Appendix VII: Other Regulations and Standards

A. FDA Informed Consent Regulations (21 CFR Part 50)

<http://www.fda.gov/oc/ohrt/irbs/appendixb.html>

**Subpart A General Provisions**

50.1 Scope.

50.3 Definitions.

**Subpart B Informed Consent of Human Subjects**

50.20 General requirements for informed consent.

50.21 Effective date.

50.23 Exception from general requirements.

50.24 Exception from informed consent requirements for emergency
research

50.25 Elements of informed consent.

50.27 Documentation of informed consent.

\[Source: 45 FR 36390, May 30, 1980, unless otherwise noted.\]

**Subpart A - General Provisions**

**§50.1 Scope.**

\(a\) This part applies to all clinical investigations regulated by the
Food and Drug Administration under sections 505(i) 507(d), and 520(g) of
the Federal Food, Drug, and Cosmetic Act, as well as clinical
investigations that support applications for research or marketing
permits for products regulated by the Food and Drug Administration,
including food and color additives, drugs for human use, medical devices
for human use, biological products for human use, and electronic
products. Additional specific obligations and commitments of, and
standards of conduct for, persons who sponsor or monitor clinical
investigations involving particular test articles may also be found in
other parts (e.g., 21 CFR parts 312 and 812). Compliance with these
parts is intended to protect the rights and safety of subjects involved
in investigations filed with the Food and Drug Administration pursuant
to sections 406, 409, 502, 503, 505, 506, 507, 510, 513-516, 518 520,
706, and 801 of the Federal Food, Drug and Cosmetic Act and sections 351
and 354-360F of the Public Health Service Act.

\(b\) References in this part to regulatory sections of the Code of
Federal Regulations are to chapter I of title 21, unless otherwise
noted.

\[45 FR 36390, May 30, 1980; 46 FR 8979, Jan. 27, 1981\]

**§50.3 Definitions.**

As used in this part:

\(a\) Act means the Federal Food, Drug, and Cosmetic Act, as amended
(secs. 201-902, 52 Stat. 1040 et seq. as amended (21 U.S.C. 321-392)).

\(b\) Application for research or marketing permit includes:

> \(1\) A color additive petition, described in part 71.
>
> \(2\) A food additive petition, described in parts 171 and 571.
>
> \(3\) Data and information about a substance submitted as part of the
> procedures for establishing that the substance is generally recognized
> as safe for use that results or may reasonably be expected to result,
> directly or indirectly, in its becoming a component or otherwise
> affecting the characteristics of any food, described in ßß 170.30 and
> 570.30.
>
> \(4\) Data and information about a food additive submitted as part of
> the procedures for food additives permitted to be used on an interim
> basis pending additional study, described in ß 180.1.
>
> \(5\) Data and information about a substance submitted as part of the
> procedures for establishing a tolerance for unavoidable contaminants
> in food and food-packaging materials described in section 406 of the
> act.
>
> \(6\) An investigational new drug application, described in part 312
> of this chapter.
>
> \(7\) A new drug application, described in part 314.
>
> \(8\) Data and information about the bioavailability or bioequivalence
> of drugs for human use submitted as part of the procedures for
> issuing, amending, or repealing a bioequivalence requirement,
> described in part 320.
>
> \(9\) Data and information about an over-the-counter drug for human
> use submitted as part of the procedures for classifying these drugs as
> generally recognized as safe and effective and not misbranded,
> described in part 330.
>
> \(10\) Data and information about a prescription drug for human use
> submitted as part of the procedures for classifying these drugs as
> generally recognized as safe and effective and not misbranded,
> described in this chapter.
>
> \(11\) Data and information about an antibiotic drug submitted as part
> of the procedures for issuing, amending or repealing regulations for
> these drugs, described in ß 314.300 of this chapter.
>
> \(12\) An application for a biological product license, described in
> part 601.
>
> \(13\) Data and information about a biological product submitted as
> part of the procedures for determining that licensed biological
> products are safe and effective and not misbranded, described in part
> 601.
>
> \(14\) Data and information about an in vitro diagnostic product
> submitted as part of the procedures for establishing, amending, or
> repealing a standard for these products, described in part 809.
>
> \(15\) An Application for an Investigational Device Exemption,
> described in part 812.
>
> \(16\) Data and information about a medical device submitted as part
> of the procedures for classifying these devices, described in section
> 513.
>
> \(17\) Data and information about a medical device submitted as part
> of the procedures for establishing, amending, or repealing a standard
> for these devices, described in section 514.
>
> \(18\) An application for premarket approval of a medical device,
> described in section 515.
>
> \(19\) A product development protocol for a medical device, described
> in section 515.
>
> \(20\) Data and information about an electronic product submitted as
> part of the procedures for establishing, amending or repealing a
> standard for these products, described in section 358 of the Public
> Health Service Act.
>
> \(21\) Data and information about an electronic product submitted as
> part of the procedures for obtaining a variance from any electronic
> product performance standard, as described in ß 1010.4.
>
> \(22\) Data and information about an electronic product submitted as
> part of the procedures for granting amending, or extending an
> exemption from a radiation safety performance standard, as described
> in ß 1010.5.

\(c\) Clinical investigation means any experiment that involves a test
article and one or more human subjects and that either is subject to
requirements for prior submission to the Food and Drug Administration
under section 505(i), 507(d), or 520(g) of the act, or is not subject to
requirements for prior submission to the Food and Drug Administration
under these sections of the act, but the results of which are intended
to be submitted later to, or held for inspection by, the Food and Drug
Administration as part of an application for a research or marketing
permit. The term does not include experiments that are subject to the
provisions of part 58 of this chapter, regarding nonclinical laboratory
studies.

\(d\) Investigator means an individual who actually conducts a clinical
investigation, i.e., under whose immediate direction the test article is
administered or dispensed to or used involving, a subject, or, in the
event of an investigation conducted by a team of individuals, is the
responsible leader of that team.

\(e\) Sponsor means a person who initiates a clinical investigation, but
who does not actually conduct the investigation, i.e., the test article
is administered or dispensed to or used involving, a subject under the
immediate direction of another individual. A person other than an
individual (e.g., corporation or agency) that uses one or more of its
own employees to conduct a clinical investigation it has initiated is
considered to be a sponsor (not a sponsor-investigator) and the
employees are considered to be investigators.

\(f\) Sponsor-investigator means an individual who both initiates and
actually conducts, alone or with others a clinical investigation, i.e.,
under whose immediate direction the test article is administered or
dispensed to, or used involving, a subject. The term does not include
any person other than an individual, e.g., corporation or agency.

\(g\) Human subject means an individual who is or becomes a participant
in research, either as a recipient of the test article as a control. A
subject may be either a healthy human or a patient.

\(h\) Institution means any public or private entity or Agency
(including Federal, State, and other agencies). The word facility as
used in section 520(g) of the act is deemed to be synonymous with the
term institution for purposes of this part.

\(i\) Institutional review board (IRB) means any board, committee, or
other group formally designated by an institution to review biomedical
research involving humans as subjects, to approve the initiation of and
conduct periodic review of such research. The term has the same meaning
as the phrase institutional review committee as used in section 520(g)
of the act.

\(j\) Test article means any drug (including a biological product for
human use), medical device for human use, human food additive, color
additive, electronic product, or any other article subject to regulation
under the act or under sections 351 and 354-360F of the Public Health
Service Act (42 U.S.C. 262 and 263b-263n).

\(k\) Minimal risk means that the probability and magnitude of harm or
discomfort anticipated in the research are not greater in and of
themselves than those ordinarily encountered in daily life or during the
performance of routine physical or psychological examinations or tests.

\(l\) Legally authorized representative means an individual or judicial
or other body authorized under applicable law to consent on behalf of a
prospective subject to the subject\'s participation in the procedure(s)
involved in the research.

\(m\) Family member means any one of the following legally competent
persons: Spouse; parents; children (including adopted children);
brothers and sisters; and any individual related by blood or affinity
whose close association with the subject is the equivalent of a family
relationship.

\[45 FR 36390, May 30, 1980, as amended at 46 FR 8950 Jan. 27,1981; 54
FR 9038, Mar. 3, 1989; 56 FR 28028, June 18, 1991; 61 FR 51497, Oct. 2,
1996; 62 FR 39440, July 23, 1997\]

##### Subpart B - Informed Consent of Human Subjects 

Source: 46 FR 8951, Jan. 27, 1981, unless otherwise noted.

**§50.20 General requirements for informed consent.**

Except as provided in Sections. 50.23 and 50.24, no investigator may
involve a human being as a subject in research covered by these
regulations unless the investigator has obtained the legally effective
informed consent of the subject or the subject\'s legally authorized
representative. An investigator shall seek such consent only under
circumstances that provide the prospective subject or the representative
sufficient opportunity to consider whether or not to participate and
that minimize the possibility of coercion or undue influence. The
information that is given to the subject or the representative shall be
in language understandable to the subject or the representative. No
informed consent, whether oral or written, may include any exculpatory
language through which the subject or the representative is made to
waive or appear to waive any of the subject\'s legal rights, or releases
or appears to release the investigator, the sponsor, the institution, or
its agents from liability for negligence.

\[46 FR 8951, Jan. 27, 1981, as amended at 64 FR 10942, Mar. 8, 1999\]

**§50.23 Exception from general requirements.**

\(a\) The obtaining of informed consent shall be deemed feasible unless,
before use of the test article (except as provided in paragraph (b) of
this section), both the investigator and a physician who is not
otherwise participating in the clinical investigation certify in writing
all of the following:

> \(1\) The human subject is confronted by a life-threatening situation
> necessitating the use of the test article.
>
> \(2\) Informed consent cannot be obtained from the subject because of
> an inability to communicate with, or obtain legally effective consent
> from, the subject.
>
> \(3\) Time is not sufficient to obtain consent from the subject\'s
> legal representative.
>
> \(4\) There is available no alternative method of approved or
> generally recognized therapy that provides an equal or greater
> likelihood of saving the life of the subject.

\(b\) If immediate use of the test article is, in the investigator\'s
opinion, required to preserve the life of the subject, and time is not
sufficient to obtain the independent determination required in paragraph
(a) of this section in advance of using the test article, the
determinations of the clinical investigator shall be made and, within 5
working days after the use of the article, be reviewed and evaluated in
writing by a physician who is not participating in the clinical
investigation.

\(c\) The documentation required in paragraph (a) or (b) of this section
shall be submitted to the IRB within 5 working days after the use of the
test article.

\(d\) (1) Under 10 U.S.C. 1107(f) the President may waive the prior
consent requirement for the administration of an investigational new
drug to a member of the armed forces in connection with the member\'s
participation in a particular military operation. The statute specifies
that only the President may waive informed consent in this connection
and the President may grant such a waiver only if the President
determines in writing that obtaining consent: Is not feasible; is
contrary to the best interests of the military member; or is not in the
interests of national security. The statute further provides that in
making a determination to waive prior informed consent on the ground
that it is not feasible or the ground that it is contrary to the best
interests of the military members involved, the President shall apply
the standards and criteria that are set forth in the relevant FDA
regulations for a waiver of the prior informed consent requirements of
section 505(i)(4) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C.
355(i)(4)). Before such a determination may be made that obtaining
informed consent from military personnel prior to the use of an
investigational drug (including an antibiotic or biological product) in
a specific protocol under an investigational new drug application (IND)
sponsored by the Department of Defense (DOD) and limited to specific
military personnel involved in a particular military operation is not
feasible or is contrary to the best interests of the military members
involved the Secretary of Defense must first request such a
determination from the President, and certify and document to the
President that the following standards and criteria contained in
paragraphs (d)(1) through (d)(4) of this section have been met.

> \(i\) The extent and strength of evidence of the safety and
> effectiveness of the investigational new drug in relation to the
> medical risk that could be encountered during the military operation
> supports the drug\'s administration under an IND.
>
> \(ii\) The military operation presents a substantial risk that
> military personnel may be subject to a chemical, biological, nuclear,
> or other exposure likely to produce death or serious or
> life-threatening injury or illness.
>
> \(iii\) There is no available satisfactory alternative therapeutic or
> preventive treatment in relation to the intended use of the
> investigational new drug.
>
> \(iv\) Conditioning use of the investigational new drug on the
> voluntary participation of each member could significantly risk the
> safety and health of any individual member who would decline its use,
> the safety of other military personnel, and the accomplishment of the
> military mission.
>
> \(v\) A duly constituted institutional review board (IRB) established
> and operated in accordance with the requirements of paragraphs (d)(2)
> and (d)(3) of this section, responsible for review of the study, has
> reviewed and approved the investigational new drug protocol and the
> administration of the investigational new drug without informed
> consent. DOD\'s request is to include the documentation required by
> Sec. 56.115(a)(2) of this chapter.
>
> \(vi\) DOD has explained:
>
> \(A\) The context in which the investigational drug will be
> administered, e.g., the setting or whether it will be
> self-administered or it will be administered by a health professional;
>
> \(B\) The nature of the disease or condition for which the preventive
> or therapeutic treatment is intended; and
>
> \(C\) To the extent there are existing data or information available,
> information on conditions that could alter the effects of the
> investigational drug.
>
> \(vii\) DOD\'s recordkeeping system is capable of tracking and will be
> used to track the proposed treatment from supplier to the individual
> recipient.
>
> \(viii\) Each member involved in the military operation will be given,
> prior to the administration of the investigational new drug, a
> specific written information sheet (including information required by
> 10 U.S.C. 1107(d)) concerning the investigational new drug, the risks
> and benefits of its use, potential side effects, and other pertinent
> information about the appropriate use of the product.
>
> \(ix\) Medical records of members involved in the military operation
> will accurately document the receipt by members of the notification
> required by paragraph (d)(1)(viii) of this section.
>
> \(x\) Medical records of members involved in the military operation
> will accurately document the receipt by members of any investigational
> new drugs in accordance with FDA regulations including part 312 of
> this chapter.
>
> \(xi\) DOD will provide adequate followup to assess whether there are
> beneficial or adverse health consequences that result from the use of
> the investigational product.
>
> \(xii\) DOD is pursuing drug development, including a time line, and
> marketing approval with due diligence.
>
> \(xiii\) FDA has concluded that the investigational new drug protocol
> may proceed subject to a decision by the President on the informed
> consent waiver request.
>
> \(xiv\) DOD will provide training to the appropriate medical personnel
> and potential recipients on the specific investigational new drug to
> be administered prior to its use.
>
> \(xv\) DOD has stated and justified the time period for which the
> waiver is needed, not to exceed one year, unless separately renewed
> under these standards and criteria.
>
> \(xvi\) DOD shall have a continuing obligation to report to the FDA
> and to the President any changed circumstances relating to these
> standards and criteria (including the time period referred to in
> paragraph (d)(1)(xv) of this section) or that otherwise might affect
> the determination to use an investigational new drug without informed
> consent.
>
> \(xvii\) DOD is to provide public notice as soon as practicable and
> consistent with classification requirements through notice in the
> Federal Register describing each waiver of informed consent
> determination, a summary of the most updated scientific information on
> the products used, and other pertinent information.
>
> \(xviii\) Use of the investigational drug without informed consent
> otherwise conforms with applicable law.
>
> \(2\) The duly constituted institutional review board, described in
> paragraph (d)(1)(v) of this section, must include at least 3
> nonaffiliated members who shall not be employees or officers of the
> Federal Government (other than for purposes of membership on the IRB)
> and shall be required to obtain any necessary security clearances.
> This IRB shall review the proposed IND protocol at a convened meeting
> at which a majority of the members are present including at least one
> member whose primary concerns are in nonscientific areas and, if
> feasible, including a majority of the nonaffiliated members. The
> information required by Sec. 56.115(a)(2) of this chapter is to be
> provided to the Secretary of Defense for further review.
>
> \(3\) The duly constituted institutional review board, described in
> paragraph (d)(1)(v) of this section, must review and approve:
>
> \(i\) The required information sheet;
>
> \(ii\) The adequacy of the plan to disseminate information, including
> distribution of the information sheet to potential recipients, on the
> investigational product (e.g., in forms other than written);
>
> \(iii\) The adequacy of the information and plans for its
> dissemination to health care providers, including potential side
> effects, contraindications, potential interactions, and other
> pertinent considerations; and
>
> \(iv\) An informed consent form as required by part 50 of this
> chapter, in those circumstances in which DOD determines that informed
> consent may be obtained from some or all personnel involved.
>
> \(4\) DOD is to submit to FDA summaries of institutional review board
> meetings at which the proposed protocol has been reviewed.
>
> \(5\) Nothing in these criteria or standards is intended to preempt or
> limit FDA\'s and DOD\'s authority or obligations under applicable
> statutes and regulations.

\[46 FR 8951, Jan. 27, 1981, as amended at 55 FR 52817, Dec. 21, 1990;
64

FR 399, Jan. 5, 1999; 64 FR 54188, Oct. 5, 1999\]

**§50.24 Exception from informed consent requirements for emergency
research.**

\(a\) The IRB responsible for the review, approval, and continuing
review of the clinical investigation described in this section may
approve that investigation without requiring that informed consent of
all research subjects be obtained if the IRB (with the concurrence of a
licensed physician who is a member of or consultant to the IRB and who
is not otherwise participating in the clinical investigation) finds and
documents each of the following:

> \(1\) The human subjects are in a life-threatening situation,
> available treatments are unproven or unsatisfactory, and the
> collection of valid scientific evidence, which may include evidence
> obtained through randomized placebo-controlled investigations, is
> necessary to determine the safety and effectiveness of particular
> interventions.
>
> \(2\) Obtaining informed consent is not feasible because:
>
> \(i\) The subjects will not be able to give their informed consent as
> a result of their medical condition;
>
> \(ii\) The intervention under investigation must be administered
> before consent from the subjects\' legally authorized representatives
> is feasible; and
>
> \(iii\) There is no reasonable way to identify prospectively the
> individuals likely to become eligible for participation in the
> clinical investigation.
>
> \(3\) Participation in the research holds out the prospect of direct
> benefit to the subjects because:
>
> \(i\) Subjects are facing a life-threatening situation that
> necessitates intervention;
>
> \(ii\) Appropriate animal and other preclinical studies have been
> conducted, and the information derived from those studies and related
> evidence support the potential for the intervention to provide a
> direct benefit to the individual subjects; and
>
> \(iii\) Risks associated with the investigation are reasonable in
> relation to what is known about the medical condition of the potential
> class of subjects, the risks and benefits of standard therapy, if any,
> and what is known about the risks and benefits of the proposed
> intervention or activity.
>
> \(4\) The clinical investigation could not practicably be carried out
> without the waiver.
>
> \(5\) The proposed investigational plan defines the length of the
> potential therapeutic window based on scientific evidence, and the
> investigator has committed to attempting to contact a legally
> authorized representative for each subject within that window of time
> and, if feasible, to asking the legally authorized representative
> contacted for consent within that window rather than proceeding
> without consent. The investigator will summarize efforts made to
> contact legally authorized representatives and make this information
> available to the IRB at the time of continuing review.
>
> \(6\) The IRB has reviewed and approved informed consent procedures
> and an informed consent document consistent with Sec. 50.25. These
> procedures and the informed consent document are to be used with
> subjects or their legally authorized representatives in situations
> where use of such procedures and documents is feasible. The IRB has
> reviewed and approved procedures and information to be used when
> providing an opportunity for a family member to object to a subject\'s
> participation in the clinical investigation consistent with paragraph
> (a)(7)(v) of this section.
>
> \(7\) Additional protections of the rights and welfare of the subjects
> will be provided, including, at least:
>
> \(i\) Consultation (including, where appropriate, consultation carried
> out by the IRB) with representatives of the communities in which the
> clinical investigation will be conducted and from which the subjects
> will be drawn;
>
> \(ii\) Public disclosure to the communities in which the clinical
> investigation will be conducted and from which the subjects will be
> drawn, prior to initiation of the clinical investigation, of plans for
> the investigation and its risks and expected benefits;
>
> \(iii\) Public disclosure of sufficient information following
> completion of the clinical investigation to apprise the community and
> researchers of the study, including the demographic characteristics of
> the research population, and its results;
>
> \(iv\) Establishment of an independent data monitoring committee to
> exercise oversight of the clinical investigation; and
>
> \(v\) If obtaining informed consent is not feasible and a legally
> authorized representative is not reasonably available, the
> investigator has committed, if feasible, to attempting to contact
> within the therapeutic window the subject\'s family member who is not
> a legally authorized representative, and asking whether he or she
> objects to the subject\'s participation in the clinical investigation.
> The investigator will summarize efforts made to contact family members
> and make this information available to the IRB at the time of
> continuing review.

\(b\) The IRB is responsible for ensuring that procedures are in place
to inform, at the earliest feasible opportunity, each subject, or if the
subject remains incapacitated, a legally authorized representative of
the subject, or if such a representative is not reasonably available, a
family member, of the subject\'s inclusion in the clinical
investigation, the details of the investigation and other information
contained in the informed consent document. The IRB shall also ensure
that there is a procedure to inform the subject, or if the subject
remains incapacitated, a legally authorized representative of the
subject, or if such a representative is not reasonably available, a
family member, that he or she may discontinue the subject\'s
participation at any time without penalty or loss of benefits to which
the subject is otherwise entitled. If a legally authorized
representative or family member is told about the clinical investigation
and the subject\'s condition improves, the subject is also to be
informed as soon as feasible. If a subject is entered into a clinical
investigation with waived consent and the subject dies before a legally
authorized representative or family member can be contacted, information
about the clinical investigation is to be provided to the subject\'s
legally authorized representative or family member, if feasible.

\(c\) The IRB determinations required by paragraph (a) of this section
and the documentation required by paragraph (e) of this section are to
be retained by the IRB for at least 3 years after completion of the
clinical investigation, and the records shall be accessible for
inspection and copying by FDA in accordance with Sec. 56.115(b) of this
chapter.

\(d\) Protocols involving an exception to the informed consent
requirement under this section must be performed under a separate
investigational new drug application (IND) or investigational device
exemption (IDE) that clearly identifies such protocols as protocols that
may include subjects who are unable to consent. The submission of those
protocols in a separate IND/IDE is required even if an IND for the same
drug product or an IDE for the same device already exists. Applications
for investigations under this section may not be submitted as amendments
under Sections. 312.30 or 812.35 of this chapter.

\(e\) If an IRB determines that it cannot approve a clinical
investigation because the investigation does not meet the criteria in
the exception provided under paragraph (a) of this section or because of
other relevant ethical concerns, the IRB must document its findings and
provide these findings promptly in writing to the clinical investigator
and to the sponsor of the clinical investigation. The sponsor of the
clinical investigation must promptly disclose this information to FDA
and to the sponsor\'s clinical investigators who are participating or
are asked to participate in this or a substantially equivalent clinical
investigation of the sponsor, and to other IRB\'s that have been, or
are, asked to review this or a substantially equivalent investigation by
that sponsor.

\[61 FR 51528, Oct. 2, 1996\]

**§50.25 Elements of informed consent.**

\(a\) Basic elements of informed consent. In seeking informed consent,
the following information shall be provided to each subject:

> \(1\) A statement that the study involves research, an explanation of
> the purposes of the research and the expected duration of the
> subject\'s participation, a description of the procedures to be
> followed, and identification of any procedures which are experimental.
>
> \(2\) A description of any reasonably foreseeable risks or discomforts
> to the subject.
>
> \(3\) A description of any benefits to the subject or to others which
> may reasonably be expected from the research.
>
> \(4\) A disclosure of appropriate alternative procedures or courses of
> treatment, if any, that might be advantageous to the subject.
>
> \(5\) A statement describing the extent, if any, to which
> confidentiality of records identifying the subject will be maintained
> and that notes the possibility that the Food and Drug Administration
> may inspect the records.
>
> \(6\) For research involving more than minimal risk, an explanation as
> to whether any compensation and an explanation as to whether any
> medical treatments are available if injury occurs and, if so, what
> they consist of, or where further information may be obtained.
>
> \(7\) An explanation of whom to contact for answers to pertinent
> questions about the research and research subjects\' rights, and whom
> to contact in the event of a research-related injury to the subject.
>
> \(8\) A statement that participation is voluntary, that refusal to
> participate will involve no penalty or loss of benefits to which the
> subject is otherwise entitled, and that the subject may discontinue
> participation at any time without penalty or loss of benefits to which
> the subject is otherwise entitled.

\(b\) Additional elements of informed consent. When appropriate, one or
more of the following elements of information shall also be provided to
each subject:

> \(1\) A statement that the particular treatment or procedure may
> involve risks to the subject (or to the embryo or fetus, if the
> subject is or may become pregnant) which are currently unforeseeable.
>
> \(2\) Anticipated circumstances under which the subject\'s
> participation may be terminated by the investigator without regard to
> the subject\'s consent.
>
> \(3\) Any additional costs to the subject that may result from
> participation in the research.
>
> \(4\) The consequences of a subject\'s decision to withdraw from the
> research and procedures for orderly termination of participation by
> the subject.
>
> \(5\) A statement that significant new findings developed during the
> course of the research which may relate to the subject\'s willingness
> to continue participation will be provided to the subject.
>
> \(6\) The approximate number of subjects involved in the study.

\(c\) The informed consent requirements in these regulations are not
intended to preempt any applicable Federal, State, or local laws which
require additional information to be disclosed for informed consent to
be legally effective.

\(d\) Nothing in these regulations is intended to limit the authority of
a physician to provide emergency medical care to the extent the
physician is permitted to do so under applicable Federal, State, or
local law.

**§50.27 Documentation of informed consent.**

\(a\) Except as provided in Sec. 56.109(c), informed consent shall be
documented by the use of a written consent form approved by the IRB and
signed and dated by the subject or the subject\'s legally authorized
representative at the time of consent. A copy shall be given to the
person signing the form.

\(b\) Except as provided in Sec. 56.109(c), the consent form may be
either of the following:

> \(1\) A written consent document that embodies the elements of
> informed consent required by Sec. 50.25. This form may be read to the
> subject or the subject\'s legally authorized representative, but, in
> any event, the investigator shall give either the subject or the
> representative adequate opportunity to read it before it is signed.
>
> \(2\) A short form written consent document stating that the elements
> of informed consent required by Sec. 50.25 have been presented orally
> to the subject or the subject\'s legally authorized representative.
> When this method is used, there shall be a witness to the oral
> presentation. Also, the IRB shall approve a written summary of what is
> to be said to the subject or the representative. Only the short form
> itself is to be signed by the subject or the representative. However,
> the witness shall sign both the short form and a copy of the summary,
> and the person actually obtaining the consent shall sign a copy of the
> summary. A copy of the summary shall be given to the subject or the
> representative in addition to a copy of the short form.

\[46 FR 8951, Jan. 27, 1981, as amended at 61 FR 57280, Nov. 5, 1996\]

\[61FR 51497, October 2, 1996\]

**B. FDA Financial Disclosure Regulations (21 CFR Part 54)**

# 

> 21 CFR Part 54 may be found at
> <http://www.fda.gov/cdrh/devadvice/ide/regulations/21cfr54.pdf>

# 

GUIDANCE

FINANCIAL DISCLOSURE BY CLINICAL INVESTIGATORS

March 20, 2001

This guidance has been prepared by the Implementation Team for Financial
Disclosure, comprised of individuals in the Office of the Commissioner,
the Center for Drug Evaluation and Research (CDER), Center Biologics
Evaluation and Research (CBER) and Center Devices and Radiological
Health (CDRH) at the Food and Drug Administration. For further
information, contact (OC) Ms. Mary Gross, (301) 827-3450, (CDER) Ms.
Linda Carter, (301) 594-6758, (CBER) Dr. Jerry Donlon, (301) 827-3028,
or (CDRH) Dr. Joanne Less, (301) 594-1190.

**\
**

**GUIDANCE FOR INDUSTRY**

Financial Disclosure by Clinical Investigators

*This guidance represents the Food and Drug Administration\'s current
thinking on this topic. It does not create or confer any rights for or
on any person and does not operate to bind FDA or the public. An
alternative approach may be used if such approach satisfies the
requirements of the applicable statute, regulations, or both.*

I. Introduction

On February 2, 1998, FDA published a final rule requiring anyone who
submits a marketing application of any drug, biological product or
device to submit certain information concerning the compensation to, and
financial interests of, any clinical investigator conducting clinical
studies covered by the rule. This requirement, which became effective on
February 2, 1999, applies to any clinical study submitted in a marketing
application that the applicant or FDA relies on to establish that the
product is effective, and any study in which a single investigator makes
a significant contribution to the demonstration of safety. This final
rule requires applicants to certify to the absence of certain financial
interests of clinical investigators or to disclose those financial
interests. If the applicant does not include certification and/or
disclosure, or does not certify that it was not possible to obtain the
information, the agency may refuse to file the application. On December
31, 1998, FDA published an amended final rule that reduced the need to
gather certain financial information for studies completed before
February 2, 1999. On October 26, 1999, FDA published a draft guidance to
provide clarification in interpreting and complying with these
regulations. The burden hours required for Section 21 CFR Part 54 are
reported and approved under OMB Control Number 0910 0396.

II\. Financial Disclosure Requirements

Under the applicable regulations (21 CFR Parts 54, 312, 314, 320, 330,
601, 807, 812, 814, and 860), an applicant is required to submit to FDA
a list of clinical investigators who conducted covered clinical studies
and certify and/or disclose certain financial arrangements as follows:

1\. Certification that no financial arrangements with an investigator
have been made where study outcome could affect compensation; that the
investigator has no proprietary interest in the tested product; that the
investigator does not have a significant equity interest in the sponsor
of the covered study; and that the investigator has not received
significant payments of other sorts; and/or

2\. Disclosure of specified financial arrangements and any steps taken
to minimize the potential for bias.

**Disclosable Financial Arrangements**:

A.  Compensation made to the investigator in which the value of
    compensation could be affected by study outcome. This requirement
    applies to all covered studies, whether ongoing or completed as of
    February 2, 1999.

B.  A proprietary interest in the tested product, including, but not
    limited to, a patent, trademark, copyright or licensing agreement.
    This requirement applies to all covered studies, whether ongoing or
    completed as of February 2, 1999.

C.  Any equity interest in the sponsor of a covered study, i.e., any
    ownership interest, stock options, or other financial interest whose
    value cannot be readily determined through reference to public
    prices. This requirement applies to all covered studies, whether
    ongoing or completed;

D.  Any equity interest in a publicly held company that exceeds \$50,000
    in value. These must be disclosed only for covered clinical studies
    that are ongoing on or after February 2, 1999. The requirement
    applies to interests held during the time the clinical investigator
    is carrying out the study and for 1 year following completion of the
    study; and

E.  Significant payments of other sorts, which are payments that have a
    cumulative monetary value of \$25,000 or more made by the sponsor of
    a covered study to the investigator or the investigators\'
    institution to support activities of the investigator exclusive of
    the costs of conducting the clinical study or other clinical
    studies, (e.g., a grant to fund ongoing research, compensation in
    the form of equipment or retainers for ongoing consultation or
    honoraria) during the time the clinical investigator is carrying out
    the study and for 1 year following completion of the study. This
    requirement applies to payments made on or after February 2, 1999.

####### Agency Actions

If FDA determines that the financial interests of any clinical
investigator raise a serious question about the integrity of the data,
FDA will take any action it deems necessary to ensure the reliability of
the data including:

Initiating agency audits of the data derived from the clinical
investigator in question;

Requesting that the applicant submit further analyses of data, e.g., to
evaluate the effect of the clinical investigator\'s data on the overall
study outcome;

Requesting that the applicant conduct additional independent studies to
confirm the results of the questioned study; and

Refusing to treat the covered clinical study as providing data that can
be the basis for an agency action.

**Definitions**

**Clinical Investigator** - means any listed or identified investigator
or subinvestigator who is directly involved in the treatment or
evaluation of research subjects. The term also includes the spouse and
each dependent child of the investigator.

**Covered clinical study** - means any study of a drug, biological
product or device in humans submitted in a marketing application or
reclassification petition that the applicant or FDA relies on to
establish that the product is effective (including studies that show
equivalence to an effective product) or any study in which a single
investigator makes a significant contribution to the demonstration of
safety. This would, in general, not include phase 1 tolerance studies or
pharmacokinetic studies, most clinical pharmacology studies (unless they
are critical to an efficacy determination), large open safety studies
conducted at multiple sites, treatment protocols and parallel track
protocols. An applicant may consult with FDA as to which clinical
studies constitute \"covered clinical studies\" for purposes of
complying with financial disclosure requirements.

**Applicant** - means the party who submits a marketing application to
FDA for approval of a drug, device or biologic product or who submits a
reclassification petition. The applicant is responsible for submitting
the required certification and disclosure statements.

**Sponsor of the covered clinical study** - means the party providing
support for a particular study at the time it was carried out.

III\. PURPOSE

The financial disclosure regulations were intended to ensure that
financial interests and arrangements of clinical investigators that
could affect the reliability of data submitted to FDA are identified and
disclosed by the applicant. FDA has received many questions concerning
the implementation of this final rule. The agency is issuing this
guidance to respond to these questions. FDA encourages applicants and
sponsors to contact the agency for advice concerning specific
circumstances that may raise concerns as early in the product
development process as possible.

IV\. QUESTIONS AND ANSWERS

1.  **Q. Why did FDA develop financial disclosure regulations?**

    A: In June 1991, the Inspector General of the Department of Health
    and Human Services submitted a management advisory report to FDA
    stating that FDA\'s failure to have a mechanism for collecting
    information on \"financial conflicts of interest\" of clinical
    investigators who study products that undergo FDA review could
    constitute a material weakness under the Federal Manager\'s
    Financial Integrity Act. Although FDA determined that a material
    weakness did not exist, the agency did conclude that there was a
    need to address this issue through rulemaking. During the rulemaking
    process, FDA also learned about potentially problematic financial
    arrangements through published newspaper articles, Congressional
    inquiries, public testimony, and comments. Based on the information
    gathered, FDA determined that it was appropriate to require the
    submission of certain financial information with marketing
    applications that include certain types of clinical data.

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1.  **Q: Are applicants required to use FDA forms 3454 and 3455 in
    reporting this information?**

    A:Yes. The regulations require that the applicant submit one
    completed Form 3454 for all clinical investigators certifying to the
    absence of financial interests and arrangements. The applicant may
    append a list of investigator names to Form 3454 for those
    investigators certifying that those investigators hold none of the
    identifiable disclosable financial arrangements. For any clinical
    investigator for whom the applicant does not submit the
    certification, the applicant must submit a completed Form 3455
    disclosing the financial interests and arrangements and steps taken
    to minimize the potential for bias.

    Where an applicant cannot provide a blanket certification for all
    investigators because of the existence of disclosable financial
    arrangements for one or more investigators, an applicant should
    complete a disclosure form 3455 for each investigator having
    disclosable financial arrangements. The applicant should identify
    the specific covered clinical study (or studies) at issue and
    provide detailed information about the specific relationship that is
    being disclosed, (e.g., the nature of the contingent payment or the
    equity holdings of the investigator or the investigator\'s spouse or
    dependent child that exceeded the threshold). This disclosure needs
    to be linked to the specific covered clinical study (or studies) in
    which the investigators participated.

    In those instances where the applicant cannot provide complete
    certification or disclosure on all arrangements (e.g., the applicant
    has information about 2 of the 4 requirements but has been unable to
    obtain the rest of the information), the applicant should certify
    that despite the applicant\'s due diligence in attempting to obtain
    the information, the applicant was unable to obtain the information
    and should include an explanation of how the applicant attempted to
    obtain the information and why the information was not obtainable.

2.  **Q: What does FDA mean by the term \"due diligence\"?**

    A: \"Due diligence\" is a measure of activity expected from a
    reasonable and prudent person under a particular circumstance. In
    complying with these rules, sponsors and applicants should use
    reasonable judgement in deciding how much effort needs to be
    expended to collect this information. If sponsors/applicants find it
    impossible to obtain the financial information in question,
    applicants should explain why this information was not obtainable
    and document attempts made in an effort to collect the information.

3.  **Q:Who, specifically, is responsible for signing the financial
    certification/disclosure forms?**

    A: The forms are to be signed and dated by a responsible corporate
    official or representative of the applicant (e.g., the chief
    financial officer).

4.  **Q. Where in a drug/biologic application should an applicant
    include certification that financial arrangements of concern do not
    exist or the disclosure of those arrangements that do exist? Where
    should the information be included in a device application?**

    For drugs and biological product applications, applicants should
    include the financial certification/disclosure forms as part of item
    19 (other) of the application. See form 356h. FDA is revising the
    current form 356h and upon completion of this revision, financial
    certification and disclosure information will become number 19 and
    (other) will become number 20. For device applications, applicants
    should submit the financial certification/disclosure forms according
    to the format outlined in the appropriate submission checklist.

5.  **Q: What obligations do IND and IDE sponsors have regarding
    information collection prior to study start?**

    A: The regulations, 21 CFR 312.53 and 21 CFR 812.43, provide that
    before permitting an investigator to begin participation in an
    investigation, the IND/IDE sponsor shall obtain sufficient accurate
    financial information that will allow an applicant to submit
    complete and accurate certification or disclosure statements
    required under Part 54. The sponsor is also required to obtain the
    investigator\'s commitment to promptly update this information if
    any relevant changes occur during the course of the investigation
    and for one year following completion of the study. By collecting
    the information prior to study start, the sponsor will be aware of
    any potential problems, can consult with the agency early on, and
    take steps to minimize the potential for bias. See question and
    answer 7 for additional information.

6.  **Q: What is the responsibility of the IND/IDE sponsor for obtaining
    financial information from investigators at the IND/IDE stage when
    the IND/IDE sponsor is not the party who will be submitting a
    marketing application?**

    The term \"sponsor\" has somewhat different meanings in the
    regulations at 312.53/812.43 and 54.2. An applicant must report
    financial interests in the sponsor of the covered study. Under 21
    CFR 54.2, \"sponsor\" is defined as the party \"supporting a
    particular study at the time it was carried out.\" FDA interprets
    support to include those who provide \"material support\",e.g.,
    monetary support or test product under study. The sponsor of an IND
    or IDE, as defined in 21 CFR 312 and 812 is the \"party or parties
    who take responsibility for and initiate a clinical investigation\".
    The term \"sponsor\" is also used in 312.53 and 812.43 to refer to
    the party who will be submitting a marketing application (who is
    also responsible for submitting the certification and disclosure
    statement required by Part 54).

    In most cases, the IND/IDE sponsor, the sponsor of the covered
    study, and the applicant company are the same party, but there are
    times where they may be different. For example, when an academic or
    government institution or CRO conducts a covered study and is the
    IND/IDE sponsor (Part 312/812 sponsor), a drug or device company
    that provides funding or the test article used in the study is a
    Part 54 sponsor, and is likely to be the applicant if a marketing
    application is submitted to FDA. If the drug or device company that
    was a sponsor of the covered study sold the drug/device to another
    company, the applicant could be neither the IND/IDE sponsor nor a
    Part 54 sponsor.

    The responsibility for reporting financial information to FDA falls
    upon the applicant; that is, the final rule (Part 54) requires that
    the applicant company submit financial information on clinical
    investigators at the time the marketing application is submitted to
    the agency. The information that the applicant must report, apart
    from compensation that may be affected by study outcome and
    proprietary interests is:

    1\. equity interests in a Part 54 sponsor of a covered study (e.g.,
    any interest that cannot be valued through reference to public
    prices and interest in excess of \$50,000 in a publicly held
    company), and

    2\. significant payments of other sorts by a Part 54 sponsor of a
    covered study.

    Although reporting to the FDA is the responsibility of the
    applicant, the IND/IDE holder (part 312/812 sponsor) is required to
    collect the financial information before permitting an investigator
    to participate in a clinical study (312.53 and 812.43). The purpose
    of this requirement is two fold:

    1\. to alert the IND/IDE sponsor of the study to any potentially
    problematic financial interest as early in the drug development
    process as possible in order to minimize the potential for study
    bias and

    2\. to facilitate accurate collection of data that may be submitted
    many years later.

    The IND/IDE sponsor, who is in contact with the investigator, is
    best placed to inquire as to the financial arrangements of
    investigators, and this obligation applies to any IND/IDE sponsor
    (e.g., commercial, government or CRO). The IND/IDE sponsor shall
    maintain complete and accurate records showing any financial
    interest as described in Section 54.4 (a) (3) (i-iv) in a sponsor of
    the covered study. The IND/IDE sponsor is responsible for ensuring
    that required financial information is collected and is made
    available to the applicant company, so that, the information can be
    included in the NDA/BLA/PMA submission.

7.  **Q. The applicant is obligated to disclose financial interests
    related only to \>covered studies, specifically those relied upon to
    provide support for the effectiveness of a product and certain
    others. An IND holder (IND sponsor), acting much earlier, must
    inquire into investigator financial interests before the ultimate
    role of a study in the application is determined. How will the IND
    sponsor determine which studies will ultimately require
    certification/disclosure statements?**

    A: The IND sponsor will need to consider the potential role of a
    particular study based on study size, design and other
    considerations. Almost any controlled effectiveness study could,
    depending on outcome, become part of a marketing application, but
    other studies might be critical too, such as a pharmacodynamic study
    in a population subset or a bioequivalence study supporting a new
    dosage form.

8.  **Q. If a Contract Research Organization (CRO) is conducting a
    covered clinical study on behalf of another company, should the CRO
    collect the financial information from investigators? Is it
    necessary to collect financial information from investigators who
    have financial interests in CROs?**

    A: With regard to CRO and commercial sponsor arrangements, the same
    principles as articulated in answer 6 would apply. For example, if a
    CRO meets the definition of an IND/IDE sponsor or has contracted to
    collect financial information from investigators on behalf of an
    IND/IDE sponsor, the CRO must collect financial information on
    clinical investigators\' interests in Part 54 sponsors (312.53,
    812.43). If the CRO provides material support for a covered study,
    financial information on clinical investigators\' interests in the
    CRO is to be collected. If another entity provided material support
    for the study, the CRO also would collect financial information
    relative to that entity.

9.  **Q: Suppose a public or academic institution conducts a study
    without any support from a commercial sponsor, but the study is then
    used by an applicant to support its marketing application. In that
    case, who is the \"sponsor\" of the study and what information
    should the applicant submit?**

    A: In this case, the Part 54 sponsor of the study is the public or
    academic institution. Because such institutions are not commercial
    entities, in many instances, there will not be relevant equity
    interests to report. However, any relevant interests under 54.4,
    such as any proprietary interest in the tested product, including
    but not limited to a patent, trademark, copyright or licensing
    agreement are to be reported.

10. **Q: Does FDA have expectations about how the financial information
    should be collected? Will FDA consider it acceptable practice for a
    company to use a questionnaire to collect financial information from
    investigators rather than constructing an internal system to collect
    and report this information?**

    A: FDA has no preference as to how this information is collected
    from investigators. Under this rule, sponsors/applicants have the
    flexibility to collect the information in the most efficient and
    least burdensome manner that will be effective, for example, through
    questionnaires completed by the clinical investigators or by using
    information already available to the sponsor. FDA does not require
    sponsors to establish elaborate tracking systems to collect the
    information.

11. **Q. What does FDA mean by the definition of clinical investigator
    and subinvestigator? Is it necessary to collect financial
    information on spouses and dependent children of subinvestigators?**

    A: The definition of \"clinical investigator\" in Part 54 is
    intended to identify the individuals who should be considered
    investigators for purposes of reporting under the rule, generally,
    the people taking responsibility for the study at a given study
    site. For drugs, biological products and devices, it should be noted
    that hospital staff, including nurses, residents, or fellows and
    office staff who provide ancillary or intermittent care but who do
    not make direct and significant contribution to the data are not
    meant to be included under the definition of clinical investigator.
    For purposes of this financial disclosure regulation, the term
    investigator also includes the spouse and each dependent child of
    the investigator and subinvestigator.

    For drugs and biological products, clinical investigator means the
    individual(s) who actually conduct(s) and take(s) responsibility for
    an investigation, i.e. under whose immediate direction the drug or
    biologic is administered or dispensed to a subject or who is
    directly involved in the evaluation of research subjects. Where an
    investigation is directed by more than one person at a site, there
    may be more than one investigator who must report. For purposes of
    this rule, the terms investigators and subinvestigators include
    persons who fit any of these criteria: sign the Form FDA 1572, are
    identified as an investigator in initial submissions or protocol
    amendments under an IND, or are identified as an investigator in the
    NDA/BLA. For studies not conducted under an IND, the sponsor will
    need to identify the investigators and subinvestigators they
    consider covered by the rule in form 3454 and/or 3455. We expect
    that there will be at least one such person at each clinical site.
    If, however, there are other persons who are responsible for a study
    at a site, those persons should also be included as investigators.

    For medical devices, clinical investigators are defined as
    individual(s), under whose immediate direction the subject is
    treated and the investigational device is administered, including
    follow-up evaluations and treatments. Where an investigation is
    conducted by a team of individuals, the investigator is the
    responsible leader of the team. In general, investigators and
    subinvestigators sign \"investigator agreements\" in accordance with
    21 CFR 812.43(c ) and it is these individuals whose interests should
    be reported. For studies not conducted under an FDA-approved IDE,
    (that is, a non-significant risk IDE or an exempt study), the
    sponsor would need to identify the investigators and
    subinvestigators they considered covered by the rule in form 3454
    and 3455. We expect that there will be at least one such person at
    each site.

12. **Q: Do the reporting requirements apply to efficacy studies that
    include large numbers of investigators and multiple sites? Will the
    agency consider a waiver mechanism to exempt applicants from
    collecting information from clinical investigators conducting these
    kinds of studies?**

    A: Large multi-center efficacy studies with many investigators are
    considered covered clinical studies within the meaning of the final
    rule. See 21 CFR 54.2(c). Data from investigators having only a
    small percentage of the total subject population (in a study with
    large numbers of investigators and multiple sites) may still affect
    the overall study results. For example, if a sponsor submitted data
    collected during a large, multi-center, double blind study that
    included several thousand subjects and a single clinical
    investigator at one of the largest sites enrolled one percent of
    subjects, that investigator could still be responsible for a
    significant number of subjects. If the investigator fabricated data
    or otherwise affected the integrity of the data, remaining data for
    the drug may not meet the statistical criteria for efficacy as
    defined prospectively in the protocol.

    Because the regulations (see 21 CFR 312.10, 812.10, 314.90 and
    814.20) allow a sponsor to seek a waiver of certain requirements,
    applicants may seek waivers of the financial disclosure
    requirements. FDA believes it is highly unlikely, however, that any
    waivers will be justified for studies begun after February 2, 1999,
    because the sponsor should already have begun collecting the
    information on an ongoing basis. FDA will evaluate any request for
    waiver on a case-by-case basis.

13. **Q: The rule requires that investigators provide information on
    financial interests during the course of the study and for one year
    after completion of the study (see 54.4(b))? What does \"completion
    of the study\" mean?**

    A: Completion of the study means that all study subjects have been
    enrolled and follow up of primary endpoint data on all subjects has
    been completed in accordance with the clinical protocol. Many
    studies have more than one stage (e.g., a study could have a short
    term endpoint and a longer term follow up phase). Completion of the
    study here refers to that part of the study being submitted in the
    application. If there were a subsequent application based on longer
    term data, completion of the study would be defined similarly for
    the new data. It is not required that an applicant submit updated
    financial information to FDA after submission of the application,
    but applicants must retain complete records. Where there is more
    than one study site, the sponsor may consider completion of the
    study to be when the last study site is complete, or may consider
    each study site individually as it is completed.

14. **Q: Do applicant companies need to collect information for a year
    after completion of the study? Who is responsible for
    collecting/providing this information?**

    A: According to the February 2, 1998 final rule, the investigator
    must provide updated information when the investigator holds any
    equity interest in a privately held company or if stock holdings in
    a publicly held company exceed \$50,000 in value during the one year
    period following completion of the study. In addition,
    sponsors/applicants must keep records on file when significant
    payments of other sorts are paid by the sponsor of the covered study
    to the investigator or the investigator\'s institution to support
    activities of the investigator that have a cumulative monetary value
    of more than \$25,000, exclusive of the costs of conducting the
    covered clinical studies, during the study and for one year
    following completion of the study. FDA specified the one-year time
    frame because anticipation of payments may be as influential as
    payments already received. Applicants need only report on these
    arrangements when the marketing application is submitted, but
    sponsors/applicants are responsible for keeping updated financial
    information from the investigators in company files.

15. **Q: What information about a financial interest should be disclosed
    to the agency? For example, if an investigator owns more than
    \$50,000 of stock in a publicly held company, can the applicant just
    disclose that there is an interest that exceeds the \$50,000
    threshold or is it necessary to disclose in written detail the
    arrangement in question?**

    A: The applicant must disclose specific details of the financial
    interest including the size and nature of the financial interest in
    question and any steps taken to minimize the potential for study
    bias that such an interest represents.

16. **Q: Is the clinical investigator required to report all
    fluctuations above and below the \$50,000 level during the course of
    the investigation and one year after completion of the study?**

    A: The rule requires sponsors/applicants to obtain financial
    information from clinical investigators and a commitment from
    clinical investigators to promptly update financial information, if
    any relevant changes occur during the course of the covered clinical
    study and for one year following the completion of the study \[21
    CFR 312.53(c)(4), 312.64(d), 812.43(c)(5), 812.110(d)\]. In light of
    the potential volatility of stock prices, FDA recognizes that the
    dollar value of an investigator\'s equity holding in a
    sponsoring/applicant company is likely to fluctuate during the
    course of a trial. Clinical investigators should report an equity
    interest when the investigator becomes aware that the holding has
    exceeded the threshold and the investigator should use judgement in
    updating and reporting on fluctuations in equity interests exceeding
    \$50,000. FDA does not expect the investigator to report when that
    equity interest fluctuates below that threshold.

17. **Are equity interests in mutual funds and 401K(s) reportable?**

    A: Because an investigator would not have control over buying or
    selling stocks in mutual funds, these would not be reportable. In
    most circumstances, interests in 401K(s) would not be reportable,
    although equity interest in a product over \$50,000 would be
    reportable if it is a holding in a self directed 401K.

18. **Q: Does the rule include ANDAs? Does the rule include 510(k)s that
    do not include clinical data?**

    A: The rule applies to any clinical study of a drug (including a
    biological product) or device submitted in a marketing application
    that the applicant or FDA relies on to establish that the product is
    effective, including studies of drugs that show equivalence to an
    approved product. This means that ANDAs are covered by the final
    rule. 510(k)s that do not include clinical data would not contain
    covered studies and therefore, no financial information from device
    manufacturers is needed for those applications.

19. **Q: Do applicants need to provide information on investigators who
    participate in foreign studies?**

    A: Yes, applicants should include either a certification or
    disclosure of information for investigators participating in foreign
    covered studies. Where the applicant is unable to obtain the
    information despite acting with due diligence, the applicant may
    submit a statement documenting its efforts to obtain the
    information. In this case, it is unnecessary to submit a
    certification or disclosure form.

20. **Q: Does the rule apply to studies in support of labeling
    changes?**

    A: The rule applies to studies submitted in a supplement when those
    studies meet the definition of a covered clinical study. It also
    applies to studies to support safety labeling changes where
    individual investigators make a significant contribution to the
    safety information.

21. **Q:In the case where a subsidiary company of a larger parent
    company is conducting a covered clinical trial, is the applicant
    (subsidiary company) required to report information from clinical
    investigators about financial interests in only the subsidiary
    company, or is the applicant also required to report financial
    holdings, if any, of the investigator in the larger parent
    company?**

    A: If the subsidiary company meets the definition of sponsor of the
    covered study as defined under Part 54, the IND/IDE holder is
    required to collect from clinical investigators financial
    information related to the subsidiary company. The IND/IDE holder
    also must collect financial information related to the parent
    company if the parent company is a Part 54 sponsor of the study in
    question. If there are multiple companies providing material support
    for a covered study, the IND/IDE holder is responsible for
    collecting financial information from clinical investigators related
    to all companies providing that support. The applicant company is
    ultimately responsible for submitting financial information to the
    Agency at the time the marketing application is submitted.

22. **Q: Do \"actual use studies\" to support a request to switch a drug
    product from prescription to over-the-counter (OTC) status fit the
    definition of covered clinical study?**

    A: Applicants who file supplements requesting that FDA approve a
    switch of a prescription drug to OTC status or who file a new drug
    application for direct OTC use often conduct \"actual use studies.\"
    These may be intended to demonstrate that the product is safe and
    effective when used without the supervision of a licensed
    practitioner; in other cases, they may test labeling comprehension
    or other aspects of treatment. Actual use studies performed to
    support these applications would be considered covered clinical
    studies if they were used to demonstrate effectiveness in the OTC
    setting or if it is a safety study where any investigator makes a
    significant contribution.

23. **Q: Are clinical investigators of in vitro diagnostics (IVDs)
    covered under this regulation since they often involve specimens,
    not human subjects?**

    A: Yes. Applicants who submit marketing applications for IVDs must
    include the appropriate financial certification or disclosure
    information. Under section 21 CFR 812.3(p), \"subject\" is defined
    as a \"human who participates in an investigation, either as an
    individual on whom or on whose specimen an investigational device is
    used or as a control.\" Thus, an investigation of an IVD is
    considered a clinical investigation and, if it is used to support a
    marketing application, it would be subject to this regulation.

24. **Q: How do significant payments of other sorts (SPOOS) relate to
    the variety of payments the sponsor might make to an individual or
    institution for various activities?**

    A: The term \"significant payments of other sorts\" was intended to
    capture substantial payments or other support provided to an
    investigator that could create a sense of obligation to the sponsor.

    These payments do not include payments for the conduct of the
    clinical trial of the product under consideration or clinical trials
    of other products, under a contractual arrangement, but do include
    other payments made directly to the investigator or to an
    institution for direct support of the investigator. These payments
    would include honoraria, consulting fees, grant support for
    laboratory activities and equipment or actual equipment for the
    laboratory/clinic. This means that if an investigator were given
    equipment or money to purchase equipment for use in the
    laboratory/clinic, but not in relation to the conduct of the
    clinical trial, the payment would be considered a significant
    payment of other sorts and should be reported. If however, the
    investigator were provided with computer software or money to buy
    the software needed for use in the clinical trial, that would not
    need to be reported. Finally, payments made to the institution or to
    other nonstudy participating investigators that are not made on
    behalf of the investigator do not need to be reported.

25. **Q: Are payments made to investigators to cover travel expenses
    (such as transportation, lodgings and meal expenses) trackable under
    significant payments of other sorts (SPOOS)?**

    A: Generally, reasonable payments made to investigators to cover
    reimbursable expenses such as transportation, lodgings and meals do
    not fall within the purview of SPOOS and, therefore, would not need
    to be tracked. Travel costs associated with transporting, providing
    lodgings and meals for family members of investigators are
    considered unnecessary and should be tracked as SPOOS. In addition,
    other payments that exceed reasonable expectations, (for example, an
    investigator is flown to a resort location for an extra week of
    vacation) are considered outside of normal reimbursable expenditures
    and are not considered expenses that are necessary to conduct the
    study. Therefore, these types of expenses are also reportable and
    should be tracked as SPOOS.

26. **Q: Under what circumstances would FDA refuse to file an
    application?\
    **A: FDA may refuse to file any marketing application that does not
    contain either a certification that no specified financial
    arrangement exists or a disclosure statement identifying the
    specified arrangements or a statement that the applicant has acted
    with due diligence to obtain the required information, and an
    explanation of why it was unable to do so. The agency does not
    anticipate that it will be necessary to use its refuse to file
    authority often in the context of this financial disclosure rule.
    Applicants are encouraged to discuss their concerns on particular
    matters about financial information with FDA.

27. **Q: Who will review a disclosure of the specified financial
    arrangements when such information is submitted in a marketing
    application? How will the financial information be handled during
    the review of the application?**

    A: Applicants are required to disclose specified financial
    information and any steps taken to minimize the potential for bias
    in any drug, biological product or device marketing application
    submitted to the agency on or after February 2, 1999. (See 21 CFR
    54.4(a)(3)). FDA review staff, including project managers, consumer
    safety officers, medical officers and others in the supervisory
    chain will review this information on a case-by-case basis.

28. **Q: Under what circumstances will FDA publicly discuss financial
    arrangements disclosed to the agency?**

    A: In the preamble to the final rule, FDA stated that certain types
    of financial information requested under the rule, notably clinical
    investigators\' equity interests would be protected from public
    disclosure unless circumstances relating to the public interest
    clearly outweigh the clinical investigator\'s identified privacy
    interest. FDA cited the example of a financial arrangement so
    affecting the reliability of a study as to warrant its public
    disclosure during evaluation of the study by an advisory panel. FDA
    expects that only rarely would an investigator\'s privacy interest
    be outweighed by the public interest and thus warrant disclosure of
    the financial interest. It is difficult to predict all possible
    situations that may result in public disclosure of financial
    interests of a clinical investigator. The agency will carefully
    evaluate each circumstance on a case-by-case basis.

29. **Q: Can FDA have access to documents related to financial
    disclosure or certification documents during an inspection?\
    ***A:* Yes, FDA has the authority to have access to and to copy
    documents supporting an applicant\'s certification or disclosure
    statement submitted to the agency in a marketing application.
    Regulations implementing sections 505(i), 519, and 520(g) of the Act
    require sponsors to establish and maintain records of data
    (including but not limited to analytical reports by investigators)
    obtained during investigational studies of drugs, biological
    products, and devices, that will enable the Secretary to evaluate a
    product\'s safety and effectiveness. Under 54.6, applicants must
    retain certain information on clinical investigators\' financial
    interests and permits FDA employees to have access to and copy them
    at reasonable times.

30. **Q: What kind of documentation is necessary for manufacturers to
    keep in case questions about certification and/or disclosure
    arise?**

    A: To the extent that applicants have relied on investigators as the
    source of information about potentially disclosable financial
    interests in any of the four categories, the underlying
    documentation \-- e.g., copies of executed questionnaires returned
    by investigators , correspondence on the subject of financial
    disclosure, mail receipts, etc. should be retained. Likewise, to the
    extent that applicants who did not sponsor a covered clinical study
    rely on information furnished by the sponsor, the underlying
    documentation, including all relevant correspondence with and
    reports from the sponsor should be retained. To the extent that
    applicants rely upon information available internally, all
    appropriate financial documentation regarding the financial
    interests or arrangements in question should be retained. For
    example, in the case of \"significant payments of other sorts,\"
    sponsors should keep documentation including, but not limited to,
    check stubs, canceled checks, records of electronic financial
    transactions, certified mail deliver receipts, etc.

31. **Q: Where are forms FDA 3454 and 3455 located on the Web?**

    The forms are located at the following Internet address:

    <http://www.fda.gov/opacom/morechoices/fdaforms/cder.html>

32. **Q: Who are the contact persons in each FDA Center to answer
    questions during this implementation phase?**

    The following persons may be contacted: Ms. Linda Carter in the
    Center for Drug Evaluation and Research, phone 301-594-6758, Dr.
    Joanne Less in the Center for Devices and Radiological Health, phone
    301-594-1190, and Dr. Jerome Donlon in the Center for Biologics
    Evaluation and Research, phone 301-827-3028.

# C. FDA IRB Regulations (21 CFR Part 56)

<http://www.fda.gov/oc/ohrt/irbs/appendixc.html>

**Subpart A General Provisions**

56.101 Scope.\
56.102 Definitions.\
56.103 Circumstances in which IRB review is required.\
56.104 Exemptions from IRB requirement.\
56.105 Waiver of IRB requirement.

**Subpart B Organization and Personnel**

56.107 IRB membership.

**Subpart C IRB Functions and Operations**

56.108 IRB functions and operations.\
56.109 IRB review of research.\
56.110 Expedited review procedures for certain kinds of \... research.\
56.111 Criteria for IRB approval of research.\
56.112 Review by institution.\
56.113 Suspension or termination of IRB approval of research.\
56.114 Cooperative research.

**Subpart D Records and Reports**

56.115 IRB records.

Subpart E Administrative Action for Noncompliance

56.120 Lesser administrative actions.\
56.121 Disqualification of an IRB or an institution.\
56.122 Public disclosure of information regarding revocation.\
56.123 Reinstatement of an IRB or an institution.\
56.124 Actions alternative or additional to disqualification.\
\[Source: 46 FR 8975, Jan 27, 1981, unless otherwise noted.\]

**Subpart A - General Provisions**

**§56.101 Scope.**

\(a\) This part contains the general standards for the composition
operation, and responsibility of an Institutional Review Board (IRB)
that reviews clinical investigations regulated by the Food and Drug
Administration under sections 505(i) 507(d), and 520(g) of the act, as
well as clinical investigations that support applications for research
or marketing permits for products regulated by the Food and Drug
Administration including food and color additives, drugs for human use
medical devices for human use, biological products for human use, and
electronic products. Compliance with this part is intended to protect
the rights and welfare of human subjects involved in such
investigations.

\(b\) References in this part to regulatory sections of the Code of
Federal Regulations are to Chapter I of Title 21, unless otherwise
noted.

**§56.102 Definitions.**

As used in this part:

\(a\) Act means the Federal Food, Drug, and Cosmetic Act, as amended
(secs. 201-902, 52 Stat. 1040 et seq., as amended (21 U.S.C. 321-392)).

\(b\) Application for research or marketing permit includes:

> \(1\) A color additive petition, described in part 71.
>
> \(2\) Data and information regarding a substance submitted as part of
> the procedures for establishing that a substance is generally
> recognized as safe for a use which results or may reasonably be
> expected to result, directly or indirectly, in its becoming a
> component or otherwise affecting the characteristics of any food,
> described in ß 170.35.
>
> \(3\) A food additive petition, described in part 171.
>
> \(4\) Data and information regarding a food additive submitted as part
> of the procedures regarding food additives permitted to be used on an
> interim basis pending additional study, described in ß 180.1.
>
> \(5\) Data and information regarding a substance submitted as part of
> the procedures for establishing a tolerance for unavoidable
> contaminants in food and food-packaging materials described in section
> 406 of the act.
>
> \(6\) An investigational new drug application, described in part 312
> of this chapter.
>
> \(7\) A new drug application, described in part 314.
>
> \(8\) Data and information regarding the bioavailability or
> bioequivalence of drugs for human use submitted as part of the
> procedures for issuing, amending, or repealing a bioequivalence
> requirement, described in part 320.
>
> \(9\) Data and information regarding an over-the-counter drug for
> human use submitted as part of the procedures for classifying such
> drugs as generally recognized as safe and effective and not
> misbranded, described in part 330.
>
> \(10\) Data and information regarding an antibiotic drug submitted as
> part of the procedures for issuing amending, or repealing regulations
> for such drugs, described in ß 314.300 of this chapter.
>
> \(11\) An application for a biological product license, described in
> part 601.
>
> \(12\) Data and information regarding a biological product submitted
> as part of the procedures for determining that licensed biological
> products are safe and effective and not misbranded, as described in
> part 601.
>
> \(13\) An Application for an Investigational Device Exemption,
> described in parts 812 and 813.
>
> \(14\) Data and information regarding a medical device for human use
> submitted as part of the procedures for classifying such devices,
> described in part 860.
>
> \(15\) Data and information regarding a medical device for human use
> submitted as part of the procedures for establishing, amending, or
> repealing a standard for such device, described in part 861.
>
> \(16\) An application for premarket approval of a medical device for
> human use, described in section 515 of the act.
>
> \(17\) A product development protocol for a medical device for human
> use, described in section 515 of the act.
>
> \(18\) Data and information regarding an electronic product submitted
> as part of the procedures for establishing, amending, or repealing a
> standard for such products, described in section 358 of the Public
> Health Service Act.
>
> \(19\) Data and information regarding an electronic product submitted
> as part of the procedures for obtaining a variance from any electronic
> product performance standard, as described in ß 1010.4.
>
> \(20\) Data and information regarding an electronic product submitted
> as part of the procedures for granting, amending, or extending an
> exemption from a radiation safety performance standard as described in
> ß 1010.5.
>
> \(21\) Data and information regarding an electronic product submitted
> as part of the procedures for obtaining an exemption from notification
> of a radiation safety defect or failure of compliance with a radiation
> safety performance standard, described in subpart D of part 1003.

\(c\) Clinical investigation means any experiment that involves a test
article and one or more human subjects, and that either must meet the
requirements for prior submission to the Food and Drug Administration
under section 505(i), 507(d), or 520(g) of the act, or need not meet the
requirements for prior submission to the Food and Drug Administration
under these sections of the act, but the results of which are intended
to be later submitted to, or held for inspection by, the Food and Drug
Administration as part of an application for a research or marketing
permit. The term does not include experiments that must meet the
provisions of part 58, regarding nonclinical laboratory studies. The
terms research, clinical research, clinical study, study, and clinical
investigation are deemed to be synonymous for purposes of this part.

\(d\) Emergency use means the use of a test article on a human subject
in a life-threatening situation in which no standard acceptable
treatment is available, and in which there is not sufficient time to
obtain IRB approval.

\(e\) Human subject means an individual who is or becomes a participant
in research, either as a recipient of the test article or as a control.
A subject may be either a healthy individual or a patient.

\(f\) Institution means any public or private entity or Agency
(including Federal State, and other agencies). The term facility as used
in section 520(g) of the act is deemed to be synonymous with the term
institution for purposes of this part.

\(g\) Institutional Review Board (IRB) means any board committee, or
other group formally designated by an institution to review, to approve
the initiation of, and to conduct periodic review of, biomedical
research involving human subjects. The primary purpose of such review is
to assure the protection of the rights and welfare of the human
subjects. The term has the same meaning as the phrase institutional
review committee as used in section 520(g) of the act.

\(h\) Investigator means an individual who actually conducts a clinical
investigation (i.e., under whose immediate direction the test article is
administered or dispensed to or used involving,, a subject) or, in the
event of an investigation conducted by a team of individuals, is the
responsible leader of that team.

\(i\) Minimal risk means that the probability and magnitude of harm or
discomfort anticipated in the research are not greater in and of
themselves than those ordinarily encountered in daily life or during the
performance of routine physical or psychological examinations or tests.

\(j\) Sponsor means a person or other entity that initiates a clinical
investigation, but that does not actually conduct the investigation,
i.e., the test article is administered or dispensed to, or used
involving, a subject under the immediate direction of another
individual. A person other than an individual (e.g., a corporation or
agency) that uses one or more of its own employees to conduct an
investigation that it has initiated is considered to be a sponsor (not a
sponsor-investigator) and the employees are considered to be
investigators.

\(k\) Sponsor-investigator means an individual who both initiates and
actually conducts, alone or with others a clinical investigation, i.e.,
under whose immediate direction the test article is administered or
dispensed to, or used involving, a subject. The term does not include
any person other than an individual, e.g., it does not include a
corporation or agency. The obligations of a sponsor-investigator under
this part include both those of a sponsor and those of an investigator.

\(l\) Test article means any drug for human use, biological product for
human use, medical device for human use, human food additive, color
additive, electronic product, or any other article subject to regulation
under the act or under sections 351 or 354-360F of the Public Health
Service Act.

\(m\) IRB approval means the determination of the IRB that the clinical
investigation has been reviewed and may be conducted at an institution
within the constraints set forth by the IRB and by other institutional
and Federal requirements.

\[46 FR 8975, Jan. 27, 1981, as amended at 54 FR 9038 Mar. 3, 1989; 56
FR 28028, June 18, 1991\]

**§56.103 Circumstances in which IRB review is required.**

\(a\) Except as provided in ßß 56.104 and 56.105, any clinical
investigation which must meet the requirements for prior submission (as
required in parts 312, 812, and 813) to the Food and Drug Administration
shall not be initiated unless that investigation has been reviewed and
approved by, and remains subject to continuing review by, an IRB meeting
the requirements of this part.

\(b\) Except as provided in ßß 56.104 and 56.105, the Food and Drug
Administration may decide not to consider in support of an application
for a research or marketing permit any data or information that has been
derived from a clinical investigation that has not been approved by, and
that was not subject to initial and continuing review by, an IRB meeting
the requirements of this part. The determination that a clinical
investigation may not be considered in support of an application for a
research or marketing permit does not, however, relieve the applicant
for such a permit of any obligation under any other applicable
regulations to submit the results of the investigation to the Food and
Drug Administration.

\(c\) Compliance with these regulations will in no way render
inapplicable pertinent Federal, State, or local laws or regulations.

\[46 FR 8975, Jan. 27, 1981; 46 FR 14340, Feb. 27, 1981\]

**§56.104 Exemptions from IRB requirement.**

The following categories of clinical investigations are exempt from the
requirements of this part for IRB review:

\(a\) Any investigation which commenced before July 27, 1981 and was
subject to requirements for IRB review under FDA regulations before that
date, provided that the investigation remains subject to review of an
IRB which meets the FDA requirements in effect before July 27, 1981.

\(b\) Any investigation commenced before July 27, 1981 and was not
otherwise subject to requirements for IRB review under Food and Drug
Administration regulations before that date.

\(c\) Emergency use of a test article, provided that such emergency use
is reported to the IRB within 5 working days. Any subsequent use of the
test article at the institution is subject to IRB review.

\(d\) Taste and food quality evaluations and consumer acceptance
studies, if wholesome foods without additives are consumed or if a food
is consumed that contains a food ingredient at or below the level and
for a use found to be safe, or agricultural, chemical, or environmental
contaminant at or below the level found to be safe, by the Food and Drug
Administration or approved by the Environmental Protection Agency or the
Food Safety and Inspection Service of the U.S. Department of
Agriculture.

\[46 FR 8975, Jan. 27 1981, as amended at 56 FR 28028, June 18, 1991\]

**§56.105 Waiver of IRB requirement.**

On the application of a sponsor or sponsor-investigator, the Food and
Drug Administration may waive any of the requirements contained in these
regulations including the requirements for IRB review, for specific
research activities or for classes of research activities otherwise
covered by these regulations.

**SUBPART B - ORGANIZATION AND PERSONNEL**

**§56.107 IRB membership.**

\(a\) Each IRB shall have at least five members, with varying
backgrounds to promote complete and adequate review of research
activities commonly conducted by the institution. The IRB shall be
sufficiently qualified through the experience and expertise of its
members and the diversity of the members, including consideration of
race, gender, cultural backgrounds, and sensitivity to such issues as
community attitudes, to promote respect for its advice and counsel in
safeguarding the rights and welfare of human subjects. In addition to
possessing the professional competence necessary to review the specific
research activities, the IRB shall be able to ascertain the
acceptability of proposed research in terms of institutional commitments
and regulations applicable law, and standards of professional conduct
and practice. The IRB shall therefore include persons knowledgeable in
these areas. If an IRB regularly reviews research that involves a
vulnerable category of subjects, such as children, prisoners, pregnant
women, or handicapped or mentally disabled persons, consideration shall
be given to the inclusion of one or more individuals who are
knowledgeable about and experienced in working with those subjects.

\(b\) Every nondiscriminatory effort will be made to ensure that no IRB
consists entirely of men or entirely of women, including the
institution\'s consideration of qualified persons of both sexes, so long
as no selection is made to the IRB on the basis of gender. No IRB may
consist entirely of members of one profession.

\(c\) Each IRB shall include at least one member whose primary concerns
are in the scientific area and at least one member whose primary
concerns are in nonscientific areas.

\(d\) Each IRB shall include at least one member who is not otherwise
affiliated with the institution and who is not part of the immediate
family of a person who is affiliated with the institution.

\(e\) No IRB may have a member participate in the IRB\'s initial or
continuing review of any project in which the member has a conflicting
interest, except to provide information requested by the IRB.

\(f\) An IRB may, in its discretion, invite individuals with competence
in special areas to assist in the review of complex issues which require
expertise beyond or in addition to that available on the IRB. These
individuals may not vote with the IRB.

\[46 FR 8975, Jan 27 1981, as amended at 56 FR 28028, June 18, 1991; 56
FR 29756 June 28, 1991\]

**Subpart C - IRB Functions and Operations**

**§56.108 IRB functions and operations.**

In order to fulfill the requirements of these regulations, each IRB
shall:

\(a\) Follow written procedures: (1) For conducting its initial and
continuing review of research and for reporting its findings and actions
to the investigator and the institution; (2) for determining which
projects require review more often than annually and which projects need
verification from sources other than the investigator that no material
changes have occurred since previous IRB review; (3) for ensuring prompt
reporting to the IRB of changes in research activity; and (4) for
ensuring that changes in approved research, during the period for which
IRB approval has already been given may not be initiated without IRB
review and approval except where necessary to eliminate apparent
immediate hazards to the human subjects.

\(b\) Follow written procedures for ensuring prompt reporting to the
IRB, appropriate institutional officials, and the Food and Drug
Administration of: (1) Any unanticipated problems involving risks to
human subjects or others; (2) any instance of serious or continuing
noncompliance with these regulations or the requirements or
determinations of the IRB; or (3) any suspension or termination of IRB
approval.

\(c\) Except when an expedited review procedure is used (see ß 56.110),
review proposed research at convened meetings at which a majority of the
members of the IRB are present including at least one member whose
primary concerns are in nonscientific areas. In order for the research
to be approved it shall receive the approval of a majority of those
members present at the meeting.

\[46 FR 8975, Jan. 27, 1981, as amended at 56 FR 28028, June 18, 1991\]

**§56.109 IRB review of research.**

\(a\) An IRB shall review and have authority to approve, require
modifications in (to secure approval), or disapprove all research
activities covered by these regulations.

\(b\) An IRB shall require that information given to subjects as part of
informed consent is in accordance with ß 50.25. The IRB may require that
information in addition to that specifically mentioned in ß 50.25, be
given to the subjects when in the IRB\'s judgment the information would
meaningfully add to the protection of the rights and welfare of
subjects.

\(c\) An IRB shall require documentation of informed consent in
accordance with Sec. 50.27 of this chapter, except as follows: (1) The
IRB may, for some or all subjects, waive the requirement that the
subject, or the subject\'s legally authorized representative, sign a
written consent form if it finds that the research presents no more than
minimal risk of harm to subjects and involves no procedures for which
written consent is normally required outside the research context; or
(2) The IRB may, for some or all subjects, find that the requirements in
Sec. 50.24 of this chapter for an exception from informed consent for
emergency research are met.

\(d\) In cases where the documentation requirement is waived under
paragraph (c)(1) of this section, the IRB may require the investigator
to provide subjects with a written statement regarding the research.

\(e\) An IRB shall notify investigators and the institution in writing
of its decision to approve or disapprove the proposed research activity,
or of modifications required to secure IRB approval of the research
activity. If the IRB decides to disapprove a research activity, it shall
include in its written notification a statement of the reasons for its
decision and give the investigator an opportunity to respond in person
or in writing. For investigations involving an exception to informed
consent under Sec. 50.24 of this chapter, an IRB shall promptly notify
in writing the investigator and the sponsor of the research when an IRB
determines that it cannot approve the research because it does not meet
the criteria in the exception provided under Sec. 50.24(a) of this
chapter or because of other relevant ethical concerns. The written
notification shall include a statement of the reasons for the IRB\'s
determination.

\(f\) An IRB shall conduct continuing review of research covered by
these regulations at intervals appropriate to the degree of risk, but
not less than once per year, and shall have authority to observe or have
a third party observe the consent process and the research.

\(g\) An IRB shall provide in writing to the sponsor of research
involving an exception to informed consent under Sec. 50.24 of this
chapter a copy of information that has been publicly disclosed under
Sec. 50.24(a)(7)(ii) and (a)(7)(iii) of this chapter. The IRB shall
provide this information to the sponsor promptly so that the sponsor is
aware that such disclosure has occurred. Upon receipt, the sponsor shall
provide copies of the information disclosed to FDA.

\[46 FR 8975, Jan. 27, 1981, as amended at 56 FR 28028, June 18, 1991,
and at 61 FR 51497, Oct. 2, 1996\]

**§56.110 Expedited review procedures for certain kinds of research
involving no more than minimal risk, and for minor changes in approved
research.**

\(a\) The Food and Drug Administration has established, and published in
the Federal Register, a list of categories of research that may be
reviewed by the IRB through an expedited review procedure. The list will
be amended, as appropriate through periodic republication in the Federal
Register.

\(b\) An IRB may use the expedited review procedure to review either or
both of the following: (1) Some or all of the research appearing on the
list and found by the reviewer(s) to involve no more than minimal risk,
(2) minor changes in previously approved research during the period (of
1 year or less) for which approval is authorized. Under an expedited
review procedure the review may be carried out by the IRB chairperson or
by one or more experienced reviewers designated by the IRB chairperson
from among the members of the IRB. In reviewing the research, the
reviewers may exercise all of the authorities of the IRB except that the
reviewers may not disapprove the research. A research activity may be
disapproved only after review in accordance with the non-expedited
review procedure set forth in ß 56.108(c).

\(c\) Each IRB which uses an expedited review procedure shall adopt a
method for keeping all members advised of research proposals which have
been approved under the procedure.

\(d\) The Food and Drug Administration may restrict, suspend, or
terminate an institution\'s or IRB\'s use of the expedited review
procedure when necessary to protect the rights or welfare of subjects.

\[46 FR 8975, Jan. 27, 1981, as amended at 56 FR 28029, June 18, 1991\]

**§56.111 Criteria for IRB approval of research.**

\(a\) In order to approve research covered by these regulations the IRB
shall determine that all of the following requirements are satisfied:

> \(1\) Risks to subjects are minimized: (i) By using procedures which
> are consistent with sound research design and which do not
> unnecessarily expose subjects to risk, and (ii) whenever appropriate,
> by using procedures already being performed on the subjects for
> diagnostic or treatment purposes.
>
> \(2\) Risks to subjects are reasonable in relation to anticipated
> benefits, if any, to subjects and the importance of the knowledge that
> may be expected to result. In evaluating risks and benefits, the IRB
> should consider only those risks and benefits that may result from the
> research (as distinguished from risks and benefits therapies that
> subjects would receive even if not participating in the research). The
> IRB should not consider possible long-range effects of applying
> knowledge gained in the research (for example, the possible effects of
> the research on public policy) as among those research risks that fall
> within the purview of its responsibility.
>
> \(3\) Selection of subjects is equitable. In making this assessment
> the IRB should take into account the purposes of the research and the
> setting in which the research will be conducted and should be
> particularly cognizant of the special problems of research involving
> vulnerable populations, such as children, prisoners, pregnant women,
> handicapped, or mentally disabled persons, or economically or
> educationally disadvantaged persons.
>
> \(4\) Informed consent will be sought from each prospective subject or
> the subject\'s legally authorized representative, in accordance with
> and to the extent required by part 50.
>
> \(5\) Informed consent will be appropriately documented, in accordance
> with and to the extent required by ß 50.27.
>
> \(6\) Where appropriate, the research plan makes adequate provision
> for monitoring the data collected to ensure the safety of subjects.
>
> \(7\) Where appropriate, there are adequate provisions to protect the
> privacy of subjects and to maintain the confidentiality of data.

\(b\) When some or all of the subjects, such as children, prisoners,
pregnant women, handicapped, or mentally disabled persons, or
economically or educationally disadvantaged persons, are likely to be
vulnerable to coercion or undue influence additional safeguards have
been included in the study to protect the rights and welfare of these
subjects.

\[46 FR 8975, Jan. 27, 1981, as amended at 56 FR 28029, June 18, 1991\]

**§56.112 Review by institution.**

Research covered by these regulations that has been approved by an IRB
may be subject to further appropriate review and approval or disapproval
by officials of the institution. However, those officials may not
approve the research if it has not been approved by an IRB.

**§56.113 Suspension or termination of IRB approval of research.**

An IRB shall have authority to suspend or terminate approval of research
that is not being conducted in accordance with the IRB\'s requirements
or that has been associated with unexpected serious harm to subjects.
Any suspension or termination of approval shall include a statement of
the reasons for the IRB\'s action and shall be reported promptly to the
investigator appropriate institutional officials, and the Food and Drug
Administration.

**§56.114 Cooperative research.**

In complying with these regulations, institutions involved in
multi-institutional studies may use joint review, reliance upon the
review of another qualified IRB, or similar arrangements aimed at
avoidance of duplication of effort.

**Subpart D - Records and Reports.**

**§56.115 IRB records.**

\(a\) An institution, or where appropriate an IRB, shall prepare and
maintain adequate documentation of IRB activities including the
following:

> \(1\) Copies of all research proposals reviewed, scientific
> evaluations, if any, that accompany the proposals, approved sample
> consent documents progress reports submitted by investigators, and
> reports of injuries to subjects.
>
> \(2\) Minutes of IRB meetings which shall be in sufficient detail to
> show attendance at the meetings; actions taken by the IRB; the vote on
> these actions including the number of members voting for, against and
> abstaining; the basis for requiring changes in or disapproving
> research; and a written summary of the discussion of controverted
> issues and their resolution.
>
> \(3\) Records of continuing review activities.
>
> \(4\) Copies of all correspondence between the IRB and the
> investigators.
>
> \(5\) A list of IRB members identified by name; earned degrees;
> representative capacity; indications of experience such as board
> certifications licenses, etc., sufficient to describe each member\'s
> chief anticipated contributions to IRB deliberations; and any
> employment or other relationship between each member and the
> institution; for example: full-time employee, part-time employee, a
> member of governing panel or board, stockholder, paid or unpaid
> consultant.
>
> \(6\) Written procedures for the IRB as required by ß 56.108(a) and
> (b).
>
> \(7\) Statements of significant new findings provided to subjects, as
> required by ß 50.25.

\(b\) The records required by this regulation shall be retained for at
least 3 years after completion of the research, and the records shall be
accessible for inspection and copying by authorized representatives of
the Food and Drug Administration at reasonable times and in a reasonable
manner.

\(c\) The Food and Drug Administration may refuse to consider a clinical
investigation in support of an application for a research or marketing
permit if the institution or the IRB that reviewed the investigation
refuses to allow an inspection under this section.

\[46 FR 8975, Jan. 27, 1981, as amended at 56 FR 28029, June 18, 1991\]

**Subpart E - Administrative Actions for Noncompliance**

**§56.120 Lesser administrative actions.**

\(a\) If apparent noncompliance with these regulations in the operation
of an IRB is observed by an FDA investigator during an inspection, the
inspector will present an oral or written summary of observations to an
appropriate representative of the IRB. The Food and Drug Administration
may subsequently send a letter describing the noncompliance to the IRB
and to the parent institution. The Agency will require that the IRB or
the parent institution respond to this letter within a time period
specified by FDA and describe the corrective actions that will be taken
by the IRB, the institution, or both to achieve compliance with these
regulations.

\(b\) On the basis of the IRB\'s or the institution\'s response FDA may
schedule a reinspection to confirm the adequacy of corrective actions.
In addition, until the IRB or the parent institution takes appropriate
corrective action, the Agency may:

> \(1\) Withhold approval of new studies subject to the requirements of
> this part that are conducted at the institution or reviewed by the
> IRB;
>
> \(2\) Direct that no new subjects be added to ongoing studies subject
> to this part;
>
> \(3\) Terminate ongoing studies subject to this part when doing so
> would not subjects; or
>
> \(4\) When the apparent noncompliance creates a significant threat to
> the rights and welfare of human subjects notify relevant State and
> Federal regulatory agencies and other parties with a direct interest
> in the agency\'s action of the deficiencies in the operation of the
> IRB.

\(c\) The parent institution is presumed to be responsible for the
operation of an IRB, and the Food and Drug Administration will
ordinarily direct any administrative action under this subpart against
the institution. However, depending on the evidence of responsibility
for deficiencies, determined during the investigation, the Food and Drug
Administration may restrict its administrative actions to the IRB or to
a component of the parent institution determined to be responsible for
formal designation of the IRB.

**§56.121** Disqualification of an IRB or an institution.

\(a\) Whenever the IRB or the institution has failed to take adequate
steps to correct the noncompliance stated in the letter sent by the
Agency under ß 56.120(a), and the Commissioner of Food and Drugs
determines that this noncompliance may justify the disqualification of
the IRB or of the parent institution, the Commissioner will institute
proceedings in accordance with the requirements for a regulatory hearing
set forth in part 16.

\(b\) The Commissioner may disqualify an IRB or the parent if the
Commissioner determines that:

> \(1\) The IRB has refused or repeatedly failed to comply with any of
> the regulations set forth in this part, and;
>
> \(2\) The noncompliance adversely affects the rights or welfare of the
> human subjects in a clinical investigation.

\(c\) If the Commissioner determines that disqualification is
appropriate, the Commissioner will issue an order that explains the
basis for the determination and that prescribes any actions to be taken
with regard to ongoing clinical research conducted under the review of
the IRB. The Food and Drug Administration will send notice of the
disqualification to the IRB and the parent institution. Other parties
with a direct interest, such as sponsors and clinical investigators, may
also be sent a notice of the disqualification. In addition, the Agency
may elect to publish a notice of its action in the Federal Register.

\(d\) The Food and Drug Administration will not approve an application
for a research permit for a clinical investigation that is to be under
the review of a disqualified IRB or that is to be conducted at a
disqualified institution, and it may refuse to consider in support of a
marketing permit the data from a clinical investigation that was
reviewed by a disqualified IRB as conducted at a disqualified
institution unless the IRB or the parent institution is reinstated as
provided in ß 56.123.

**§56.122 Public disclosure of information regarding revocation.**

A determination that the Food and Drug Administration has disqualified
an institution and the administrative record regarding that
determination are disclosable to the public under part 20.

**§56.123 Reinstatement of an IRB or an institution.**

An IRB or an institution may be reinstated if the Commissioner
determines upon an evaluation of a written submission from the IRB or
institution that explains the corrective action that the institution or
IRB plans to take, that the IRB or institution has provided adequate
assurance that it will operate in compliance with the standards set
forth in this part. Notification of reinstatement shall be provided to
all persons notified under §56.121(c).

**§56.124 Actions alternative or additional to disqualification.**

Disqualification of an IRB or of an institution is independent of, and
neither in lieu of nor a precondition to, other proceedings or actions
authorized by the act. The Food and Drug Administration may at any time,
through the Department of Justice institute any appropriate judicial
proceedings (civil or criminal) and any other appropriate regulatory
action, in addition to or in lieu of, and before, at the time of, or
after, disqualification. The Agency may also refer pertinent matters to
another Federal State, or local government Agency for any action that
Agency determines to be appropriate.

# Appendix VII: Other Regulations and Standards

# 

# D. FDA Investigational New Drug (IND) Application

#  Regulations (21 CFR Part 312)

<http://www.fda.gov/cber/ind/21cfr312.pdf>

**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.

\[52 FR 8831, Mar. 19, 1987, as amended at 61 FR 51529, Oct. 2, 1996; 64

FR 401, Jan. 5, 1999\]

**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.

\[52 FR 8831, Mar. 19, 1987, as amended at 64 FR 401, Jan. 5, 1999; 64
FR

56449, Oct. 20, 1999\]

**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.

(Collection of information requirements approved by the Office of

Management and Budget under control number 0910-0014)

\[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 19476, May 22, 1987\]

**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.

(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)

\[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987\]

**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.

\[52 FR 8831, Mar. 19, 1987, as amended at 61 FR 51529, Oct. 2, 1996; 62

FR 32479, June 16, 1997\]

**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.]{.underline} A statement of the objectives and purpose of the
> study.
>
> [b.]{.underline} The name and address and a statement of the
> qualifications (curriculum vitae 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.]{.underline} The criteria for patient selection and for exclusion
> of patients and an estimate of the number of patients to be studied.
>
> [d.]{.underline} 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.]{.underline} 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.]{.underline} A description of the observations and measurements to
> be made to fulfill the objectives of the study.
>
> [g.]{.underline} 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.]{.underline} 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.]{.underline} 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.]{.underline} A brief general description of the composition,
> manufacture, and control of any placebo used in a controlled clinical
> trial.
>
> [d.]{.underline} Labeling. A copy of all labels and labeling to be
> provided to each investigator.
>
> [e.]{.underline} 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.]{.underline} 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.]{.underline} 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.

(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)

\[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987;
53 FR 1918, Jan. 25, 1988; 61 FR 51529, Oct. 2, 1996; 62 FR 40599, July
29, 1997; 63 FR 66669, Dec. 2, 1998\]

**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.]{.underline} The sponsor has submitted the change to FDA for its
> review; and
>
> [b.]{.underline} 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.

(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)

\[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987;
53 FR 1918, Jan. 25, 1988; 61 FR 51530, Oct. 2, 1996\]

**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.

(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)

\[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987;
53 FR 1918, Jan. 25, 1988\]

**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.]{.underline} Any adverse experience associated with the use of the
> drug that is both serious and unexpected; or
>
> [b.]{.underline} 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 previous, 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.

(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)

\[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987;
55 FR 11579, Mar. 29, 1990; 62 FR 52250, Oct. 7, 1997\]

**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.

(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)

\[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987;
63 FR 6862, Feb. 11, 1998\]

**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.]{.underline} May be effective for its intended use in its intended
> patient population; or
>
> [b.]{.underline} 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.

\[52 FR 19476, May 22, 1987, as amended at 57 FR 13248, Apr. 15, 1992\]

**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 practioner 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.

(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)

\[52 FR 19477, May 22, 1987, as amended at 57 FR 13249, Apr. 15, 1992\]

**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.

(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)

\[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987;
55 FR 11579, Mar. 29, 1990\]

**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.

(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)

\[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987\]

**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.

(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)

\[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987\]

**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.]{.underline} The pertinent criteria in Sec. 312.34(b) for
> permitting the treatment use to begin are not satisfied; or
>
> [b.]{.underline} 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.]{.underline} 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.]{.underline} 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.]{.underline} The sponsor of the controlled clinical trial is not
> pursuing marketing approval with due diligence;
>
> [d.]{.underline} 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.]{.underline} 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.]{.underline} May be effective for its intended use in its intended
> population; or
>
> [2.]{.underline} 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.

\[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 19477, May 22, 1987; 57
FR 13249, Apr. 15, 1992; 61 FR 51530, Oct. 2, 1996; 63 FR 68678, Dec.
14, 1998; 64 FR 54189, Oct. 5, 1999\]

**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 injury.
>
> \(ii\) 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.

(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)

\[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987;
55 FR 11579, Mar. 29, 1990; 57 FR 13249, Apr. 15, 1992\]

**Sec. 312.45 Inactive status.**

\(a\) If no subjects are entered into clinical studies for a period of 2
years or more under an IND, or if all investigations under an IND remain
on clinical hold for 1 year or more, the IND may be placed by FDA on
inactive status. This action may be taken by FDA either on request of
the sponsor or on FDA\'s own initiative. If FDA seeks to act on its own
initiative under this section, it shall first notify the sponsor in
writing of the proposed inactive status. Upon receipt of such
notification, the sponsor shall have 30 days to respond as to why the
IND should continue to remain active.

\(b\) If an IND is placed on inactive status, all investigators shall be
so notified and all stocks of the drug shall be returned or otherwise
disposed of in accordance with Sec. 312.59.

\(c\) A sponsor is not required to submit annual reports to an IND on
inactive status. An inactive IND is, however, still in effect for
purposes of the public disclosure of data and information under Sec.
312.130.

\(d\) A sponsor who intends to resume clinical investigation under an
IND placed on inactive status shall submit a protocol amendment under
Sec. 312.30 containing the proposed general investigational plan for the
coming year and appropriate protocols. If the protocol amendment relies
on information previously submitted, the plan shall reference such
information. Additional information supporting the proposed
investigation, if any, shall be submitted in an information amendment.
Notwithstanding the provisions of Sec. 312.30, clinical investigations
under an IND on inactive status may only resume (1) 30 days after FDA
receives the protocol amendment, unless FDA notifies the sponsor that
the investigations described in the amendment are subject to a clinical
hold under Sec. 312.42, or (2) on earlier notification by FDA that the
clinical investigations described in the protocol amendment may begin.

\(e\) An IND that remains on inactive status for 5 years or more may be
terminated under Sec. 312.44.

(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)

\[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987\]

**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.

(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)

\[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987;
55 FR 11580, Mar. 29, 1990; 63 FR 66669, Dec. 2, 1998\]

**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.

\[52 FR 8831, Mar. 19, 1987, as amended at 55 FR 11580, Mar. 29, 1990\]

**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,]{.underline} 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.]{.underline} Will comply with all requirements regarding the
> obligations of clinical investigators and all other pertinent
> requirements in this part;
>
> [c.]{.underline} Will personally conduct or supervise the described
> investigation(s);
>
> [d.]{.underline} 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.]{.underline} Will report to the sponsor adverse experiences that
> occur in the course of the investigation(s) in accordance with Sec.
> 312.64;
>
> [f.]{.underline} Has read and understands the information in the
> investigator\'s brochure, including the potential risks and side
> effects of the drug; and
>
> [g.]{.underline} 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.

(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)

\[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987;
61 FR 57280, Nov. 5, 1996; 63 FR 5252, Feb. 2, 1998\]

**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.\[61 FR 51530, Oct. 2,
1996\]

**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.

(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)

\[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987\]

**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.

(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)

\[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987\]

**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.

(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)

\[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987;
58 FR 25926, Apr. 28, 1993; 63 FR 5252, Feb. 2, 1998\]

**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.

(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)

\[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987\]

**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.

\[52 FR 8831, Mar. 19, 1987, as amended at 61 FR 51530, Oct. 2, 1996\]

**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.

(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)

\[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987;
61 FR 57280, Nov. 5, 1996\]

**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.

(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)

\[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987;
63 FR 5252, Feb. 2, 1998\]

**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.

(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)

\[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987\]

**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.

(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)

\[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987;
55 FR 11580, Mar. 29, 1990; 62 FR 46876, Sept. 5, 1997\]

**Sec. 312.80 Purpose.**

Authority: 21 U.S.C. 351, 352, 353, 355, 371; 42 U.S.C. 262.

Source: 53 FR 41523, Oct. 21, 1988, unless otherwise noted.

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.

\[53 FR 41523, Oct. 21, 1988, as amended at 64 FR 401, Jan. 5, 1999\]

**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.

\[53 FR 41523, Oct. 21, 1988, as amended at 63 FR 66669, Dec. 2, 1998\]

**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).

**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 the Public Health Service Act
> (42 U.S.C. 262(h)(1)(A)).

(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)

\[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987;
64 FR 401, Jan. 5, 1999\]

**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.

(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)

\[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987;
56 FR 22113, May 14, 1991; 64 FR 401, Jan. 5, 1999\]

**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.

\[52 FR 8831, Mar. 19, 1987. Redesignated at 53 FR 41523, Oct. 21, 1988,
as amended at 61 FR 51530, Oct. 2, 1996; 64 FR 401, Jan. 5, 1999\]

**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.

(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)

\[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987;
55 FR 11580, Mar. 29, 1990\]

**Sec. 312.145 Guidelines.**

\(a\) FDA has made available guidelines under Sec. 10.90(b) to help
persons to comply with certain requirements of this part.

\(b\) The Center for Drug Evaluation and Research and the Center for
Biologics Evaluation and Research maintain lists of guidelines that
apply to the Centers\' regulations. The lists state how a person can
obtain a copy of each guideline. A request for a copy of the lists
should be directed to the CDER Executive Secretariat Staff (HFD-8),
Center for Drug Evaluation and Research, Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857, for drug products, and the
Congressional, Consumer, and International Affairs Staff (HFB-142),
Center for Biologics Evaluation and Research, Food and Drug
Administration, 8800 Rockville Pike, Bethesda, MD 20892, for biological
products.

\[52 FR 8831, Mar. 19, 1987, as amended at 55 FR 11580, Mar. 29, 1990;
56 FR 3776, Jan. 31, 1991; 57 FR 10814, Mar. 31, 1992\]

**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.

(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)

\[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987.
Redesignated at 53 FR 41523, Oct. 21, 1988\]

# E. FDA Diagnostic Radiopharmaceuticals Regulations (21 CFR Part 315)

# 

<http://www.access.gpo.gov/nara/cfr/waisidx_00/21cfr315_00.html>

NOTE:

FDA RADIOLOGY DEVICES REGULATIONS AT 21 CFR 892 MAY BE FOUND AT
<http://www.access.gpo.gov/nara/cfr/waisidx_00/21cfr892_00.html>

**315.1** **Scope**

The regulations in this part apply to radiopharmaceuticals intended for
in vivo administration for diagnostic and monitoring use. They do not
apply to radiopharmaceuticals intended for therapeutic purposes. In
situations where a particular radiopharmaceutical is proposed for both
diagnostic and therapeutic uses, the radiopharmaceutical must be
evaluated taking into account each intended use.

**315.2 Definition.**

For purposes of this part, diagnostic radiopharmaceutical means: (a) An
article that is intended for use in the diagnosis or monitoring of a
disease or a manifestation of a disease in humans and that exhibits
spontaneous disintegration of unstable nuclei with the emission of
nuclear particles or photons; or (b) Any nonradioactive reagent kit or
nuclide generator that is intended to be used in the preparation of such
article as defined in paragraph (a) of this section.

**315.3** **General factors relevant to safety and effectiveness.**

FDA\'s determination of the safety and effectiveness of a diagnostic
radiopharmaceutical includes consideration of the following: (a) The
proposed use of the diagnostic radiopharmaceutical in the practice of
medicine, (b) The pharmacological and toxicological activity of the
diagnostic radiopharmaceutical (including any carrier or ligand
component of the diagnostic radiopharmaceutical), and (c) The estimated
absorbed radiation dose of the diagnostic radiopharmaceutical.

**315.4** **Indications.**

\(a\) For diagnostic radiopharmaceuticals, the categories of proposed
indications for use include, but are not limited to, the following: (1)
Structure delineation; (2) Functional, physiological, or biochemical
assessment; (3) Disease or pathology detection or assessment; and (4)
Diagnostic or therapeutic patient management.

\(b\) Where a diagnostic radiopharmaceutical is not intended to provide
disease-specific information, the proposed indications for use may refer
to a biochemical, physiological, anatomical, or pathological process or
to more than one disease or condition.

**315.5** **Evaluation of effectiveness.**

\(a\) The effectiveness of a diagnostic radiopharmaceutical is assessed
by evaluating its ability to provide useful clinical information related
to its proposed indications for use. The method of this evaluation
varies depending upon the proposed indication(s) and may use one or more
of the following criteria: (1) The claim of structure delineation is
established by demonstrating in a defined clinical setting the ability
to locate anatomical structures and to characterize their anatomy. (2)
The claim of functional, physiological, or biochemical assessment is
established by demonstrating in a defined clinical setting reliable
measurement of function(s) or physiological, biochemical, or molecular
process(es). (3) The claim of disease or pathology detection or
assessment is established by demonstrating in a defined clinical setting
that the diagnostic radiopharmaceutical has sufficient accuracy in
identifying or characterizing the disease or pathology. (4) The claim of
diagnostic or therapeutic patient management is established by
demonstrating in a defined clinical setting that the test is useful in
diagnostic or therapeutic patient management. (5) For a claim that does
not fall within the indication categories identified in Sec. 315.4, the
applicant or sponsor should consult FDA on how to establish the
effectiveness of the diagnostic radiopharmaceutical for the claim.

\(b\) The accuracy and usefulness of the diagnostic information is
determined by comparison with a reliable assessment of actual clinical
status. A reliable assessment of actual clinical status may be provided
by a diagnostic standard or standards of demonstrated accuracy. In the
absence of such diagnostic standard(s), the actual clinical status must
be established in another manner, e.g., patient followup.

315.6 Evaluation of safety.

\(a\) Factors considered in the safety assessment of a diagnostic
radiopharmaceutical include, among others, the following: (1) The
radiation dose; (2) The pharmacology and toxicology of the
radiopharmaceutical, including any radionuclide, carrier, or ligand; (3)
The risks of an incorrect diagnostic determination; (4) The adverse
reaction profile of the drug; (5) Results of human experience with the
radiopharmaceutical for other uses; and (6) Results of any previous
human experience with the carrier or ligand of the radiopharmaceutical
when the same chemical entity as the carrier or ligand has been used in
a previously studied product.

\(b\) The assessment of the adverse reaction profile includes, but is
not limited to, an evaluation of the potential of the diagnostic
radiopharmaceutical, including the carrier or ligand, to elicit the
following: (1) Allergic or hypersensitivity responses, (2) Immunologic
responses, (3) Changes in the physiologic or biochemical function of the
target and nontarget tissues, and (4) Clinically detectable signs or
symptoms.

(c)(1) To establish the safety of a diagnostic radiopharmaceutical, FDA
may require, among other information, the following types of data: (i)
Pharmacology data, (ii) Toxicology data, (iii) Clinical adverse event
data, and (iv) Radiation safety assessment. (2) The amount of new safety
data required will depend on the characteristics of the product and
available information regarding the safety of the diagnostic
radiopharmaceutical, and its carrier or ligand, obtained from other
studies and uses. Such information may include, but is not limited to,
the dose, route of administration, frequency of use, half-life of the
ligand or carrier, half-life of the radionuclide, and results of
clinical and preclinical studies. FDA will establish categories of
diagnostic radiopharmaceuticals based on defined characteristics
relevant to risk and will specify the amount and type of safety data
that are appropriate for each category (e.g., required safety data may
be limited for diagnostic radiopharmaceuticals with a well established,
low-risk profile). Upon reviewing the relevant product characteristics
and safety information, FDA will place each diagnostic
radiopharmaceutical into the appropriate safety risk category. (d)
Radiation safety assessment. The radiation safety assessment must
establish the radiation dose of a diagnostic radiopharmaceutical by
radiation dosimetry evaluations in humans and appropriate animal models.
The maximum tolerated dose need not be established.

# F. FDA Radioactive Drugs for Certain Research Uses (21 CFR Part 361.1)

**PART 361\--PRESCRIPTION DRUGS FOR HUMAN USE GENERALLY RECOGNIZED AS
SAFE AND EFFECTIVE AND NOT MISBRANDED: DRUGS USED IN RESEARCH**

**361.1 Radioactive drugs for certain research uses.**

\(a\) Radioactive drugs (as defined in Sec. 310.3(n) of this chapter)
are generally recognized as safe and effective when administered, under
the conditions set forth in paragraph (b) of this section, to human
research subjects during the course of a research project intended to
obtain basic information regarding the metabolism (including kinetics,
distribution, and localization) of a radioactively labeled drug or
regarding human physiology, pathophysiology, or biochemistry, but not
intended for immediate therapeutic, diagnostic, or similar purposes or
to determine the safety and effectiveness of the drug in humans for such
purposes (i.e., to carry out a clinical trial). Certain basic research
studies, e.g., studies to determine whether a drug localizes in a
particular organ or fluid space and to describe the kinetics of that
localization, may have eventual therapeutic or diagnostic implications,
but the initial studies are considered to be basic research within the
meaning of this section.

\(b\) The conditions under which use of radioactive drugs for research
are considered safe and effective are: (1) Approval by Radioactive Drug
Research Committee. A Radioactive Drug Research Committee, composed and
approved by the Food and Drug Administration in accordance with
paragraph (c) of this section, has determined, in accordance with the
standards set forth in paragraph (d) of this section, that: (i) The
pharmacological dose is within the limits set forth in paragraph (b)(2)
of this section; (ii) The radiation dose is within the limits set forth
in paragraph (b)(3) of this section; (iii) The radiation exposure is
justified by the quality of the study being undertaken and the
importance of the information it seeks to obtain; (iv) The study meets
the other requirements set forth in paragraph (d) of this section
regarding qualifications of the investigator, proper licensure for
handling radioactive materials, selection and consent of research
subjects, quality of radioactive drugs used, research protocol design,
reporting of adverse reactions, and approval by an appropriate
Institutional Review Committee; and (v) The use of the radioactive drug
in human subjects has the approval of the Radioactive Drug Research
Committee. (2) Limit on pharmacological dose. The amount of active
ingredient or combination of active ingredients to be administered shall
be known not to cause any clinically detectable pharmacological effect
in human beings. If the same active ingredients (exclusive of the
radionuclide) are to be administered simultaneously, e.g., under a
"Investigational New Drug Application" or for a therapeutic use in
accordance with labeling for a drug approved under part 314 of this
chapter, the total amount of active ingredients including the
radionuclide shall be known not to exceed the dose limitations
applicable to the separate administration of the active ingredients
excluding the radionuclide. (3) Limit on radiation dose. The amount of
radioactive material to be administered shall be such that the subject
receives the smallest radiation dose with which it is practical to
perform the study without jeopardizing the benefits to be obtained from
the study. (i) Under no circumstances may the radiation dose to an adult
research subject from a single study or cumulatively from a number of
studies conducted within **1** year be generally recognized as safe if
such dose exceeds the following:

Whole body, active blood-forming organs, lens of the eye, and gonads:
(Rems)

Single dose 3

Annual and total dose commitment 5

Other organs: Single dose 5

Annual and total dose commitment 15

\(ii\) For a research subject under 18 years of age at his last
birthday, the radiation dose shall not exceed 10 percent of that set
forth in paragraph (b)(3)(i) of this section. (iii) All radioactive
material included in the drug either as essential material or as a
significant contaminant or impurity shall be included when determining
the total radiation doses and dose commitments. Radiation doses from
x-ray procedures that are part of the research study (i.e., would not
have occurred but for the study) shall also be included. The possibility
of followup studies shall be considered for inclusion in the dose
calculations. (iv) Numerical definitions of dose shall be based on an
absorbed fraction method of radiation absorbed dose calculation, such as
the system set forth by the Medical Internal Radiation Dose Committee of
the Society of Nuclear Medicine, or the system set forth by the
International Commission on Radiological Protection.

\(c\) A Radioactive Drug Research Committee, in order to comply with
paragraph (b)(**1**) of this section, shall be composed, shall function,
and shall obtain and maintain approval of the Food and Drug
Administration in conformity with the following: (**1**) Membership. A
Radioactive Drug Research Committee shall consist of at least five
individuals. Each committee shall include the following three
individuals: (i) A physician recognized as a specialist in nuclear
medicine, (ii) a person qualified by training and experience to
formulate radioactive drugs, and (iii) a person with special competence
in radiation safety and radiation dosimetry. The remainder of the
committee shall consist of individuals qualified in various disciplines
pertinent to the field of nuclear medicine (e.g., radiology, internal
medicine, clinical pathology, hematology, endocrinology, radiation
therapy, radiation physics, radiation biophysics, health physics, and
radiopharmacy). Membership shall be sufficiently diverse to permit
expert review of the technical and scientific aspects of proposals
submitted to the committee. The addition of consultants in other
pertinent medical disciplines is encouraged. A Radioactive Drug Research
Committee shall be either associated with a medical institution operated
for care of patients and with sufficient scientific expertise to allow
for selection of committee members from its faculty, or with a committee
established by a State authority to provide advice on radiation health
matters. Joint committees involving more than one medical institution
which have been established in order to achieve a high level and
diversity of experience will be acceptable. The Director of the Center
for Drug Evaluation and Research may modify any of the foregoing
requirements in a particular situation where alternative factors provide
substantially the same composition and association. (2) Function. Each
Radioactive Drug Research Committee shall select a chairman, who shall
sign all applications, minutes, and reports of the committee. Each
committee shall meet at least once each quarter in which research
activity has been authorized or conducted. A quorum consisting of more
than 50 percent of the membership must be present with appropriate
representation of the required fields of specialization. Minutes shall
be kept and shall include the numerical results of votes on protocols
involving use in human subjects. No member shall vote on a protocol in
which he is an investigator. (3) Reports. Each Radioactive Drug Research
Committee shall submit an annual report on or before January 31 of each
year to the Food and Drug Administration, Center for Drug Evaluation and
Research, HFD-160, 5600 Fishers Lane, Rockville, MD 20857. The annual
report shall include the names and qualifications of the members of, and
of any consultants used by, the Radioactive Drug Research Committee,
and, for each study conducted during the preceding year, a summary of
information presented in the following format:

Report on Research Use of Radioactive Drug

1\. Title of the research project.

2\. Brief description of the purpose of the research project.

3\. Name of the investigator responsible.

4\. Pharmacological dose: a. Active ingredients. b. Maximum amount
administered per subject.

5\. Name of the radionuclide(s) used, including any present, as
significant contaminants or impurities.

6\. Radiation absorbed dose. Provide the maximum dose commitement to the
whole body and each organ specified in 21 CFR 361.1(b)(3)(i) that was
received by a representative subject and the calculations or references
that were used to estimate these maximum dose commitments. The report
shall include the dose contribution of both the administered
radionuclide(s) and any X-ray procedures associated with the study. If
the study elicits data on the uptake or excretion of the radioactive
drug pertinent to the estimation of dose commitment, report the mean
value and range of values. For each subject provide: (a) Age, sex, and
approximate weight. (b) Total activity of each radionuclide administered
for each radioactive drug used in the study. Report each X-ray procedure
used in conjunction with the study. (c) If the subject has participated
in other radioactive drug research studies, report the name of the
radioactive drug used in these other studies, the date of
administration, and the total activity of each radionuclide
administered. If any X-ray procedures were used, identify the X-ray
procedure(s) and include an estimate of the absorbed radiation doses.
(d) If more than one administration of a radioactive drug per subject,
cumulative radiation dose and dose commitment, expressed as whole body,
active blood-forming organs, lens of the eye, gonads, and other organ
doses from the administered radionuclides.

7\. A claim of confidentiality, if any. Note: Contents of this report
are available for public disclosure unless confidentiality is requested
by the investigator and it is adequately shown by the investigator that
the report constitutes a trade secret or confidential commercial
information as defined in 21 CFR 20.61.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ Investigator

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ Chairman, Radioactive Drug
Research Committee

At any time a proposal is approved which involves exposure either of
more than 30 research subjects, or of any research subject under 18
years of age, the committee shall immediately submit to the Food and
Drug Administration a special summary of information in the format shown
in this paragraph. Contents of these reports are available for public
disclosure, unless confidentiality is requested by the investigator and
it is adequately shown by the investigator that the report constitutes a
trade secret or confidential commercial information as defined in Sec.
20.61 of this chapter. (4) Approval. Each Radioactive Drug Research
Committee shall be specifically approved by the Center for Drug
Evaluation and Research of the Food and Drug Administration.
Applications shall be submitted to the Food and Drug Administration,
Center for Drug Evaluation and Research, HFD-160, 5600 Fishers Lane,
Rockville, MD 20857, and shall contain the names and qualifications of
the members of the committee, and a statement that the committee agrees
to comply with the requirements set forth in this section. Approval
shall be based upon an assessment of the qualifications of the members
of the committee, and the assurance that all necessary fields of
expertise are covered. Approval of a committee may be withdrawn at any
time for failure of the committee to comply with any of the requirements
of this section. Approval of a committee shall remain effective unless
and until the FDA withdraws such approval. Changes in membership and
applications for new members shall be submitted to the Food and Drug
Administration as soon as, or before, vacancies occur on the committee.
(5) Monitoring. The Food and Drug Administration shall conduct periodic
reviews of approved committees. Monitoring of the activities of the
committee shall be conducted through review of its annual report,
through review of minutes and full protocols for certain studies, and
through on-site inspections.

\(d\) In making the determination required in paragraph (b)(**1**) of
this section, a Radioactive Drug Research Committee shall consider the
following requirements and assure that each is met: (1) Radiation dose
to subjects. To assure that the radiation dose to research subjects is
as low as practicable to perform the study and meet the criteria of Sec.
361.1(b)(3), the Radioactive Drug Research Committee shall require that:
(i) The investigator provide absorbed dose calculations based on
biologic distribution data available from published literature or from
other valid studies. (ii) The investigator provide for an acceptable
method of radioassay of the radioactive drug prior to its use to assure
that the dose calculations actually reflect the administered dose. (iii)
The radioactive drug chosen for the study has that combination of
half-life, types of radiations, radiation energy, metabolism, chemical
properties, etc., which results in the lowest dose to the whole body or
specific organs with which it is possible to obtain the necessary
information. (iv) The investigator utilize adequate and appropriate
instrumentation for the detection and measurement of the specific
radionuclide. (2) Pharmacological dosage. To determine that the amount
of active ingredients to be administered does not exceed the limitations
set forth in paragraph (b)(2) of this section, the committee shall
require that the investigator provide pharmacological dose calculations
based on data available from published literature or from other valid
human studies. (3) Qualifications of investigators. Each investigator
shall be qualified by training and experience to conduct the proposed
research studies. (4) License to handle radioactive materials. The
responsible investigator or institutions shall, in the case of
reactor-produced isotopes, be licensed by the Nuclear Regulatory
Commission or Agreement State to possess and use the specific
radionuclides for research use or be a listed investigator under a broad
license, or in the case of non-reactor-produced isotopes, be licensed by
other appropriate State or local authorities, when required by State or
local law, to possess and use the specific radionuclides for research
use. (5) Human research subjects. Each investigator shall select
appropriate human subjects and shall obtain the review and approval of
an institutional review committee that conforms to the requirements of
part 56 of this chapter, and shall obtain the consent of the subjects or
their legal representatives in accordance with part 50 of this chapter.
The research subjects shall be at least 18 years of age and legally
competent. Exceptions are permitted only in those special situations
when it can be demonstrated to the committee that the study presents a
unique opportunity to gain information not currently available, requires
the use of research subjects less than 18 years of age, and is without
significant risk to the subject. Studies involving minors shall be
supported with review by qualified pediatric consultants to the
Radioactive Drug Research Committee. Each female research subject of
childbearing potential shall state in writing that she is not pregnant,
or, on the basis of a pregnancy test be confirmed as not pregnant,
before she may participate in any study. (6) Quality of radioactive
drug. The radioactive drug used in the research study shall meet
appropriate chemical, pharmaceutical, radiochemical, and radionuclidic
standards of identity, strength, quality, and purity as needed for
safety and be of such uniform and reproducible quality as to give
significance to the research study conducted. The Radioactive Drug
Research Committee shall determine that radioactive materials for
parenteral use are prepared in sterile and pyrogen-free form. (7)
Research protocol. No matter how small the amount of radioactivity, no
study involving administration of a radioactive drug, as defined in Sec.
310.3(n) of this chapter, to research subjects under this section, shall
be permitted unless the Radioactive Drug Research Committee concludes,
in its judgment, that scientific knowledge and benefit is likely to
result from that study. Therefore, the protocol shall be based upon a
sound rationale derived from appropriate animal studies or published
literature and shall be of sound design such that information of
scientific value may result. The radiation dose shall be both sufficient
and no greater than necessary to obtain valid measurement. The projected
number of subjects shall be sufficient but no greater than necessary for
the purpose of the study. The number of subjects shall also reflect the
fact that the study is intended to obtain basic research information
referred to in paragraph (a) of this section and not intended for
immediate therapeutic, diagnostic or similar purposes or to determine
the safety and effectiveness of the drug in humans for such purposes
(i.e., to carry out a clinical trial). (8) Adverse reactions. The
investigator shall immediately report to the Radioactive Drug Research
Committee all adverse effects associated with the use of the radioactive
drug in the research study. All adverse reactions probably attributable
to the use of the radioactive drug in the research study shall be
immediately reported by the Radioactive Drug Research Committee to the
Food and Drug Administration, Center for Drug Evaluation and Research,
HFD-160, 5600 Fishers Lane, Rockville, MD 20857. (9) Approval by an
institutional review board. The investigator shall obtain the review and
approval of an institutional review board that conforms to the
requirements of part 56 of this chapter.

\(e\) The results of any research conducted pursuant to this section as
part of the evaluation of a drug pursuant to part 312 of this chapter
shall be included in the submissions required under part 312 of this
chapter.

\(f\) A radioactive drug prepared, packaged, distributed, and primarily
intended for use in accordance with the requirements of this section
shall be exempt from section 502(f)(**1**) of the act and Secs. 201.5
and 201.100 of this chapter if the packaging, label, and labeling are in
compliance with Federal, State, and local law regarding radioactive
materials and if the label of the immediate container and shielded
container, if any, either separate from or as part of any label and
labeling required for radioactive materials by the Nuclear Regulatory
Commission or by State or local radiological health authorities bear the
following: (1) The statement "Caution: Federal law prohibits dispensing
without prescription"; (2) The statement "To be administered in
compliance with the requirements of Federal regulations regarding
radioactive drugs for research use (21 CFR 361.1)"; (3) The established
name of the drug, if any; (4) The established name and quantity of each
active ingredient; (5) The name and half-life of the radionuclide, total
quantity of radioactivity in the drug product\'s immediate container,
and amount of radioactivity per unit volume or unit mass at a designated
referenced time; (6) The route of administration, if it is for the other
than oral use; (7) The net quantity of contents; (8) An identifying lot
or control number from which it is possible to determine the complete
manufacturing history of the package of the drug; (9) The name and
address of the manufacturer, packer, or distributor; (10) The expiration
date, if any; (11) If the drug is intended for parenteral use, a
statement as to whether the contents are sterile; (12) If the drug is
for other than oral use, the names of all inactive ingredients, except
that: (i) Trace amounts of harmless substances added solely for
individual product identification need not be named. (ii) If the drug is
intended for parenteral use, the quantity or proportion of all inactive
ingredients, except that ingredients added to adjust pH or to make the
drug isotonic may be declared by name and a statement of their effect;
if the vehicle is water for injection, it need not be named. Provided,
however, That in the case of containers too small or otherwise unable to
accommodate a label with sufficient space to bear all such information,
the information required by paragraphs (f) (**1**) and (12) of this
section may be placed on the shielded container only.

\[40 FR 31308, July 25, 1975, as amended at 40 FR 44543, Sept. 29, 1975;
42 FR 15674, Mar. 22, 1977; 43 FR 14646, Apr. 7, 1978; 46 FR 8955, Jan.
27, 1981; 49 FR 44460, Nov. 7, 1984; 50 FR 8996, Mar. 6, 1985; 55 FR
11582, Mar. 29, 1990; 56 FR 10806, Mar. 14, 1991\]

# G. FDA Biological Products Regulations---General (21 CFR Part 600)

# 

# [**http://www.fda.gov/cber/ind/21cfr600.pdf**](http://www.fda.gov/cber/ind/21cfr600.pdf)

**Subpart A\--General Provisions**

**600.3 Definitions.** As used in this subchapter:

\(a\) Act means the Public Health Service Act (58 Stat. 682), approved
July 1, 1944.

\(b\) Secretary means the Secretary of Health and Human Services and any
other officer or employee of the Department of Health and Human Services
to whom the authority involved has been delegated.

\(c\) Commissioner of Food and Drugs means the Commissioner of the Food
and Drug Administration.

\(d\) Center for Biologics Evaluation and Research means Center for
Biologics Evaluation and Research of the Food and Drug Administration.

\(e\) State means a State or the District of Columbia, Puerto Rico, or
the Virgin Islands.

\(f\) Possession includes among other possessions, Puerto Rico and the
Virgin Islands.

\(g\) Products includes biological products and trivalent organic
arsenicals.

\(h\) Biological product means any virus, therapeutic serum, toxin,
antitoxin, or analogous product applicable to the prevention, treatment
or cure of diseases or injuries of man: (1) A virus is interpreted to be
a product containing the minute living cause of an infectious disease
and includes but is not limited to filterable viruses, bacteria,
rickettsia, fungi, and protozoa. (2) A therapeutic serum is a product
obtained from blood by removing the clot or clot components and the
blood cells. (**3**) A toxin is a product containing a soluble substance
poisonous to laboratory animals or to man in doses of 1 milliliter or
less (or equivalent in weight) of the product, and having the property,
following the injection of non-fatal doses into an animal, of causing to
be produced therein another soluble substance which specifically
neutralizes the poisonous substance and which is demonstrable in the
serum of the animal thus immunized. (4) An antitoxin is a product
containing the soluble substance in serum or other body fluid of an
immunized animal which specifically neutralizes the toxin against which
the animal is immune. (5) A product is analogous: (i) To a virus if
prepared from or with a virus or agent actually or potentially
infectious, without regard to the degree of virulence or toxicogenicity
of the specific strain used. (ii) To a therapeutic serum, if composed of
whole blood or plasma or containing some organic constituent or product
other than a hormone or an amino acid, derived from whole blood, plasma,
or serum. (iii) To a toxin or antitoxin, if intended, irrespective of
its source of origin, to be applicable to the prevention, treatment, or
cure of disease or injuries of man through a specific immune process.

\(i\) Trivalent organic arsenicals means arsphenamine and its
derivatives (or any other trivalent organic arsenic compound) applicable
to the prevention, treatment, or cure of diseases or injuries of man.

\(j\) A product is deemed applicable to the prevention, treatment, or
cure of diseases or injuries of man irrespective of the mode of
administration or application recommended, including use when intended
through administration or application to a person as an aid in
diagnosis, or in evaluating the degree of susceptibility or immunity
possessed by a person, and including also any other use for purposes of
diagnosis if the diagnostic substance so used is prepared from or with
the aid of a biological product.

\(k\) Proper name, as applied to a product, means the name designated in
the license for use upon each package of the product.

\(l\) Dating period means the period beyond which the product cannot be
expected beyond reasonable doubt to yield its specific results.

\(m\) Expiration date means the calendar month and year, and where
applicable, the day and hour, that the dating period ends.

\(n\) The word standards means specifications and procedures applicable
to an establishment or to the manufacture or release of products, which
are prescribed in this subchapter or established in the biologics
license application designed to insure the continued safety, purity, and
potency of such products.

\(o\) The word continued as applied to the safety, purity and potency of
products is interpreted to apply to the dating period.

\(p\) The word safety means the relative freedom from harmful effect to
persons affected, directly or indirectly, by a product when prudently
administered, taking into consideration the character of the product in
relation to the condition of the recipient at the time.

\(q\) The word sterility is interpreted to mean freedom from viable
contaminating microorganisms, as determined by the tests prescribed in
Sec. 610.12 of this chapter.

\(r\) Purity means relative freedom from extraneous matter in the
finished product, whether or not harmful to the recipient or deleterious
to the product. Purity includes but is not limited to relative freedom
from residual moisture or other volatile substances and pyrogenic
substances.

\(s\) The word potency is interpreted to mean the specific ability or
capacity of the product, as indicated by appropriate laboratory tests or
by adequately controlled clinical data obtained through the
administration of the product in the manner intended, to effect a given
result.

\(t\) Manufacturer means any legal person or entity engaged in the
manufacture of a product subject to license under the act;
"Manufacturer" also includes any legal person or entity who is an
applicant for a license where the applicant assumes responsibility for
compliance with the applicable product and establishment standards.

\(u\) Manufacture means all steps in propagation or manufacture and
preparation of products and includes but is not limited to filling,
testing, labeling, packaging, and storage by the manufacturer.

\(v\) Location includes all buildings, appurtenances, equipment and
animals used, and personnel engaged by a manufacturer within a
particular area designated by an address adequate for identification.

\(w\) Establishment has the same meaning as "facility" in section 351 of
the Public Health Service Act and includes all locations.

\(x\) Lot means that quantity of uniform material identified by the
manufacturer as having been thoroughly mixed in a single vessel.

\(y\) A filling refers to a group of final containers identical in all
respects, which have been filled with the same product from the same
bulk lot without any change that will affect the integrity of the
filling assembly.

\(z\) Process refers to a manufacturing step that is performed on the
product itself which may affect its safety, purity or potency, in
contrast to such manufacturing steps which do not affect intrinsically
the safety, purity or potency of the product.

(aa) Selling agent or distributor means any person engaged in the
unrestricted distribution, other than by sale at retail, of products
subject to license.

(bb) Container (referred to also as "final container") is the immediate
unit, bottle, vial, ampule, tube, or other receptacle containing the
product as distributed for sale, barter, or exchange.

\(cc\) Package means the immediate carton, receptacle, or wrapper,
including all labeling matter therein and thereon, and the contents of
the one or more enclosed containers. If no package, as defined in the
preceding sentence, is used, the container shall be deemed to be the
package.

(dd) Label means any written, printed, or graphic matter on the
container or package or any such matter clearly visible through the
immediate carton, receptacle, or wrapper.

(ee) Radioactive biological product means a biological product which is
labeled with a radionuclide or intended solely to be labeled with a
radionuclide.

(ff) Amendment is the submission of information to a pending license
application or supplement, to revise or modify the application as
originally submitted.

(gg) Supplement is a request to the Director, Center for Biologics
Evaluation and Research, to approve a change in an approved license
application.

\[38 FR 32048, Nov. 20, 1973, as amended at 40 FR 31313, July 25, 1975;
55 FR 11014, Mar. 26, 1990; 61 FR 24232, May 14, 1996; 62 FR 39901, July
24, 1997; 64 FR 56449, Oct. 20, 1999\]

# 

**Subpart B\--Establishment Standards**

**600.10 Personnel.**

\(a\) \[Reserved\]

\(b\) Personnel. Personnel shall have capabilities commensurate with
their assigned functions, a thorough understanding of the manufacturing
operations which they perform, the necessary training and experience
relating to individual products, and adequate information concerning the
application of the pertinent provisions of this subchapter to their
respective functions. Personnel shall include such professionally
trained persons as are necessary to insure the competent performance of
all manufacturing processes.

\(c\) Restrictions on personnel\--(1) Specific duties. Persons whose
presence can affect adversely the safety and purity of a product shall
be excluded from the room where the manufacture of a product is in
progress. (2) Sterile operations. Personnel performing sterile
operations shall wear clean or sterilized protective clothing and
devices to the extent necessary to protect the product from
contamination. (3) Pathogenic viruses and spore-bearing organisms.
Persons working with viruses pathogenic for man or with spore-bearing
microorganisms, and persons engaged in the care of animals or animal
quarters, shall be excluded from areas where other products are
manufactured, or such persons shall change outer clothing, including
shoes, or wear protective covering prior to entering such areas. (4)
Live vaccine work areas. Persons may not enter a live vaccine processing
area after having worked with other infectious agents in any other
laboratory during the same working day. Only persons actually concerned
with propagation of the culture, production of the vaccine, and unit
maintenance, shall be allowed in live vaccine processing areas when
active work is in progress. Casual visitors shall be excluded from such
units at all times and all others having business in such areas shall be
admitted only under supervision. Street clothing, including shoes, shall
be replaced or covered by suitable laboratory clothing before entering a
live vaccine processing unit. Persons caring for animals used in the
manufacture of live vaccines shall be excluded from other animal
quarters and from contact with other animals during the same working
day.\[38 FR 32048, Nov. 20, 1973, as amended at 49 FR 23833, June 8,
1984; 55 FR 11014, Mar. 26, 1990; 62 FR 53538, Oct. 15, 1997\]

**600**.**11 Physical establishment, equipment, animals, and care.**

\(a\) Work areas. All rooms and work areas where products are
manufactured or stored shall be kept orderly, clean, and free of dirt,
dust, vermin and objects not required for manufacturing. Precautions
shall be taken to avoid clogging and back-siphonage of drainage systems.
Precautions shall be taken to exclude extraneous infectious agents from
manufacturing areas. Work rooms shall be well lighted and ventilated.
The ventilation system shall be arranged so as to prevent the
dissemination of microorganisms from one manufacturing area to another
and to avoid other conditions unfavorable to the safety of the product.
Filling rooms, and other rooms where open, sterile operations are
conducted, shall be adequate to meet manufacturing needs and such rooms
shall be constructed and equipped to permit thorough cleaning and to
keep air-borne contaminants at a minimum. If such rooms are used for
other purposes, they shall be cleaned and prepared prior to use for
sterile operations. Refrigerators, incubators and warm rooms shall be
maintained at temperatures within applicable ranges and shall be free of
extraneous material which might affect the safety of the product.

\(b\) Equipment. Apparatus for sterilizing equipment and the method of
operation shall be such as to insure the destruction of contaminating
microorganisms. The effectiveness of the sterilization procedure shall
be no less than that achieved by an attained temperature of 121.5 deg. C
maintained for 20 minutes by saturated steam or by an attained
temperature of 170 deg. C maintained for 2 hours with dry heat.
Processing and storage containers, filters, filling apparatus, and other
pieces of apparatus and accessory equipment, including pipes and tubing,
shall be designed and constructed to permit thorough cleaning and, where
possible, inspection for cleanliness. All surfaces that come in contact
with products shall be clean and free of surface solids, leachable
contaminants, and other materials that will hasten the deterioration of
the product or otherwise render it less suitable for the intended use.
For products for which sterility is a factor, equipment shall be
sterile, unless sterility of the product is assured by subsequent
procedures.

\(c\) Laboratory and bleeding rooms. Rooms used for the processing of
products, including bleeding rooms, shall be effectively fly-proofed and
kept free of flies and vermin. Such rooms shall be so constructed as to
insure freedom from dust, smoke and other deleterious substances and to
permit thorough cleaning and disinfection. Rooms for animal injection
and bleeding, and rooms for smallpox vaccine animals, shall be
disinfected and be provided with the necessary water, electrical and
other services.

\(d\) Animal quarters and stables. Animal quarters, stables and food
storage areas shall be of appropriate construction, fly-proofed,
adequately lighted and ventilated, and maintained in a clean,
vermin-free and sanitary condition. No manure or refuse shall be stored
as to permit the breeding of flies on the premises, nor shall the
establishment be located in close proximity to off-property manure or
refuse storage capable of engendering fly breeding.

\(e\) Restrictions on building and equipment use\--(1) Work of a
diagnostic nature. Laboratory procedures of a clinical diagnostic nature
involving materials that may be contaminated, shall not be performed in
space used for the manufacture of products except that manufacturing
space which is used only occasionally may be used for diagnostic work
provided spore-bearing pathogenic microorganisms are not involved and
provided the space is thoroughly cleaned and disinfected before the
manufacture of products is resumed. (2) Spore-bearing organisms for
supplemental sterilization procedure control test. Spore-bearing
organisms used as an additional control in sterilization procedures may
be introduced into areas used for the manufacture of products, only for
the purposes of the test and only immediately before use for such
purposes: Provided, That (i) the organism is not pathogenic for man or
animals and does not produce pyrogens or toxins, (ii) the culture is
demonstrated to be pure, (iii) transfer of test cultures to culture
media shall be limited to the sterility test area or areas designated
for work with spore-bearing organisms, (iv) each culture be labeled with
the name of the microorganism and the statement "Caution: microbial
spores. See directions for storage, use and disposition.", and (v) the
container of each culture is designed to withstand handling without
breaking. (3) Work with spore-bearing organisms. Except as provided in
the previous paragraph, all work with spore-bearing microorganisms shall
be done in an entirely separate building: Provided, That such work may
be done in a portion of a building used in the manufacture of products
not containing spore-bearing microorganisms if such portion is
completely walled-off and is constructed so as to prevent contamination
of other areas and if entrances to such portion are independent of the
remainder of the building. All vessels, apparatus and equipment used for
spore-bearing microorganisms shall be permanently identified and
reserved exclusively for use with those organisms. Materials destined
for further manufacturing may be removed from such an area only under
conditions which will prevent the introduction of spores into other
manufacturing areas. (4) Live vaccine processing. Space used for
processing a live vaccine shall not be used for any other purpose during
the processing period for that vaccine and such space shall be
decontaminated prior to initiation of the processing. Live vaccine
processing areas shall be isolated from and independent of any space
used for any other purpose by being either in a separate building, in a
separate wing of a building, or in quarters at the blind end of a
corridor and shall include adequate space and equipment for all
processing steps up to filling into final containers. Test procedures
which potentially involve the presence of microorganisms other than the
vaccine strains, or the use of tissue culture cell lines other than
primary cultures, shall not be conducted in space used for processing
live vaccine. (5) Equipment and supplies\--contamination. Equipment and
supplies used in work on or otherwise exposed to any pathogenic or
potentially pathogenic agent shall be kept separated from equipment and
supplies used in the manufacture of products to the extent necessary to
prevent cross-contamination.

\(f\) Animals used in manufacture\--(1) Care of animals used in
manufacturing. Caretakers and attendants for animals used for the
manufacture of products shall be sufficient in number and have adequate
experience to insure adequate care. Animal quarters and cages shall be
kept in sanitary condition. Animals on production shall be inspected
daily to observe response to production procedures. Animals that become
ill for reasons not related to production shall be isolated from other
animals and shall not be used for production until recovery is complete.
Competent veterinary care shall be provided as needed. (2) Quarantine of
animals\--(i) General. No animal shall be used in processing unless kept
under competent daily inspection and preliminary quarantine for a period
of at least 7 days before use, or as otherwise provided in this
subchapter. Only healthy animals free from detectable communicable
diseases shall be used. Animals must remain in overt good health
throughout the quarantine periods and particular care shall be taken
during the quarantine periods to reject animals of the equine genus
which may be infected with glanders and animals which may be infected
with tuberculosis. (ii) Quarantine of monkeys. In addition to observing
the pertinent general quarantine requirements, monkeys used as a source
of tissue in the manufacture of vaccine shall be maintained in
quarantine for at least 6 weeks prior to use, except when otherwise
provided in this part. Only monkeys that have reacted negatively to
tuberculin at the start of the quarantine period and again within 2
weeks prior to use shall be used in the manufacture of vaccine. Due
precaution shall be taken to prevent cross-infection from any infected
or potentially infected monkeys on the premises. Monkeys to be used in
the manufacture of a live vaccine shall be maintained throughout the
quarantine period in cages closed on all sides with solid materials
except the front which shall be screened, with no more than two monkeys
housed in one cage. Cage mates shall not be interchanged. (3)
Immunization against tetanus. Horses and other animals susceptible to
tetanus, that are used in the processing steps of the manufacture of
biological products, shall be treated adequately to maintain immunity to
tetanus. (4) Immunization and bleeding of animals used as a source of
products. Toxins or other nonviable antigens administered in the
immunization of animals used in the manufacture of products shall be
sterile. Viable antigens, when so used, shall be free of contaminants,
as determined by appropriate tests prior to use. Injections shall not be
made into horses within 6 inches of bleeding site. Horses shall not be
bled for manufacturing purposes while showing persistent general
reaction or local reaction near the site of bleeding. Blood shall not be
used if it was drawn within 5 days of injecting the animals with viable
microorganisms. Animals shall not be bled for manufacturing purposes
when they have an intercurrent disease. Blood intended for use as a
source of a biological product shall be collected in clean, sterile
vessels. When the product is intended for use by injection, such vessels
shall also be pyrogen-free. (5) \[Reserved\] (6) Reporting of certain
diseases. In cases of actual or suspected infection with foot and mouth
disease, glanders, tetanus, anthrax, gas gangrene, equine infectious
anemia; equine encephalomyelitis, or any of the pock diseases among
animals intended for use or used in the manufacture of products, the
manufacturer shall immediately notify the Director, Center for Biologics
Evaluation and Research. (7) Monkeys used previously for experimental or
test purposes. Monkeys that have been used previously for experimental
or test purposes with live microbiological agents shall not be used as a
source of kidney tissue for the manufacture of vaccine. Except as
provided otherwise in this subchapter, monkeys that have been used
previously for other experimental or test purposes may be used as a
source of kidney tissue upon their return to a normal condition,
provided all quarantine requirements have been met. (8) Necropsy
examination of monkeys. Each monkey used in the manufacture of vaccine
shall be examined at necropsy under the direction of a qualified
pathologist, physician, or veterinarian having experience with diseases
of monkeys, for evidence of ill health, particularly for (i) evidence of
tuberculosis, (ii) presence of herpes-like lesions, including eruptions
or plaques on or around the lips, in the buccal cavity or on the gums,
and (iii) signs of conjunctivitis. If there are any such signs or other
significant gross pathological lesions, the tissue shall not be used in
the manufacture of vaccine.

\(g\) Filling procedures. Filling procedures shall be such as will not
affect adversely the safety, purity or potency of the product.

\(h\) Containers and closures. All final containers and closures shall
be made of material that will not hasten the deterioration of the
product or otherwise render it less suitable for the intended use. All
final containers and closures shall be clean and free of surface solids,
leachable contaminants and other materials that will hasten the
deterioration of the product or otherwise render it less suitable for
the intended use. After filling, sealing shall be performed in a manner
that will maintain the integrity of the product during the dating
period. In addition, final containers and closures for products intended
for use by injection shall be sterile and free from pyrogens. Except as
otherwise provided in the regulations of this subchapter, final
containers for products intended for use by injection shall be colorless
and sufficiently transparent to permit visual examination of the
contents under normal light. As soon as possible after filling final
containers shall be labeled as prescribed in Sec. 610.60 et seq. of this
chapter, except that final containers may be stored without such
prescribed labeling provided they are stored in a sealed receptacle
labeled both inside and outside with at least the name of the product,
the lot number, and the filling identification.

\[38 FR 32048, Nov. 20, 1973, as amended at 41 FR 10428, Mar. **11**,
1976; 49 FR 23833, June 8, 1984; 55 FR 11013, Mar. 26, 1990\]

600.12 Records.

\(a\) Maintenance of records. Records shall be made, concurrently with
the performance, of each step in the manufacture and distribution of
products, in such a manner that at any time successive steps in the
manufacture and distribution of any lot may be traced by an inspector.
Such records shall be legible and indelible, shall identify the person
immediately responsible, shall include dates of the various steps, and
be as detailed as necessary for clear understanding of each step by one
experienced in the manufacture of products.

\(b\) Records retention\--(1) General. Records shall be retained for
such interval beyond the expiration date as is necessary for the
individual product, to permit the return of any clinical report of
unfavorable reactions. The retention period shall be no less than five
years after the records of manufacture have been completed or six months
after the latest expiration date for the individual product, whichever
represents a later date. (2) Records of recall. Complete records shall
be maintained pertaining to the recall from distribution of any product
upon notification by the Director, Center for Biologics Evaluation and
Research, to recall for failure to conform with the standards prescribed
in the regulations of this subchapter, because of deterioration of the
product or for any other factor by reason of which the distribution of
the product would constitute a danger to health. (3) Suspension of
requirement for retention. The Director, Center for Biologics Evaluation
and Research, may authorize the suspension of the requirement to retain
records of a specific manufacturing step upon a showing that such
records no longer have significance for the purposes for which they were
made: Provided, That a summary of such records shall be retained.

\(c\) Records of sterilization of equipment and supplies. Records
relating to the mode of sterilization, date, duration, temperature and
other conditions relating to each sterilization of equipment and
supplies used in the processing of products shall be made by means of
automatic recording devices or by means of a system of recording which
gives equivalent assurance of the accuracy and reliability of the
record. Such records shall be maintained in a manner that permits an
identification of the product with the particular manufacturing process
to which the sterilization relates.

\(d\) Animal necropsy records. A necropsy record shall be kept on each
animal from which a biological product has been obtained and which dies
or is sacrificed while being so used.

\(e\) Records in case of divided manufacturing responsibility. If two or
more establishments participate in the manufacture of a product, the
records of each such establishment must show plainly the degree of its
responsibility. In addition, each participating manufacturer shall
furnish to the manufacturer who prepares the product in final form for
sale, barter or exchange, a copy of all records relating to the
manufacturing operations performed by such participating manufacturer
insofar as they concern the safety, purity and potency of the lots of
the product involved, and the manufacturer who prepares the product in
final form shall retain a complete record of all the manufacturing
operations relating to the product.

\[38 FR 32048, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984;
55 FR 11013, Mar. 26, 1990\]

600.13 Retention samples.

Manufacturers shall retain for a period of at least 6 months after the
expiration date, unless a different time period is specified in
additional standards, a quantity of representative material of each lot
of each product, sufficient for examination and testing for safety and
potency, except Whole Blood, Cryoprecipitated AHF, Platelets, Red Blood
Cells, Plasma, and Source Plasma and Allergenic Products prepared to a
physician\'s prescription. Samples so retained shall be selected at
random from either final container material, or from bulk and final
containers, provided they include at least one final container as a
final package, or package-equivalent of such filling of each lot of the
product as intended for distribution. Such sample material shall be
stored at temperatures and under conditions which will maintain the
identity and integrity of the product. Samples retained as required in
this section shall be in addition to samples of specific products
required to be submitted to the Center for Biologics Evaluation and
Research. Exceptions may be authorized by the Director, Center for
Biologics Evaluation and Research, when the lot yields relatively few
final containers and when such lots are prepared by the same method in
large number and in close succession.

\[41 FR 10428, Mar. 11, 1976, as amended at 49 FR 23833, June 8, 1984;
50 FR 4133, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990\]

600.14 Reporting of errors.

\(a\) The Director, Office of Compliance, Center for Biologics
Evaluation and Research (HFB-100), 8800 Rockville Pike, Bethesda, MD
20892, shall be notified promptly of errors or accidents in the
manufacture of products that may affect the safety, purity, or potency
of any product.

\(b\) Manufacturers of licensed in vitro diagnostic products, and
manufacturers of unlicensed in vitro diagnostic products which are
required to be registered under part 607 of this chapter, shall notify
the Director in accordance with paragraph (a) of this section.
Manufacturers of other in vitro diagnostic products which are required
to be registered under part 807 of this chapter, shall report in
accordance with part 803 of this chapter.

\[38 FR 32048, Nov. 20, 1973, as amended at 49 FR 23833, June 8, 1984;
49 FR 36348, Sept. 14, 1984; 55 FR 11014, Mar. 26, 1990\]

600.15 Temperatures during shipment.

The following products shall be maintained during shipment at the
specified temperatures:

\(a\) Products. ..........Product Temperature

Cryoprecipitated AHF\...\...\...\...\...\...\.... -18 C or colder.

Measles and Rubella Virus Vaccine Live\.... 10 C or colder.

Measles Live and Smallpox Vaccine\...\...\... Do.

Measles, Mumps, and Rubella Virus Vaccine Do.

Live.Measles and Mumps Virus Vaccine Live\...\... Do.

Measles Virus Vaccine Live\...\...\...\...\.... Do.

Mumps Virus Vaccine Live\...\...\...\...\...\... Do.

Fresh Frozen Plasma\...\...\...\...\...\...\..... -18 C or colder.

Liquid Plasma\...\...\...\...\...\...\...\...\..... 1 to 10 C.

Plasma\...\...\...\...\...\...\...\...\...\...\...\... -18 C or colder.

Platelet Rich Plasma\...\...\...\...\...\...\.... Between 1 and 10 C if
the label indicates storage between 1 and 6 C, or all reasonable methods
to maintain the temperature as close as possible to a range between 20
and 24 C, if the label indicates storage between 20 and 24C.

Platelets\...\...\...\...\...\...\...\...\...\...\... Between 1 and 10 C
if the label indicates storage between 1 and 6C, or all reasonable
methods to maintain the temperature as close as possible to a
rangebetween 20 to 24 C, if the label indicates storage between 20 and
24 C.

Poliovirus Vaccine Live Oral Trivalent\.... 0 C or colder.

Poliovirus Vaccine Live Oral Type I\...\.... Do.

Poliovirus Vaccine Live Oral Type II\...\... Do.

Poliovirus Vaccine Live Oral Type III\..... Do.

Red Blood Cells (liquid product)\...\...\.... Between 1 and 10 C.

Red Blood Cells Frozen\...\...\...\...\...\..... -65 C or colder.

Rubella and Mumps Virus Vaccine Live\...\... 10 C or colder.

Rubella Virus Vaccine Live\...\...\...\...\.... Do.

Smallpox Vaccine (Liquid Product)\...\...\... 0 C or colder.

Source Plasma\...\...\...\...\...\...\...\...\..... -5 C or colder.

Source Plasma Liquid\...\...\...\...\...\...\.... 10 C or colder.

Whole Blood\...\...\...\...\...\...\...\...\...\.... Blood that is
transported from the collecting facility to the processing facility
shall be transported in an environment capable of continuously cooling
the blood toward a temperature range of 1 to 10 C, or at a temperature
as close as possible to 20 to 24 C for a period not to exceed 6 hours.
Blood transported from the storage facility shall be placed in an
appropriate environment to maintain a temperature range between 1 to 10
C during shipment.

Yellow Fever Vaccine\...\...\...\...\...\...\.... 0 C or colder.

\(b\) Exemptions. Exemptions or modifications shall be made only upon
written approval, in the form of a supplement to the biologics license
application, approved by the Director, Center for Biologics Evaluation
and Research.

\[39 FR 39872, Nov. 12, 1974, as amended at 49 FR 23833, June 8, 1984;
50 FR 4133, Jan. 29, 1985; 50 FR 9000, Mar. 6, 1985; 55 FR 11013, Mar.
26, 1990; 59 FR 49351, Sept. 28, 1994; 64 FR 56449, Oct. 20, 1999\]

Subpart C\--Establishment Inspection

600.20 Inspectors.

Inspections shall be made by an officer of the Food and Drug
Administration having special knowledge of the methods used in the
manufacture and control of products and designated for such purposes by
the Commissioner of Food and Drugs, or by any officer, agent, or
employee of the Department of Health and Human Services specifically
designated for such purpose by the Secretary.

\[38 FR 32048, Nov. 20, 1973\]

600.21 Time of inspection.

The inspection of an establishment for which a biologics license
application is pending need not be made until the establishment is in
operation and is manufacturing the complete product for which a
biologics license is desired. In case the license is denied following
inspection for the original license, no reinspection need be made until
assurance has been received that the faulty conditions which were the
basis of the denial have been corrected. An inspection of each licensed
establishment and its additional location(s) shall be made at least once
every 2 years. Inspections may be made with or without notice, and shall
be made during regular business hours unless otherwise directed.

\[38 FR 32048, Nov. 20, 1973, as amended at 48 FR 26314, June 7, 1983;
64 FR 56449, Oct. 20, 1999\]

Subpart D\--Reporting of Adverse Experiences

600.80 Postmarketing reporting of adverse experiences. Source: 59 FR
54042, Oct. 27, 1994, unless otherwise noted.

\(a\) Definitions. The following definitions of terms apply to this
section: Adverse experience. Any adverse event associated with the use
of a biological product in humans, whether or not considered product
related, including the following: An adverse event occurring in the
course of the use of a biological product in professional practice; an
adverse event occurring from overdose of the product whether accidental
or intentional; an adverse event occurring from abuse of the product; an
adverse event occurring from withdrawal of the product; and any failure
of expected pharmacological action. Blood Component. As defined in Sec.
606.3(c) of this chapter. Disability. A substantial disruption of a
person\'s ability to conduct normal life functions. Life-threatening
adverse experience. Any adverse experience that places the patient, in
the view of the initial reporter, at immediate risk of death from the
adverse experience as it occurred, i.e., it does not include an adverse
experience that, had it occurred in a more severe form, might have
caused death. Serious adverse experience. Any adverse experience
occurring at any dose that results in any of the following outcomes:
Death, a life-threatening adverse 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 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
experience: Any adverse experience that is not listed in the current
labeling for the biological product. This includes events that may be
symptomatically and pathophysiologically related to an event listed in
the labeling, but differ from the event because of greater severity or
specificity. For example, under this definition, hepatic necrosis would
be unexpected (by virtue of greater severity) if the labeling only
referred to elevated hepatic enzymes or hepatitis. Similarly, cerebral
thromboembolism and cerebral vasculitis would be unexpected (by virtue
of greater specificity) if the labeling only listed cerebral vascular
accidents. "Unexpected," as used in this definition, refers to an
adverse experience that has not been previously observed (i.e., included
in the labeling) rather than from the perspective of such experience not
being anticipated from the pharmacological properties of the
pharmaceutical product.

\(b\) Review of adverse experiences. Any person having a biologics
license under Sec. 601.20 of this chapter shall promptly review all
adverse experience information pertaining to its product obtained or
otherwise received by the licensed manufacturer from any source, foreign
or domestic, including information derived from commercial marketing
experience, postmarketing clinical investigations, postmarketing
epidemiological/surveillance studies, reports in the scientific
literature, and unpublished scientific papers. Licensed manufacturers
are not required to resubmit to FDA adverse product experience reports
forwarded to the licensed manufacturer by FDA; licensed manufacturers,
however, must submit all followup information on such reports to FDA.
Any person subject to the reporting requirements under paragraph (c) of
this section shall also develop written procedures for the surveillance,
receipt, evaluation, and reporting of postmarketing adverse experiences
to FDA.

\(c\) Reporting requirements. The licensed manufacturer shall report to
FDA adverse experience information, as described in this section. The
licensed manufacturer shall submit two copies of each report described
in this section for nonvaccine biological products, to the Center for
Biologics Evaluation and Research (HFM-210), Food and Drug
Administration, 1401 Rockville Pike, suite 200 N., Rockville, MD
20852-1448. Submit all vaccine adverse experience reports to: Vaccine
Adverse Event Reporting System (VAERS), P.O. Box 1100, Rockville, MD
20849-1100. FDA may waive the requirement for the second copy in
appropriate instances. (1)(i) Postmarketing 15-day "Alert reports". The
licensed manufacturer shall report each adverse experience that is both
serious and unexpected, whether foreign or domestic, as soon as possible
but in no case later than 15 calendar days of initial receipt of the
information by the licensed manufacturer. (ii) Postmarketing 15-day
"Alert reports"\--followup. The licensed manufacturer shall promptly
investigate all adverse experiences that are the subject of these
postmarketing 15-day Alert reports and shall submit followup reports
within 15 calendar days of receipt of new information or as requested by
FDA. If additional information is not obtainable, records should be
maintained of the unsuccessful steps taken to seek additional
information. Postmarketing 15-day Alert reports and followups to them
shall be submitted under separate cover. (iii) Submission of reports.
The requirements of paragraphs (c)(1)(i) and (c)(1)(ii) of this section,
concerning the submission of postmarketing 15-day Alert reports, shall
also apply to any person whose name appears on the label of a licensed
biological product as a manufacturer, packer, distributor, shared
manufacturer, joint manufacturer, or any other participant involved in
divided manufacturing. To avoid unnecessary duplication in the
submission to FDA of reports required by paragraphs (c)(1)(i) and
(c)(1)(ii) of this section, obligations of persons other than the
licensed manufacturer of the final biological product may be met by
submission of all reports of serious adverse experiences to the licensed
manufacturer of the final product. If a person elects to submit adverse
experience reports to the licensed manufacturer of the final product
rather than to FDA, the person shall submit each report to the licensed
manufacturer of the final product within 5 calendar days of receipt of
the report by the person, and the licensed manufacturer of the final
product shall then comply with the requirements of this section. Under
this circumstance, a person who elects to submit reports to the licensed
manufacturer of the final product shall maintain a record of this action
which shall include: (A) A copy of all adverse biological product
experience reports submitted to the licensed manufacturer of the final
product; (B) The date the report was received by the person; (C) The
date the report was submitted to the licensed manufacturer of the final
product; and- (D) The name and address of the licensed manufacturer of
the final product. (iv) Report identification. Each report submitted
under this paragraph shall bear prominent identification as to its
contents, i.e., "15-day Alert report," or "15-day Alert
report-followup." (2) Periodic adverse experience reports. (i) The
licensed manufacturer shall report each adverse experience not reported
under paragraph (c)(1)(i) of this section at quarterly intervals, for 3
years from the date of issuance of the biologics license, and then at
annual intervals. The licensed manufacturer shall submit each quarterly
report within 30 days of the close of the quarter (the first quarter
beginning on the date of issuance of the biologics license) and each
annual report within 60 days of the anniversary date of the issuance of
the biologics license. Upon written notice, FDA may extend or
reestablish the requirement that a licensed manufacturer submit
quarterly reports, or require that the licensed manufacturer submit
reports under this section at different times than those stated.
Followup information to adverse experiences submitted in a periodic
report may be submitted in the next periodic report. (ii) Each periodic
report shall contain: (A) A narrative summary and analysis of the
information in the report and an analysis of the 15-day Alert reports
submitted during the reporting interval (all 15-day Alert reports being
appropriately referenced by the licensed manufacturer\'s patient
identification number, adverse reaction term(s), and date of submission
to FDA); (B) A form designated for Adverse Experience Reporting by FDA
for each adverse experience not reported under paragraph (c)(1)(i) of
this section (with an index consisting of a line listing of the licensed
manufacturer\'s patient identification number and adverse reaction
term(s)); and (C) A history of actions taken since the last report
because of adverse experiences (for example, labeling changes or studies
initiated). (iii) Periodic reporting, except for information regarding
15-day Alert reports, does not apply to adverse experience information
obtained from postmarketing studies (whether or not conducted under an
investigational new drug application), from reports in the scientific
literature, and from foreign marketing experience.

\(d\) Scientific literature. (1) A 15-day Alert report based on
information from the scientific literature shall be accompanied by a
copy of the published article. The 15-day Alert reporting requirements
in paragraph (c)(1)(i) of this section (i.e., serious, unexpected
adverse experiences) apply only to reports found in scientific and
medical journals either as case reports or as the result of a formal
clinical trial. (2) As with all reports submitted under paragraph
(c)(1)(i) of this section, reports based on the scientific literature
shall be submitted on the reporting form designated by FDA or comparable
format as prescribed by paragraph (f) of this section. In cases where
the licensed manufacturer believes that preparing the form designated by
FDA constitutes an undue hardship, the licensed manufacturer may arrange
with the Division of Biostatistics and Epidemiology (HFM-210) for an
acceptable alternative reporting format.

\(e\) Postmarketing studies. (1) Licensed manufacturers are not required
to submit a 15-day Alert report under paragraph (c) of this section for
an adverse experience obtained from a postmarketing clinical study
(whether or not conducted under a biological investigational new drug
application) unless the licensed manufacturer concludes that there is a
reasonable possibility that the product caused the adverse experience.
(2) The licensed manufacturer shall separate and clearly mark reports of
adverse experiences that occur during a postmarketing study as being
distinct from those experiences that are being reported spontaneously to
the licensed manufacturer.

\(f\) Reporting forms. (1) Except as provided in paragraph (f)(3) of
this section, the licensed manufacturer shall complete the reporting
form designated by FDA for each report of an adverse experience (FDA
Form 3500A, or, for vaccines, a VAERS form; foreign events including
those associated with the use of vaccines, may be submitted either on an
FDA Form 3500A or, if preferred, on a CIOMS I form). (2) Each completed
form should refer only to an individual patient or single attached
publication. (3) Instead of using a designated reporting form, a
licensed manufacturer may use a computer-generated form or other
alternative format (e.g., a computer-generated tape or tabular listing)
provided that: (i) The content of the alternative format is equivalent
in all elements of information to those specified in the form designated
by FDA; and (ii) the format is approved in advance by MEDWATCH: The FDA
Medical Products Reporting Program; or, for alternatives to the VAERS
Form, by the Division of Biostatistics and Epidemiology. (4) Copies of
the reporting form designated by FDA (FDA-3500A) for nonvaccine
biological products may be obtained from the Center for Biologics
Evaluation and Research (address above). Additional supplies of the form
may be obtained from the Consolidated Forms and Publications
Distribution Center, 3222 Hubbard Rd., Landover, MD 20785. Supplies of
the VAERS form may be obtained from VAERS by calling 1-800-822-7967.

\(g\) Multiple reports. A licensed manufacturer should not include in
reports under this section any adverse experience that occurred in
clinical trials if they were previously submitted as part of the
biologics license application. If a report refers to more than one
biological product marketed by a licensed manufacturer, the licensed
manufacturer should submit the report to the biologics license
application for the product listed first in the report.

\(h\) Patient privacy. For nonvaccine biological products, a licensed
manufacturer should not include in reports under this section the names
and addresses of individual patients; instead, the licensed manufacturer
should assign a unique code number to each report, preferably not more
than eight characters in length. The licensed manufacturer should
include the name of the reporter from whom the information was received.
The names of patients, health care professionals, hospitals, and
geographical identifiers in adverse experience reports are not
releasable to the public under FDA\'s public information regulations in
part 20 this of chapter. For vaccine adverse experience reports, these
data will become part of the CDC Privacy Act System 09-20-0136,
"Epidemiologic Studies and Surveillance of Disease Problems."
Information identifying the person who received the vaccine or that
person\'s legal representative will not be made available to the public,
but may be available to the vaccinee or legal representative. (i)
Recordkeeping. The licensed manufacturer shall maintain for a period of
10 years records of all adverse experiences known to the licensed
manufacturer, including raw data and any correspondence relating to the
adverse experiences.

\(j\) Revocation of biologics license. If a licensed manufacturer fails
to establish and maintain records and make reports required under this
section with respect to a licensed biological product, FDA may revoke
the biologics license for such a product in accordance with the
procedures of Sec. 601.5 of this chapter.

\(k\) Exemptions. Manufacturers of the following listed products are not
required to submit adverse experience reports under this section: (1)
Whole blood or components of whole blood. (2) In vitro diagnostic
products, including assay systems for the detection of antibodies or
antigens to retroviruses. These products are subject to the reporting
requirements for devices. (l) Disclaimer. A report or information
submitted by a licensed manufacturer under this section (and any release
by FDA of that report or information) does not necessarily reflect a
conclusion by the licensed manufacturer or FDA that the report or
information constitutes an admission that the biological product caused
or contributed to an adverse effect. A licensed manufacturer need not
admit, and may deny, that the report or information submitted under this
section constitutes an admission that the biological product caused or
contributed to an adverse effect. For purposes of this provision, this
paragraph also includes any person reporting under paragraph (c)(1)(iii)
of this section.

\[59 FR 54042, Oct. 27, 1994, as amended at 62 FR 34168, June 25, 1997;
62 FR 52252, Oct. 7, 1997; 63 FR 14612, Mar. 26, 1998; 64 FR 56449, Oct.
20, 1999\]

# 

**600.81** **Distribution reports.**

The licensed manufacturer shall submit information about the quantity of
the product distributed under the biologics license, including the
quantity distributed to distributors. The interval between distribution
reports shall be 6 months. Upon written notice, FDA may require that the
licensed manufacturer submit distribution reports under this section at
times other than every 6 months. The distribution report shall consist
of the bulk lot number (from which the final container was filled), the
fill lot numbers for the total number of dosage units of each strength
or potency distributed (e.g., fifty thousand per 10-milliliter vials),
the label lot number (if different from fill lot number), labeled date
of expiration, number of doses in fill lot/label lot, date of release of
fill lot/label lot for distribution at that time. If any significant
amount of a fill lot/label lot is returned, include this information.
Disclosure of financial or pricing data is not required. As needed, FDA
may require submission of more detailed product distribution
information. Upon written notice, FDA may require that the licensed
manufacturer submit reports under this section at times other than those
stated. Requests by a licensed manufacturer to submit reports at times
other than those stated should be made as a request for a waiver under
Sec. 600.90.\[59 FR 54042, Oct. 27, 1994, as amended at 64 FR 56449,
Oct. 20, 1999\]

# 

**600.90** **Waivers.**

\(a\) A licensed manufacturer may ask the Food and Drug Administration
to waive under this section any requirement that applies to the licensed
manufacturer under Secs. 600.80 and 600.81. A waiver request under this
section is required to be submitted with supporting documentation. The
waiver request is required to contain one of the following: (1) An
explanation why the licensed manufacturer\'s compliance with the
requirement is unnecessary or cannot be achieved, (2) A description of
an alternative submission that satisfies the purpose of the requirement,
or (3) Other information justifying a waiver. (b) FDA may grant a waiver
if it finds one of the following: (1) The licensed manufacturer\'s
compliance with the requirement is unnecessary or cannot be achieved,
(2) The licensed manufacturer\'s alternative submission satisfies the
requirement, or (3) The licensed manufacturer\'s submission otherwise
justifies a waiver.

#  

# H. FDA Investigational Device Exemptions (IDE) Regulations (21 CFR Part 812)

<http://www.fda.gov/cdrh/manual/appenda.html>

**Subpart A - General Provisions**

812.1 Scope.

812.2 Applicability.

812.3 Definitions.

812.5 Labeling of investigational devices.

812.7 Prohibition of promotion and other practices.

812.10 Waivers.

812.18 Import and export requirements.

812.19 Address for IDE correspondence.

**Subpart B - Application and Administrative Action**

812.20 Application.

812.25 Investigational plan.

812.27 Report of prior investigations.

812.30 FDA action on applications.

812.35 Supplemental applications.

812.38 Confidentiality of data and information.

**Subpart C - Responsibilities of Sponsors**

812.40 General responsibilities of sponsors.

812.42 FDA and IRB approval.

812.43 Selecting investigators and monitors.

812.45 Informing investigators.

812.46 Monitoring investigations.

**Subpart D - IRB Review and Approval**

812.60 IRB composition, duties, and functions.

812.62 IRB approval.

812.64 IRB\'s continuing review.

812.65 \[Reserved\]

812.66 Significant risk device determinations.

**Subpart E - Responsibilities of Investigators**

812.100 General responsibilities of investigators.

812.110 Specific responsibilities of investigators.

**Subpart F - \[Reserved\]**

**Subpart G - Records and Reports**

812.140 Records.

812.145 Inspections.

812.150 Reports.

Authority: Secs. 301, 501, 502, 503, 505, 506, 507, 510, 513 ­ 516, 518 -
520, 701, 702, 704, 721, 801 of the Federal Food, Drug, and Cosmetic Act
(21 U.S.C. 331, 351, 352, 353, 355, 356, 357, 360, 360c ­ 360f, 360h ­
360j, 371, 372, 374, 379e, 381); secs. 215, 301, 351, 354 ­ 360F of the
Public Health Service Act (42 U.S.C. 216, 241, 262, 263b ­ 263n). Source:
45 FR 3751, Jan. 18, 1980, unless otherwise noted.

**Subpart A - General Provisions**

**§ 812.1 Scope.**

\(a\) The purpose of this part is to encourage, to the extent consistent
with the protection of public health and safety and with ethical
standards, the discovery and development of useful devices intended for
human use, and to that end to maintain optimum freedom for scientific
investigators in their pursuit of this purpose. This part provides
procedures for the conduct of clinical investigations of devices. An
approved investigational device exemption (IDE) permits a device that
otherwise would be required to comply with a performance standard or to
have premarket approval to be shipped lawfully for the purpose of
conducting investigations of that device. An IDE approved under § 812.30
or considered approved under § 812.2(b) exempts a device from the
requirements of the following sections of the act and regulations issued
thereunder: Misbranding under section 502, registration, listing, and
premarket notification under section 510, performance standards under
section 514, premarket approval under section 515, a banned device
regulation under section 516, records and reports under section 519,
restricted device requirements under section 520(e), good manufacturing
practice requirements under section 520(f) (unless the sponsor states an
intention to comply with these requirements under § 812.20(b)(3) or §
812.140(b)(4)(v)) and color additive requirements under section 721.

\(b\) References in this part to regulatory sections of the Code of
Federal Regulations are to chapter I of title 21, unless otherwise
noted.

\[45 FR 3751, Jan. 18, 1980, as amended at 59 FR 14366, Mar. 28, 1994\]

**§ 812.2 Applicability.**

\(a\) General. This part applies to all clinical investigations of
devices to determine safety and effectiveness, except as provided in
paragraph (c) of this section.

\(b\) Abbreviated requirements. The following categories of
investigations are considered to have approved applications for IDE\'s,
unless FDA has notified a sponsor under § 812.20(a) that approval of an
application is required:

> \(1\) An investigation of a device other than a significant risk
> device, if the device is not a banned device and the sponsor:
>
> \(i\) Labels the device in accordance with § 812.5;
>
> \(ii\) Obtains IRB approval of the investigation after presenting the
> reviewing IRB with a brief explanation of why the device is not a
> significant risk device, and maintains such approval;
>
> \(iii\) Ensures that each investigator participating in an
> investigation of the device obtains from each subject under the
> investigator\'s care, informed consent under Part 50 and documents it,
> unless documentation is waived by an IRB under § 56.109(c).
>
> \(iv\) Complies with the requirements of § 812.46 with respect to
> monitoring investigations;
>
> \(v\) Maintains the records required under § 812.140(b) (4) and (5)
> and makes the reports required under § 812.150(b) (1) through (3) and
> (5) through (10);
>
> \(vi\) Ensures that participating investigators maintain the records
> required by § 812.140(a)(3)(i) and make the reports required under §
> 812.150(a) (1), (2), (5), and (7); and
>
> \(vii\) Complies with the prohibitions in § 812.7 against promotion
> and other practices.
>
> \(2\) An investigation of a device other than one subject to paragraph
> (e) of this section, if the investigation was begun on or before July
> 16, 1980, and to be completed, and is completed, on or before January
> 19, 1981.

\(c\) Exempted investigations. This part does not apply to
investigations of the following categories of devices:

> \(1\) A device, other than a transitional device, in commercial
> distribution immediately before May 28, 1976, when used or
> investigated in accordance with the indications in labeling in effect
> at that time.
>
> \(2\) A device, other than a transitional device, introduced into
> commercial distribution on or after May 28, 1976, that FDA has
> determined to be substantially equivalent to a device in commercial
> distribution immediately before May 28, 1976, and that is used or
> investigated in accordance with the indications in the labeling FDA
> reviewed under Subpart E of Part 807 in determining substantial
> equivalence.
>
> \(3\) A diagnostic device, if the sponsor complies with applicable
> requirements in § 809.10(c) and if the testing:
>
> \(i\) Is noninvasive,
>
> \(ii\) Does not require an invasive sampling procedure that presents
> significant risk,
>
> \(iii\) Does not by design or intention introduce energy into a
> subject, and
>
> \(iv\) Is not used as a diagnostic procedure without confirmation of
> the diagnosis by another, medically established diagnostic product or
> procedure.
>
> \(4\) A device undergoing consumer preference testing, testing of a
> modification, or testing of a combination of two or more devices in
> commercial distribution, if the testing is not for the purpose of
> determining safety or effectiveness and does not put subjects at risk.
>
> \(5\) A device intended solely for veterinary use.
>
> \(6\) A device shipped solely for research on or with laboratory
> animals and labeled in accordance with § 812.5(c).
>
> \(7\) A custom device as defined in § 812.3(b), unless the device is
> being used to determine safety or effectiveness for commercial
> distribution.
>
> \(8\) An intraocular lens. An intraocular lens shall not be used
> unless it is subject to an approved IDE under Part 813 or an approved
> application for premarket approval under section 515 of the act.

\(d\) Limit on certain exemptions. In the case of class II or class III
device described in paragraph (c)(1) or (2) of this section, this part
applies beginning on the date stipulated in an FDA regulation or order
that calls for the submission of premarket approval applications for an
unapproved class III device, or establishes a performance standard for a
class II device.

\(e\) Investigations subject to IND\'s. A sponsor that, on July 16,
1980, has an effective investigational new drug application (IND) for an
investigation of a device shall continue to comply with the requirements
of Part 312 until 90 days after that date. To continue the investigation
after that date, a sponsor shall comply with paragraph (b)(1) of this
section, if the device is not a significant risk device, or shall have
obtained FDA approval under § 812.30 of an IDE application for the
investigation of the device.

\[45 FR 3751, Jan. 18, 1980, as amended at 46 FR 8956, Jan. 27, 1981; 46
FR 14340, Feb. 27, 1981; 53 FR 11252, Apr. 6, 1988\]

**§ 812.3 Definitions.**

\(a\) Act means the Federal Food, Drug, and Cosmetic Act (sections 201
901, 52 Stat. 1040 et seq., as amended (21 U.S.C. 301 ­ 392)).

\(b\) Custom device means a device that:

> \(1\) Necessarily deviates from devices generally available or from an
> applicable performance standard or premarket approval requirement in
> order to comply with the order of an individual physician or dentist;
>
> \(2\) Is not generally available to, or generally used by, other
> physicians or dentists;
>
> \(3\) Is not generally available in finished form for purchase or for
> dispensing upon prescription;
>
> \(4\) Is not offered for commercial distribution through labeling or
> advertising; and
>
> \(5\) Is intended for use by an individual patient named in the order
> of a physician or dentist, and is to be made in a specific form for
> that patient, or is intended to meet the special needs of the
> physician or dentist in the course of professional practice.

\(c\) FDA means the Food and Drug Administration.

\(d\) Implant means a device that is placed into a surgically or
naturally formed cavity of the human body if it is intended to remain
there for a period of 30 days or more. FDA may, in order to protect
public health, determine that devices placed in subjects for shorter
periods are also \"implants\" for purposes of this part.

\(e\) Institution means a person, other than an individual, who engages
in the conduct of research on subjects or in the delivery of medical
services to individuals as a primary activity or as an adjunct to
providing residential or custodial care to humans. The term includes,
for example, a hospital, retirement home, confinement facility, academic
establishment, and device manufacturer. The term has the same meaning as
\"facility\" in section 520(g) of the act.

\(f\) Institutional review board (IRB) means any board, committee, or
other group formally designated by an institution to review biomedical
research involving subjects and established, operated, and functioning
in conformance with part 56. The term has the same meaning as
\"institutional review committee\" in section 520(g) of the act.

\(g\) Investigational device means a device, including a transitional
device, that is the object of an investigation.

\(h\) Investigation means a clinical investigation or research involving
one or more subjects to determine the safety or effectiveness of a
device.

\(i\) Investigator means an individual who actually conducts a clinical
investigation, i.e., under whose immediate direction the test article is
administered or dispensed to, or used involving, a subject, or, in the
event of an investigation conducted by a team of individuals, is the
responsible leader of that team.

\(j\) Monitor, when used as a noun, means an individual designated by a
sponsor or contract research organization to oversee the progress of an
investigation. The monitor may be an employee of a sponsor or a
consultant to the sponsor, or an employee of or consultant to a contract
research organization. Monitor, when used as a verb, means to oversee an
investigation.

\(k\) Noninvasive, when applied to a diagnostic device or procedure,
means one that does not by design or intention: (1) Penetrate or pierce
the skin or mucous membranes of the body, the ocular cavity, or the
urethra, or (2) enter the ear beyond the external auditory canal, the
nose beyond the nares, the mouth beyond the pharynx, the anal canal
beyond the rectum, or the vagina beyond the cervical os. For purposes of
this part, blood sampling that involves simple venipuncture is
considered noninvasive, and the use of surplus samples of body fluids or
tissues that are left over from samples taken for noninvestigational
purposes is also considered noninvasive.

\(l\) Person includes any individual, partnership, corporation,
association, scientific or academic establishment, Government agency or
organizational unit of a Government agency, and any other legal entity.

\(m\) Significant risk device means an investigational device that:

> \(1\) Is intended as an implant and presents a potential for serious
> risk to the health, safety, or welfare of a subject;
>
> \(2\) Is purported or represented to be for a use in supporting or
> sustaining human life and presents a potential for serious risk to the
> health, safety, or welfare of a subject;
>
> \(3\) Is for a use of substantial importance in diagnosing, curing,
> mitigating, or treating disease, or otherwise preventing impairment of
> human health and presents a potential for serious risk to the health,
> safety, or welfare of a subject; or
>
> \(4\) Otherwise presents a potential for serious risk to the health,
> safety, or welfare of a subject.

\(n\) Sponsor means a person who initiates, but who does not actually
conduct, the investigation, that is, the investigational device is
administered, dispensed, or used under the immediate direction of
another individual. 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.

\(o\) Sponsor-investigator means an individual who both initiates and
actually conducts, alone or with others, an investigation, that is,
under whose immediate direction the investigational device is
administered, dispensed, or used. The term does not include any person
other than an individual. The obligations of a sponsor­investigator under
this part include those of an investigator and those of a sponsor.

\(p\) Subject means a human who participates in an investigation, either
as an individual on whom or on whose specimen an investigational device
is used or as a control. A subject may be in normal health or may have a
medical condition or disease.

\(q\) Termination means a discontinuance, by sponsor or by withdrawal of
IRB or FDA approval, of an investigation before completion.

\(r\) Transitional device means a device subject to section 520(l) of
the act, that is, a device that FDA considered to be a new drug or an
antibiotic drug before May 28, 1976.

\(s\) Unanticipated adverse device effect means any serious adverse
effect on health or safety or any life­threatening problem or death
caused by, or associated with, a device, if that effect, problem, or
death was not previously identified in nature, severity, or degree of
incidence in the investigational plan or application (including a
supplementary plan or application), or any other unanticipated serious
problem associated with a device that relates to the rights, safety, or
welfare of subjects.

\[45 FR 3751, Jan. 18, 1980, as amended at 46 FR 8956, Jan. 27, 1981; 48
FR 15622, Apr. 12, 1983\]

**§ 812.5 Labeling of investigational devices.**

\(a\) Contents. An investigational device or its immediate package shall
bear a label with the following information: the name and place of
business of the manufacturer, packer, or distributor (in accordance with
§ 801.1), the quantity of contents, if appropriate, and the following
statement: \"CAUTION - Investigational device. Limited by Federal (or
United States) law to investigational use.\" The label or other labeling
shall describe all relevant contraindications, hazards, adverse effects,
interfering substances or devices, warnings, and precautions.

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

\(c\) Animal research. An investigational device shipped solely for
research on or with laboratory animals shall bear on its label the
following statement: \"CAUTION - Device for investigational use in
laboratory animals or other tests that do not involve human subjects.\"

\[45 FR 3751, Jan. 18, 1980, as amended at 45 FR 58842, Sept. 5, 1980\]

**§ 812.7 Prohibition of promotion and other practices.**

A sponsor, investigator, or any person acting for or on behalf of a
sponsor or investigator shall not:

\(a\) Promote or test market an investigational device, until after FDA
has approved the device for commercial distribution.

\(b\) Commercialize an investigational device by charging the subjects
or investigators for a device a price larger than that necessary to
recover costs of manufacture, research, development, and handling.

\(c\) Unduly prolong an investigation. If data developed by the
investigation indicate in the case of a class III device that premarket
approval cannot be justified or in the case of a class II device that it
will not comply with an applicable performance standard or an amendment
to that standard, the sponsor shall promptly terminate the
investigation.

\(d\) Represent that an investigational device is safe or effective for
the purposes for which it is being investigated.

**§ 812.10 Waivers.**

\(a\) Request. A sponsor may request FDA to waive any requirement of
this part. A waiver request, with supporting documentation, may be
submitted separately or as part of an application to the address in §
812.19.

\(b\) FDA action. FDA may by letter grant a waiver of any requirement
that FDA finds is not required by the act and is unnecessary to protect
the rights, safety, or welfare of human subjects.

\(c\) Effect of request. Any requirement shall continue to apply unless
and until FDA waives it.

**§ 812.18 Import and export requirements.**

\(a\) Imports. In addition to complying with other requirements of this
part, a person who imports or offers for importation an investigational
device subject to this part shall be the agent of the foreign exporter
with respect to investigations of the device and shall act as the
sponsor of the clinical investigation, or ensure that another person
acts as the agent of the foreign exporter and the sponsor of the
investigation.

\(b\) Exports. A person exporting an investigational device subject to
this part shall obtain FDA\'s prior approval, as required by section
801(d) of the act.

**§ 812.19 Address for IDE correspondence**.

All applications, supplemental applications, reports, requests for
waivers, requests for import or export approval, and other
correspondence relating to matters covered by this part shall be
addressed to the Center for Devices and Radiological Health, Document
Mail Center (HFZ ­ 401), Food and Drug Administration, 9200 Corporate
Blvd, Rockville, MD 20850. The outside wrapper of each submission shall
state what the submission is, for example an \"IDE application,\" a
\"supplemental IDE application,\" or \"correspondence concerning an IDE
(or an IDE application).\"

\[45 FR 3751, Jan. 18, 1980, as amended at 53 FR 11252, Apr. 6, 1988; 55
FR 11169, Mar. 27, 1990\]

**Subpart B - Application and Administrative Action**

**§ 812.20 Application.**

\(a\) Submission.

> \(1\) A sponsor shall submit an application to FDA if the sponsor
> intends to use a significant risk device in an investigation or if FDA
> notifies the sponsor that an application is required for an
> investigation.
>
> \(2\) A sponsor shall not begin an investigation for which FDA\'s
> approval of an application is required until FDA has approved the
> application.
>
> \(3\) A sponsor shall submit three copies of a signed \"Application
> for an Investigational Device Exemption\" (IDE application), together
> with accompanying materials, by registered mail or by hand to the
> address in § 812.19. Subsequent correspondence concerning an
> application or a supplemental application shall be submitted by
> registered mail or by hand.

\(b\) Contents. An IDE application shall include, in the following
order:

> \(1\) The name and address of the sponsor.
>
> \(2\) A complete report of prior investigations of the device and an
> accurate summary of those sections of the investigational plan
> described in § 812.25(a) through (e) or, in lieu of the summary, the
> complete plan. The sponsor shall submit to FDA a complete
> investigational plan and a complete report of prior investigations of
> the device if no IRB has reviewed them, if FDA has found an IRB\'s
> review inadequate, or if FDA requests them.
>
> \(3\) A description of the methods, facilities, and controls used for
> the manufacture, processing, packing, storage, and, where appropriate,
> installation of the device, in sufficient detail so that a person
> generally familiar with good manufacturing practices can make a
> knowledgeable judgment about the quality control used in the
> manufacture of the device.
>
> \(4\) An example of the agreements to be entered into by all
> investigators to comply with investigator obligations under this part,
> and a list of the names and addresses of all investigators who have
> signed the agreement.
>
> \(5\) A certification that all investigators who will participate in
> the investigation have signed the agreement, that the list of
> investigators includes all the investigators participating in the
> investigation, and that no investigators will be added to the
> investigation until they have signed the agreement.
>
> \(6\) A list of the name, address, and chairperson of each IRB that
> has been or will be asked to review the investigation and a
> certification of the action concerning the investigation taken by each
> such IRB.
>
> \(7\) The name and address of any institution at which a part of the
> investigation may be conducted that has not been identified in
> accordance with paragraph (b)(6) of this section.
>
> \(8\) If the device is to be sold, the amount to be charged and an
> explanation of why sale does not constitute commercialization of the
> device.
>
> \(9\) A claim for categorical exclusion under § 25.24 or an
> environmental assessment under § 25.31.
>
> \(10\) Copies of all labeling for the device.
>
> \(11\) Copies of all forms and informational materials to be provided
> to subjects to obtain informed consent.
>
> \(12\) Any other relevant information FDA requests for review of the
> application.

\(c\) Additional information. FDA may request additional information
concerning an investigation or revision in the investigational plan. The
sponsor may treat such a request as a disapproval of the application for
purposes of requesting a hearing under Part 16.

\(d\) Information previously submitted. Information previously submitted
to the Center for Devices and Radiological Health in accordance with
this chapter ordinarily need not be resubmitted, but may be incorporated
by reference.

\[45 FR 3751, Jan. 18, 1980, as amended at 46 FR 8956, Jan. 27, 1981; 50
FR 16669, Apr. 26, 1985; 53 FR 11252, Apr. 6, 1988\]

**§ 812.25 Investigational plan.**

The investigational plan shall include, in the following order:

\(a\) Purpose. The name and intended use of the device and the
objectives and duration of the investigation.

\(b\) Protocol. A written protocol describing the methodology to be used
and an analysis of the protocol demonstrating that the investigation is
scientifically sound.

\(c\) Risk analysis. A description and analysis of all increased risks
to which subjects will be exposed by the investigation; the manner in
which these risks will be minimized; a justification for the
investigation; and a description of the patient population, including
the number, age, sex, and condition.

\(d\) Description of device. A description of each important component,
ingredient, property, and principle of operation of the device and of
each anticipated change in the device during the course of the
investigation.

\(e\) Monitoring procedures. The sponsor\'s written procedures for
monitoring the investigation and the name and address of any monitor.

\(f\) Labeling. Copies of all labeling for the device.

\(g\) Consent materials. Copies of all forms and informational materials
to be provided to subjects to obtain informed consent.

\(h\) IRB information. A list of the names, locations, and chairpersons
of all IRB\'s that have been or will be asked to review the
investigation, and a certification of any action taken by any of those
IRB\'s with respect to the investigation.

\(i\) Other institutions. The name and address of each institution at
which a part of the investigation may be conducted that has not been
identified in paragraph (h) of this section.

\(j\) Additional records and reports. A description of records and
reports that will be maintained on the investigation in addition to
those prescribed in Subpart G.

**§ 812.27 Report of prior investigations.**

\(a\) General. The report of prior investigations shall include reports
of all prior clinical, animal, and laboratory testing of the device and
shall be comprehensive and adequate to justify the proposed
investigation.

\(b\) Specific contents. The report also shall include:

> \(1\) A bibliography of all publications, whether adverse or
> supportive, that are relevant to an evaluation of the safety or
> effectiveness of the device, copies of all published and unpublished
> adverse information, and, if requested by an IRB or FDA, copies of
> other significant publications.
>
> \(2\) A summary of all other unpublished information (whether adverse
> or supportive) in the possession of, or reasonably obtainable by, the
> sponsor that is relevant to an evaluation of the safety or
> effectiveness of the device.
>
> \(3\) If information on nonclinical laboratory studies is provided, a
> statement that all such studies have been conducted in compliance with
> applicable requirements in the good laboratory practice regulations in
> Part 58, or if any such study was not conducted in compliance with
> such regulations, a brief statement of the reason for the
> noncompliance. Failure or inability to comply with this requirement
> does not justify failure to provide information on a relevant
> nonclinical test study.

\[45 FR 3751, Jan. 18, 1980, as amended at 50 FR 7518, Feb. 22, 1985\]

**§ 812.30 FDA action on applications.**

\(a\) Approval or disapproval. FDA will notify the sponsor in writing of
the date it receives an application. FDA may approve an investigation as
proposed, approve it with modifications, or disapprove it. An
investigation may not begin until:

> \(1\) Thirty days after FDA receives the application at the address in
> § 812.19 for the investigation of a device other than a banned device,
> unless FDA notifies the sponsor that the investigation may not begin;
> or
>
> \(2\) FDA approves, by order, an IDE for the investigation.

\(b\) Grounds for disapproval or withdrawal. FDA may disapprove or
withdraw approval of an application if FDA finds that:

> \(1\) There has been a failure to comply with any requirement of this
> part or the act, any other applicable regulation or statute, or any
> condition of approval imposed by an IRB or FDA.
>
> \(2\) The application or a report contains an untrue statement of a
> material fact, or omits material information required by this part.
>
> \(3\) The sponsor fails to respond to a request for additional
> information within the time prescribed by FDA.
>
> \(4\) There is reason to believe that the risks to the subjects are
> not outweighed by the anticipated benefits to the subjects and the
> importance of the knowledge to be gained, or informed consent is
> inadequate, or the investigation is scientifically unsound, or there
> is reason to believe that the device as used is ineffective.
>
> \(5\) It is otherwise unreasonable to begin or to continue the
> investigation owing to the way in which the device is used or the
> inadequacy of:
>
> \(i\) The report of prior investigations or the investigational plan;
>
> \(ii\) The methods, facilities, and controls used for the
> manufacturing, processing, packaging, storage, and, where appropriate,
> installation of the device; or
>
> \(iii\) Monitoring and review of the investigation.

\(c\) Notice of disapproval or withdrawal. If FDA disapproves an
application or proposes to withdraw approval of an application, FDA will
notify the sponsor in writing.

> \(1\) A disapproval order will contain a complete statement of the
> reasons for disapproval and a statement that the sponsor has an
> opportunity to request a hearing under Part 16.
>
> \(2\) A notice of a proposed withdrawal of approval will contain a
> complete statement of the reasons for withdrawal and a statement that
> the sponsor has an opportunity to request a hearing under Part 16. FDA
> will provide the opportunity for hearing before withdrawal of
> approval, unless FDA determines in the notice that continuation of
> testing under the exemption will result in an unreasonable risk to the
> public health and orders withdrawal of approval before any hearing.

\[45 FR 3751, Jan. 18, 1980, as amended at 45 FR 58842, Sept. 5, 1980\]

**§ 812.35 Supplemental applications.**

\(a\) Changes in investigational plan. A sponsor shall: (1) Submit to
FDA a supplemental application if the sponsor or an investigator
proposes a change in the investigational plan that may affect its
scientific soundness or the rights, safety, or welfare of subjects, and
(2) obtain FDA approval under § 812.30(a) of any such change, and IRB
approval when the change involves the rights, safety, or welfare of
subjects (see "56.110 and 56.111), before implementation. These
requirements do not apply in the case of a deviation from the
investigational plan to protect the life or physical well being of a
subject in an emergency, which deviation shall be reported to FDA within
5 working days after the sponsor learns of it (see § 812.150(a)(4)).

\(b\) IRB approval for new facilities. A sponsor shall submit to FDA a
certification of any IRB approval of an investigation or a part of an
investigation not included in the IDE application. If the investigation
is otherwise unchanged, the supplemental application shall consist of an
updating of the information required by § 812.20(b) and

\(c\) a description of any modifications in the investigational plan
required by the IRB as a condition of approval. A certification of IRB
approval need not be included in the initial submission of the
supplemental application, and such certification is not a precondition
for agency consideration of the application. Nevertheless, a sponsor may
not begin a part of an investigation at a facility until the IRB has
approved the investigation, FDA has received the certification of IRB
approval, and FDA, under § 812.30(a), has approved the supplemental
application relating to that part of the investigation (see §
56.103(a)).

\[50 FR 25909, June 24, 1985; 50 FR 28932, July 17, 1985\]

**§ 812.38 Confidentiality of data and information.**

\(a\) Existence of IDE. FDA will not disclose the existence of an IDE
unless its existence has previously been publicly disclosed or
acknowledged, until FDA approves an application for premarket approval
of the device subject to the IDE; or a notice of completion of a product
development protocol for the device has become effective.

\(b\) Availability of summaries or data.

> \(1\) FDA will make publicly available, upon request, a detailed
> summary of information concerning the safety and effectiveness of the
> device that was the basis for an order approving, disapproving, or
> withdrawing approval of an application for an IDE for a banned device.
> The summary shall include information on any adverse effect on health
> caused by the device.
>
> \(2\) If a device is a banned device or if the existence of an IDE has
> been publicly disclosed or acknowledged, data or information contained
> in the file is not available for public disclosure before approval of
> an application for premarket approval or the effective date of a
> notice of completion of a product development protocol except as
> provided in this section. FDA may, in its discretion, disclose a
> summary of selected portions of the safety and effectiveness data,
> that is, clinical, animal, or laboratory studies and tests of the
> device, for public consideration of a specific pending issue.
>
> \(3\) If the existence of an IDE file has not been publicly disclosed
> or acknowledged, no data or information in the file are available for
> public disclosure except as provided in paragraphs (b)(1) and (c) of
> this section.

\(c\) Reports of adverse effects. Upon request or on its own initiative,
FDA shall disclose to an individual on whom an investigational device
has been used a copy of a report of adverse device effects relating to
that use.

\(d\) Other rules. Except as otherwise provided in this section, the
availability for public disclosure of data and information in an IDE
file shall be handled in accordance with § 814.9.

\[45 FR 3751, Jan. 18, 1980, as amended at 53 FR 11253, Apr. 6, 1988\]

**Subpart C - Responsibilities of Sponsors**

**§ 812.40 General responsibilities of sponsors.**

Sponsors are responsible for selecting qualified investigators and
providing them with the information they need to conduct the
investigation properly, ensuring proper monitoring of the investigation,
ensuring that IRB review and approval are obtained, submitting an IDE
application to FDA, and ensuring that any reviewing IRB and FDA are
promptly informed of significant new information about an investigation.
Additional responsibilities of sponsors are described in Subparts B and
G.

**§ 812.42 FDA and IRB approval.**

A sponsor shall not begin an investigation or part of an investigation
until an IRB and FDA have both approved the application or supplemental
application relating to the investigation or part of an investigation.

\[46 FR 8957, Jan. 27, 1981\]

**§ 812.43 Selecting investigators and monitors.**

\(a\) Selecting investigators. A sponsor shall select investigators
qualified by training and experience to investigate the device.

\(b\) Control of device. A sponsor shall ship investigational devices
only to qualified investigators participating in the investigation.

\(c\) Obtaining agreements. A sponsor shall obtain from each
participating investigator a signed agreement that includes:

> \(1\) The investigator\'s curriculum vitae.
>
> \(2\) Where applicable, a statement of the investigator\'s relevant
> experience, including the dates, location, extent, and type of
> experience.
>
> \(3\) If the investigator was involved in an investigation or other
> research that was terminated, an explanation of the circumstances that
> led to termination.
>
> \(4\) A statement of the investigator\'s commitment to:
>
> \(i\) Conduct the investigation in accordance with the agreement, the
> investigational plan, this part and other applicable FDA regulations,
> and conditions of approval imposed by the reviewing IRB or FDA;
>
> \(ii\) Supervise all testing of the device involving human subjects;
> and
>
> \(iii\) Ensure that the requirements for obtaining informed consent
> are met.

\(d\) Selecting monitors. A sponsor shall select monitors qualified by
training and experience to monitor the investigational study in
accordance with this part and other applicable FDA regulations.

**§ 812.45 Informing investigators.**

A sponsor shall supply all investigators participating in the
investigation with copies of the investigational plan and the report of
prior investigations of the device.

**§ 812.46 Monitoring investigations.**

\(a\) Securing compliance. A sponsor who discovers that an investigator
is not complying with the signed agreement, the investigational plan,
the requirements of this part or other applicable FDA regulations, or
any conditions of approval imposed by the reviewing IRB or FDA shall
promptly either secure compliance, or discontinue shipments of the
device to the investigator and terminate the investigator\'s
participation in the investigation. A sponsor shall also require such an
investigator to dispose of or return the device, unless this action
would jeopardize the rights, safety, or welfare of a subject.

\(b\) Unanticipated adverse device effects.

> \(1\) A sponsor shall immediately conduct an evaluation of any
> unanticipated adverse device effect.
>
> \(2\) A sponsor who determines that an unanticipated adverse device
> effect presents an unreasonable risk to subjects shall terminate all
> investigations or parts of investigations presenting that risk as soon
> as possible. Termination shall occur not later than 5 working days
> after the sponsor makes this determination and not later than 15
> working days after the sponsor first received notice of the effect.

\(c\) Resumption of terminated studies. If the device is a significant
risk device, a sponsor may not resume a terminated investigation without
IRB and FDA approval. If the device is not a significant risk device, a
sponsor may not resume a terminated investigation without IRB approval
and, if the investigation was terminated under paragraph (b)(2) of this
section, FDA approval.

**Subpart D - IRB Review and Approval**

**§ 812.60 IRB composition, duties, and functions.**

An IRB reviewing and approving investigations under this part shall
comply with the requirements of Part 56 in all respects, including its
composition, duties, and functions.

\[46 FR 8957, Jan. 27, 1981\]

**§ 812.62 IRB approval.**

\(a\) An IRB shall review and have authority to approve, require
modifications in (to secure approval), or disapprove all investigations
covered by this part.

\(b\) If no IRB exists or if FDA finds that an IRB\'s review is
inadequate, a sponsor may submit an application to FDA.

\[46 FR 8957, Jan. 27, 1981\]

**§ 812.64 IRB\'s continuing review.**

The IRB shall conduct its continuing review of an investigation in
accordance with Part 56. \[46 FR 8957, Jan. 27, 1981\]

**§ 812.65 \[Reserved\]**

**§ 812.66 Significant risk device determinations.**

If an IRB determines that an investigation, presented for approval under
§ 812.2(b)(1)(ii), involves a significant risk device, it shall so
notify the investigator and, where appropriate, the sponsor. A sponsor
may not begin the investigation except as provided in § 812.30(a).

\[46 FR 8957, Jan. 27, 1981\]

**Subpart E - Responsibilities of Investigators**

**§ 812.100 General responsibilities of investigators.**

An investigator is responsible for ensuring that an investigation is
conducted according to the signed agreement, the investigational plan
and applicable FDA regulations, for protecting the rights, safety, and
welfare of subjects under the investigator\'s care, and for the control
of devices under investigation. An investigator also is responsible for
ensuring that informed consent is obtained in accordance with Part 50 of
this chapter. Additional responsibilities of investigators are described
in Subpart G.

\[45 FR 3751, Jan. 18, 1980, as amended at 46 FR 8957, Jan. 27, 1981\]

**§ 812.110 Specific responsibilities of investigators.**

\(a\) Awaiting approval. An investigator may determine whether potential
subjects would be interested in participating in an investigation, but
shall not request the written informed consent of any subject to
participate, and shall not allow any subject to participate before
obtaining IRB and FDA approval.

\(b\) Compliance. An investigator shall conduct an investigation in
accordance with the signed agreement with the sponsor, the
investigational plan, this part and other applicable FDA regulations,
and any conditions of approval imposed by an IRB or FDA.

\(c\) Supervising device use. An investigator shall permit an
investigational device to be used only with subjects under the
investigator\'s supervision. An investigator shall not supply an
investigational device to any person not authorized under this part to
receive it.

\(d\) Disposing of device. Upon completion or termination of a clinical
investigation or the investigator\'s part of an investigation, or at the
sponsor\'s request, an investigator shall return to the sponsor any
remaining supply of the device or otherwise dispose of the device as the
sponsor directs.

**Subpart F - \[Reserved\]**

**Subpart G - Records and Reports**

**§ 812.140 Records.**

\(a\) Investigator records. A participating investigator shall maintain
the following accurate, complete, and current records relating to the
investigator\'s participation in an investigation:

> \(1\) All correspondence with another investigator, an IRB, the
> sponsor, a monitor, or FDA, including required reports.
>
> \(2\) Records of receipt, use or disposition of a device that relate
> to:
>
> \(i\) The type and quantity of the device, the dates of its receipt,
> and the batch number or code mark.
>
> (ii)The names of all persons who received, used, or disposed of each
> device.
>
> \(iii\) Why and how many units of the device have been returned to the
> sponsor, repaired, or otherwise disposed of.
>
> \(3\) Records of each subject\'s case history and exposure to the
> device. Such records shall include:
>
> \(i\) Documents evidencing informed consent and, for any use of a
> device by the investigator without informed consent, any written
> concurrence of a licensed physician and a brief description of the
> circumstances justifying the failure to obtain informed consent.
>
> \(ii\) All relevant observations, including records concerning adverse
> device effects (whether anticipated or unanticipated), information and
> data on the condition of each subject upon entering, and during the
> course of, the investigation, including information about relevant
> previous medical history and the results of all diagnostic tests.
>
> \(iii\) A record of the exposure of each subject to the
> investigational device, including the date and time of each use, and
> any other therapy.
>
> \(4\) The protocol, with documents showing the dates of and reasons
> for each deviation from the protocol.
>
> \(5\) Any other records that FDA requires to be maintained by
> regulation or by specific requirement for a category of investigations
> or a particular investigation.

\(b\) Sponsor records. A sponsor shall maintain the following accurate,
complete, and current records relating to an investigation:

> \(1\) All correspondence with another sponsor, a monitor, an
> investigator, an IRB, or FDA, including required reports.
>
> \(2\) Records of shipment and disposition. Records of shipment shall
> include the name and address of the consignee, type and quantity of
> device, date of shipment, and batch number or code mark. Records of
> disposition shall describe the batch number or code marks of any
> devices returned to the sponsor, repaired, or disposed of in other
> ways by the investigator or another person, and the reasons for and
> method of disposal.
>
> \(3\) Signed investigator agreements.
>
> \(4\) For each investigation subject to § 812.2(b)(1) of a device
> other than a significant risk device, the records described in
> paragraph (b)(5) of this section and the following records,
> consolidated in one location and available for FDA inspection and
> copying:
>
> \(i\) The name and intended use of the device and the objectives of
> the investigation;
>
> \(ii\) A brief explanation of why the device is not a significant risk
> device:
>
> \(iii\) The name and address of each investigator:
>
> \(iv\) The name and address of each IRB that has reviewed the
> investigation:
>
> \(v\) A statement of the extent to which the good manufacturing
> practice regulation in Part 820 will be followed in manufacturing the
> device; and
>
> \(vi\) Any other information required by FDA.
>
> \(5\) Records concerning adverse device effects (whether anticipated
> or unanticipated) and complaints and
>
> \(6\) Any other records that FDA requires to be maintained by
> regulation or by specific requirement for a category of investigation
> or a particular investigation.

\(c\) IRB records. An IRB shall maintain records in accordance with Part
56 of this chapter.

\(d\) Retention period. An investigator or sponsor shall maintain the
records required by this subpart during the investigation and for a
period of 2 years after the latter of the following two dates: The date
on which the investigation is terminated or completed, or the date that
the records are no longer required for purposes of supporting a
premarket approval application or a notice of completion of a product
development protocol.

\(e\) Records custody. An investigator or sponsor may withdraw from the
responsibility to maintain records for the period required in paragraph
(d) of this section and transfer custody of the records to any other
person who will accept responsibility for them under this part,
including the requirements of § 812.145. Notice of a transfer shall be
given to FDA not later than 10 working days after transfer occurs.

\[45 FR 3751, Jan. 18, 1980, as amended at 45 FR 58843, Sept. 5, 1980;
46 FR 8957, Jan. 27, 1981\]

**§ 812.145 Inspections.**

\(a\) Entry and inspection. A sponsor or an investigator who has
authority to grant access shall permit authorized FDA employees, at
reasonable times and in a reasonable manner, to enter and inspect any
establishment where devices are held (including any establishment where
devices are manufactured, processed, packed, installed, used, or
implanted or where records of results from use of devices are kept).

\(b\) Records inspection. A sponsor, IRB, or investigator, or any other
person acting on behalf of such a person with respect to an
investigation, shall permit authorized FDA employees, at reasonable
times and in a reasonable manner, to inspect and copy all records
relating to an investigation.

\(c\) Records identifying subjects. An investigator shall permit
authorized FDA employees to inspect and copy records that identify
subjects, upon notice that FDA has reason to suspect that adequate
informed consent was not obtained, or that reports required to be
submitted by the investigator to the sponsor or IRB have not been
submitted or are incomplete, inaccurate, false, or misleading.

**§ 812.150 Reports.**

\(a\) Investigator reports. An investigator shall prepare and submit the
following complete, accurate, and timely reports:

> \(1\) Unanticipated adverse device effects. An investigator shall
> submit to the sponsor and to the reviewing IRB a report of any
> unanticipated adverse device effect occurring during an investigation
> as soon as possible, but in no event later than 10 working days after
> the investigator first learns of the effect.
>
> \(2\) Withdrawal of IRB approval. An investigator shall report to the
> sponsor, within 5 working days, a withdrawal of approval by the
> reviewing IRB of the investigator\'s part of an investigation.
>
> \(3\) Progress. An investigator shall submit progress reports on the
> investigation to the sponsor, the monitor, and the reviewing IRB at
> regular intervals, but in no event less often than yearly.
>
> \(4\) Deviations from the investigational plan. An investigator shall
> notify the sponsor and the reviewing IRB (see § 56.108(a) (3) and (4))
> of any deviation from the investigational plan to protect the life or
> physical well being of a subject in an emergency. Such notice shall be
> given as soon as possible, but in no event later than 5 working days
> after the emergency occurred. Except in such an emergency, prior
> approval by the sponsor is required for changes in or deviations from
> a plan, and if these changes or deviations may affect the scientific
> soundness of the plan or the rights, safety, or welfare of human
> subjects, FDA and IRB in accordance with § 812.35(a) also is required.
>
> \(5\) Informed consent. If an investigator uses a device without
> obtaining informed consent, the investigator shall report such use to
> the sponsor and the reviewing IRB within 5 working days after the use
> occurs.
>
> \(6\) Final report. An investigator shall, within 3 months after
> termination or completion of the investigation or the investigator\'s
> part of the investigation, submit a final report to the sponsor and
> the reviewing IRB.
>
> \(7\) Other. An investigator shall, upon request by a reviewing IRB or
> FDA, provide accurate, complete, and current information about any
> aspect of the investigation.

\(b\) Sponsor reports. A sponsor shall prepare and submit the following
complete, accurate, and timely reports:

> \(1\) Unanticipated adverse device effects. A sponsor who conducts an
> evaluation of an unanticipated adverse device effect under § 812.46(b)
> shall report the results of such evaluation to FDA and to all
> reviewing IRB\'s and participating investigators within 10 working
> days after the sponsor first receives notice of the effect. Thereafter
> the sponsor shall submit such additional reports concerning the effect
> as FDA requests.
>
> \(2\) Withdrawal of IRB approval. A sponsor shall notify FDA and all
> reviewing IRB\'s and participating investigators of any withdrawal of
> approval of an investigation or a part of an investigation by a
> reviewing IRB within 5 working days after receipt of the withdrawal of
> approval.
>
> \(3\) Withdrawal of FDA approval. A sponsor shall notify all reviewing
> IRB\'s and participating investigators of any withdrawal of FDA
> approval of the investigation, and shall do so within 5 working days
> after receipt of notice of the withdrawal of approval.
>
> \(4\) Current investigator list. A sponsor shall submit to FDA, at 6
> month intervals, a current list of the names and addresses of all
> investigators participating in the investigation. The sponsor shall
> submit the first such list 6 months after FDA approval.
>
> \(5\) Progress reports. At regular intervals, and at least yearly, a
> sponsor shall submit progress reports to all reviewing IRB\'s. In the
> case of a significant risk device, the sponsor shall also submit
> progress reports to FDA.
>
> \(6\) Recall and device disposition. A sponsor shall notify FDA and
> all reviewing IRB\'s of any request that an investigator return,
> repair, or otherwise dispose of any units of a device. Such notice
> shall occur within 30 working days after the request is made and shall
> state why the request was made.
>
> \(7\) Final report. In the case of a significant risk device, the
> sponsor shall notify FDA within 30 working days of the completion or
> termination of the investigation and shall submit a final report to
> FDA and all reviewing the IRB\'s and participating investigators
> within 6 months after completion or termination. In the case of a
> device that is not a significant risk device, the sponsor shall submit
> a final report to all reviewing IRB\'s within 6 months after
> termination or completion.
>
> \(8\) Informed consent. A sponsor shall submit to FDA a copy of any
> report by an investigator under paragraph (a)(5) of this section of
> use of a device without obtaining informed consent, within 5 working
> days of receipt of notice of such use.
>
> \(9\) Significant risk device determinations. If an IRB determines
> that a device is a significant risk device, and the sponsor had
> proposed that the IRB consider the device not to be a significant risk
> device, the sponsor shall submit to FDA a report of the IRB\'s
> determination within 5 working days after the sponsor first learns of
> the IRB\'s determination.
>
> \(10\) Other. A sponsor shall, upon request by a reviewing IRB or FDA,
> provide accurate, complete, and current information about any aspect
> of the investigation.