnostic
and therapeutic methods.

3\. In any medical study, every patient\--including those of a control
group, if any\--should be assured of the best proven diagnostic and
therapeutic method.

4\. The refusal of the patient to participate in a study must never
interfere with the physician-patient relationship.

5\. If the physician considers it essential not to obtain informed
consent, the specific reasons for this proposal should be stated in the
experimental protocol for transmission to the independent committee (I,
2).

6\. The physician can combine medical research with professional care,
the objective being the acquisition of new medical knowledge, only to
the extent that medical research is justified by its potential
diagnostic or therapeutic value for the patient.

III\. Non-Therapeutic Biomedical Research Involving Human Subjects
(Non-Clinical Biomedical Research)

1\. In the purely scientific application of medical research carried out
on a human being, it is the duty of the physician to remain the

protector of the life and health of that person on whom biomedical
research is being carried out.

2\. The subjects should be volunteers\--either healthy persons or
patients for whom the experimental design is not related to the
patient\'s illness.

3\. The investigator or the investigating team should discontinue the
research if in his/her or their judgment it may, if continued, be
harmful to the individual.

4\. In research on man, the interest of science and society should never
take precedence over considerations related to the well-being of the
subject.

**Sec. 312.130 Availability for public disclosure of data and
information in an IND.**

\(a\) The existence of an investigational new drug application will not
be disclosed by FDA unless it has previously been publicly disclosed or
acknowledged.

\(b\) The availability for public disclosure of all data and information
in an investigational new drug application for a new drug will be
handled in accordance with the provisions established in Sec. 314.430
for the confidentiality of data and information in applications
submitted in part 314. The availability for public disclosure of all
data and information in an investigational new drug application for a
biological product will be governed by the provisions of Secs. 601.50
and 601.51.

\(c\) Notwithstanding the provisions of Sec. 314.430, FDA shall disclose
upon request to an individual to whom an investigational new drug has
been given a copy of any IND safety report relating to the use in the
individual.

\(d\) The availability of information required to be publicly disclosed
for investigations involving an exception from informed consent under
Sec. 50.24 of this chapter will be handled as follows: Persons wishing
to request the publicly disclosable information in the IND that was
required to be filed in Docket Number 95S-0158 in the Dockets Management
Branch (HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm.
1-23, Rockville, MD 20857, shall submit a request under the Freedom of
Information Act.

**Sec. 312.140** **Address for correspondence.**

\(a\) Except as provided in paragraph (b) of this section, a sponsor
shall send an initial IND submission to the Central Document Room,
Center for Drug Evaluation and Research, Food and Drug Administration,
Park Bldg., Rm. 214, 12420 Parklawn Dr., Rockville, MD 20852. On
receiving the IND, FDA will inform the sponsor which one of the
divisions in the Center for Drug Evaluation and Research or the Center
for Biologics Evaluation and Research is responsible for the IND.
Amendments, reports, and other correspondence relating to matters
covered by the IND should be directed to the appropriate division. The
outside wrapper of each submission shall state what is contained in the
submission, for example, \`\`IND Application\'\', \`\`Protocol
Amendment\'\', etc.

\(b\) Applications for the products listed below should be submitted to
the Division of Biological Investigational New Drugs (HFB-230), Center
for Biologics Evaluation and Research, Food and Drug Administration,
8800 Rockville Pike, Bethesda, MD 20892. (1) Products subject to the
licensing provisions of the Public Health Service Act of July 1, 1944
(58 Stat. 682, as amended (42 U.S.C. 201 et seq.)) or subject to part
600; (2) ingredients packaged together with containers intended for the
collection, processing, or storage of blood or blood components; (3)
urokinase products; (4) plasma volume expanders and hydroxyethyl starch
for leukapheresis; and (5) coupled antibodies, i.e., products that
consist of an antibody component coupled with a drug or radionuclide
component in which both components provide a pharmacological effect but
the biological component determines the site of action.

\(c\) All correspondence relating to biological products for human use
which are also radioactive drugs shall be submitted to the Division of
Oncology and Radiopharmaceutical Drug Products (HFD-150), Center for
Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers
Lane, Rockville, MD 20857, except that applications for coupled
antibodies shall be submitted in accordance with paragraph (b) of this
section.

\(d\) All correspondence relating to export of an investigational drug
under Sec. 312.110(b)(2) shall be submitted to the International Affairs
Staff (HFY-50), Office of Health Affairs, Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857.

**Sec. 312.145** **Guidance documents.**

\(a\) FDA has made available guidance documents under Sec. 10.115 of
this chapter to help you to comply with certain requirements of this
part.

\(b\) The Center for Drug Evaluation and Research (CDER) and the Center
for Biologics Evaluation and Research (CBER) maintain lists of guidance
documents that apply to the centers\' regulations. The lists are
maintained on the Internet and are published annually in the Federal
Register. A request for a copy of the CDER list should be directed to
the Office of Training and Communications, Division of Communications
Management, Drug Information Branch (HFD-210), Center for Drug
Evaluation and Research, Food and Drug Administration, 5600 Fishers
Lane, Rockville, MD 20857. A request for a copy of the CBER list should
be directed to the Office of Communication, Training, and Manufacturers
Assistance (HFM-40), Center for Biologics Evaluation and Research, Food
and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852-1448.

**Sec. 312.160** **Drugs for investigational use in laboratory research
animals or in vitro tests.**

\(a\) Authorization to ship. (1)(i) A person may ship a drug intended
solely for tests in vitro or in animals used only for laboratory
research purposes if it is labeled as follows:

CAUTION: Contains a new drug for investigational use only in laboratory
research animals, or for tests in vitro. Not for use in humans.

\(ii\) A person may ship a biological product for investigational in
vitro diagnostic use that is listed in Sec. 312.2(b)(2)(ii) if it is
labeled as follows:

CAUTION: Contains a biological product for investigational in vitro
diagnostic tests only.

\(2\) A person shipping a drug under paragraph (a) of this section shall
use due diligence to assure that the consignee is regularly engaged in
conducting such tests and that the shipment of the new drug will
actually be used for tests in vitro or in animals used only for
laboratory research.

\(3\) A person who ships a drug under paragraph (a) of this section
shall maintain adequate records showing the name and post office address
of the expert to whom the drug is shipped and the date, quantity, and
batch or code mark of each shipment and delivery. Records of shipments
under paragraph (a)(1)(i) of this section are to be maintained for a
period of 2 years after the shipment. Records and reports of data and
shipments under paragraph (a)(1)(ii) of this section are to be
maintained in accordance with Sec. 312.57(b). The person who ships the
drug shall upon request from any properly authorized officer or employee
of the Food and Drug Administration, at reasonable times, permit such
officer or employee to have access to and copy and verify records
required to be maintained under this section.

\(b\) Termination of authorization to ship. FDA may terminate
authorization to ship a drug under this section if it finds that:

\(1\) The sponsor of the investigation has failed to comply with any of
the conditions for shipment established under this section; or

\(2\) The continuance of the investigation is unsafe or otherwise
contrary to the public interest or the drug is used for purposes other
than bona fide scientific investigation. FDA will notify the person
shipping the drug of its finding and invite immediate correction. If
correction is not immediately made, the person shall have an opportunity
for a regulatory hearing before FDA pursuant to part 16.

\(c\) Disposition of unused drug. The person who ships the drug under
paragraph (a) of this section shall assure the return of all unused
supplies of the drug from individual investigators whenever the
investigation discontinues or the investigation is terminated. The
person who ships the drug may authorize in writing alternative
disposition of unused supplies of the drug provided this alternative
disposition does not expose humans to risks from the drug, either
directly or indirectly (e.g., through food-producing animals). The
shipper shall maintain records of any alternative disposition.