Guidance for Industry and 
FDA Staff 
FDA Acceptance of Foreign Clinical 
Studies Not Conducted Under an IND   
Frequently Asked Questions 
 
  
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research  
Center for Biologics Evaluation and Research  
Office of Good Clinical Practice  
March 2012 
   
Guidance for Industry and 
FDA Staff 
FDA Acceptance of Foreign Clinical 
Studies Not Conducted Under an IND   
Frequently Asked Questions 
Additional copies are available from: 
Division of Drug Information, WO51-2201 
Office of Communication 
Center for Drug Evaluation and Research 
 Food and Drug Administration 
10903 New Hampshire Ave. 
Silver Spring, MD 20993-002  
 http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
Email: DRUGINFO@fda.hhs.gov  
(Tel) 301-796-3400; (Fax): 301-847-8714 
and/or 
 Office of Communication, Outreach and  
Development, HFM-40  
Center for Biologics Evaluation and Research 
 Food and Drug Administration 
1401 Rockville Pike  
Rockville, MD 20852-1448  
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm 
Email: ocod@fda.hhs.gov  
(Tel) 800-835-4709 or 301-827-1800 
and/or 
Office of Good Clinical Practice 
Office of the Commissioner 
http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/default.htm  
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research  
Center for Biologics Evaluation and Research  
Office of Good Clinical Practice  
March 2012 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
I.  INTRODUCTION.............................................................................................................1 
II.  BACKGROUND...............................................................................................................2 
III.  DISCUSSION....................................................................................................................3 
A.  ACCEPTANCE OF STUDIES (21 CFR 312.120(a)).....................................................4 
B.  SUPPORTING INFORMATION (21 CFR 312.120(b))................................................5 
1.  Investigator Qualifications (Section 312.120(b)(1))....................................................................6 
   What documentation should the sponsor or applicant provide regarding investigator 
  qualifications?.................................................................................................................................6 
2.  Description of the Research Facilities (Section 312.120(b)(2))...................................................7 
   Is the name and address of the research facility a sufficient description to address this 
  requirement?....................................................................................................................................7 
3.  Detailed Summary of the Protocol and Study Results and, If Requested, Case Records or 
  Additional Background Data (Section 312.120(b)(3))................................................................7 
a. Would a study report Synopsis (as shown in ICH E3, Annex I) provide a sufficiently detailed 
  summary of the protocol and study results?....................................................................................7 
b. Will FDA need access to case records maintained by the investigator or additional background 
  data such as hospital or other institutional records?......................................................................8 
4.  Description of the Drug Substance and Drug Product, Including the Components, 
  Formulation, Specifications, and, If Available, the Bioavailability of the Drug Product 
  (Section 312.120(b)(4))...................................................................................................................8 
   What information should the sponsor or applicant provide to meet the requirement in 21 CFR 
  312.120(b)(4)?.................................................................................................................................8 
5.  Information Showing that the Effectiveness Study is Adequate and Well Controlled Under 
  21 CFR 314.126 (Section 312.120(b)(5)).......................................................................................9 
   What information should the sponsor or applicant submit to FDA to show that the study is 
  adequate and well controlled under 21 CFR 314.126?...................................................................9 
6.  The Name and Address of the IEC that Reviewed the Study and a Statement that the IEC 
  Meets the Definition in 21 CFR 312.3 (Section 312.120(b)(6))...................................................9 
a. What does FDA consider an adequately constituted IEC?.........................................................9 
b. What information must the sponsor or applicant provide to FDA and what information must the 
  sponsor or applicant maintain with respect to the names and qualifications of all IEC members?
  .................................................................................................................................10 
7.  Summary of the IECs Decision to Approve or Modify and Approve the Study, or to 
  Provide a Favorable Opinion (Section 312.120(b)(7))..............................................................10 
a. How much detail should the sponsor or applicant provide regarding the IECs decisions?........10 
b. After submitting this required documentation in the IND/NDA/BLA, is the sponsor required to 
  submit IEC actions on continuing review to FDA?.......................................................................10 
8.  Description of How Informed Consent Was Obtained (Section 312.120(b)(8)).....................11 
   What level of detail is needed in this description?.........................................................................11 
9.  Description of What Incentives, If Any, Were Provided to Subjects to Participate (Section 
  312.120(b)(9))................................................................................................................................11 
   What information should sponsors or applicants provide to address this requirement?..............11 
10.  Description of How The Sponsor Monitored the Study and Ensured that the Study Was 
  Carried Out Consistently with the Study Protocol (Section 312.120(b)(10))..........................11 
   What documentation fulfills the requirement for a description of how the sponsor monitored the 
  study and ensured that the study was consistent with the protocol?..............................................11 
  Contains Nonbinding Recommendations 
 
11.  Description of How Investigators were Trained to Comply with GCP and to Conduct the 
  Study in Accordance with the Study Protocol, and Written Commitments by Investigators 
  to Comply with GCP and the Protocol (Section 312.120(b)(11)).............................................12 
a. What documentation fulfills this requirement?..............................................................................12 
b. Is a sponsor required by 21 CFR 312.120(b)(11) to obtain signed commitments from 
  investigators to comply with GCP and the protocol?....................................................................12 
C. WAIVERS (21 CFR 312.120(c))...........................................................................................12 
1.  Required Contents and Submission of a Waiver Request (Section 312.120(c)(1)).................13 
a. What are the criteria for a waiver?...............................................................................................13 
b. When and how should a waiver request be submitted?.................................................................14 
c. Should a sponsor or applicant expect a response to a waiver request?........................................14 
        d. What if the sponsor or applicant does not hear back from FDA regarding a waiver request?.....14 
2.  Public Health Implications of Waiver Requests (Section 312.120(c)(2)).................................15 
   Under what circumstances would a waiver be granted?...............................................................15 
D.  RECORDS (21 CFR 312.120(d)).........................................................................................15 
  How long must a sponsor or applicant retain records required under 21 CFR 312.120?............15 
  Contains Nonbinding Recommendations 
  
1
Guidance for Industry and FDA Staff  
FDA Acceptance of Foreign Clinical Studies  
Not Conducted Under an IND   
Frequently Asked Questions 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this topic.  It 
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.  
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance.  
 
 
 
I.  INTRODUCTION  
 
On April 28, 2008, the Food and Drug Administration (FDA or Agency) amended its regulations 
on the acceptance of foreign clinical studies not conducted under an investigational new drug 
application (IND) (non-IND foreign clinical studies) as support for an IND or a new drug 
application (NDA), abbreviated new drug application (ANDA), or a biologics license application 
(BLA) (collectively known as marketing applications or applications for marketing 
approval).2  The final rule requires that such studies be conducted in accordance with good 
clinical practice (GCP), including review and approval by an independent ethics committee 
(IEC) and informed consent from subjects.  The GCP requirements in the final rule encompass 
both ethical and data integrity standards for clinical studies.  This final rule, which took effect on 
October 27, 2008, is codified at 21 CFR 312.120.  It is intended to help ensure the protection of 
human subjects enrolled in non-IND foreign clinical studies as well as the quality and integrity 
of the resulting data.   
 
This guidance document is intended to clarify for sponsors and applicants how they can 
demonstrate compliance with the requirements of 21 CFR 312.120.3  It provides 
recommendations for the submission of information, whether in an IND or application for 
marketing approval for a drug or biological drug product,4 to demonstrate that a non-IND foreign 
clinical study was conducted in accordance with GCP. 
 
                                                 
1 This guidance has been prepared by the Office of Good Clinical Practice (OGCP) in the Office of the 
Commissioner (OC) in coordination with the Center for Drug Evaluation and Research (CDER) and the Center for 
Biologics Evaluation and Research (CBER) at the Food and Drug Administration.  
2 73 Fed. Reg. 22800 (April 28, 2008). 
3 This guidance is applicable to all applications submitted under section 505 of the Federal Food, Drug, and 
Cosmetic Act (FD& C Act) (21 U.S.C. 355) or section 351 of the Public Health Service Act (the PHS Act) (42 
U.S.C. 262). 
4 For the purposes of this guidance, all references to drugs, drug products, and drug substances include both human 
drug products and biological drug products regulated by CDER and CBER, unless otherwise specified. 
  1 Contains Nonbinding Recommendations 
  
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agencys current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited.  The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required.  
 
II.  BACKGROUND 
 
Clinical research is becoming increasingly global, as detailed in reports by the Office of 
Inspector General (OIG) of the Department of Health and Human Services (HHS) (OIG 
Reports).5  FDA recognizes that sponsors may choose to conduct multinational clinical studies 
under a variety of scenarios.  Multinational studies may include domestic sites conducted under 
an IND, foreign sites conducted under an IND, and/or foreign sites not conducted under an 
IND.6  Sponsors may decide to use the data that is obtained from non-IND foreign sites to 
support clinical investigations and/or marketing approval(s) in the United States.  Some sponsors 
may even seek to rely solely on foreign clinical data as support for an IND or application for 
marketing approval in the U.S.7  Indeed, the number of INDs and applications for marketing 
approval supported by foreign clinical trials has increased in recent years and will likely continue 
to increase in the future. 
 
This increasing globalization of clinical trials presents challenges to both U.S. and foreign 
regulators, many of which are detailed in the OIG reports.  Among other challenges, resource 
constraints limit the number of foreign clinical site inspections that can be conducted.  To 
address these challenges, FDA has sought to leverage its resources more efficiently by:  (1) 
encouraging sponsors to utilize data standardization in their INDs and applications for marketing 
approval, in order to improve review and analysis of data and facilitate implementation of a site 
selection model to prioritize sites for inspection; (2) engaging in collaboration and outreach with 
international regulatory authorities; and (3) considering alternative mechanisms of clinical trial 
oversight both by sponsors and FDA, such as a quality management system approach which 
emphasizes building quality into the research process.  
 
This guidance document is part of FDAs overall efforts to strengthen oversight of foreign 
clinical trials.8  Specifically, FDA is issuing this guidance as part of its efforts to encourage 
sponsors and applicants to standardize information relating to foreign clinical trials in their INDs 
and applications for marketing approval (see (1), above).  This guidance should help sponsors 
                                                 
5 See HHS OIG Report, Challenges to FDAs Ability to Monitor and Inspect Foreign Clinical Trials (June 2010), 
OEI-01-08-00510, available at http://oig.hhs.gov/oei/reports/oei-01-08-00510.pdf; HHS OIG Report, The 
Globalization of Clinical Trials: A Growing Challenge in Protecting Human Subjects (September 2001), OEI-01-
00-00190, available at http://oig.hhs.gov/oei/reports/oei-01-00-00190.pdf. 
6 For information on how conducting both IND and non-IND studies affects the requirement for investigators to sign 
the Form FDA 1572, see FDAs Guidance, Information Sheet Guidance for Sponsors, Clinical Investigators, and 
IRBs:  Frequently Asked Questions  Statement of Investigator (Form FDA 1572), available at 
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM214282.pdf. 
7 Marketing approval of a new drug based solely on foreign clinical data is governed by 21 CFR 314.106.   
8 See, for example, FDAs HSP/BIMO Modernization Initiative: Update September 2010, at 
http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm226306.htm.  
  2 Contains Nonbinding Recommendations 
  
and applicants submit information in a consistent and standardized manner to demonstrate 
compliance with the requirements in 21 CFR 312.120.   
 
Much of the information in this guidance comes from the preamble to the final rule, 73 Fed. Reg. 
22800 (April 28, 2008).  It is organized in a question and answer format that tracks the 
regulatory provisions.  In addition to addressing the substantive requirements of the final rule, 
this guidance addresses organization and submission procedures.  Specifically, as described in 
Section III.B, when sponsors or applicants submit information about a non-IND foreign clinical 
study, they should clearly identify in the cover letter (a) that the material is being submitted in 
accordance with 21 CFR 312.120, and (b) where in the submission the information required by 
21 CFR 312.120(b) can be located.   
 
Although FDA will not accept as support for an IND or application for marketing approval any 
study that does not meet the conditions of 21 CFR 312.120, FDA will examine the data from 
such a study because the data may have a bearing on the safe use of the product.9  Sponsors and 
applicants are reminded that they must submit all studies and other information as required under 
the applicable regulations for drugs,10 including studies that do not comply with the requirements 
of 21 CFR 312.120.  
   
 
III.  DISCUSSION 
 
A sponsor may choose, but is not required, to conduct a foreign clinical study under an IND.  
When a foreign clinical study is conducted under an IND, all FDA IND requirements must be 
met unless waived.11  When the foreign clinical study is not conducted under an IND, the 
sponsor must ensure that the study complies with the requirements in 21 CFR 312.120 in order to 
use the study as support for an IND or application for marketing approval.  Under 21 CFR 
312.120, FDA will accept a well-designed, well-conducted, non-IND foreign study as support for 
an IND or application for marketing approval if the study was conducted in accordance with 
GCP and if FDA is able to validate the data from the study through an onsite inspection, if 
necessary.12  Note that marketing approval of a new drug based solely on foreign clinical data is 
governed by 21 CFR 314.106.   
 
The GCP requirements at 21 CFR 312.120 help protect human subjects and enhance the quality 
and integrity of the resulting clinical data.13  They further help ensure that non-IND foreign 
studies are conducted in a manner comparable to that required for IND studies.14  Many of the 
requirements at 21 CFR 312.120 are already incorporated into the IND regulations at 21 CFR 
part 312, as well as 21 CFR parts 50 and 56,15 and are consistent with certain international 
ethical and policy standards for clinical trials (e.g., International Conference on Harmonisation 
of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good 
                                                 
9 21 CFR 312.120(a)(2); 73 Fed. Reg. at 22807. 
10 See, for example, 21 CFR 314.50, 314.80, 600.80, and 601.2. 
11 21 CFR part 312. 
12 73 Fed. Reg. at 22801. 
13 Ibid. 
14 73 Fed. Reg. at 22802. 
15 73 Fed. Reg. at 22807. 
  3 Contains Nonbinding Recommendations 
  
Clinical Practice: Consolidated Guideline (ICH E6), which FDA adopted for use as guidance 
for industry in 1997).16  
 
A.  ACCEPTANCE OF STUDIES (21 CFR 312.120(a)) 
 
FDA regulations define GCP as a standard for the design, conduct, performance, 
monitoring, auditing, recording, analysis, and reporting of clinical trials in a way that 
provides assurance that the data are credible and accurate and that the rights, safety, and 
well-being of trial subjects are protected.17   
 
GCP includes review and approval (or provision of a favorable opinion) by an 
independent ethics committee (IEC) before initiating a study, continuing review of an 
ongoing study by an IEC, and obtaining and documenting the freely given informed 
consent of the subject (or a subject's legally authorized representative, if the subject is 
unable to provide informed consent) before initiating a study.   
 
As defined at 21 CFR 312.3(b), an IEC is a review panel that is responsible for ensuring 
the protection of the rights, safety, and well-being of human subjects involved in a 
clinical investigation, and is adequately constituted to provide assurance of that 
protection.  We consider an IEC to be adequately constituted if it includes a 
reasonable number of members with the qualifications and experience to perform the 
IECs functions.  One type of IEC is an institutional review board (IRB) as defined in 21 
CFR 56.102(g) and subject to the requirements of 21 CFR part 56.  Another type of IEC 
is one that adheres to section 3.2.1 of ICH E6.  Compliance with 21 CFR part 56 or ICH 
E6 is not required, however, for an IEC to be considered adequately constituted under 
21 CFR 312.120.  We have expressly allowed for flexibility in how to meet the 
requirements of this regulation in recognition that the organization and membership of 
IECs may differ among countries because of local needs.18  For more information on IEC 
membership, see Section III.B.6 of this guidance document, below.   
 
ICH E6 defines informed consent as a process by which a subject voluntarily confirms 
his or her willingness to participate in a particular trial, after having been informed of all 
aspects of the trial that are relevant to the subject's decision to participate.19  Informed 
consent is documented by means of a written, signed, and dated informed consent 
form.20  In obtaining and documenting informed consent, an investigator should comply 
with the applicable regulatory requirement(s) and should adhere to principles of GCP.21  
Prior to the beginning of the trial, the investigator should obtain the IECs written 
approval of the informed consent form and any additional written information that will be 
provided to study subjects.22    
                                                 
16 ICH E6 and other FDA guidance documents adopted from the ICH are available electronically at 
http://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 
17 21 CFR 312.120(a)(1)(i). 
18 73 Fed. Reg. at 22805. 
19 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073122.pdf. 
20 Ibid. 
21 Ibid. 
22 For additional information concerning the informed consent process, refer to ICH E6, section 4.8. 
  4 Contains Nonbinding Recommendations 
  
 
B.  SUPPORTING INFORMATION (21 CFR 312.120(b)) 
 
A sponsor or applicant submitting non-IND foreign data in support of an IND or an 
application for marketing approval for a drug must include a description of the actions the 
sponsor or applicant took to ensure that the research conformed to GCP.  Because the 
description is not required to duplicate information already submitted in the IND or the 
application for marketing approval, the sponsor or applicant may indicate the location of 
the required information by providing cross-references (and/or hyperlinks) to relevant 
sections of the IND application, to relevant sections of an application for marketing 
approval, or to relevant sections of previously submitted materials.   
 
The location of all information required by 21 CFR 312.120 should be clearly delineated 
in the submission.  FDA recommends that the sponsor or applicant clearly indicate the 
following: 
 
 
1.  whether each clinical study was conducted at both foreign and domestic sites or 
only foreign sites;  
2.  whether each foreign site was under an IND or was subject to the requirements 
of 21 CFR 312.120; and  
3.  for each clinical study subject to 21 CFR 312.120, where in the submission or in 
previously submitted materials the following information can be found:  
a.  each of the elements required under 21 CFR 312.120(b) (e.g., 
Information showing that the study is adequate and well controlled, 21 
CFR 312.120(b)(5) -- See IND Application, Section X.1, pp. y-z); and  
b.  any waiver requests as applicable under 21 CFR 312.120(c) (e.g., 
Waiver request for certain requirements applicable to Study [X] -- see 
IND  Application, Section X.6, pp. y-z).  
 
Clearly delineating where the required information can be found will facilitate FDAs 
review of the IND or marketing application by enabling Agency confirmation of the 
sponsors/applicants compliance with the requirements of 21 CFR 312.120.   
 
Within an eCTD format of an application (for marketing approval or an IND), FDA 
recommends that a sponsor or applicant list the studies subject to the requirements of 21 
CFR 312.120 in Section 5.2 of Module 5.  The listing can be part of an overall tabular 
listing or be constructed as an accompanying table and appropriately identified as such.  
A sponsor or applicant might also use a submissions cover letter, particularly in the case 
of an IND, to indicate whether the submission contains studies subject to 21 CFR 
312.120. Whether in Module 5 or in a cover letter, the submission should contain page 
references and/or links to the respective individual full Clinical Study Reports (CSRs) for 
the identified studies.  
 
Within a CSR of a study, using an ICH E3 format as an example, FDA recommends that 
a sponsor or applicant identify on the Title Page that the study is being submitted in 
accordance with 21 CFR 312.120.  The Title Page should contain a reference and/or a 
  5 Contains Nonbinding Recommendations 
  
link to a section or an appendix which specifically addresses the sponsors compliance 
with 21 CFR 312.120.  (In ICH E3 format, such an Appendix would be in addition to the 
kind of Appendices already listed in the ICH E3 Guidance, e.g. 16.5).  FDA further 
recommends identifying specific foreign non-IND clinical sites using Appendix 16.1.4 
(List and Description of Investigators) in ICH E3 format or a similarly designated 
section. 
 
The section or appendix specifically intended to address compliance with 21 CFR 
312.120 should include a brief statement describing actions the sponsor has taken and 
should provide supporting information in accordance with all the required elements as 
listed in the regulations (see below).  FDA anticipates that for each such element the 
sponsor would provide the necessary information or provide reference and/or links to 
other sections of the study report which contain the information.  FDA strongly advises 
against duplicating information provided elsewhere in the application.   
 
The regulation allows for flexibility in how the requirements are to be met.  For example, 
a full CSR prepared in accordance with ICH E3 Structure and Content of Clinical Study 
Reports23 may meet many of the requirements under 21 CFR 312.120, but adherence to 
ICH E3 is not required.  The same holds for ICH E6:  a sponsor or applicant may choose 
but is not required to meet many of the requirements of this rule through adherence to 
ICH E6.  Note, however, that even if studies are submitted according to ICH E3 or E6, in 
some cases it may be necessary to provide additional information to FDA to meet the 
requirements of 21 CFR 312.120, as well as other applicable requirements in 21 CFR 
parts 312, 314, or 601.24   
 
Below, we discuss in more detail each of the required elements of 21 CFR 312.120(b) 
(Supporting Information).  Although we make reference throughout these answers to 
relevant portions of ICH E3 and E6, we remind sponsors and applicants that they may 
choose to meet the requirements of 21 CFR 312.120 through other means.  FDA 
encourages sponsors and applicants to discuss any questions or concerns they may have 
about the format and content of the required information during pre-submission meetings 
with FDA (e.g., pre-IND and pre-NDA/BLA meetings).   
 
1.  Investigator Qualifications (Section 312.120(b)(1)) 
 
What documentation should the sponsor or applicant provide regarding 
investigator qualifications? 
 
Answer:  FDA requires documentation to show that the investigator is 
qualified to serve as a study investigator based on their training and 
experience specifically related to the proposed clinical investigation.25 
                                                 
23 This guidance and other ICH guidance documents are available at 
http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/GuidancesInformationSheetsandNotices/
ucm219488.htm. 
24 73 Fed. Reg. at 22808. 
25 21 CFR 312.120(b)(1). 
  6 Contains Nonbinding Recommendations 
  
Such documentation generally includes a curriculum vitae or summary of 
training.  If this information is already included as part of the CSR, 
referencing the appropriate section within the CSR is acceptable.  For 
research involving novel technologies and/or the potential for increased 
risk of morbidity and/or mortality, the sponsor or applicant may wish to 
include additional documentation identifying the clinical investigators 
specific experience in this field (e.g., as demonstrated by recent 
presentations or publications) and with the test article.   
 
2.  Description of the Research Facilities (Section 312.120(b)(2)) 
 
Is the name and address of the research facility a sufficient description to 
address this requirement? 
 
Answer:  No, the name and address of the research facility is generally not 
a sufficient description to meet the requirement in 21 CFR 312.120(b)(2). 
Because FDA is generally less likely to be familiar with the research 
facilities in which foreign non-IND studies are conducted, greater detail is 
usually needed.  For example, it would generally be adequate to identify 
and briefly describe the academic medical center, hospital, physicians 
office, clinical research unit or other type of facility at which the research 
is being conducted.  The description should include enough information to 
enable FDA to determine the adequacy of the facilities to execute the 
protocol requirements (e.g., whether the site is appropriately staffed and 
equipped to conduct the proposed research and is able to provide the 
appropriate emergent or specialized care, if required). 
 
3.  Detailed Summary of the Protocol and Study Results and, If Requested, 
Case Records or Additional Background Data (Section 312.120(b)(3)) 
 
a.  Would a study report Synopsis (as shown in ICH E3, Annex I)26 provide 
a sufficiently detailed summary of the protocol and study results?  
 
Answer:  No, as stated in the preamble to the final rule, submitting only 
the Synopsis from Annex I of ICH E3 would not be adequate to meet the 
requirement in 21 CFR 312.120(b)(3), because the Synopsis would not 
provide sufficient detail about the study protocol or results.27  By contrast, 
submitting an integrated, full CSR in accordance with ICH E3 would meet 
this requirement, although alternative approaches are also acceptable.  
 
Integrated, full CSRs are commonly submitted for clinical and human 
pharmacology investigations that contribute to the evaluation of 
effectiveness for the proposed indication or that otherwise support 
                                                 
26 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073113.pdf 
27 73 Fed. Reg. at 22808. 
  7 Contains Nonbinding Recommendations 
  
information included in proposed labeling for the product.28  Sponsors and 
applicants are reminded that, even if they submit such integrated, full 
CSRs, they must also submit any additional information that is required by 
21 CFR parts 312, 314, or 601.   
 
b.  Will FDA need access to case records maintained by the investigator or 
additional background data such as hospital or other institutional 
records?  
 
Answer:  Yes, FDA may need to review source documents such as 
hospital records to verify data, whether during an on-site inspection or 
upon request.29 For example, a review division within FDA may request 
submission of investigator, hospital, or institutional records outside of an 
inspectional context.  If so, these records must be made available to the 
Agency for FDA to rely on the data.30  In addition, FDA believes that 
informed consent documents should notify subjects that international 
regulatory authorities may need to have direct access to the subjects 
original medical records for verification of clinical study procedures and 
data.31 This position is consistent with ICH E6, section 4.8.10(n).32 
 
If the necessary records are not available, FDA may not accept the study 
data in support of an IND or application for marketing approval.  If the 
records exist but a sponsor or applicant cannot disclose them to FDA 
because such disclosure is prohibited by applicable foreign law, the 
sponsor or applicant may seek a waiver of this requirement, as described 
below in Section III.C.  For FDA to rely on such data that cannot be 
disclosed, the sponsor and FDA would need to agree on an alternative 
validation procedure.33 
 
4.  Description of the Drug Substance and Drug Product, Including the 
Components, Formulation, Specifications, and, If Available, the 
Bioavailability of the Drug Product (Section 312.120(b)(4))   
 
What information should the sponsor or applicant provide to meet the 
requirement in 21 CFR 312.120(b)(4)? 
 
  Answer:  In general, the description of the drug required under 21 CFR 
312.120(b)(4) would already be included in other sections of the IND or 
                                                 
28 For more information, see FDAs Guidance, Submission of Abbreviated Reports and Synopses in Support of 
Marketing Applications, available at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072053.pdf. 
29 21 CFR 312.120(a)(ii) and (b)(3). 
30 Ibid. 
31 Note that the submission of case report forms (CRF) as specified by 21 CFR 314.50 are required for submission of 
an application for marketing approval. 
32 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073122.pdf 
33 73 Fed. Reg. at 22808. 
  8 Contains Nonbinding Recommendations 
  
application for marketing approval.34 This requirement can therefore 
generally be met through cross-references to other sections of the 
submission.   
 
5.  Information Showing that the Effectiveness Study is Adequate and Well 
Controlled Under 21 CFR 314.126 (Section 312.120(b)(5)) 
 
What information should the sponsor or applicant submit to FDA to show 
that the study is adequate and well controlled under 21 CFR 314.126? 
 
  Answer:  As an example, integrated, full CSRs in accordance with ICH E3 
generally provide appropriate detail to show that the study is adequate and 
well-controlled as described in 21 CFR 314.126.  Note: the sponsor or 
applicant should also explain how the foreign data are applicable to the 
U.S. population and U.S. medical practice.35   
 
6.  The Name and Address of the IEC that Reviewed the Study and a 
Statement that the IEC Meets the Definition in 21 CFR 312.3(b) (Section 
312.120(b)(6)) 
 
a.  What does FDA consider an adequately constituted IEC? 
 
  Answer:  FDA regulations at 21 CFR 312.3(b) define an IEC as a review 
panel that is responsible for ensuring the protections of the rights, safety, 
and well-being of human subjects involved in a clinical investigation and 
is adequately constituted to provide assurance of that protection.  FDA 
believes an adequately constituted IEC is one that consists of a 
reasonable number of members who collectively have the qualifications 
and experience to review and evaluate the science, medical aspects and 
ethics of the proposed trial.  As provided in ICH E6, section 3.2, an IEC 
includes at least five members, including at least one member whose 
primary area is in a nonscientific area and at least one member who is 
independent of the institution where the research will be conducted (i.e., 
not otherwise affiliated with the institution and not part of the immediate 
family of a person who is affiliated with the institution).  FDA 
recommends that every nondiscriminatory effort be made to ensure that 
the IEC composition is not limited to only one gender and that it reflects 
the social and cultural diversity of the community(ies) from which 
research participants are most likely to be drawn.36  It is further advised 
that only those members who are independent of the investigator and the 
sponsor of the trial vote on trial-related matters.37  
 
                                                 
34 21 CFR 312.23, 21 CFR 314.50, 21 CFR 314.94, and 21 CFR 601.2. 
35 See 21 CFR 314.106. 
36 See 21 CFR 56.107(b). 
37 ICH E6, section 3.2. 
  9 Contains Nonbinding Recommendations 
  
FDA recognizes that the organization and membership of IECs may differ 
among countries because of local needs of the host country.  Such 
variation is acceptable as long as the IEC can assure the protection of the 
rights, safety, and well-being of human subjects involved in the clinical 
investigation. 
 
b.  What information must the sponsor or applicant provide to FDA and what 
information must the sponsor or applicant maintain with respect to the 
names and qualifications of all IEC members? 
   
  Answer:  The sponsor or applicant is required by 21 CFR 312.120(b)(6) to 
provide only the name and address of the IEC that reviewed the study and 
a statement that the IEC meets the definition of an IEC in 21 CFR 
312.3(b).  However, as provided in 21 CFR 312.120(b)(6), the sponsor or 
applicant must maintain records supporting the statement, including the 
names and qualifications (e.g., occupation, training, and experience) of all 
IEC members, and must make these records available for Agency review 
upon request.  If that is not possible because of governing law relating to 
privacy concerns, FDA recommends that sponsors and applicants clearly 
document the attempts made to obtain IEC member names along with an 
explanation as to why the IEC member names cannot be obtained or 
disclosed.  Such information can then be submitted to FDA in a waiver 
request, as described below in Section III.C. 
 
7.  Summary of the IECs Decision to Approve or Modify and Approve the 
Study, or to Provide a Favorable Opinion (Section 312.120(b)(7)) 
 
a.  How much detail should the sponsor or applicant provide regarding the 
IECs decisions? 
 
  Answer:  In most cases, a brief summary of the IEC actions to approve or 
modify and approve the clinical investigation would be sufficient.  For 
example, it may suffice to provide FDA with the name of the IEC and a 
list of IEC actions and dates (e.g., initial approval date, date of approval of 
modification, etc.), or alternatively to provide FDA with the approval 
letters from the IEC (including those for protocol amendments).  If FDA 
determines that additional information is necessary to understand the 
IECs decisions on the clinical investigation, the Agency will request this 
information from the sponsor or applicant.   
 
b.  After submitting this required documentation in the IND/NDA/BLA, is the 
sponsor required to submit IEC actions on continuing review to FDA? 
 
  Answer:  No, although continuing review by the IEC is required under 21 
CFR 312.120(a)(1)(i), documentation of such review need not be 
  10 Contains Nonbinding Recommendations 
  
submitted under 21 CFR 312.120(b)(7).  However, such continuing review 
information should be maintained and available to FDA upon request. 
 
8.  Description of How Informed Consent Was Obtained (Section 
312.120(b)(8)) 
 
What level of detail is needed in this description? 
 
  Answer:  Submitting documentation of the informed consent process 
detailed in ICH E6, section 4.8, and/or relevant sections of ICH E3 is one 
acceptable means of meeting the requirement in 21 CFR 312.120(b)(8) to 
describe how informed consent was obtained.   
 
9.  Description of What Incentives, If Any, Were Provided to Subjects to 
Participate (Section 312.120(b)(9)) 
 
What information should sponsors or applicants provide to address this 
requirement? 
 
Answer: FDA believes that there should be some flexibility in how 
sponsors or applicants comply with 21 CFR 312.120(b)(9).  The sponsor 
or applicant may follow ICH E6 or ICH E3, providing a sample or model 
informed consent form that describes any incentives provided (section 
4.8.10 of ICH E6 and appendix 16.1.3 of ICH E3), to satisfy 21 CFR 
312.120(b)(9).  Alternatively, a sponsor or applicant may satisfy this 
requirement by submitting a brief narrative description of any incentives 
provided to subjects who participate in the study.38  
 
10. Description of How the Sponsor Monitored the Study and Ensured that 
the Study Was Carried Out Consistently with the Study Protocol (Section 
312.120(b)(10)) 
 
What documentation fulfills the requirement for a description of how the 
sponsor monitored the study and ensured that the study was conducted 
consistent with the protocol? 
 
Answer: Following ICH E3, section 9.6, is one acceptable way to meet 
this requirement.  The sponsor or applicant should describe the methods 
used to oversee the conduct of and reporting of data from clinical 
investigations.  The sponsor or applicant should also provide a cross-
reference to audit-related information for the investigations, as applicable 
(e.g., audit certificates).39  
 
                                                 
38 73 Fed. Reg. at 22810. 
39 21 CFR 314.50(d)(5)(xi). 
  11 Contains Nonbinding Recommendations 
  
11. Description of How Investigators were Trained to Comply with GCP and 
to Conduct the Study in Accordance with the Study Protocol, and 
Written Commitments by Investigators to Comply with GCP and the 
Protocol (Section 312.120(b)(11)) 
 
a.  What documentation fulfills this requirement? 
   
Answer: Submitting a statement in accordance with ICH E3, section 9.6 
(i.e., whether investigator meetings or other steps were taken to prepare 
investigators and standardize performance), is one acceptable means of 
complying with 21 CFR 312.120(b)(11), provided that the description 
includes how investigators were trained to comply with GCP and to 
conduct the study in accordance with the study protocol.40 
 
b.  Is a sponsor required by 21 CFR 312.120(b)(11) to obtain signed 
commitments from investigators to comply with GCP and the protocol? 
 
Answer: No, although FDA encourages sponsors to obtain written 
commitments from investigators, such commitments may not be required 
or may even be prohibited in some countries, and FDA does not want to 
preclude submission of well-designed and ethically conducted foreign 
clinical studies solely because a written commitment was not obtained.41  
To meet the requirement in 21 CFR 312.120(b)(11), sponsors or applicants 
must submit a statement indicating whether written commitments by 
investigators to comply with GCP and the protocol were obtained and, if 
so, to maintain such commitments on file to be provided upon the 
Agencys request.42  For those sponsors following ICH E3 and E6, these 
documents would be either submitted with the CSR or kept on file with 
the sponsor or applicant.  
 
C. WAIVERS (21 CFR 312.120(c)) 
 
FDA believes that many sponsors and applicants will be able to comply with 21 
CFR 312.120, and therefore will not request waivers, because many foreign 
clinical investigations are conducted in accordance with GCP principles.  For this 
reason, when publishing the rule, FDA anticipated relatively few waiver requests.  
Experience to date has confirmed that waiver requests are rare. 
 
Sponsors or applicants may nonetheless ask FDA to waive any applicable 
requirements under 21 CFR 312.120(a)(1) and (b) by submitting a waiver request 
                                                 
40 73 Fed. Reg. at 22810. 
41 For more on this issue, see FDAs Guidance, Information Sheet Guidance for Sponsors, Clinical Investigators, 
and IRBs:  Frequently Asked Questions  Statement of Investigator (Form FDA 1572), available at 
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM214282.pdf. 
42 73 Fed. Reg. at 22810-22811. 
  12 Contains Nonbinding Recommendations 
  
under 21 CFR 312.120(c).  FDA will decide whether to grant or deny waivers on 
a case-by-case basis, taking into account all appropriate circumstances.43   
 
FDA anticipates that waivers may be sought, for example, in the following 
circumstances: 
 
  To allow for acceptance of a non-IND foreign clinical study conducted 
before the effective date of the revised 21 CFR 312.120 (April 28, 2008).  
The sponsor or applicant may submit a request for waiver if the study was 
in compliance with the provisions of 21 CFR 312.120 at the time it was 
conducted but was out of technical compliance with the terms of the 
revised 21 CFR 312.120. 
  If FDA requests case records maintained by the investigator or additional 
background data, such as hospital or other institutional records, but these 
documents cannot be provided as required by 21 CFR 312.120(b)(3) 
because disclosure is prohibited by governing law.  In this case, the 
sponsor or applicant should document this disclosure prohibition by the 
foreign entity (e.g., the countries that prohibit such disclosure, the nature 
of the prohibitions, and the extent to which these prohibitions may impede 
sponsors in carrying out other obligations requiring record access).  The 
sponsor or applicant can then submit such information in a waiver request 
to FDA.  For FDA to rely on the affected data, the sponsor and FDA 
would need to agree on an alternative validation procedure.44  
  If the sponsor or applicant cannot obtain IEC member names as required 
by 21 CFR 312.120(b)(6), because of governing law relating to privacy 
concerns.  In this instance, FDA recommends that the sponsor or applicant 
clearly document attempts made to obtain the names along with an 
explanation as to why the names cannot be obtained.  Such information 
can be submitted to FDA in a waiver request. 
 
1.  Required Contents and Submission of a Waiver Request (Section 
312.120(c)(1)) 
 
a.  What are the criteria for a waiver? 
 
Answer:  Pursuant to 21 CFR 312.120(c)(1), a waiver request is 
required to contain at least one of the following: 
(i) An explanation why the sponsor's or applicant's 
compliance with the requirement is unnecessary or cannot 
be achieved; 
(ii) A description of an alternative submission or course of 
action that satisfies the purpose of the requirement; or 
(iii) Other information justifying a waiver. 
 
                                                 
43 73 Fed. Reg. at 22811. 
44 73 Fed. Reg. at 22808. 
  13 Contains Nonbinding Recommendations 
  
b.  When and how should a waiver request be submitted? 
 
Answer:  Waiver requests may be submitted as a part of an original 
IND or application for marketing approval, a supplemental 
application, or an amendment to an application submitted under 21 
CFR Parts 314 and 601.45  The affected application should use the 
waiver section of Module 1 in eCTD format and/or include a cover 
letter that clearly states that a waiver under 21 CFR 312.120(c) is 
being requested.  The waiver section or the cover letter should 
identify the affected studies and the relevant sections of the 
application.  If a waiver has already been requested and granted by 
FDA, the previously submitted materials that include the waiver 
request should be referenced in the cover letter (or in Module 1). 
 
In addition, FDA recognizes that there may be certain 
circumstances where, before submitting a waiver request, sponsors 
may wish to discuss with FDA concerns regarding their ability to 
meet all of the regulatory requirements under 21 CFR 312.120.  
Depending on the circumstances, these issues may be discussed 
with FDA during a pre-IND or pre-NDA/BLA meeting.  For 
example, a sponsor who is considering locating sites in a foreign 
country where privacy laws would prohibit them from obtaining 
IEC member names may wish to discuss their concerns during the 
early stages of planning a study. 
 
c.  Should a sponsor or applicant expect a response to a waiver 
request? 
 
Answer:  FDA will notify the sponsor or applicant in writing as to 
whether the waiver request is granted or denied.     
 
d.  What if the sponsor or applicant does not hear back from FDA 
regarding a waiver request? 
 
Answer:   The sponsor or applicant should contact the FDA review 
division to which the waiver was submitted to inquire about the 
status of the waiver request.  Although specific timelines cannot be 
provided, the FDA will attempt to respond to waiver requests as 
quickly as possible.  The sponsor or applicant should not assume 
that no response means that the request for waiver has been 
granted. 
 
 
 
                                                 
45 21 CFR 312.120(c)(1). 
  14 Contains Nonbinding Recommendations 
  
2.  Public Health Implications of Waiver Requests (Section 312.120(c)(2)) 
 
Under what circumstances would a waiver be granted? 
 
Answer:  FDA may grant a waiver if it finds that doing so would be in the 
interest of the public health.46  The regulation allows the Agency to decide 
on a case-by-case basis whether to grant or deny a waiver, taking into 
account all appropriate circumstances.  
 
D.  RECORDS (21 CFR 312.120(d)) 
 
How long must a sponsor or applicant retain records required under 21 
CFR 312.120? 
 
Answer:  A sponsor or applicant must retain the required records for a 
foreign clinical study not conducted under an IND for at least 2 years after 
an Agency decision on the supporting marketing application or, if the 
study is submitted in support of an IND but not a marketing application, 
for 2 years after submission of the IND.47 
 
 
                                                 
46 21 CFR 312.120(c)(2). 
47 21 CFR 312.120(d). 
  15