Guidance for Industry 
and Investigators 
Safety Reporting Requirements 
for INDs and BA/BE Studies- 
Small Entity Compliance Guide 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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) 
 
 
 December 2012 
Drug Safety 
   
Guidance for Industry 
and Investigators 
Safety Reporting Requirements 
for INDs and BA/BE Studies- 
Small Entity Compliance Guide 
 
 
Additional copies are available from: 
Office of Communications 
Division of Drug Information, WO51, Room 2201 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave. 
Silver Spring, MD 20993-0002  
Phone: 301-796-3400; Fax: 301-847-8714 
druginfo@fda.hhs.gov  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
or 
 
 Office of Communication, Outreach and Development, HFM-40  
Center for Biologics Evaluation and Research 
 Food and Drug Administration 
1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448  
ocod@fda.hhs.gov; Phone: 800-835-4709 or 301-827-1800 
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) 
December 2012 
Drug Safety 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION.............................................................................................................1 
II.        BACKGROUND...............................................................................................................1 
III.      QUESTIONS AND ANSWERS.......................................................................................2 
  Contains Nonbinding Recommendations 
1
Guidance for Industry and Investigators  
Safety Reporting Requirements for INDs and BA/BE Studies-  
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  
 
This guidance is intended to help small businesses understand and comply with FDAs safety 
reporting regulations for human drug and biological products that are being investigated under an 
investigational new drug application (IND) and for drugs that are the subjects of bioavailability 
(BA) and bioequivalence (BE) studies that are exempt from the IND requirements.  The FDA has 
prepared this guidance in accordance with section 212 of the Small Business Regulatory 
Enforcement Fairness Act (Public Law 104-121). 
 
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 of September 29, 2010,2 FDA published a final rule that revised the IND 
safety reporting requirements for human drug and biological products under 21 CFR part 312, 
and added safety reporting requirements for persons conducting BA and BE studies under 21 
CFR part 320.  The final rule revised the definitions used for safety reporting and made clear 
when to submit expedited safety reports.  FDA issued a guidance for industry and investigators, 
entitled Safety Reporting Requirements for INDs and BA/BE Studies that is intended to help 
sponsors and investigators comply with the revised requirements for IND safety reporting (21 
CFR 312.32 and 312.64(b)) and safety reporting for BA/BE studies (21 CFR 320.31(d)).3  This 
                                                 
1 This guidance has been prepared by the Office of Medical Policy in the Center for Drug Evaluation and Research 
(CDER) in conjunction with the Center for Biologics Evaluation and Research (CBER) at the Food and Drug 
Administration.  
2 75 FR 59935, September 29, 2010. 
3 FDA guidance for industry and investigators on Safety Reporting Requirements for INDs and BA/BE Studies, 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
  Contains Nonbinding Recommendations 
 
Small Entity Compliance Guide is intended to complement that guidance and provide further 
clarification to small businesses by answering several frequently asked questions from 
investigators and sponsors regarding the amended safety reporting requirements.  
 
III.  QUESTIONS AND ANSWERS 
 
Question:  Do the amended safety reporting requirements for INDs and BA/BE studies 
apply to small entities? 
 
Answer:  Yes, small entities are required to follow the safety reporting regulations for INDs 
under 21 CFR 312.32, 312.64(b), and for BA/BE studies under 21 CFR 320.31(d)(3).   
 
Question:  What is a sponsor-investigator?  Do these safety reporting regulations apply to 
sponsor-investigators?   
 
Answer:  A sponsor-investigator, as defined in  312.3, is an individual who both initiates 
and conducts an investigation, and under whose immediate direction the 
investigational drug is administered or dispensed.  The term does not include any 
person other than an individual.  The requirements applicable to a sponsor-
investigator under this part [312] include both those applicable to an investigator and 
a sponsor.  Therefore, the amended IND safety reporting requirements under  
312.32 and 312.64(b) apply to a study conducted by a sponsor-investigator (often 
called an investigator-initiated study). 
 
Question:  How do I comply with the safety reporting requirements if I am a sponsor or 
sponsor-investigator conducting one trial and do not have access to all of the 
safety data from other entities (e.g., a commercial sponsor)? 
 
Answer:  For IND safety reporting, the Agency recognizes that a sponsor or sponsor-
investigator may not have access to the complete safety data maintained by a 
commercial sponsor, but sponsors and sponsor-investigators are required to evaluate 
all safety information that is available to them to determine whether the information 
qualifies for reporting (21 CFR 312.32).  For example, sponsors and sponsor-
investigators should examine reports in the scientific literature and perform literature 
searches to actively seek new safety information about the drug under investigation.  
To protect human subjects, the Agency recommends that entities that provide drug to 
or receive drug from other entities share safety information with each other.  
 
Question:  The regulations require reporting in an IND safety report when an aggregate 
analysis of specific events observed in a clinical trial indicates those events occur 
more frequently in the drug treatment group than in a control group (21 CFR 
312.32(c)(1)(i)(C)).  How do sponsors comply with this aggregate reporting 
requirement?   
 
Answer:  For IND safety reporting in general, sponsors should have a predefined safety 
monitoring plan that includes processes and procedures for the review, evaluation, 
  2 Contains Nonbinding Recommendations 
 
and management of safety information.  For reporting events in the aggregate, 
sponsors should perform an aggregate analysis of specific events both for individual 
studies and across all studies, including across INDs of the drug, to determine 
whether they meet the criteria for expedited reporting under 21 CFR 
312.32(c)(1)(i)(C) or 312.32(c)(1)(iv).  As discussed in the previous question, the 
sponsor should perform these analyses on the data available to them.   
 
Question:  Does this final rule change how sponsors report safety information in the IND 
annual report (21 CFR 312.33)? 
 
Answer:  No, the revised IND safety reporting requirements did not make any changes to the 
IND annual report requirements. 
 
Question:  Does this final rule change what investigators report to their institutional review 
board (IRB)? 
 
Answer:  No, the final rule did not change the reporting requirements to IRBs.  FDAs 
guidance on Adverse Event Reporting to IRBs  Improving Human Subject 
Protection provides recommendations on reporting to IRBs.4   
 
Question:  Where can I find additional information on the safety reporting requirements 
for INDs and BA/BE studies?   
 
Answer:  For information on the safety reporting requirements for INDs and BA/BE studies, 
see FDAs guidance for industry and investigators on Safety Reporting Requirements 
for INDs and BA/BE Studies.5 
 
Question:  If I have questions about how to comply with this rule, who should I contact at 
FDA? 
 
Answer:  For IND safety reporting, you should contact the review division in the Center for 
Drug Evaluation and Research or Center for Biologics Evaluation and Research that 
has responsibility for review of the IND.  For BA/BE safety reporting, you should 
contact OGD-PremarketSafetyReports@fda.hhs.gov. 
 
 
 
                                                 
4 Guidance for clinical investigators, sponsors, and IRBs on Adverse Event Reporting to IRBs  Improving Human 
Subject Protection, http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
5 See footnote 3 for the link to that guidance. 
  3