Guidance for Sponsors, 
Investigators, and Institutional 
Review Boards 
 
Questions and Answers on 
Informed Consent Elements,  
21 CFR  50.25(c) 
 
 (Small Entity Compliance Guide)  
 
 
 
 
 
 
 
U.S. Department of Health and Human Services  
Food and Drug Administration  
Office of Policy and Office of Good Clinical Practice 
Office of the Commissioner 
 
February 2012  
   
Guidance for Sponsors, 
Investigators, and Institutional 
Review Boards 
 
Questions and Answers on 
Informed Consent Elements,  
21 CFR  50.25(c) 
 
 (Small Entity Compliance Guide)  
 
 
 
 
Additional copies are available from:  
Office of Good Clinical Practice 
 Office of Special Medical Programs  
Office of Commissioner  
Food and Drug Administration 
10903 New Hampshire Ave., WO32-5103 
Silver Spring, MD 20993  
 (Tel) 301-796-8340  
gcp.questions@fda.hhs.gov  
http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/default.htm.    
 
 
 
U.S. Department of Health and Human Services  
Food and Drug Administration  
Office of Policy and Office of Good Clinical Practice 
Office of the Commissioner 
 
February 2012   
 
  Guidance for Sponsors, Investigators, 
 and Institutional Review Boards 
 
Questions and Answers  
on Informed Consent Elements,  
21 CFR  50.25(c) 
 
 (Small Entity Compliance Guide)  
 
 
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  
 
FDA has prepared this guidance in accordance with section 212 of the Small Business 
Regulatory Enforcement Fairness Act.  It is intended to help small businesses better 
understand the new informed consent requirements set forth in 21 CFR  50.25(c).  
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  
 
In the Federal Register (FR) of January 4, 2011 (76 FR 256), FDA published a final 
regulation (21 CFR  50.25(c)) amending the current informed consent regulations to 
require that informed consent documents and processes for applicable drug (including 
biological products) and device clinical trials include a specific statement that clinical 
trial information will be entered into a databank.  The databank referred to in this final 
rule is the clinical trial registry databank maintained by the National Institutes of 
Health/National Library of Medicine (NIH/NLM) which was created by statute.  The 
submission of clinical trial information to this data bank also is required by statute.  The 
amendment to the informed consent regulations was required by the Food and Drug 
Administration Amendments Act of 2007 (FDAAA), Public Law 110-85 (September 27, 
2007), and is designed to promote transparency of clinical research to participants and 
patients.    Contains Nonbinding Recommendations 
III. Questions and Answers on Informed Consent Elements (21 CFR  50.25(c)) 
 
1. What is the new requirement for informed consent documents? 
 
For applicable clinical trials initiated on or after March 7, 2012, informed consent 
documents must be in compliance with the new requirement in 21 CFR  50.25(c) and 
include a specific statement that refers to the trials description on 
www.ClinicalTrials.gov. 
 
2. Why is it necessary to include this new statement in informed consent documents? 
 
The requirement for this provision was included in section 801 of FDAAA.  This law also 
provided for mandatory registration and results reporting of certain applicable clinical 
trials on www.ClinicalTrials.gov.  The statement is the means by which the statute 
provided for investigators/sponsors to inform applicable clinical trial participants of the 
availability of the clinical trial information on the public website located at 
www.ClinicalTrials.gov.  
 
3. FDAs final rule refers to an applicable clinical trialwhat is an applicable 
clinical trial and how do I know if my trial is an applicable clinical trial? 
 
FDAAA provided a definition of applicable clinical trial in 42 U.S.C.  282(j)(1)(A).  
Applicable clinical trials generally include controlled interventional studies (with one 
or more arms) of drugs, biological products, or devices that are subject to FDA 
regulation, meaning that the trial has one or more sites in the United States, involves a 
drug, biologic, or device that is manufactured in the United States (or its territories), or is 
conducted under an investigational new drug application (IND) or investigational device 
exemption (IDE).  Trial sponsors and investigators have the responsibility of determining 
whether or not a trial is an applicable clinical trial.  Definitions vary for applicable 
device and drug trials including biologics. 
 
The trial is an applicable clinical device trial if: (I) the trial prospectively compares a 
device-based intervention subject to FDA regulation against a control in human subjects; 
or (II) the trial is a pediatric post-market surveillance trial.  42 U.S.C.  282(j)(1)(A)(ii). 
 
The trial is an applicable clinical drug trial if the trial is a controlled clinical 
investigation, other than a phase I clinical investigation, of a drug subject to FDA 
regulation.  42 U.S.C.  282(j)(1)(A)(iii)(I).  For the purposes of this definition, a 
clinical investigation is any experiment in which a drug is administered or dispensed 
to, or used involving, one or more human subjects.  21 CFR  312.3. 
 
NIH/NLM has the statutory authority to interpret the definition of applicable clinical 
trial, and provides a discussion of the current thinking on the meaning of the term at 
http://prsinfo.clinicaltrials.gov/fdaaa.html. 
 
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  Contains Nonbinding Recommendations 
4. What clinical trials are specifically excluded from the definition of applicable 
clinical trials? 
 
For devices, small feasibility trials and larger clinical trials of prototype devices with a 
primary measure of feasibility rather than health outcomes are not applicable clinical 
trials.  42 U.S.C.  282(j)(1)(A)(ii).  Under current guidance contained on NIHs website 
at http://prsinfo.clinicaltrials.gov/ElaborationsOnDefinitions.pdf, a device trial is not an 
applicable device clinical trial when the trial includes only de-identified human 
specimens and does not include human subjects (a requirement to be considered an 
applicable clinical trial).  The website states: For purposes only of the requirements 
under 402(j) of the PHS Act, this definition of human subject does not apply to de-
identified human specimens. (See, Guidance on Informed Consent for In Vitro 
Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually 
Identifiable, April 25, 2006 http://www.fda.gov/RegulatoryInformation/Guidances/ 
ucm127022.htm) 
 
For drugs, phase 1 clinical investigations (defined in 21 C.F.R.  312.21) are not 
categorized as applicable clinical trials.  42 U.S.C.  282(j)(1)(A)(iii).  Uncontrolled 
clinical investigations of drugs or devices also are not considered applicable clinical 
trials. 
 
See, also, the responses to questions 3 and 17.  
  
5. Where has FDA published this new regulation? 
 
We published the final rule requiring this statement on page 256, volume 76 of the FR 
(January 4, 2011, 76 FR 256).  The regulation may be found at 21 CFR  50.25(c). 
 
6. What is the exact statement required to be included in informed consent 
documents? 
 
Under new 21 CFR 50.25(c), the following statement must be reproduced word-for-word 
in informed consent documents for applicable clinical trials: 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This Web site will not include information that can identify you.  
At most, the Web site will include a summary of the results.  You can search this Web 
site at any time. 
 
7. Why is it necessary to include the specific statement without any changes? 
 
The four required sentences fulfill the need for a standardized, specific statement 
concerning the availability of trial data on www.ClinicalTrials.gov for every applicable 
clinical trial.  After much careful thought, consideration of all comments submitted to the 
proposed rule docket, and input from Institutional Review Board (IRB) members, clinical 
trial directors, ethicists, and communication experts, we formulated the statement 
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  Contains Nonbinding Recommendations 
provided in the regulation.  21 CFR  50.25(c).  Requiring word-for-word reproduction of 
the statement avoids the need for individual analysis and determination of what is 
appropriate to be included.  The use of the statement also avoids different statements for 
different trials. 
 
8. When must sponsors and investigators begin including the new statement in 
informed consent documents? 
 
Applicable clinical trials initiated on or after March 7, 2012, must be in compliance with 
the new requirement and include the new statement in all informed consent documents.  
For the purposes of this rule only, we consider initiation of a clinical trial to be the 
clearance or approval of any informed consent documents by an IRB or other ethics 
review committee. 
 
9. Will the new informed consent rule be applied retroactively? 
 
No, applicable clinical trials initiated on or after March 7, 2012, must be in compliance 
with the new rule and are subject to the rule.  See the response to question 8. 
 
10. What if my study has received approval only for particular sites by March 7, 
2012? 
 
If an IRB has already approved any informed consent documents for the applicable 
clinical trial prior to March 7, 2012, then the trial will be considered initiated before the 
compliance date, and the new statement will not be required.  For example, if an IRB 
approves consent documents for a particular site for a multi-site trial before March 7, 
2012, but documents for another site have not been approved by that date, then all 
documents for the entire applicable clinical trial will be exempt from including the 
statement and do not need to be in compliance with the provision.  If an IRB has not 
approved any informed consent documents for the applicable clinical trial by March 7, 
2012, then all informed consent documents associated with the applicable clinical trial 
must in compliance with the requirement and include the new statement. 
 
If the multi-site applicable clinical trial includes multiple IRBs or the multi-site 
applicable clinical trial is under one IRB, the effect is still the same.  The sponsor of the 
trial is responsible for determining the applicable clinical trial initiation date. 
 
11. Will re-consent be required for ongoing trials after March 7, 2012? 
 
No, if the applicable clinical trial was initiated before March 7, 2012, then these informed 
consent documents do not have to be in compliance with the new requirement.  Subjects 
who consent to an applicable clinical trial via documents approved before March 7, 2012, 
will not need to be re-consented based solely on the new regulations.   
 
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  Contains Nonbinding Recommendations 
Even if sponsors or investigators revise consent documents for other reasons, as long as 
the documents were initially approved before March 7, 2012, the revised consent forms 
do not have to include the statement. 
 
12. How should sponsors and/or investigators obtain approval for informed consent 
documents with the new statement? 
 
The new requirement of including the statement has not altered the IRB approval process.  
However, IRBs cannot modify or delete the exact statement regarding 
www.ClinicalTrials.gov as stated in 21 CFR  50.25(c).  Investigators, sponsors, and 
IRBs are not restricted from providing additional explanation, if determined to be needed.  
It is essential, however, that the required common statement consistently be included in 
all informed consent documents and processes if the trial is an applicable clinical trial.  
 
13. What are the responsibilities of an IRB under the new rule? 
 
IRBs continue to have the responsibility to review and approve informed consent 
documents.  21 CFR  56.109(b).  The waivers to documentation of informed consent 
regarding certain studies still apply.  21 CFR  56.109(c)(1).  Even if documentation is 
waived under 21 CFR  56.109(c)(1), the trial participant still provides consent and the 
statement is required during the oral presentation of the research and/or in the written 
statement regarding the research, if required by the IRB under 21 CFR  56.109(d).  
Under 21 CFR  50.23 and 50.24 regarding exceptions to informed consent, the 
statement is also required in the informed consent documents if these trials are applicable 
clinical trials.   
 
14. In what situations may the new requirement be waived? 
 
Section 801 of FDAAA does not provide for a waiver of the new requirement to include 
the new statement in the informed consent documents and process for applicable clinical 
trials.  FDAs regulations require informed consent for participation in FDA-regulated 
clinical investigations except under limited circumstances as described in 21 CFR  50.23 
(involving certain life-threatening situations, military operations, or public health 
emergencies) and 21 CFR  50.24 (involving emergency research).   Please see the 
response to question 13 for further information.  
 
15. Does the new statement have to be featured in a particular place in the informed 
consent document? 
 
No, the regulation does not require the new statement to be located in any particular 
section of the consent form.  Investigators, sponsors, and IRBs have the flexibility to 
place the new statement wherever they believe best serves participants interests. 
 
16. What if non-compliant informed consent documents (documents without the 
new statement as required) are submitted to and approved by the IRB?  
 
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The investigator and sponsor are responsible for determining whether a trial is an 
applicable clinical trial and to include the required statement in the informed consent 
document, as appropriate, for approval by the IRB.  If an error is made, the IRB should 
be notified as soon as possible and a revised consent form that includes the required 
statement should be provided to the IRB for review and approval.  
 
17. Does the new statement have to be included in informed consent documents for 
trials with de-identified datathat is, trials that are not subject to the Health 
Information Portability and Accountability Act (HIPAA)? 
 
If the trial is determined to be an applicable clinical trial, the investigator or sponsor must 
comply with the new regulation regardless of any determinations concerning HIPAA 
requirements.  
 
18. If a clinical trial is not subject to the rule, do investigators have to inform trial 
participants about the availability of clinical trial information on 
www.ClinicalTrials.gov? 
 
No, if the clinical trial is not subject to the rule (not an applicable clinical trial), then 
investigators/sponsors do not need to inform participants about the availability of 
information on the www.ClinicalTrials.gov website.  The required statement should not 
be included in informed consent documents or processes for clinical trials that are not 
applicable clinical trials.  However, if investigators/sponsors independently believe that 
reporting data on www.ClinicalTrials.gov may influence subjects willingness to 
participate, nothing in this regulation prevents investigators/sponsors from voluntarily 
reporting trial data and informing trial participants in an appropriate manner.  
 
19. Should investigators/sponsors include the statement in consent documents for a 
trial that is not an applicable clinical trial? 
 
Because U.S. law only requires that applicable clinical trials be submitted to 
www.ClinicalTrials.gov, the new statement only applies to the legal requirements for 
applicable clinical trial informed consent documents.  Again, the new rule does not 
prevent investigators from voluntarily reporting data from clinical trials that do not meet 
the definition of an applicable clinical trial to www.ClinicalTrials.gov and sharing that 
information with participants. 
 
20. If an organization has used the same model template for informed consent 
documents for years, must they update the template? 
 
Yes, the compliance deadline of March 7, 2012, provided sufficient time for all 
institutions involved in applicable clinical trials to update their model forms and 
templates. 
 
21. Do informed consent documents for studies conducted outside of the United 
States have to comply with the new regulations?  
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  Contains Nonbinding Recommendations 
 
Yes, any applicable clinical trial, including applicable clinical trials conducted outside the 
United States, must comply with the new regulation (21 CFR  50.25(c)) and include the 
statement regarding www.ClinicalTrials.gov in informed consent forms.  The statute 
defines applicable clinical trials as trials of drugs and devices that are subject to FDA 
regulation.  If the clinical trial is not of a drug or device subject to FDA regulation, and, 
thus, not an applicable clinical trial, at the time of the initiation of the trial, then the 
statement is not required.  See the response to questions 3 and 4 concerning the definition 
of an applicable clinical trial.  
 
FDA accepts data from foreign clinical trials not under an IND when in compliance with 
21 CFR  312.120.  The mere fact that we accept data from a foreign clinical trial in 
connection with a marketing application does not make it an applicable clinical trial; the 
foreign clinical trial constitutes an applicable clinical trial only when it meets the 
definitions set forth in 42 U.S.C.  282(j)(1)(A).  See, also, the response to questions 3 
and 4. 
 
This requirement does not preclude the inclusion of mandatory or recommended 
language from non-U.S. governments, and it does not preclude reference to other clinical 
trial registries or regulatory bodies. 
 
22. What if the new statement conflicts with foreign informed consent 
requirements? 
 
Congress did not provide an exemption from the statutory requirement.  If the clinical 
trial is an applicable clinical trial, then it must include the new statement. 
 
23. Can sponsors or investigators translate the new required statement? 
 
Yes, if potential participants are non-English speaking or the clinical investigator or IRB 
anticipates that the consent interviews will be conducted in a language other than English, 
the IRB should require investigators or sponsors to prepare translated consent documents.  
FDA recommends that the IRB review, and if appropriate, approve procedures for 
ensuring that the translations will be prepared by a qualified individual or entity.  
However, FDA will not provide translations of the statement.  We have written the 
required statement to use simpler language and do not believe that the statement will pose 
translation difficulties. 
 
24. Are clinical trials that are funded, conducted, or supported by the Department 
of Health and Human Services (HHS) (i.e., subject to 45 CFR  46) subject to the 
new regulation? 
 
As a general matter, applicable clinical trials involving FDA-regulated products and 
conducted or supported by HHS must meet the requirements of both 45 CFR  46 and 21 
CFR  50.   
 
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  Contains Nonbinding Recommendations 
 
 
 
25. How does the new rule affect informed consent for children? 
 
Parent or guardian permission, as defined in 21 CFR  50.3(r), must include the elements 
of informed consent.  Therefore, the parent and guardian consent forms must include the 
new statement word for word. 
 
26. What are the consequences of not including the new language in consent 
documents for applicable clinical trials? 
 
FDA has several options that enable enforcement of the new informed consent 
requirement.  FDA has the authority to regulate the protection of human subjects and the 
authority to impose penalties for violations of these regulations.  The Food, Drug, and 
Cosmetic Act (FD&C Act) prohibits the failure to establish or maintain any record or 
make any report required under section 505(i) and the failure or refusal to comply with 
any requirement under 520(g).  21 U.S.C.  331(e)  The FD&C Act and implementing 
regulations allow FDA to seek administrative, civil, and criminal penalties for violations 
of section 301 of the FD&C Act. 21 U.S.C.  303(a);  312.44(b)(1)(ix), 312.70(a), 
812.30(b)(4), 812.119(a), 56.121(b).  76 FR 256 at 265. 
 
27. Where can I find general information about FDA informed consent 
requirements? 
 
FDAs Office of Good Clinical Practice maintains a website with relevant information 
and links to other websites at 
http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/default.htm.    
 
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