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DRAFT GUIDANCE
 
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 

 
 
 
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Center for Drug Evaluation  and Research 

Food and  Drug Administration 
 
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http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 

or 
 
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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. 	  Investigators 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 
Investigational New Drug Applications Prepared and  
1 
Submitted by Sponsor-Investigators 
2 
1 
Guidance for Industry  
3 
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-investigators 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
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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, FDAs guidance documents do not establish legally enforceable responsibilities.  
51  Instead, guidances describe the Agencys 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 FDAs 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 drugs effectiveness and safety.   
64   
                                                 
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 FDAs 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.   
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  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     Investigators 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. 
  3
  Contains Nonbinding Recommendations 
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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 sponsors 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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  Contains Nonbinding Recommendations 
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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 sponsors 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 sponsors 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 sponsors current 
142  investigators 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 sponsors investigators 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 CDERs and ONDs 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 CBERs 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 CDERs 
162  Division of Drug Information or CBERs Division of Manufacturers 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-investigators 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-investigators 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-investigators 
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 drugs 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 drugs 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.  Investigators Brochure ( 312.23(a)(5), 312.55) 
263   
264  Although an investigators brochure is not required for sponsor-investigator investigations,15 a 
265  sponsor-investigator should obtain access to an investigators brochure when there is a 
266  concurrent or otherwise related commercial investigation for which an investigators brochure 
267  was developed. A sponsor-investigator should be aware of and understand the content in the 
268  commercial sponsors investigators 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 investigators 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 investigators 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 investigators 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-investigators 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 drugs 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-investigators 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  drugs 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 drugs 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 combinations 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  trials rationale must be provided.   
490   
491  Any published material relevant to the safety of the proposed trial or to an assessment of the 
492  drugs 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-investigators 
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) 
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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 divisions 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 drugs 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   
                                                 
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.   
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588  Figure 1: The IND Review Process 
589   
Sponsor-investigator 
submits initial IND to 
the FDA 
30-day multidisciplinary review by  
clinical, chemistry, 
pharmacology/toxicology, and 
Sponsor-
statistical reviewers, and other 
investigator 
consultants 
submits 
response to 
address the 
FDAs 
Safe to  Yes 
concerns  
proceed? 
No  
Sponsor-
Drug may  
investigator 
Clinical hold  be shipped  
may  not 
letter sent to 
sponsor- initiate trial  
investigator 
including the 
basis for the  The FDA notifies  Sponsor-
hold  sponsor-investigator of  investigator 
concerns (usually by   may initiate 
telephone)   trial 
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 investigators 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 FDAs 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. 
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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 FDAs current thinking on this topic. 
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  Contains Nonbinding Recommendations 
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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 drugs 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. 
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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. 
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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   
                                                 
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 FDAs current  thinking on this topic. 
 
35  When final, this guidance will represent the FDAs current  thinking on this topic. 
  24
  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