Investigational New Drug Applications Prepared and Submitted by Sponsor-Investigators

Administrative draft guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Investigational New Drug
Applications Prepared
and Submitted by
Sponsor-Investigators
Guidance for Industry
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 60 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit electronic comments to http://www.regulations.gov. Submit written
comments to the Division of Dockets Management (HFA-305), Food and Drug Administration,
5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with
the docket number listed in the notice of availability that publishes in the Federal Register.
For questions regarding this draft document contact (CDER) Amalia Himaya at 301-796-0700 or
(CBER) the Office of Communication, Outreach, and Development at 800-835-4709 or 240-402-
7800.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
May 2015
Procedural
8061dft.doc
04/29/15

Investigational New Drug
Applications Prepared
and Submitted by
Sponsor-Investigators
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Tel: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
or
Office of Communication, Outreach, and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, rm. 3128
Silver Spring, MD 20993-0002
Tel: 800-835-4709 or 240-402-7800; Email: ocod@fda.hhs.gov
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
May 2015
Procedural

TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND (§§ 312.1 - 312.3, 312.20 - 312.23)...................................................... 2
III. 	ACQUIRING INFORMATION NEEDED FOR THE IND AND
COMMUNICATING WITH THE FDA (§§ 312.22, 312.23) ........................................ 4
IV. 	CERTAIN INFORMATION REQUIRED FOR AN IND SUBMISSION .................. 6
A. 	Required Forms (§§ 312.23(a)(1), 312.53(c)) ............................................................................... 6
B. 	Table of Contents (§ 312.23(a)(2)) ................................................................................................ 7
C. 	Introductory Statement and General Investigational Plan (§ 312.23(a)(3)) ............................. 7
D. 	Investigator’s Brochure (§§ 312.23(a)(5), 312.55) ....................................................................... 8
E. 	Protocols (§ 312.23(a)(6))............................................................................................................... 8
F. 	Chemistry, Manufacturing, and Control Information (§ 312.23(a)(7)) .................................. 10
G. 	Pharmacology and Toxicology Information (§ 312.23(a)(8)) ................................................... 12
H. 	Previous Human Experience With the Investigational Drug (§ 312.23(a)(9)) ........................ 13
I. 	Other Important Information (§ 312.23(a)(10)(i) – (iii)) .......................................................... 13
J. 	Relevant Information (§ 312.23(a)(11)) ...................................................................................... 14
V. 	SUBMISSION INFORMATION (§ 312.22(D)) ........................................................... 14
VI. 	THE IND PROCESS AND REVIEW PROCEDURES (§§ 312.30, 312.31, 312.40 –
312.42, 312.110) ............................................................................................................... 15
A. 	Clinical Holds and Requests for Modifications (§ 312.42) ....................................................... 16
B. 	IND Amendments (§§ 312.30, 312.31) ........................................................................................ 18
C. 	Import and Export Requirements (§ 312.110) .......................................................................... 18
VII. 	OTHER SPONSOR-INVESTIGATOR RESPONSIBILITIES ................................. 19
A. 	Good Clinical Practice, Including Human Subject Protection and IRB Review and
Approval (§ 312.40, 21 CFR Parts 50 and 56) ........................................................................... 19
B. 	Monitoring Ongoing Investigations (§ 312.50) .......................................................................... 19
C. 	Promotion of or Charging for Investigational Drug (§§ 312.7, 312.8) .................................... 20
D. 	Records and Reports (§§ 312.57, 312.58, 312.62, 312.68) ......................................................... 20
E. 	IND Safety Reports (§ 312.32) .................................................................................................... 20
F. 	IND Annual Reports (§ 312.33) .................................................................................................. 21
VIII. 	WITHDRAWING, TERMINATING, INACTIVATING, OR REACTIVATING AN
IND (§§ 312.38, 312.44, 312.45)...................................................................................... 22
REFERENCES............................................................................................................................ 23

Contains Nonbinding Recommendations
Draft — Not for Implementation
1 	Investigational New Drug Applications Prepared and
2 	Submitted by Sponsor-Investigators
3 	Guidance for Industry1
4
5
6
7
8 	This draft guidance, when finalized, will represent the current thinking of the Food and Drug
9 	Administration (FDA or Agency) on this topic. It does not create any rights for any person and is not
10 	binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the
11 	applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible
12 	for this guidance as listed on the title page.
13
14
15
16
17 	I. 	INTRODUCTION
18
19 	The purpose of this guidance is to assist sponsor-investigators in preparing and submitting
20 	complete investigational new drug applications (INDs) to the Center for Drug Evaluation and
21 	Research (CDER) and the Center for Biologics Evaluation and Research (CBER) at the Food and
22 	Drug Administration (FDA). Sponsor-investigators seeking to do clinical research often do not
23 	have the regulatory knowledge or the resources to hire experts to help them with the IND
24 	submission process. Although not an exhaustive step-by-step instruction manual, this guidance
25 	highlights certain elements of this process to facilitate a sponsor-investigator’s successful
26 	submission of an IND. This guidance also discusses the IND review process and general
27 	responsibilities of sponsor-investigators related to clinical investigations.
28
29 	It is important to note that this guidance does not include discussions of all of the requirements
30 	that apply to the IND submission and review process or to conducting clinical research.
31 	Sponsor-investigators should review in full these requirements, which are described in the Code
32 	of Federal Regulations (CFR).2 Many sections of the regulations that apply to INDs are
33 	described or referred to in this guidance (e.g., 21 CFR parts 50, 56, and 312). Details of the
34 	informational content of an IND as well as information needed to complete required forms also
35 	are provided throughout this guidance. In addition, the guidance provides useful references to
36 	other IND-related information resources.
37
1 This guidance has been prepared by the Office of New Drugs in the Center for Drug Evaluation and Research
(CDER) in cooperation with the Center for Biologics Evaluation and Research (CBER) at the Food and Drug
Administration (FDA).
2 The CFR is the codification of the general and permanent rules published in the Federal Register by the executive
departments and agencies of the Federal government. It is divided into 50 titles that represent broad areas subject to
Federal regulation. The CFR references that relate to the IND regulations are provided in parentheses in the
appropriate section titles of this guidance. An electronic version of the CFR is available at http://www.fda.gov.
1

Contains Nonbinding Recommendations
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38 	This guidance is directed primarily at those sponsor-investigators who are seeking to evaluate a
39 	drug that is either currently approved or is being investigated under an existing IND for a
40 	different indication.3 This guidance is not intended for sponsor-investigators who are developing
41 	a drug for commercial purposes (i.e., seeking market approval or licensure) and thus does not
42 	focus on certain regulatory requirements that involve exchange of information or materials
43 	between a sponsor and investigator. This guidance does not apply to clinical trials that do not
44 	need to be conducted under an IND (i.e., that qualify for an IND exemption).4 This guidance
45 	also is not intended to address expanded access INDs or biologic devices.5 Sponsor-investigators
46 	should refer to available FDA regulations and guidances and/or contact the relevant CDER or
47 	CBER review division to discuss and obtain additional information for preparing INDs not
48 	covered by this guidance (if necessary).
49
50 	In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
51 	Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
52 	as recommendations, unless specific regulatory or statutory requirements are cited. The use of
53 	the word should in Agency guidances means that something is suggested or recommended, but
54 	not required.
55
56
57 	II. 	BACKGROUND (§§ 312.1 - 312.3, 312.20 - 312.23)
58
59 	Generally, FDA regulations require sponsors, including sponsor-investigators, who wish to
60 	evaluate a drug or biological product in humans to submit an IND to the FDA (21 CFR part
61 	312).6 The FDA’s primary objectives in reviewing an IND are to help protect the rights and
62 	safety of subjects and, in phases 2 and 3, to help ensure that the quality of the clinical trial is
63 	adequate to evaluate the drug’s effectiveness and safety.
64
2
3 Sponsor-investigators who are seeking to evaluate a marketed unapproved new drug (i.e., a drug marketed in the
United States that does not have the required FDA approval for marketing) in a clinical trial should contact the
relevant CDER or CBER review division.
4 For information about whether a trial has to be conducted under an IND, see 21 CFR 312.2, and the guidance for
clinical investigators, sponsors, and IRBs Investigational New Drug Applications (INDs) — Determining Whether
Human Research Studies Can Be Conducted Without an IND. We update guidances periodically. To make sure you
have the most recent version of a guidance, check the FDA Drugs guidance Web page at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
5 See the draft guidance for industry Expanded Access to Investigational Drugs for Treatment Use — Qs & As.
When final, this guidance will represent the FDA’s current thinking on this topic.
6 Part 312 applies, with certain exceptions, to all clinical investigations of drugs and biological products that are
subject to section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355) or to the licensing provisions of
the Public Health Service Act (58 Stat. 632, as amended (42 U.S.C. 201 et seq.)). An investigational new drug for
which an IND that complies with part 312 is in effect, is exempt from the premarketing approval requirements that
would otherwise apply to new drugs and may be shipped lawfully for the purpose of conducting clinical
investigations of that drug.

Contains Nonbinding Recommendations
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65 	A sponsor takes responsibility for and initiates a clinical investigation. A sponsor can be an
66 	individual or pharmaceutical company, governmental agency, academic institution, private
67 	organization, or other organization.7 An investigator is the individual who actually conducts the
68 	investigation (i.e., under whose immediate direction the investigational drug is administered or
69 	dispensed to a subject).
70
71 	A sponsor-investigator is an individual who both initiates and conducts an investigation, and
72 	under whose immediate direction the investigational drug is administered or dispensed. The
73 	term, as defined in FDA regulations, does not include any entity other than an individual.8 As
74 	the name suggests, a sponsor-investigator assumes the responsibilities of, and must comply with,
75 	FDA regulations applicable to both a sponsor and an investigator. These responsibilities include
76 	the submission and maintenance of an IND.9
77
78 	The information needed to be included in initial IND submissions falls within the broad
79 	categories listed below. See section IV., Certain Information Required for an IND Submission,
80 	for additional details and 21 CFR 312.23 for a comprehensive list.
81
82 	 	Sponsor-investigator information: Information on the qualifications of the sponsor-
83 	investigator who intends to conduct the clinical trial. This information allows assessment
84 	of whether he or she is qualified to fulfill his or her clinical trial commitments.
85
86 	 	Investigator’s brochure (required of sponsors, and recommended but not required of
87 	sponsor-investigators): A summary of the chemical, toxicological, and pharmacokinetic
88 	aspects of an investigational drug including any information on its safety and efficacy
89 	obtained from any prior clinical trials, and a description of any anticipated risks, side
90 	effects, precautions, and special monitoring.
91
7 A person other than an individual who 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. Not all employees or
individuals who are involved in the conduct of an investigation are considered investigators. For more information,
see the information sheet guidance for sponsors, clinical investigators, and IRBs Frequently Asked Questions —
Statement of Investigator (Form FDA 1572), section VII., 31-33, and the guidance for industry Investigator
Responsibilities — Protecting the Rights, Safety, and Welfare of Study Subjects, section III.
8 See 21 CFR 312.3(b). Under certain circumstances, a subinvestigator can assist a sponsor-investigator in the
conduct of the investigation. For more information about the use of subinvestigators, see the guidance for industry
Investigator Responsibilities — Protecting the Rights, Safety, and Welfare of Study Subjects.
9 An individual who both initiates and conducts an investigation, and uses an investigator or investigators to conduct
the investigation, is not a sponsor-investigator, but must comply with all regulations applicable to sponsors and
investigators. This guidance generally refers to the roles and responsibilities of sponsor-investigators, but is also
intended to be useful for certain individuals who initiate and conduct an investigation, and who also use
investigators to conduct the investigation (e.g., a sponsor who is an individual and who is not developing a drug for
commercial purposes but helps conduct a trial and also uses investigators to conduct the trial at multiple sites).
However, because the purpose of this guidance is to assist sponsor-investigators, it does not focus on certain
regulatory requirements that involve the exchange of information or materials between a sponsor and investigator.
For additional information about the preparation and submission of INDs, sponsors should refer to available FDA
regulations and guidances, including the references listed at the end of this guidance.
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92 	 	Clinical trial protocol: A detailed description of the intended investigation, depending
93 	on the drug development phase.
94
95 	 	Chemistry, manufacturing, and control (CMC) information: Sufficient information that
96 	ensures the proper identification, quality, purity, and strength of the investigational drug.
97
98 	 	Pharmacology and toxicology information: A summary of nonclinical (in vitro or
99 	animal) data that is intended to support the safety of the proposed clinical trial.
100
101 	 	Summary of previous human experience: If applicable, a summary of all clinical trial
102 	results intended to support the safety of the proposed clinical trial.
103
104 	A sponsor-investigator may not be required to submit an IND for, for example, a study of a
105 	lawfully marketed drug if the criteria for an IND exemption are met.10 Furthermore, in some
106 	circumstances, even if a sponsor-investigator is required to submit an IND, the IND may not
107 	need to include all of the information listed above. For example, if a sponsor-investigator is
108 	proposing to evaluate a drug that is the subject of an existing IND, a sponsor-investigator can
109 	seek a letter of cross-reference authorization from the sponsor of that IND (called the
110 	commercial sponsor)11,12 that permits the sponsor-investigator to refer the FDA to the
111 	information contained in the commercial sponsor’s IND. If the sponsor-investigator is studying
112 	an FDA-approved prescription or nonprescription drug, even if an IND is required, some of the
113 	information needed for an IND submission can be found in the FDA-approved labeling.
114
115
116 	III. 	ACQUIRING INFORMATION NEEDED FOR THE IND AND
117 	COMMUNICATING WITH THE FDA (§§ 312.22, 312.23)
118
119 	After a sponsor-investigator determines that an IND needs to be submitted to the FDA, he or she
120 	should acquire the relevant information for the IND related to the proposed trial. This
121 	information is outlined in more depth in section IV., Certain Information Required for an IND
122 	Submission. As noted above, if the drug is an FDA-approved prescription or nonprescription
123 	drug, the FDA-approved labeling may provide some of the information needed for FDA review
124 	of the new IND, but there may be cases in which information that the commercial sponsor has
125 	collected for the drug is not part of the labeling or otherwise publicly available and may be
126 	needed to support the new IND. In such cases, the commercial sponsor can provide the sponsor-
127 	investigator with a letter of cross-reference authorization identifying the IND, new drug
128 	application (NDA), or biologics license application (BLA) file by name, reference number,
129 	volume, and page number where the information can be found and giving its permission for the
10 See the guidance for clinical investigators, sponsors, and IRBs Investigational New Drug Applications (INDs) —
Determining Whether Human Research Studies Can Be Conducted Without an IND.
11 In this guidance, the term commercial sponsor refers to a pharmaceutical company or drug manufacturer that is
developing, or has developed, a drug for commercial purposes (market approval or licensure or changes to drug
labeling) and has submitted an IND for the drug.
12 A sponsor-investigator may also seek a letter of cross-reference authorization from noncommercial sponsors of
INDs or holders of drug master files.
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130 	sponsor-investigator to cross-reference the application. This letter of cross-reference
131 	authorization should be included in the IND. The commercial sponsor also can submit a copy of
132 	the letter of cross-reference authorization to its cited IND.
133
134 	The letter of cross-reference authorization allows the FDA to review the specified content in the
135 	referenced IND, NDA, or BLA and to rely on its previous reviews of information already
136 	submitted in the commercial sponsor’s application, so that the sponsor-investigator does not need
137 	to provide that information again (e.g., CMC, nonclinical, and previous human experience data).
138 	Sponsor-investigators should note that although a letter of cross-reference authorization allows
139 	the FDA to refer to the commercial sponsor’s content, it does not give sponsor-investigators the
140 	right to directly access and read confidential material contained in the referenced IND, NDA, or
141 	BLA. However, sponsor-investigators should have access to the commercial sponsor’s current
142 	investigator’s brochure to help protect subjects. An IND submission that does not provide, or
143 	incorporate by reference, information about adverse effects and supporting safe use (information
144 	that would be found in the commercial sponsor’s investigator’s brochure) would be inadequate.
145
146 	Acquiring the necessary information when it is not available from a commercial sponsor,
147 	planning a clinical trial, and submitting a complete application for FDA review can be a complex
148 	task. If a sponsor-investigator has any questions regarding preparation of the application, he or
149 	she should contact the appropriate review division before submitting the application.
150
151 	In CDER, the review divisions for all drugs and most biologics are located in the Office of New
152 	Drugs (OND). Web sites containing CDER’s and OND’s organizational charts and contact
153 	information can be found in the References section.
154
155 	In CBER, the review divisions for the review of blood products; cellular, tissue, and gene
156 	therapies; and vaccines are located in the Office of Blood Research and Review; the Office of
157 	Cellular, Tissue and Gene Therapies; and the Office of Vaccines Research and Review,
158 	respectively. Web sites containing CBER’s organizational charts and contact information can be
159 	found in the References section.
160
161 	If the relevant review division is not known, the sponsor-investigator should contact CDER’s
162 	Division of Drug Information or CBER’s Division of Manufacturer’s Assistance and Training,
163 	Office of Communication, Outreach and Development (both addresses and telephone numbers
164 	are provided on the second title page of this guidance).
165
166 	Sponsor-investigators should include accurate contact information (e.g., telephone numbers and
167 	email addresses) that the FDA can use to communicate with the sponsor-investigator.
168 	Communications between the sponsor-investigator and the FDA can facilitate review of a
169 	submission. Therefore, the sponsor-investigator should be readily available for communications
170 	with the FDA, particularly during the 30-day period after a new IND submission.
171
172
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173 	IV. 	CERTAIN INFORMATION REQUIRED FOR AN IND SUBMISSION
174
175 	A. 	Required Forms (§§ 312.23(a)(1), 312.53(c))
176
177 	Form FDA 1571 Investigational New Drug Application
178
179 	Under § 312.23(a)(1), a sponsor-investigator’s initial IND submission must be accompanied by a
180 	signed Form FDA 1571 Investigational New Drug Application (Form FDA 1571).
181
182 	A signed Form FDA 1571 is required for the submission of an IND to the FDA. A signed Form
183 	FDA 1571 documents the sponsor-investigator’s agreement to refrain from beginning a clinical
184 	trial until 30 days after the official date that the FDA receives the IND (or unless the sponsor-
185 	investigator receives earlier notification from the FDA that the trial may begin), to refrain from
186 	beginning or continuing a clinical trial covered by the IND if that trial is placed on clinical hold,
187 	to ensure that an institutional review board (IRB) in compliance with FDA regulations will be
188 	responsible for the initial and continuing review and approval of each proposed trial, and to
189 	conduct the trial in accordance with all other applicable regulations. This form is largely self-
190 	explanatory and contains a brief series of fill-in-the-blanks and check boxes that describe and
191 	catalog the contents of the application. As such, it can serve as a road map for the sponsor-
192 	investigator, a checklist, and as a cover sheet for the initial IND submission.
193
194 	Form FDA 1572 Statement of Investigator
195
196 	Before permitting an investigator to begin participation in an investigation, a sponsor is required
197 	to obtain a signed investigator statement, Form FDA 1572 Statement of Investigator (Form FDA
198 	1572). As an investigator, a sponsor-investigator is also required to sign Form FDA 1572. By
199 	signing Form FDA 1572, the sponsor-investigator agrees to, among other things, conduct the
200 	trial in accordance with the protocol, ensure that the requirements relating to obtaining informed
201 	consent and IRB review are met, and comply with all requirements regarding the obligations of
202 	clinical investigators (e.g., recordkeeping, reporting adverse experiences). Note that IRB
203 	approval does not need to be obtained before IND submission; rather, the sponsor-investigator’s
204 	signature on Form FDA 1572 is a commitment to obtain IRB approval before initiating the trial.
205
206 	Form FDA 3674 Certification of Compliance, under 42 U.S.C. 282(j)(5)(B), with
207 	Requirements of ClinicalTrials.gov Data Bank (42 U.S.C. 282(j))
208
209 	The Food and Drug Administration Amendments Act of 2007 (FDAAA) was enacted on
210 	September 27, 2007. Title VIII of FDAAA added new section 402(j) to the Public Health
211 	Service Act (PHS Act) (42 U.S.C. 282(j)) and expanded the current National Institutes of Health
212 	(NIH) data bank known as ClinicalTrials.gov. FDAAA requires the responsible party, who
213 	could be the sponsor, or in certain instances, the principal investigator of particular clinical trials
214 	of human drugs, biological products, and devices (referred to in FDAAA as applicable clinical
215 	trials), to register the trials and to submit results information for inclusion in the
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216 	ClinicalTrials.gov data bank. Sponsor-investigators may be responsible for submitting certain
217 	clinical trial information to ClinicalTrials.gov.13
218
219 	One provision of FDAAA requires that certain human drug, biological product, and device
220 	applications and submissions to the FDA, including applications under section 505 of the Federal
221 	Food, Drug, and Cosmetic Act, be accompanied by a certification that all applicable
222 	requirements of section 402(j) of the PHS Act have been met (42 U.S.C. 282(j)(5)(B)). The
223 	FDA has concluded that the statutory requirement to submit a certification also applies to INDs
224 	and the submissions of new protocols to INDs.14 Where available, such certification must
225 	include the appropriate National Clinical Trial numbers issued by NIH at trial registration to
226 	ClinicalTrials.gov. Sponsor-investigators should use Form FDA 3674 to certify compliance with
227 	42 U.S.C. 282(j). When completing Form FDA 3674, sponsor-investigators should review 42
228 	U.S.C. 282(j) to determine whether the requirements of that subsection apply to any clinical
229 	trial(s) referenced in the IND.
230
231 	See the References section for Web sites where Forms FDA 1571, 1572, and 3674, as well as
232 	instructions for filling out the forms, can be found.
233
234 	B. 	Table of Contents (§ 312.23(a)(2))
235
236 	A sponsor-investigator is required to provide a table of contents and should provide pagination
237 	and tabbed breaks between sections to allow FDA reviewers to more easily navigate the
238 	submission.
239
240 	C. 	Introductory Statement and General Investigational Plan (§ 312.23(a)(3))
241
242 	The introductory statement must include the investigational drug’s name and all of its active
243 	ingredients, pharmacologic class, structural formula (if known), formulation of the dosage form
244 	to be used, the route of administration, and the broad objectives of the proposed clinical trial.
245 	There also must be a brief summary of previous human experience with the investigational drug
246 	including any investigational and marketing experience in other countries. For an investigational
247 	drug under commercial development, this information can be obtained from the commercial
248 	sponsor, and is most commonly submitted through a letter of cross-reference authorization to the
249 	commercial IND. For an FDA-approved prescription drug, the sponsor-investigator should be
250 	able to obtain all or most of this information from the drug’s FDA-approved labeling, but
251 	additional information may be needed if the sponsor-investigator is studying an unapproved use
252 	or dose of the drug.
253
254 	The general investigational plan must summarize the rationale supporting the proposed clinical
255 	trial (including the dose, schedule, and patient population), the indications to be investigated, the
13 See http://www.clinicaltrials.gov for additional information about responsibilities for trial registration and results
reporting.
14 See the guidance for sponsors, industry, researchers, investigators, and Food and Drug Administration staff
Certifications to Accompany Drug, Biological Product, and Device Applications/Submissions: Compliance With
Section 402(j) of The Public Health Service Act, Added By Title III of the Food and Drug Administration
Amendments Act of 2007.
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256 	general approach to evaluating the investigational drug, the planned trial duration, any trial plans
257 	for the following year (along with an estimated number of subjects to be given the
258 	investigational drug in the trial), and any risks of particular severity or seriousness anticipated on
259 	the basis of toxicology. When the IND is for a single trial, the information should be directed at
260 	supporting and describing that trial.
261
262 	D. 	Investigator’s Brochure (§§ 312.23(a)(5), 312.55)
263
264 	Although an investigator’s brochure is not required for sponsor-investigator investigations,15 a
265 	sponsor-investigator should obtain access to an investigator’s brochure when there is a
266 	concurrent or otherwise related commercial investigation for which an investigator’s brochure
267 	was developed. A sponsor-investigator should be aware of and understand the content in the
268 	commercial sponsor’s investigator’s brochure to the extent necessary to ensure subject safety and
269 	to facilitate identification of serious and unexpected suspected adverse reactions that may require
270 	expedited reporting to the FDA. The purpose of the investigator’s brochure is to make
271 	particularly vital information regarding the investigational drug available to the other
272 	investigators involved, who may be located at different geographic locations. If a commercial
273 	sponsor provides the sponsor-investigator with an investigator’s brochure, including it with the
274 	IND will be useful to both the sponsor-investigator and the FDA review team.
275
276 	E. 	Protocols (§ 312.23(a)(6))
277
278 	Sponsor-investigators must describe the trial to be conducted under the IND. IND regulations
279 	allow a protocol outline, rather than a complete protocol, to be submitted for phase 1 trials with
280 	the following information:16
281
282 	 	An estimate of the number of subjects involved.
283
284 	 	A description of safety exclusions (and of inclusion criteria).
285
286 	 	A description of the dosing plan including the duration, dose, dose escalation, schedule,
287 	or method to be used in determining dose.
288
289 	 	All of the details that describe those elements of the trial that are critical to safety, such as
290 	necessary monitoring of vital signs and blood chemistries. The protocol outline should
291 	also include dosing escalation rules and stopping criteria. For clinical investigations of
292 	cell and gene therapies, including xenogeneic cellular products, protocols may need to
293 	include procedures for long-term monitoring of subjects, in accordance with FDA and
294 	PHS regulations and PHS guidelines. Sponsor-investigators should contact the
295 	appropriate CBER reviewing division for consultation.
296
15 Note that, under § 312.55, before an investigation begins, a sponsor must give each participating clinical
investigator an investigator’s brochure.
16 For drugs that may carry significant risk of toxicity, or depending on the trial population, more complete protocols
for phase 1 trials may be needed. If uncertain, the investigator should contact the appropriate review division.
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297 	For phase 2 and phase 3 trials, detailed protocols describing all aspects of the trials should be
298 	submitted and must contain the following information:
299
300 	 	A statement of the objectives and purpose of the trial
301
302 	 	For a sponsor-investigator, the sponsor-investigator’s name, address, and statement of
303 	qualifications and the name of each subinvestigator (a trial team member such as a
304 	research fellow, resident) working under the direct supervision of the investigator; the
305 	name and address of the research facilities to be used; and the name and address of the
306 	reviewing IRB
307
308 	 	The criteria for subject selection (inclusion criteria), reasons for excluding subjects
309 	(exclusion criteria), and an estimate of the number of trial subjects
310
311 	 	A description of the trial design including the type of control group to be used, if any, and
312 	a description of methods to be used to minimize bias on the part of subjects, the sponsor-
313 	investigators, and analysts
314
315 	 	The method for determining the doses to be administered, the planned maximum dosage,
316 	and the duration of individual subject exposure to the investigational drug
317
318 	 	A description of the observations and measurements to be made to fulfill the trial
319 	objectives
320
321 	 	A description of the clinical procedures, laboratory tests, or other measures to be taken to
322 	monitor the effects of the investigational drug in human subjects and to minimize risk
323
324 	For phase 2 and phase 3 trials, the sponsor-investigator should include a description in the trial
325 	design of plans to deviate from the original trial design should this become necessary as the
326 	investigation progresses. For example, a protocol for a controlled short-term clinical trial might
327 	include a plan for an early crossover of nonresponders to an alternative therapy.
328
329 	Each protocol submitted must be reviewed and approved by the appropriate IRB before subjects
330 	can be enrolled.17 Informed consent forms frequently are included with protocols and we
331 	encourage their submission.18
332
17 Certain categories of clinical investigations are exempt from the requirements for IRB review in 21 CFR part 56:
(1) certain investigations that commenced before July 27, 1981; (2) emergency use of a test article provided that
such use is reported to the IRB within 5 working days; and (3) taste and food quality evaluations and consumer
acceptance studies, if certain conditions are met. See 21 CFR 56.104, Exemptions From IRB requirement.
18 For more information about informed consent, see 21 CFR part 50, subpart B. See also FDA information sheets
and guidances for industry regarding informed consent and IRB review at
http://www.fda.gov/RegulatoryInformation/Guidances/ucm126431.htm and
http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/GuidancesInformationSheetsandNotices/
default.htm, respectively.
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333 	F. 	Chemistry, Manufacturing, and Control Information (§ 312.23(a)(7))
334
335 	An IND must include sufficient CMC information to ensure the proper identity, strength, quality,
336 	and purity of the investigational drug. The amount of CMC information that should be provided
337 	will vary with the phase of the investigation, the proposed duration of the investigation, the
338 	dosage form, and the amount of information otherwise available.
339
340 	In all cases, the sponsor-investigator must include the following information in the IND:
341
342 	 	The label for the immediate packaging of the investigational drug, which must contain
343 	the statement “Caution: New Drug — Limited by Federal (or United States) law to
344 	investigational use” (§ 312.6(a))
345
346 	 	An environmental assessment under 21 CFR 25.40 or a statement requesting a categorical
347 	exclusion from an environmental assessment under provisions provided for in 21 CFR
348 	25.31(e) (§ 312.23(a)(7)(iv)(e))19
349
350 	The amount of CMC information that should be provided depends on the nature of the
351 	investigational drug and whether it has been lawfully marketed in the United States (or in a
352 	foreign country) or is the subject of a previously filed IND.
353
354 	If the investigational drug is not lawfully marketed in the United States, and there is either no
355 	existing IND to reference or an existing IND cannot be referenced, then complete CMC
356 	information on the investigational drug must be provided. The sponsor-investigator should
357 	consult applicable guidances for industry for information on preparing the CMC section,20 or
358 	contact the relevant review division.
359
360 	If the investigational drug is not lawfully marketed in the United States but is being investigated
361 	under an existing IND, then the sponsor-investigator can seek a letter of cross-reference
362 	authorization from the commercial sponsor of that IND to provide to the FDA (see section II.,
363 	Background). The letter of cross-reference authorization should specify the name, strength, and
364 	dosage form of the investigational drug being studied under the other IND(s).
365
366 	If the investigational drug is an FDA-approved prescription or nonprescription drug, the CMC
367 	information that should be provided by the sponsor-investigator depends on how the drug will be
368 	administered. If the investigational drug will be administered using the dosage form, strength,
369 	and route of administration described in its current labeling, the sponsor-investigator should
370 	include in the IND the current drug labeling and a statement indicating that the investigational
371 	drug will be administered using the dosage form, strength, and route of administration described
372 	in its current labeling. If any change to the labeled dosage form, strength, or route of
19 See the guidance for industry Environmental Assessment of Human Drug and Biologics Applications.
20 See the guidances for industry Content and Format of Investigational New Drug Applications (INDs) for Phase 1
Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived Products and INDs for Phase
2 and Phase 3 Studies: Chemistry, Manufacturing, and Controls Information.
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373 	administration is planned, then the sponsor-investigator should provide relevant information such
374 	as release and stability data to support the proposed usage.
375
376 	If the investigational drug is not lawfully marketed in the United States, but is approved and
377 	marketed in a foreign country, or if the investigational drug is marketed, but not as a drug (e.g.,
378 	marketed as a food, including a dietary supplement), then complete CMC information on the
379 	investigational drug should be provided if it is available. However, the FDA recognizes that in
380 	many such cases the sponsor-investigator will not be able to obtain all of the CMC information
381 	required by 21 CFR 312.23(a)(7). In these circumstances, the sponsor-investigator can request
382 	that the FDA waive the requirement for complete CMC information on the investigational drug
383 	(21 CFR 312.10). The IND must include, as part of the waiver request:
384
385 	 	A sufficient explanation why compliance with the complete requirements of 21 CFR
386 	312.23(a)(7) is unnecessary or cannot be achieved;
387
388 	 	Information that will satisfy the purpose of the requirement by helping to ensure that the
389 	investigational drug will have the proper identity, strength, quality, and purity; or
390
391 	 	Other information justifying a waiver.
392
393 	Information that is relevant to whether the investigational drug will have the proper identity,
394 	strength, quality, and purity may include, for example, information indicating whether the
395 	investigational drug has been licensed by a regulatory authority that has similar scientific and
396 	regulatory standards as the FDA (e.g., International Conference on Harmonisation (ICH)
397 	countries). This should include, to the extent possible, summary approval information and
398 	current product labeling made public by the foreign regulatory authority.
399
400 	In addition to the waiver request, the sponsor-investigator should include in the IND as much of
401 	the CMC information required by 21 CFR 312.23(a)(7) as is available. This should include, at a
402 	minimum, the following:
403
404 	 	The name of the manufacturer or supplier of the investigational drug.
405
406 	 	An English version of the investigational drug’s labeling, including the package insert.
407
408 	 	Information on the conditions and containers that will be used to transport the drug
409 	product to the U.S. clinical site(s) and information on the relabeling and repackaging
410 	operations that will be used to relabel the drug product vials for investigational use. This
411 	should include information on how exposure of the drug product to light and temperature
412 	conditions outside of the recommended storage conditions will be prevented. A risk
413 	assessment on the affect the relabeling operations may have on drug product stability
414 	should also be included.
415
416 	The sponsor-investigator should also provide, if available, the following:
417
418 	 	The components and composition of the investigational new drug.
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419
420 	 	Drug product specification and/or Certificate(s) of Analysis (COA(s)) for the specified
421 	lot(s) of investigational drug to be used in the clinical trial. (If the specific batch numbers
422 	and COAs are not available at the time of IND submission, they should be submitted to
423 	the IND if they do become available.)
424
425 	The sponsor-investigator should consult with the appropriate FDA review division regarding any
426 	additional CMC information that might be warranted to support the proposed clinical trial.
427
428 	For botanical drugs, as defined in the guidance for industry Botanical Drug Products, the
429 	sponsor-investigator should refer to the guidance and consult with the FDA for special
430 	considerations in requirements of CMC information. For botanical products that are marketed as
431 	foods (including dietary supplements), the sponsor-investigator should obtain such information
432 	from the manufacturer and provide it in the IND. If information from the manufacturer cannot
433 	be obtained, the FDA may consider the specific circumstance (e.g., drug history and clinical
434 	settings) and determine the CMC requirements for each individual case.
435
436 	G. 	Pharmacology and Toxicology Information (§ 312.23(a)(8))
437
438 	The sponsor-investigator must provide adequate information about the pharmacological and
439 	toxicological studies of the investigational drug involving lab animals or in vitro to support the
440 	sponsor-investigator’s conclusion that it is reasonably safe to conduct the proposed clinical trial.
441 	The sponsor-investigator should include a discussion of the rationale for the investigational
442 	drug’s intended dose, duration, schedule, and route of administration in the proposed trial. This
443 	rationale, particularly for phase 1 trials, is best supported by in vitro and available animal data, as
444 	described in the guidance for industry Content and Format of Investigational New Drug
445 	Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic,
446 	Biotechnology-Derived Products.
447
448 	If an FDA-approved drug will be used at the same dose, duration, and route of administration as
449 	described in its current labeling, then the sponsor-investigator should include a statement to this
450 	effect and include a copy of the current label.
451
452 	If the drug has not been approved by the FDA, but is being studied under a cross-referenced
453 	IND, then the sponsor-investigator should provide a letter of cross-reference authorization to
454 	cross-reference the drug’s pharmacology and toxicology data.
455
456 	If the drug is not approved by the FDA but is approved and marketed in a country listed in
457 	section 802(b)(1)(A) of the Federal Food, Drug, and Cosmetic Act or is marketed as a food (such
458 	as a dietary supplement), additional toxicological information is dependant on the trial
459 	(population, dose, duration), the extent of foreign use, current labeling, published information,
460 	and any information available from foreign regulatory authorities. The sponsor-investigator
461 	should provide any appropriate documentation and/or a summary of this information.
462
463 	For trials that involve doses, durations, or changes in the routes of administration (e.g.,
464 	intravenous to oral) that have not been tested or for which inadequate safety information exists,
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465 	the sponsor-investigator should consult with the review division as to the appropriate toxicology
466 	studies necessary to support the proposed use.
467
468 	A justification for the use of any drug combinations to be studied should be provided in the IND.
469 	The factors to consider are possible pharmacokinetic or toxicological interactions that may affect
470 	the combination’s safety profile. If interactions are expected, then some consideration should be
471 	given to dose reduction of either one or more of the compounds in the investigational
472 	combination. For additional discussion of this topic, see the guidance for industry Nonclinical
473 	Safety Evaluation of Drug or Biologic Combinations.
474
475 	Additional nonclinical studies may be needed for studies in pediatric patients where inadequate
476 	data exist to support the safety of either an FDA-approved or unapproved drug in that patient
477 	population. For additional discussion of this topic, see the guidance for industry Nonclinical
478 	Safety Evaluation of Pediatric Drug Products.
479
480 	H. 	Previous Human Experience With the Investigational Drug (§ 312.23(a)(9))
481
482 	If there has been previous human experience with the investigational drug, the sponsor-
483 	investigator is required to provide a summary of this information. As noted previously, it may be
484 	necessary for the commercial sponsor to give permission via a letter of cross-reference
485 	authorization to cross-reference all INDs in which the investigational drug is being studied.
486
487 	If the investigational drug has been investigated or marketed previously, either in the United
488 	States or other countries, detailed information relevant to the safety of the proposed trial or the
489 	trial’s rationale must be provided.
490
491 	Any published material relevant to the safety of the proposed trial or to an assessment of the
492 	drug’s effectiveness for its proposed investigational use should be provided. A reference list and
493 	copies of significant supportive published literature related to previous human experience with
494 	the investigational drug should be included in the submission. Although a reference list and
495 	copies of published literature are useful, a consolidated assessment of the available information
496 	and how it applies to the current investigation would help to justify the sponsor-investigator’s
497 	proposed dose, duration, drug combination, populations, and other trial information.
498
499 	The sponsor-investigator should contact the review division if he or she has specific questions,
500 	especially if the drug or drug combination has not been investigated previously.
501
502 	I. 	Other Important Information (§ 312.23(a)(10)(i) – (iii))
503
504 	In certain circumstances, a sponsor-investigator may be required to provide other types of
505 	important information on special topics as noted below, especially if the investigational drug is
506 	not approved.
507
508 	 	Drug dependence and abuse potential — If the investigational drug is a psychotropic
509 	substance or otherwise has abuse potential, then information describing related clinical
510 	trials and experience as well as any appropriate animal data must be submitted.
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511
512 	 	Radioactive drugs — Sufficient data from animal studies or human clinical trials must
513 	be submitted to allow a reasonable calculation of radiation-absorbed dose to the whole
514 	body and critical organs upon administration to human subjects. Phase 1 trials of
515 	radioactive drugs must include trials that will obtain sufficient data for dosimetry
516 	calculations.
517
518 	J. 	Relevant Information (§ 312.23(a)(11))
519
520 	If a device is to be used in conjunction with the investigational drug (e.g., a nebulizer for an
521 	inhaled drug or a pump for continuous infusion for home use), the FDA may require under 21
522 	CFR 312.23(a)(11) other relevant information on the manufacturer and model of the device to be
523 	employed and a general description of relevant conditions of use (e.g., carrier gas, flow rate,
524 	temperature), and whether the device is FDA-approved or cleared for its intended use in the trial.
525 	If the sponsor-investigator intends to use the device other than for its cleared or approved
526 	intended use and/or indication, he or she should contact the review division in CDER or CBER
527 	and then the Center for Devices and Radiological Health, or alternatively, the Office of
528 	Combination Products.
529
530
531 	V. 	SUBMISSION INFORMATION (§ 312.22(D))
532
533 	After all the needed information has been acquired, the IND is ready for submission to the FDA.
534 	Even though the FDA is moving toward requiring electronic submission of an IND in the
535 	electronic common technical document format, paper submissions are acceptable. Sponsor-
536 	investigators who wish to submit INDs electronically to CDER can submit the documents in
537 	portable document format and any data in statistical analysis system transport files either by
538 	email to the review division project manager or on a CD accompanying the paper copies.
539 	Sponsor-investigators who wish to submit INDs electronically to CBER should refer to the
540 	guidance for industry Providing Regulatory Submissions to CBER in Electronic Format —
541 	Investigational New Drug Applications (INDs) and/or should contact the appropriate review
542 	division in CBER to determine the procedures for submitting INDs to CBER in electronic
543 	format.
544
545 	Paper submissions of the initial IND and each subsequent amendment must be provided in
546 	triplicate (the original and two photocopies are acceptable). Each submission related to an IND
547 	is required to be numbered serially using a single, three-digit serial number. The initial IND
548 	should be numbered “000”; each subsequent submission (e.g., amendment, report, or
549 	correspondence) is required to be numbered chronologically in sequence.
550
551 	For INDs reviewed in CDER, there are two different mailing addresses depending on whether
552 	the IND submission is related to: (1) therapeutic biological products, which include monoclonal
553 	antibodies, proteins intended for therapeutic use (e.g., cytokines, interferons, enzymes), and
554 	immunomodulators; or (2) not related to therapeutic biological products (i.e., for a drug)
14

21 For the relevant mailing addresses, see
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplicati
ons/InvestigationalNewDrugINDApplication/ucm071098.htm.
22 See
http://www.fda.gov/BiologicsBloodVaccines/DevelopmentApprovalProcess/InvestigationalNewDrugINDorDeviceE
xemptionIDEProcess/ucm094309.htm.
Contains Nonbinding Recommendations
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555 	regardless of delivery method (e.g., overnight mail and courier or U.S. Postal Service).21 For
556 	INDs reviewed in CBER, refer to the Information on Submitting an Investigational New Drug
557 	Application Web site for the mailing address.22
558
559
560 	VI. 	THE IND PROCESS AND REVIEW PROCEDURES (§§ 312.30, 312.31, 312.40 –
561 	312.42, 312.110)
562
563 	After the FDA receives the IND, an IND Acknowledgement Letter will be sent to the sponsor-
564 	investigator. The letter includes important information such as the assigned review division,
565 	IND number, division contact, and the official FDA date of receipt. The latter is important
566 	because by regulation the proposed trial may not be initiated until 30 calendar days after official
567 	FDA receipt. This time period allows the division’s multidisciplinary review team, comprised of
568 	clinical reviewers, chemists, toxicologists, clinical pharmacologists, and project managers (along
569 	with a microbiologist and/or statistician depending on the indication and development phase), to
570 	review the proposed clinical trial materials. This review generally includes, for example, the
571 	proposed investigational drug’s formulation, toxicity, nonclinical pharmacology and toxicology,
572 	and any previous human experience information provided. In addition, many teams also may
573 	consider other proprietary studies and clinical trials in similar drugs and may perform literature
574 	searches.
575
576 	By the end of this 30-day review period, if the division makes the determination that it is safe to
577 	proceed with the clinical trial, the FDA may (e.g., to convey any comments regarding the
578 	submission) or may not contact the sponsor-investigator about its determination. Unless notified
579 	by the FDA within 30 days that a clinical hold has been placed, the trial can proceed as long as
580 	IRB approval has been obtained. If the division makes the determination within the 30-day
581 	review period that the trial should be placed on clinical hold, the FDA will notify the sponsor-
582 	investigator as soon as possible after making that determination (usually by telephone) to not
583 	initiate the trial. Likewise, the sponsor-investigator will be notified promptly if the FDA makes
584 	the determination that a trial that has been initiated needs to be suspended, as further described in
585 	Figure 1, The IND Review Process, and section VI.A., Clinical Holds and Requests for
586 	Modifications.
587
15

Sponsor-investigator
submits initial IND to
the FDA
Sponsor-
investigator
submits
response to
address the
FDA’s
concerns
30-day multidisciplinary review by
clinical, chemistry,
pharmacology/toxicology, and
statistical reviewers, and other
consultants
Safe to
The FDA notifies
sponsor-investigator of
concerns (usually by
telephone)
Sponsor-
investigator
may not
initiate trial
Yes
proceed?
No
Drug may
be shipped
Sponsor-
investigator
may initiate
trial
Clinical hold
letter sent to
sponsor-
investigator
including the
basis for the
hold
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588 	Figure 1: The IND Review Process
589
590
591
592 	A. 	Clinical Holds and Requests for Modifications (§ 312.42)
593
594 	The FDA may place a proposed or ongoing trial on clinical hold if the FDA makes certain
595 	findings, including that:
596
597 	 	Human subjects are or would be exposed to an unreasonable and significant risk of illness
598 	or injury
599
600 	 	The sponsor-investigator is not qualified, by reason of his or her scientific training and
601 	expertise to conduct the trial
602
603 	 	The investigator’s brochure is misleading, erroneous, or incomplete (where applicable)
604
605 	 	The IND contains insufficient information for the FDA to assess the risks to subjects of
606 	the proposed trial
607
608 	 	The IND is for the study of a drug intended to treat certain diseases or conditions and
609 	limits the eligibility of prospective subjects because of the risk or potential risk of
610 	reproductive toxicity
611
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612 	 	For phase 2 or 3 trials, the plan or protocol for the investigation is clearly deficient in
613 	design to meet its stated objectives
614
615 	Under certain circumstances, the FDA may also place on clinical hold a proposed or ongoing
616 	trial that is not designed to be adequate and well-controlled, or if the criteria for a trial involving
617 	an exception from informed consent, as described in 21 CFR 50.24,23 are not met.
618
619 	Sponsor-investigators should familiarize themselves with the clinical hold provisions in the
620 	regulations to avoid this potential outcome.
621
622 	Whenever the FDA concludes that a deficiency exists in a clinical investigation that may be
623 	grounds for imposing a clinical hold, the FDA will, unless subjects are exposed to immediate and
624 	serious risk, attempt to discuss and satisfactorily resolve the matter with the sponsor-investigator
625 	before issuing the clinical hold order.
626
627 	The FDA will contact the sponsor-investigator to impose a clinical hold, usually by telephone, on
628 	or before day 30 after the submission of the IND; however, the FDA may place the trial on
629 	clinical hold after the 30-day period if the FDA finds the criteria for imposing a clinical hold are
630 	met. The FDA will, as soon as possible, and within no more than 30 days of imposition of the
631 	clinical hold, send a letter to the sponsor-investigator that provides the sponsor-investigator a
632 	written explanation of the basis for the hold. The letter may also describe the specific issues and
633 	deficiencies that led to the hold, what the sponsor-investigator must do for the FDA to remove
634 	the clinical hold, and other pertinent comments.
635
636 	The clinical hold means that the sponsor-investigator may not initiate or continue (if the trial has
637 	already begun but new safety concerns have been identified) the trial or trials subject to this
638 	action, and the clinical hold remains in force until the sponsor-investigator adequately addresses
639 	the deficiencies that led to the clinical hold, or otherwise satisfies the FDA that the trial or trials
640 	can proceed, and is told by the FDA that the clinical hold has been lifted. The sponsor-
641 	investigator should address these deficiencies in writing to the division with any requested data.
642 	If a sponsor-investigator of an IND that has been placed on clinical hold requests in writing that
643 	the clinical hold be removed and submits a complete response to the issues identified in the
644 	clinical hold letter, the FDA will respond in writing to the sponsor-investigator within 30
645 	calendar days of receipt of the complete response. The FDA’s response will remove, maintain,
646 	or modify the clinical hold, and the letter will state the reasons for such determination.
647
648 	Notwithstanding the 30-calendar-day response time, a sponsor-investigator may not proceed with
649 	a clinical trial on which a clinical hold has been imposed until the sponsor-investigator has been
650 	notified by the FDA that the hold has been lifted.
651
23 Note that, if an investigation involves an exception from informed consent under 21 CFR § 50.24, the sponsor-
investigator must prominently identify on Form 1571 that the investigation is subject to the requirements in § 50.24
(21 CFR 312.23(f)).
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652 	B. 	IND Amendments (§§ 312.30, 312.31)
653
654 	After the initial IND is submitted and is in effect, a sponsor-investigator must make changes to
655 	the IND as needed to ensure that the clinical investigations are conducted according to protocols
656 	included in the application. Sponsor-investigators also need to provide essential information on
657 	the IND that is not within the scope of any protocol amendment, IND safety report, or annual
658 	report. All these written communications to the FDA are called amendments to the IND. The
659 	division will review these amendments as they are received.
660
661 	It is important to identify in the amendment whether a reply from the FDA is expected. If the
662 	sponsor-investigator wants the FDA to comment on the submission, the amendment must include
663 	a request for an FDA reply (e.g., a specific request to review new information and respond by a
664 	certain proposed date), which can be included in a cover letter of an amendment. In addition to
665 	including this request in the amendment, the sponsor-investigator can also contact the review
666 	division directly (e.g., for an informal discussion or to request a teleconference).
667
668 	In contrast to the initial IND submission, if the IND is not on clinical hold, the sponsor-
669 	investigator may implement changes to the IND immediately after sending the amendment to the
670 	FDA, without waiting 30 days (though new protocols and protocol changes to ongoing trials still
671 	require prior approval by an IRB unless the change to the protocol is necessary to eliminate
672 	apparent immediate hazards to human subjects). Note that the FDA reserves the right to suspend
673 	an ongoing trial (by placing it on clinical hold, as noted in section VI.A., Clinical Holds and
674 	Requests for Modifications) at any time a suspension is warranted.
675
676 	In some situations, it may be unclear whether a change to an existing protocol or a new protocol
677 	should be communicated as an amendment to an existing IND or under a new IND, or if a new
678 	30-day review period at the FDA is warranted. In such situations, the sponsor-investigator
679 	should seek case-by-case guidance from the relevant CDER or CBER review division to
680 	minimize the chance of an unexpected clinical hold.
681
682 	C. 	Import and Export Requirements (§ 312.110)
683
684 	Sponsors importing an investigational new drug under an IND must comply with 21 CFR
685 	312.110(a). An investigational new drug offered for import into the United States complies with
686 	the requirements of this part if it is subject to an IND that is in effect for it under § 312.40 and:
687 	(1) the consignee in the United States is the sponsor of the IND; (2) the consignee is a qualified
688 	investigator named in the IND; or (3) the consignee is the domestic agent of a foreign sponsor, is
689 	responsible for the control and distribution of the investigational drug, and the IND identifies the
690 	consignee and describes what, if any, actions the consignee will take with respect to the
691 	investigational drug. For details on export requirements, see § 312.110(b).
692
693
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694 	VII. 	OTHER SPONSOR-INVESTIGATOR RESPONSIBILITIES
695
696 	Sponsor-investigators conducting trials under an IND must comply with both the sponsor and
697 	investigator responsibilities specified in 21 CFR parts 312, 50, and 56. 24 Sponsor-investigators
698 	should read these regulations in their entirety and become familiar with all of their
699 	responsibilities. Some but not all of the responsibilities discussed in these regulations are
700 	summarized below with references to more comprehensive discussions.
701
702 	A. 	Good Clinical Practice, Including Human Subject Protection and IRB
703 	Review and Approval (§ 312.40, 21 CFR Parts 50 and 56)
704
705 	In general, the sponsor-investigator should conduct trials according to good clinical practice
706 	(GCP). GCP is an international ethical and scientific quality standard for designing, conducting,
707 	recording, and reporting trials that involve the participation of human subjects.25 GCP includes
708 	human subject protection as afforded by adherence to requirements for review and approval of
709 	the trial by an IRB and requirements to obtain informed consent from each clinical trial subject
710 	(see General Information in the References section for a Web site that contains a summary of
711 	these standards). Sponsor-investigators must conduct trials in compliance with FDA regulations
712 	about the protection of human subjects26 and about IRB review and approval of studies.27
713
714 	B. 	Monitoring Ongoing Investigations (§ 312.50)
715
716 	Sponsor-investigators are responsible for ensuring proper monitoring of the investigation. We
717 	recommend that sponsor-investigators submit a brief summary to the IND to demonstrate that
718 	there is adequate monitoring of the clinical investigation to demonstrate the trial(s) are conducted
719 	in accordance with regulatory requirements, GCPs, and the protocol; that the rights and well-
720 	being of human subjects are protected; that data reporting, including safety reporting to the
721 	sponsor-investigator and the IRB, is accurate and complete; and that the sponsor-investigator has
722 	adequate oversight over the clinical investigation, as outlined in 21 CFR part 312, subpart D.28
723
24 As noted above, a person who both initiates and conducts an investigation, and uses an investigator or
investigators to conduct the investigation, is not a sponsor-investigator, but must also comply with both sponsor and
investigator responsibilities. Because the purpose of this guidance is to assist sponsor-investigators, who are single
individuals, it does not focus on certain regulatory requirements that involve the exchange of information or
materials between a sponsor and investigator (e.g., sponsors’ responsibilities to select qualified investigators,
provide them with the information they need to conduct an investigation properly, and ensure proper monitoring of
the investigation). For additional information about the preparation and submission of INDs, sponsors should refer
to available FDA regulations and guidances, including the references listed at the end of this guidance.
25 See the ICH guidance for industry E6 Good Clinical Practice: Consolidated Guidance.
26 See 21 CFR part 50, Protection of Human Subjects.
27 See 21 CFR part 56, Institutional Review Boards.
28 For additional information regarding responsibilities of sponsor-investigators in clinical trials (including
monitoring), see the ICH document on GCPs at http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/good-clinical-practice.html.
19

Contains Nonbinding Recommendations
Draft — Not for Implementation
724 	C. 	Promotion of or Charging for Investigational Drug (§§ 312.7, 312.8)29
725
726 	Promoting the investigational drug is not permitted. Charging for the investigational drug is only
727 	permitted in rare circumstances, and then only with prior written approval by the FDA.
728
729 	D. 	Records and Reports (§§ 312.57, 312.58, 312.62, 312.68)
730
731 	A sponsor-investigator must maintain adequate and accurate case histories. Case histories
732 	include case report forms (CRFs) and supporting data, including, for example, signed and dated
733 	informed consent forms, and any medical or clinical trial records that serve as source documents
734 	to support the information recorded on the CRFs. A sponsor-investigator must also maintain
735 	adequate records showing the receipt, shipment, or other disposition of the investigational drug.
736 	Records of drug disposition must include the dates of administration, quantity, and use by
737 	subjects.
738
739 	The FDA may periodically inspect trial sites to ensure that a sponsor-investigator is properly
740 	capturing and storing this critical data. Failure to adhere to the investigational plan and
741 	inadequate records (particularly, subject case histories) are among the most frequently cited GCP
742 	deficiencies at FDA inspections. Sponsor-investigators are required to retain records and reports
743 	for 2 years after a marketing application is approved for a drug or, if an application is not
744 	approved for the drug, until 2 years after shipment and delivery of the drug for investigational
745 	use is discontinued and the FDA has been notified (21 CFR 312.57(c)).
746
747 	E. 	IND Safety Reports (§ 312.32)
748
749 	A sponsor-investigator is responsible for promptly reviewing all information relevant to the
750 	safety of the investigational drug and notifying the FDA of any unexpected fatal or life-
751 	threatening suspected adverse reaction as soon as possible, but no later than 7 calendar days after
752 	receipt of the information. The sponsor-investigator must also notify the FDA (and sponsors
753 	must notify all participating investigators) in an IND safety report of potential serious risks, from
754 	clinical trials or any other source, as soon as possible, but in no case later than 15 calendar days
755 	after the sponsor determines that the information qualifies for reporting under § 312.32(c)(1)(i)-
756 	(iv).
757
758 	The IND safety reports can be submitted using Form FDA 3500A or in a narrative format, but
759 	must be marked as “IND Safety Report” (see the References section for the Web site where
760 	Form FDA 3500A can be found). Additional information may be requested by the review
761 	division.
762
763 	If other IND safety reports have been previously submitted concerning a similar suspected
764 	adverse reaction, then the sponsor-investigator must identify these reports and analyze the
765 	significance of this event in light of the previous, similar reports or any other relevant
766 	information.
767
29 See the draft guidance for industry Charging for Investigational Drugs Under an IND — Qs & As. When final,
this guidance will represent the FDA’s current thinking on this topic.
20

Contains Nonbinding Recommendations
Draft — Not for Implementation
768 	For more information about safety reporting requirements for INDs, and for information about
769 	sponsor-investigator obligations to follow up on safety information, see the guidance for industry
770 	and investigators Safety Reporting Requirements for INDs and BA/BE Studies.
771
772 	A sponsor-investigator is also responsible for promptly notifying the IRB of all unanticipated
773 	problems involving risk to human subjects or others (see § 312.66).
774
775 	F. 	IND Annual Reports (§ 312.33)
776
777 	Within 60 days of the anniversary date that an IND went into effect, a sponsor-investigator must
778 	submit a brief annual report of the progress of the trial. The annual report is intended to update
779 	the review division as to all relevant developments over the preceding year. This annual report
780 	must contain certain information, including, but not limited to, the following:
781
782 	 	Individual trial progress (i.e., enrollment, dropouts) with results, if the trial has been
783 	completed or if interim results are known
784
785 	 	A narrative or tabular summary showing the most frequent and most serious adverse
786 	events by body system
787
788 	 	A summary of all IND safety reports submitted during the previous year
789
790 	 	A list of subjects who dropped out because of adverse events and a description of the
791 	adverse events
792
793 	 	New information regarding the investigational drug’s actions (e.g., dose response),
794 	completed nonclinical studies, and any CMC changes, if available
795
796 	 	A general investigational plan for the coming year, significant foreign marketing
797 	developments
798
799 	If a trial is completed, the final report should be submitted to the FDA, as should a list of any
800 	publications that result from the clinical trial. In addition to the submissions to the FDA, the
801 	sponsor-investigator should consider any responsibilities under Title VIII of FDAAA related to
802 	submission of data for applicable clinical trials to the NIH ClinicalTrials.gov data bank.30
803 	Responsible parties have a statutory obligation to update clinical trial registration information on
804 	ClinicalTrials.gov (42 U.S.C. 282(j)(4)(C)). In addition, for certain applicable clinical trials that
805 	have been completed, summary trial results must be submitted (42 U.S.C. 282(j)(3)).
806
807
30 See note 13, supra.
21

Contains Nonbinding Recommendations
Draft — Not for Implementation
808 	VIII. 	WITHDRAWING, TERMINATING, INACTIVATING, OR REACTIVATING AN
809 	IND (§§ 312.38, 312.44, 312.45)
810
811 	In general, a sponsor-investigator may withdraw an IND at any time (e.g., after the trial has been
812 	completed) by notifying the review division. If an IND is withdrawn, all clinical trials conducted
813 	under the IND must be ended. If the sponsor-investigator is withdrawing the IND for safety
814 	reasons, the FDA and the IRB must be promptly informed.
815
816 	Under certain circumstances, the FDA may terminate an IND. If an IND is terminated, the
817 	sponsor-investigator must end all clinical investigations conducted under the IND, notify the
818 	IRB,31 and recall or otherwise provide for the disposition of all unused supplies of the drug. A
819 	termination action may be based on deficiencies in the IND or in the conduct of an investigation
820 	under an IND. In general, the FDA will only initiate an action to terminate an IND under
821 	§ 312.44 after first attempting to resolve differences informally or, when appropriate, through the
822 	clinical hold procedures described earlier in this guidance.
823
824 	A sponsor-investigator can request that an IND be placed on inactive status if no subjects are
825 	entered into clinical trials for a period of 2 years or more under an IND, or if all investigations
826 	under an IND remain on clinical hold for 1 year or more. The inactive status of an IND has the
827 	benefit of relieving the sponsor-investigator from the obligation of submitting annual reports to
828 	the FDA.
829
830 	In contrast to a withdrawal, the sponsor-investigator can seek to reactivate the inactive IND by
831 	submitting a request to reactivate the inactive IND including a protocol amendment containing
832 	the proposed general investigational plan for the coming year and appropriate protocols with IRB
833 	approval.32 If the protocol amendment relies on information previously submitted, the plan
834 	should reference such information. Additional information supporting the proposed
835 	investigation, if any, should be submitted in an information amendment. The submitted
836 	information will be subject to a new 30-day safety review as described in section VI., The IND
837 	Process and Review Procedures. A trial under an IND on inactive status can only proceed 30
838 	days after the FDA receives the protocol amendment, unless the FDA notifies the sponsor-
839 	investigator that the investigation described in the amendment is subject to a clinical hold, or on
840 	earlier notification by the FDA that the clinical investigations described in the protocol
841 	amendment may begin.
842
843
31 See 21 CFR 312.66.
32 See 21 CFR 312.66.
22

Contains Nonbinding Recommendations
Draft — Not for Implementation
844 	REFERENCES
845
846 	Contact Information
847
848 	Contact the FDA: http://www.fda.gov/AboutFDA/ContactFDA/default.htm
849
850 	CDER Ombudsman contact information:
851 	http://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/contactcder
852 	/cderombudsman/default.htm
853
854 	CDER and OND organizational charts:
855 	http://www.fda.gov/AboutFDA/CentersOffices/OrganizationCharts/ucm347877.htm
856
857 	OND contact information:
858 	http://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/ucm18442
859 	6.htm
860
861 	CBER Ombudsman contact information:
862 	http://www.fda.gov/aboutfda/centersoffices/oc/officeofscientificandmedicalprograms/ucm20056
863 	12.htm
864
865 	CBER organizational chart and contact information:
866 	http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CBER/def
867 	ault.htm
868
869 	Office of Combination Products:
870 	http://www.fda.gov/CombinationProducts/default.htm
871
872 	CDRH:
873 	http://www.fda.gov/MedicalDevices/default.htm
874
875 	General Information
876
877 	The IND process and useful links:
878 	http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/
879 	ApprovalApplications/InvestigationalNewDrugINDApplication/default.htm
880
881 	FDA-approved drugs listed in The Orange Book: Approved Drug Products With Therapeutic
882 	Equivalence Evaluations: http://www.fda.gov/Drugs/InformationOnDrugs/ucm129662.htm
883
884 	Forms 1571, 1572, 3674, and 3500A
885 	http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/default.htm
886
887 	Good clinical practice standards related to FDA-regulated clinical trials:
888 	http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/default.htm
889
23

Contains Nonbinding Recommendations
Draft — Not for Implementation
890 	Guidances for Industry33
891
892 	Draft guidance for industry Charging for Investigational Drugs Under an IND — Qs & As34
893
894 	Draft guidance for industry Expanded Access to Investigational Drugs for Treatment Use — Qs
895 	& As35
896
897 	Guidance for clinical investigators, sponsors, and IRBs Investigational New Drug Applications
898 	(INDs) — Determining Whether Human Research Studies Can Be Conducted Without an IND
899
900 	Guidance for FDA reviewers and sponsors Content and Review of Chemistry, Manufacturing,
901 	and Control (CMC) Information for Human Gene Therapy Investigational New Drug
902 	Applications (INDs)
903
904 	Guidance for FDA reviewers and sponsors Content and Review of Chemistry, Manufacturing,
905 	and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug
906 	Applications (INDs)
907
908 	Guidance for industry Botanical Drug Products
909
910 	Guidance for industry Content and Format of Investigational New Drug Applications (INDs) for
911 	Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived
912 	Products
913
914 	Guidance for industry Environmental Assessment of Human Drug and Biologics Applications
915
916 	Guidance for industry IND Exemptions for Studies of Lawfully Marketed Drug or Biological
917 	Products for the Treatment of Cancer
918
919 	Guidance for industry INDs for Phase 2 and Phase 3 Studies: Chemistry, Manufacturing, and
920 	Controls Information
921
922 	Guidance for industry Investigator Responsibilities — Protecting the Rights, Safety, and Welfare
923 	of Study Subjects
924
925 	Guidance for industry Nonclinical Safety Evaluation of Drug or Biologic Combinations
926
927 	Guidance for industry Nonclinical Safety Evaluation of Pediatric Drug Products
928
24
33 These guidances can be found on the FDA Drugs guidance Web page at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
34 When final, this guidance will represent the FDA’s current thinking on this topic.
35 When final, this guidance will represent the FDA’s current thinking on this topic.

Contains Nonbinding Recommendations
Draft — Not for Implementation
929 	Guidance for industry Providing Regulatory Submissions to CBER in Electronic Format —
930 	Investigational New Drug Applications (INDs)
931
932 	Guidance for industry and investigators Safety Reporting Requirements for INDs and BA/BE
933 	Studies
934
935 	Guidance for sponsors, industry, researchers, investigators, and Food and Drug Administration
936 	staff Certifications to Accompany Drug, Biological Product, and Device
937 	Applications/Submissions: Compliance with Section 402(j) of The Public Health Service Act,
938 	Added By Title VIII of The Food and Drug Administration Amendments Act of 2007
939
940 	ICH guidance for industry E6 Good Clinical Practice: Consolidated Guidance
941
942 	ICH guidance for industry E11 Clinical Investigation of Medicinal Products in the Pediatric
943 	Population
944
25