FOOD AND DRUG ADMINISTRATION 
COMPLIANCE PROGRAM  PROGRAM  7348.809 
 
 
CHAPTER 48: Bioresearch Monitoring 
 
SUBJECT:  IMPLEMENTATION DATE: 
Institutional Review Boards  09/26/2018 
DATA REPORTING 
PRODUCT CODES  PRODUCT/ASSIGNMENT CODES 
FACTS/eNSpect does not require  09809:  Foods 
product codes for Bioresearch 
41809:  Biologics- Human Cellular, Tissue and 
Monitoring inspections. 
Gene Transfer 
42809:  Biologics- Blood and Blood Products 
45809: Biologics- Vaccines and Allergenic 
Products 
48809: Human Drugs 
83809: Medical Devices 
98809: Tobacco Products 
 
FIELD REPORTING REQUIREMENTS: 
Copies of all establishment inspection reports (EIRs) complete with attachments, exhibits, 
and any related correspondence are to be submitted promptly to the Center (usually the 
reviewer in the Centers Bioresearch Monitoring (BIMO) program identified in the 
assignment). 
 
All EIRs should be completed in accordance with FMD No. 86, Establishment Inspection 
Report (EIR) - Inspection Conclusions and District Decisions 
(https://www.fda.gov/downloads/ICECI/Inspections/FieldManagementDirectives/UCM382035.pdf) and 
the Investigations Operation Manual (IOM), Chapter 5, Establishment Inspections. 
(http://www.fda.gov/downloads/ICECI/Inspections/IOM/UCM150576.pdf). 
 
When a Form FDA 483, Inspectional Observations (483), is issued, a copy should be 
forwarded to the Center contact (by facsimile or e-mail, or filed in a shared folder, as 
agreed to with the Center), as soon as possible, generally within 3 business days after 
being issued. 
  Date of Issuance: 09/26/2018  Page 1 of 59   
PROGRAM  7348.809 
 
Contents 
PART I  BACKGROUND ............................................................................................................... 4 
PART II - IMPLEMENTATION ...................................................................................................... 6 
     Objective ......................................................................................................................................... 6 
     Program Management Instructions ................................................................................................. 6 
     Types of Inspections ....................................................................................................................... 7 
     Communication between the Centers and the ORA BIMO Divisions ......................................... 10 
     Responsibilities of Field Investigators, Inspection Team Leaders, and Headquarters 
Participants ........................................................................................................................................... 12 
     Resolution of Disagreements ........................................................................................................ 15 
PART III - INSPECTIONAL .......................................................................................................... 16 
     Operations ..................................................................................................................................... 16 
     Reporting ....................................................................................................................................... 17 
     Establishment Inspections ............................................................................................................. 18 
     Prior Notification of Intent to Inspect ........................................................................................... 18 
     Refusal to Inspect .......................................................................................................................... 19 
     Subsequent Related Sponsor/Investigator Inspections ................................................................. 19 
     IRB Registration ............................................................................................................................ 19 
     IRB Membership ........................................................................................................................... 20 
     Meetings ........................................................................................................................................ 21 
       Written Procedures .................................................................................................................... 23 
       Initial IRB Review of Research ................................................................................................ 27 
       Continuing IRB Review of Research ........................................................................................ 29 
       Adverse Event Reporting .......................................................................................................... 30 
       IRB Reporting to the Clinical Investigator and the Institution ................................................. 31 
       Expedited Review ...................................................................................................................... 32 
       Exception from Informed Consent ............................................................................................ 33 
       Informed Consent ...................................................................................................................... 34 
       Pediatric Studies  General ....................................................................................................... 37 
       Electronic Records and Electronic Signatures .......................................................................... 40 
       Central IRBs/ Independent IRBs ................................................................................................ 42 
  Date of Issuance: 09/26/2018  Page 2 of 59   
PROGRAM  7348.809 
       Investigational New Drug (IND) Application / Investigational Device Exemption (IDE) 
Status 43 
PART IV - ANALYTICAL .......................................................................................................... 46 
PART V - REGULATORY/ADMINISTRATIVE STRATEGY ................................................... 47 
     Administrative Guidance .............................................................................................................. 47 
     Regulatory Guidance ..................................................................................................................... 48 
     Follow-Up Inspections .................................................................................................................. 53 
     Post-Inspection Information Sharing ............................................................................................ 54 
PART VI  REFERENCES, ATTACHMENTS, AND PROGRAM CONTACTS ....................... 55 
     References ..................................................................................................................................... 55 
     Program Contacts .......................................................................................................................... 56 
PART VII - HEADQUARTERS RESPONSIBILITIES ................................................................ 58 
     Centers ........................................................................................................................................... 58 
     ORA/OFFICE OF ENFORCEMENT AND IMPORT OPERATIONS (OEIO)/DIVISION OF 
ENFORCEMENT (DE) ....................................................................................................................... 58 
     ORA/OFFICE OF BIORESEARCH MONITORING OPERATIONS (OBIMO) ...................... 58 
     Office of Good Clinical Practice, Office of the Commissioner .................................................. 59 
Change History 
Item  Change  Date 
Update  Updated administrative, organizational and computer systems information  04/16/2018 
Update  Updated VA address for notification to remove Suite 574 at their request.  09/26/2018 
  Date of Issuance: 09/26/2018  Page 3 of 59   
PROGRAM  7348.809 
 
PART I  BACKGROUND 
 
Since the Investigational New Drug (IND) Regulations went into effect in 1963, the Food 
and Drug Administration (FDA) has exercised oversight of the conduct of clinical studies 
involving  FDA-regulated  products.  The  Bioresearch  Monitoring  Program  (BIMO)  was 
established in 1977 by a task force that included representatives from the drug, biologic, 
device, animal drug, and food areas. 
 
Compliance programs (CP) were developed to provide uniform guidance and specific 
instructions for inspections of Clinical Investigators (CP 7348.811), Sponsors (CP 
7348.810), In-Vivo Bioequivalence facilities (CP 7348.001), Institutional Review Boards 
(CP 7348.809), and Nonclinical Laboratories (CP 7348.808). 
 
The Kefauver-Harris Amendments to the Federal Food, Drug, and Cosmetic Act (the 
FD&C Act) increased FDAs regulatory authority over the clinical testing of new drugs. 
With the passage of the Kefauver-Harris Amendments, the Medical Device Amendments 
of 1976, and other legislation, FDA has been provided additional safeguards to protect the 
rights, safety and welfare of human subjects who participate in investigational trials 
involving FDA-regulated articles. 
 
Congress has given a mandate to institutional review boards (IRBs) to oversee research 
involving human subjects that is being conducted using FDA-regulated articles.  FDA 
has published regulations that set forth standards and procedures for IRBs in 21 CFR 
Part 56, which became a final rule in the Federal Register (FR) on January 27, 1981 (46 
FR 8958  Protection of Human Subjects; Standards for Institutional Review Boards for 
Clinical Investigators).  The requirements for informed consent, which are found in 21 
CFR Part 50,1 were published as a final rule in the Federal Register (FR) on the same 
date (46 FR 8942, January 27, 1981; Protection of Human Subjects; Informed 
Consent). 
 
The above regulations require IRB review of all clinical investigations using test articles 
regulated by FDA under sections 505(i) and 520(g) of the FD&C Act, as well as clinical 
investigations conducted in support of applications for research or marketing permits for 
other articles regulated by the agency.  The rewrite of the investigational new drug (IND) 
application regulations on March 19, 1987, includes informed consent and IRB review as 
conditions for exempting from the IND requirements certain studies involving marketed 
drugs (21 CFR 312.2(b)(1)(iv)).  Similar conditions are included in the IDE regulations (21 
CFR 812.2(b)) for abbreviated requirements of certain categories of device investigations. 
 
On June 18, 1991, the Federal Policy for the Protection of Human Subjects; Final Rule 
(Common Rule) was published in the Federal Register (FR) (56 FR 28003). 2   These 
regulations set forth requirements for the protection of human subjects involved in 
 
 
1           www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm113818.htm 
2           www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm118862.htm 
  Date of Issuance: 09/26/2018  Page 4 of 59   
PROGRAM  7348.809 
 
research conducted or funded by 15 Federal departments and agencies, including the 
Department of Health and Human Services (DHHS).  In the same issue of the FR (56 FR 
28025), amendments to the FDA regulations on IRBs and on informed consent 
requirements were published; these amendments bring 21 CFR Parts 50 and 563 into 
conformity with the above Federal Policy.  Existing FDA regulations governing the 
protection of human subjects share a common core with the Federal Policy, and 
implement the fundamental principles embodied in that policy.  The Federal Policy and the 
FDA amendments of 21 CFR Parts 50 and 56 became effective on August 19, 1991.4 
 
Please note that there are some differences between the Department of Health and 
Human Services (DHHS) human subject protection regulations found at 45 CFR 46 and 
the FDA human subject protection regulations found at 21 CFR Parts 50 and 56.  IRB 
written procedures that are compliant with the DHHS requirements will not necessarily be 
compliant with FDA regulations, i.e., IRBs that are subject to 45 CFR Part 46 will need to 
ensure that their SOPs are in compliance with both sets of regulations.  FDA inspections, 
however, should only focus on FDAs regulations. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3           www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm118296.htm 
4          
http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm118893.htm 
  Date of Issuance: 09/26/2018  Page 5 of 59   
 
 
 
PROGRAM  7348.809 
 
 
PART II - IMPLEMENTATION 
 
    Objective 
The objectives of the BIMO Program are: 
 
A.  To protect the rights, safety, and welfare of subjects involved in FDA-regulated 
clinical trials; 
B.  To verify the accuracy and reliability of clinical trial data submitted to FDA in 
support of research or marketing applications; and 
C. To assess compliance with FDAs regulations governing the conduct of clinical 
trials. 
 
The purpose of this compliance program is to provide instructions to the field and Center 
personnel for conducting inspections of IRBs and recommending associated regulatory 
and/or administrative actions. 
 
    Program Management Instructions 
A.  Coverage -- This program provides for the inspection of domestic IRBs that 
review and approve investigational studies involving human subjects and FDA- 
regulated articles (e.g., drugs including biologics, food or color additives, and 
medical devices). 
B.  Types of IRBs -- There are many types of IRBs.  They can be 
categorized as government, independent, hospital, academic, or 
central. 
C.  Due Dates -- All assignments will be issued by the Centers and will have a ninety 
(90) day completion date unless otherwise indicated. 
D. Centers should give consideration to the following factors when selecting 
IRBs for inspection: 
i.  IRBs for which the previous inspection was classified Official Action 
Indicated (OAI) (e.g., sanctions imposed, Warning letter issued). 
These IRBs should be re- inspected within one year (i.e., soon after 
the last Warning Letter correspondence was issued); 
ii.  IRBs that have never been inspected before; and 
iii.  IRBs that were recently established or have limited experience 
reviewing FDA- regulated research (for example, an IRB that 
previously only reviewed social behavioral research begins to 
review investigations of FDA-regulated articles). 
 
E.  Centers may pursue special IRB inspection initiatives, for example, inspecting IRBs 
that review particular types of studies, such as first-in-human trials, studies involving an 
exception from informed consent, or studies involving vulnerable populations (e.g., 
Alzheimers patients, pediatric populations).  Any unique focus of an inspection will 
  Date of Issuance: 09/26/2018  Page 6 of 59   
PROGRAM  7348.809 
 
generally be discussed in the assignment. 
 
 
    Types of Inspections 
FDA will periodically inspect each IRB that reviews research involving FDA-regulated 
articles.  The inspections will be either routine or directed. 
 
A.  Routine Inspections 
 
The assigning Center will provide evidence of FDA jurisdiction over the IRB by 
consulting the IRB Registration database maintained by the Office for Human 
Research Protections (OHRP) for the name and address of the institution, and when 
available, the name of a contact person at the IRB.  The assigning Center may 
provide a specific protocol to review during the inspection, when available. 
 
Those IRBs found to have no objectionable conditions (NAI classification) or 
objectionable conditions that do not meet the threshold for regulatory action 
(VAI classification) will usually be assigned for reinspection in 5 years. 
 
B.  Directed Inspections 
 
A directed inspection may be assigned when the assigning Center receives 
information that calls an IRBs practices into question.  A directed inspection may 
be limited to one area of concern or assigned to cover the entire compliance 
program. 
 
IRBs found to have major deficiencies (OAI classification) will usually be 
assigned for reinspection within one year to confirm that adequate corrections 
have been made. 
 
C.  Inspection Assignments 
 
i.  Center BIMO units issue inspection assignments of IRBs.  The Centers 
will identify IRBs to be inspected from sources such as the IRBs Official 
Establishment Inventory (OEI) file maintained by ORA BIMO Division 
offices, Center files (including complaints), the IRB Registration 
database5 maintained by the Office for Human Research Protections 
(OHRP), Web searches, journal articles, research permits, and 
marketing applications submitted to the Center. 
 
 
 
5 https://ohrp.cit.nih.gov/search/irbsearch.aspx?styp=bsc 
  Date of Issuance: 09/26/2018  Page 7 of 59   
PROGRAM  7348.809 
 
 
ii.  To ensure the appropriate and efficient use of FDA resources, IRB 
assignments will follow Field Management Directive (FMD) No. 17, 
ORA Field Assignments - Guidelines for Issuance by Headquarters, 
whether from an ORA headquarters unit or a Center. 
(http://www.fda.gov/ICECI/Inspections/FieldManagementDirectives/UCM0  
56651). 
 
iii.  The assignment should identify: 
 
a.  The program assignment code (PAC), Field Accomplishments and 
Compliance  Tracking  System  (FACTS)  number  or  eNSPect 
number, and Firm Establishment Identification (FEI) number, if 
known; 
 
b.  The name, address and phone number of the IRB, when 
available, to be inspected; 
 
c.  The type and purpose of the inspection (e.g., routine or directed 
inspection).  Occasionally, some Centers will designate sub-types 
(e.g., Surveillance, For Cause, Complaint, or OAI follow-up); 
 
d.  The background materials that are being sent from the Center 
to facilitate the inspection (e.g., information obtained from 
OHRPs IRB registry); 
 
e.  Specific issues or concerns (if applicable) that need to be 
addressed during the inspection; 
 
f.  The due date for the Center contact to receive the completed EIR; 
 
g.  The headquarters address where the EIR should be sent; and 
 
h.  The name, telephone number, fax number, and email of the Center 
contact(s). 
 
Note:  For any inspection attempt where it is determined the IRB is out of 
business or it is been determined that FDA does not have jurisdiction (e.g., 
IRB is not reviewing FDA-regulated studies), please contact the Center that 
issued the assignment in order to discuss converting the inspection request 
(Operation 12) to an Operation 13 designation. 
  Date of Issuance: 09/26/2018  Page 8 of 59   
PROGRAM  7348.809 
 
 
iv.  Inspection of the Department of Veterans Affairs (VA) as the IRB of 
FDA-regulated clinical trials. 
 
a.  Pre-Inspection 
1.  Center.  The BIMO unit in the assigning Center will 
provide the VAs office of Research Oversight (ORO)  
with written notification of FDAs intention to inspect a VA 
IRB program at the time an assignment is being issued to 
the field.  Information on the VAs ORO is at:  
http://www.va.gov/ORO/about_us.asp#sthash.ABGMdXOR.d  
puf. 
 
The notice should be sent to: 
 
Executive Director 
Office of Research Oversight (10R) Veterans Health 
Administration Department of Veterans Affairs 
810 Vermont Avenue, N.W. 
Washington, D.C. 20420 
2.  Field.  The field investigator will contact the VA IRB 
program before the inspection, as they would any other 
IRB they are assigned to inspect. 
 
b.  Post-Inspection 
1.  The Center will provide the VAs ORO redacted copies of 
post-inspection correspondence issued to VA IRB programs 
that include a discussion of deficiencies noted during the 
inspection (including the Form FDA 483).  Such materials 
should be sent to: 
 
Executive Director 
Office of Research Oversight (10R) Veterans Health 
Administration Department of Veterans Affairs 
810 Vermont Avenue, N.W. 
Washington, D.C. 20420 
 
c.  If, following receipt of the FDA correspondence, the VA-ORO 
requests a copy of the EIR, a redacted copy of the report will be 
provided to VA-ORO by the ORA BIMO Division offices. 
 
v.  All headquarters and field personnel who become aware of complaints or 
problems related to an IRB are encouraged to refer them to the 
  Date of Issuance: 09/26/2018  Page 9 of 59   
PROGRAM  7348.809 
 
appropriate Center contact with a recommendation for inspection.  All 
recommendations should include the following: 
 
a.  The name and address of the IRB; 
b.  If available, the name(s) of the test article(s) being investigated, 
and the application for research or marketing permit number(s); 
and 
c.  The basis for the recommendation and any relevant 
documentation. 
 
 
 
    Communication between the Centers and the ORA BIMO Divisions 
 
Inspectional observations documenting that an IRB is not operating in 
compliance with the regulations in 21 CFR Parts 50 and 56 may be used as 
evidence for taking appropriate administrative and/or enforcement actions. 
Ensuring that the evidence collected to support such actions is both 
appropriate and adequate requires that communication lines between the 
ORA BIMO Division offices and the Center be established early and 
maintained throughout the entire process, i.e., until post-inspectional 
correspondence is issued by the Center. 
 
i.  Prior to an inspection 
 
a.  The Center issues an assignment that includes contact information 
for the BIMO reviewer. 
 
b.  The field investigator contacts the BIMO reviewer: 
 
1.  Upon receipt of the assignment, to establish initial contact 
and/or provide an inspection start date; 
2.  When the inspection date is firmly set, to alert the BIMO 
reviewer and/or a back-up to be available and to establish 
the most appropriate means of contact for both the 
investigator and the BIMO reviewer/back-up; 
3.  To obtain any new information that may change the focus of the 
inspection; and 
4.  To coordinate inspection arrangements if Center personnel 
plan to participate in the inspection. 
 
ii.  Special Considerations 
  Date of Issuance: 09/26/2018  Page 10 of 59   
PROGRAM  7348.809 
 
 
a.  In particular cases, the Center may arrange for a consultative 
teleconference immediately prior to the inspection(s) if, for 
example, the complexity of issues, urgency of feedback, 
compliance history, etc., trigger the need to discuss issues further. 
Such conference calls are most likely when the agency encounters 
special situations (e.g., directed inspections where pertinent 
information is either complex or needs discussion between the 
Center and the field).  Unless information necessitating this 
discussion emerges after the assignment is issued, the 
assignment will usually include information as to when this 
teleconference will occur. 
 
b.  These teleconferences may include the following participants, as 
warranted and feasible: 
 
1.  BIMO reviewer (and supervisor/division director or other staff, as 
appropriate); 
 
2.  Lead application reviewer (along with branch and 
division chiefs, if appropriate) or other application 
reviewers as needed; and 
 
3.  ORA Field investigator(s) assigned to the inspection(s), the 
ORA BIMO Program Expert (PE) (when not yet specifically 
assigned), and ORA BIMO management and staff, as 
appropriate. 
 
iii.  During an Inspection 
 
a.  The BIMO reviewer contacts the field investigator if significant 
new information becomes available. 
 
b.  The field investigator contacts the BIMO reviewer or designated 
back-up person if the field investigator: 
 
1.  Needs advice or clarification.  The BIMO reviewer and field 
investigator should strive to be accessible to one another as 
much as possible during the time that the inspection is 
ongoing. 
  Date of Issuance: 09/26/2018  Page 11 of 59   
PROGRAM  7348.809 
 
2.  Uncovers other evidence of concern warranting discussion 
with Center staff. 
iv. After an Inspection 
 
a.  As soon as possible but within three (3) business days after 
conclusion of the inspection, the field investigator forwards to the 
BIMO reviewer (by facsimile, e- mail, or placement in the 
appropriate shared drive folder) any Form FDA 483 (commonly 
referred to as a 483) that is issued. 
 
b.  The field investigator/ORA BIMO Division will forward as soon 
as possible to the BIMO reviewer a copy of any written 
response to the 483 by the inspected party.  The BIMO 
reviewer will forward to the field investigator, a copy of any 
response to a 483 that does not appear to have been shared 
with the inspecting ORA BIMO Division.  If desirable, the field 
investigator provides Center contact information so that the 
response to the 483 can be sent directly to the Center for 
review in addition to sending it to the field inspector/ORA BIMO 
Division. 
 
 
c.  The BIMO reviewer consults with the field investigator and their 
supervisor as needed when reviewing the EIR. 
 
 
d.  If the Centers final classification is different from the one 
recommended by the field, the Center should ensure that ORA 
BIMO Division personnel are aware of the change and reasons for 
the change.  The Center promptly forwards to the field investigator 
and other appropriate ORA BIMO Division management by e-mail, 
if possible, copies of post-inspectional correspondence issued to 
the inspected party. 
 
e.  The Center enters the final classification. 
 
 
    Responsibilities of Field Investigators, Inspection Team Leaders, and Headquarters 
Participants 
 
i.  Solo inspections 
 
When conducting solo inspections, the field investigators responsibilities 
include, but are not limited to, the following: 
  Date of Issuance: 09/26/2018  Page 12 of 59   
PROGRAM  7348.809 
 
 
a.  Scheduling and conducting the assigned inspection; 
 
b.  Discussing with ORA BIMO Division management the need to 
adjust the workload in order to meet specific deadlines or goals 
(e.g., goals established as part of the Prescription Drug/Medical 
Device User Fee Acts); 
 
c.  Communicating inspectional observations with the institutional 
officials and IRB staff during the course of the inspection, as 
appropriate; 
 
d.  Communicating inspectional observations and issues with the 
Center contact during the course of the inspection and 
review, as appropriate; 
 
e.  Preparing, issuing, and discussing the items listed on the 483 
with the IRB at the close of the inspection; 
 
 
f.  Preparing and submitting an EIR within FDA timelines; and 
 
g.  When appropriate, participating in discussions with the Center 
regarding potential changes in the EIR classification. 
 
ii.  When conducting team inspections 
 
 
When inspections are conducted by a team, a field investigator serves as 
inspection Team Leader who is responsible for the cooperative conduct of the 
inspection.  The Team Leaders responsibilities include, but are not limited to 
the following (see also Investigations Operations Manual (IOM) at  
http://www.fda.gov/ICECI/Inspections/IOM/default.htm, Chapter 5, section 
5.1.2.5- Team Inspections): 
 
a.  Scheduling and coordinating the participation of team members; 
 
b.  Discussing inspection plans and objectives with team members; 
 
1.  Assuring that team members understand their roles and 
responsibilities in conducting the inspection, taking 
  Date of Issuance: 09/26/2018  Page 13 of 59   
PROGRAM  7348.809 
 
notes, collecting documentation, preparing sections of 
the inspection report and exhibits, and signing the report; 
 
c.  Setting team policy regarding communications with institutional 
officials and/or the IRB staff; 
 
d.  Discussing personal conduct with team members as necessary; 
and 
 
e.  Resolving disputes or differences of opinion among team 
members, including items to be listed on the 483.  If an 
agreement cannot be reached during the inspection, the final 
items included on a 483 will be decided by the ORA field 
investigator. 
 
 
iii.  Headquarters Participants 
 
A headquarters participant is a member of the inspection team who serves 
in a compliance or scientific advisory capacity to the Team Leader.  The 
headquarters participants responsibilities include, but are not limited to, the 
following: 
 
a.  Obtaining training on inspection conduct and behavior prior to 
participating in inspections; 
 
b.  Obtaining inspection credentials from the FDA Office of Security 
Operations by completing Form FDA 2115) available at 
http://inside.fda.gov:9003/downloads/Administrative/Forms/FDA/UCM0307 
i. 
99.pdf; 
c.  participate in field inspections and submitting the completed Inspection 
Participation Request Form; 
 
d.  Providing information pertinent to the inspection; 
 
e.  Attending pre-inspection discussions, if and when requested by the 
Team 
i.  Leader; 
 
f.  Participating in the on-site inspection as permitted by agency 
priorities; and 
  Date of Issuance: 09/26/2018  Page 14 of 59   
PROGRAM  7348.809 
 
g.  Providing guidance and expertise during the inspection and 
completing inspection tasks as directed by the Team Leader 
(e.g., auditing documents, preparing inspection notes and 
specific sections of the establishment inspection report within 
guidelines and timeframes). 
 
 
    Resolution of Disagreements 
If there is disagreement among members of the inspection team, the issue should be 
discussed off-site and resolved cooperatively.  Any difficulties in conducting team 
inspections should be discussed with both ORA BIMO Division management and the 
assigning Center, and, if not resolved, immediately referred to the ORAHQ BIMO Inspection 
POC. 
  Date of Issuance: 09/26/2018  Page 15 of 59   
PROGRAM  7348.809 
 
PART III - INSPECTIONAL 
 
  Operations 
 
 
ORA BIMO Divisions are encouraged to identify IRBs that have not been recently 
inspected (e.g. no inspection within the past 5 years).  The ORA BIMO Division should 
make efforts to determine the type of studies that are being reviewed by the IRB and notify 
the program contact for the appropriate Center. 
 
 
Inspections involve an evaluation of the IRBs written procedures and records to determine 
the IRBs compliance with 21 CFR Parts 50 and 56.  In general, assignments are issued 
from Headquarters and may identify several studies (generally no more than three) for 
inspection (in order to establish that FDA-regulated research has been reviewed by the 
IRB).  The field investigator should evaluate these studies during the inspection unless 
otherwise directed by the assignment. 
A.  Criteria for Selecting Studies 
If the assignment does not specify specific studies for inspection, the field investigator 
should select studies that reflect current IRB practices, preferably ones that were 
initially approved within the previous three years and are presently ongoing. 
Additionally, it might be beneficial for the field investigator to choose one study that 
has been through a continuing review cycle.  Generally, the studies should be 
selected using the following priority: 
i.  Studies specified in the inspection assignment, if any; 
ii.  Studies employing novel regulatory mechanisms, such as exploratory 
IND studies6, or involving cutting edge technologies (e.g., cell, gene, 
and tissue-based therapies); 
iii.  Studies involving vulnerable populations (e.g., pediatric studies, 
studies involving an exception from informed consent under 21 CFR 
50.24); 
iv.  Device studies that involve the IRBs determination as to whether a 
device study is significant risk (SR) or non-significant Risk (NSR); 
v.  Other safety and efficacy studies of investigational new drugs, devices 
and/or biologics performed under IND, IDE, or Biologic-IND 
applications; 
vi.  Studies where privacy/confidentiality protections may be of particular 
concern (e.g., HIV studies, etc.); 
vii.  Studies for which no FDA research permit is required, e.g., certain 
marketed drugs and non-significant risk devices; and 
viii.  Comparison studies of one or more marketed products with an 
investigational product. 
 
 
 
6             www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM078933.pdf 
  Date of Issuance: 09/26/2018  Page 16 of 59   
PROGRAM  7348.809 
 
B.  Time Period 
Selection of studies reviewed by the IRB during the 3 years prior to the inspection 
would generally assure that the IRBs records for those studies (e.g., meeting 
minutes, membership rosters, continuing review records) are available and that the 
inspection covers the IRBs current review procedures and practices.  However, if 
an IRB has revised its written procedures within the past 3 years, only studies 
reviewed by the IRB since the date the procedures were revised should be included 
in the inspection in order to avoid citing the IRB for procedures that are no longer 
applicable. For very small IRBs that presently have no active FDA-regulated 
protocols, the field investigator may need to evaluate protocols that have been 
closed within the last 3 years. 
 
If an IRB inspection assignment includes studies that are linked to specific marketing 
applications or studies that have been placed on clinical hold, and which were 
reviewed prior to a revision in the IRBs procedures, the field investigator should 
consult with the Center as to whether a particular study should be included in the  
inspection 
 
    Reporting 
A.  The ORA BIMO Divisions are responsible for conducting inspections and 
preparing EIRs.  All reports, including copies of exhibits, are to be submitted 
directly to the Center initiating the assignment. 
 
B.  When a duplicate IRB assignment has been issued or an inspection was 
recently completed, ORA BIMO Divisions should contact the assigning 
Center for instructions prior to initiating the inspection. 
 
C. The EIR should contain the headings as prescribed in the Investigations Operations 
Manual (IOM). 7 Centers encourage submitting electronic inspectional documents, 
if possible. Any adverse findings should be fully explained and documented in the 
EIR. 
 
D. A 483 should be issued under this program when deviations from the requirements in 
21 CFR Parts 50, 56, 312, 812, (and 814 when applicable) are observed. 
 
NOTE:  Reports must include the name and address of the IRB Chairperson and should 
include the name and address of the head of the institution at which the IRB is located. 
 
E.  Documents that should be collected are: 
 
 
 
 
7       http://www.fda.gov/ICECI/Inspections/IOM/default.htm 
  Date of Issuance: 09/26/2018  Page 17 of 59   
PROGRAM  7348.809 
 
i.  IRB written procedures 
ii.  IRB membership rosters for the time period covered by the inspection 
iii.  Copies of IRB minutes which show 
  Recent practices 
  Violative procedures 
  Approval and follow-up on tracked studies 
iv.  Records of tracked studies 
  Protocol and Investigator Brochure - routine collection of protocols 
and investigators brochures is not necessary, unless there are 483 
observations involving these areas. 
  Consent form 
  Correspondence between the IRB and the clinical investigator 
  Correspondence between the IRB, FDA, and appropriate institutional 
officials that report any unanticipated problems involving risk to human 
subjects or others and any instances of serious or continuing 
noncompliance with these regulations. 
 
Note: Record collection requirements vary from Center to Center. Please contact the BIMO 
reviewer before collecting records for the inspection. 
 
F.  For an inspection recommended to be No Action Indicated (NAI), please follow 
the guidelines outlined in the inspection assignment for collecting records and 
documents. 
 
G.  Please remember to collect records and documents related to all 483 
observations to support the violations noted on the form. 
 
    Establishment Inspections 
The inspections should be guided by the regulations found in 21 CFR Parts 50, 56, 312, 812, and 814. 
 
 
    Prior Notification of Intent to Inspect 
The FDA field investigator shall contact the institution to confirm the name and location of 
the IRB Chairperson to determine appropriate time for the inspection to assure that 
responsible individuals are present and that IRB records are available.  The field 
investigator shall confirm that the IRB oversees FDA-regulated research. The primary 
purpose of such prior notice is efficient use of the field investigators time. 
 
ORA BIMO Division management may elect to conduct unannounced inspections with 
approval of the assigning Center, if conditions warrant. 
  Date of Issuance: 09/26/2018  Page 18 of 59   
PROGRAM  7348.809 
 
 
Participation in an IRB meeting (Optional). FDA field investigators may consider whether 
to ask the IRB to allow them to attend a regularly scheduled meeting of the IRB.  The IRB 
would be expected to follow the agenda for the meeting and the IRBs customary 
procedures.  Attendance at the IRBs scheduled meeting would be for purposes of 
observing the IRBs processes and procedures, not to answer questions.  If the IRB has 
questions about FDA regulations or policy, the IRB should be referred to the Center contact 
or to the Office of Good Clinical Practice. 
 
 
    Refusal to Inspect 
If the institution refuses to permit either the inspection, access to records, or copying of 
records, or if delays instituted by the inspectee are such that they constitute a de facto 
refusal, inform your supervisor so he/she can advise the assigning Center promptly.  Send 
a follow-up INFO FAX to the listed Center and ORAHQ BIMO Inspection POC.  IOM 5.2.5 
provides additional guidelines. 
 
 
    Subsequent Related Sponsor/Investigator Inspections 
An IRB inspection may reveal significant regulatory deviations which may lead to clinical 
investigator and/or sponsor inspections.  ORA BIMO Divisions may carry out such 
inspections after obtaining the necessary instructions from the appropriate Center.  The 
Center may issue these assignments as directed inspections. 
 
 
    IRB Registration 
Effective September 14, 2009, every IRB that reviews FDA-regulated research is required 
to register and/or update the IRBs information on the registration Web site maintained by 
OHRP at least every three (3) years (see 21 CFR 56.106). 
 
Information at this site includes the organization with which they are registered (OHRP, 
FDA, or both) and their present registration status. 
A.  Determine whether the IRB has registered or updated its information 
(https://ohrp.cit.nih.gov/search/irbsearch.aspx?styp=bsc) as required by 21 CFR 56.106. 
 
BIMO headquarters staff also has access to the full registration information 
which includes: 
i.  Contact information (such as addresses and telephone number 
ii.  The numbers of active protocols involving FDA-regulated products 
reviewed during the preceding 12 months; and 
iii.  A description of the types of FDA-regulated products involved in the 
protocols reviewed. 
  Date of Issuance: 09/26/2018  Page 19 of 59   
PROGRAM  7348.809 
 
This information should be included in the assignment or can be requested as 
needed. 
 
The IRB registration requirements will make it easier for FDA to inspect IRBs and to 
convey information to IRBs8. 
 
 
    IRB Membership 
A.  Determine whether the IRB membership has the representation required by 21 CFR 
56.107. 
 
Each IRB shall have at least five members with varying backgrounds to promote 
complete and adequate review of research activities commonly conducted by the 
institution.  The IRB shall be sufficiently qualified through the experience and 
expertise of its members. 
 
i.  An IRB must possess the professional competence to review the research 
activities it considers; 
ii.  An IRB may not be made up of members of one profession; 
iii.  An IRB shall include at least one member whose primary concerns are in the 
scientific area and at least one member whose primary concerns are in non- 
scientific area; and 
iv.  An IRB shall include at least one member who is not otherwise affiliated with 
the institution and who is not part of the immediate family of a person who is 
affiliated with the institution 
If an IRB regularly reviews research that involves a vulnerable category of subjects, 
such as children, prisoners, pregnant women, or handicapped or mentally disabled 
persons, consideration should be given to the inclusion of one or more individuals 
who are knowledgeable about and experienced in working with those subjects.  In 
addition to possessing the professional competency necessary to review the 
specific research activities, the IRB should be able to ascertain the acceptability of 
proposed research in terms of institutional commitments and regulations, applicable 
law, and standards or professional conduct and practice. 
B.  Determine that no IRB member participates in the deliberation or voting during the 
initial or continuing review of any study in which that IRB member has a conflicting 
interest except to provide information requested by the IRB (21 CFR 56.107(e)). 
 
C. Determine if, except when an expedited review procedure was used, the IRB 
reviewed proposed research at convened meeting when a majority of the IRB 
members were present, including at least one member whose primary concerns are 
in non-scientific areas (21 CFR 56.108(c)). 
 
 
 
8 Final Rule IRB Registration Requirements - http://edocket.access.gpo.gov/2009/pdf/E9-682.pdf 
  Date of Issuance: 09/26/2018  Page 20 of 59   
PROGRAM  7348.809 
 
i.  Any IRB member with a conflict of interest should not be counted towards 
the majority for any agenda item for which the member has a conflict. 
ii.  The total number of eligible voting members present may change from one 
agenda item to the next.  Majority may be lost if: 
 
a.  the total number of IRB members voting on a particular agenda item 
falls below the required number of members that must be present for 
the IRB to conduct business; or 
b.  at least one of the IRB members counting towards majority does not 
have primary concerns in non-scientific areas. 
 
iii.  Although 21 CFR 56.107(a) does not explicitly address the use of 
alternate members, the regulations allow an IRB to use alternate 
members in case one or more of the regular members is absent or is not 
eligible for considering a proposal because of a conflict of interest.  FDA 
recommends that the names of any alternate members be included on 
the list of IRB members required by 21 CFR 56.115(a)(5). 
 
iv.  Although not regulatory requirements, FDA recommends that, if alternate 
members are used: 
 
b.  Alternate members should be appointed in advance and should 
possess the same area of expertise as primary IRB members, e.g., 
cardiology, oncology, or endocrinology specialties 
c.  Alternate members should be listed on the IRB roster and identified as to 
the primary IRB members for whom they may substitute at convened 
meetings. 
d.  IRB minutes should record when alternate members act in the absence 
of primary members. 
e.  Alternate members should receive the same information as primary 
members. 
 
    Meetings 
A.  21 CFR 56.108(c) requires that, except when an expedited procedure is used (see 21 
CFR 56.110), the IRB must review research at convened meetings at which a  
majority of the members of the IRB are present, including at least one member whose 
primary concerns are in non-scientific areas.  For research to be approved, the 
research must receive the approval of a majority of those members present at the 
meeting. 
 
Majority (often referred to as quorum) is the minimum number and type of IRB 
members that must be present for the IRB to conduct business.  IRBs often 
calculate majority by using the half-plus-one technique.  This technique works well 
for IRBs with an even number of IRB members.  For example, if the total IRB 
membership is 10, then majority is 6 (half of 10 is 5 +1 = 6). 
  Date of Issuance: 09/26/2018  Page 21 of 59   
PROGRAM  7348.809 
 
 
However, if the IRB has an odd number of members, then majority should be 
calculated by taking half of the total number of IRB members, then rounding up to 
the next whole number.  For example, if the IRB membership is 15, then majority is 
8 (half of 15 is 7.5, and rounding up to the next whole number is 8). 
 
A majority must be maintained at all times throughout the meeting in order for the 
IRB to conduct business 
 
For the selected studies, determine: 
 
i.  whether the IRBs written procedures address how a majority is calculated. 
 
ii.  whether the IRBs meeting minutes document that a majority of voting IRB 
members were present at each meeting, and that the majority was 
maintained throughout the meeting for each vote taken on FDA-regulated 
studies. 
 
iii.  21 CFR 56.107(e) prohibits a member from participating in the initial or 
continuing review of any project in which the member has a conflicting 
interest, except to provide information requested by the IRB. 
 
For the selected studies, determine: 
a.  conducting its initial and continuing review of research and for reporting 
findings and actions to the investigator and institution; 
b.  if a member has a conflict of interest, it is up to the IRB to decide 
whether that member needs to leave the room during the IRBs 
deliberations and voting. 
 
B.  21 CFR 56.107(e) prohibits a member from participating in the initial or continuing 
review of any project in which the member has a conflicting interest, except to 
provide information requested by the IRB. 
 
For the selected studies, determine: 
 
i.  whether the IRBs meeting minutes indicate whether any IRB member 
counted towards the majority on projects for which the member had a 
conflicting interest (if a member was determined to have a conflict of 
interest, that member may not vote on any action related to the study in 
which they have a conflict); and 
ii.  if a member has a conflict of interest, it is up to the IRB to decide whether 
that member needs to leave the room during the IRBs deliberations and 
voting. 
  Date of Issuance: 09/26/2018  Page 22 of 59   
PROGRAM  7348.809 
 
 Written Procedures 
A.  Determine whether the IRB has written procedures for: 
i.  conducting its initial and continuing review of research and for reporting 
findings and actions to the investigator and institution; 
ii.  determining which projects require review more often than annually and 
which projects need verification from sources other than the investigator 
that no material changes have occurred since previous IRB review; 
iii.  ensuring prompt reporting to the IRB of changes in research activity; and 
iv.  ensuring that changes in approved research, during the period for which 
IRB approval has already been given, may not be initiated without IRB 
review and approval except where necessary to eliminate apparent 
immediate hazards to human subjects. 
 
B.  Determine whether the IRB has written procedures for ensuring prompt reporting to 
the appropriate institutional officials and the FDA by the IRB, and to the IRB by the 
clinical investigator of: 
i.  any unanticipated problems involving risk to human subjects and others; 
ii.  any instance of serious or continuing noncompliance with the regulations or 
the requirements or determinations of the IRB; and 
iii.  any suspension or termination of IRB approval. 
 
 
C. IRB review of Humanitarian Use Devices (HUDs) and Humanitarian Device 
Exemptions (HDEs). 
 
 
As defined in 21 CFR 814.3(n), a HUD is a medical device intended to benefit 
patients in the treatment or diagnosis of a disease or condition that affects or is 
manifested in fewer than 4,000 individuals in the United States per year.  An HDE 
is an application similar to a premarket approval (PMA) application, but is exempt 
from the reasonable assurance of effectiveness standard.  HDE approval is 
based, in part, on evidence that the device will not expose patients to an 
unreasonable or significant risk of illness or injury and the probable benefit from 
use of the device outweighs the risk of injury or illness.  The decision must take 
into account the probable risk and benefits of currently available devices and 
alternative forms of treatment.  FDA approval of a HDE authorizes an applicant to 
market a HUD, subject to certain profit and use restrictions.  Specifically, HUDs 
cannot be sold for profit, except in narrow circumstance 9 and they can only be 
used in a facility after an IRB has approved their use in the facility, except in 
certain emergencies. 
There is a distinction between use of a HUD and investigational use/clinical 
 
 
 
9 See section 520(m)(6) of the FD&C Act, 
https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM345 
931.pdf 
  Date of Issuance: 09/26/2018  Page 23 of 59   
PROGRAM  7348.809 
 
investigation of a HUD. 
i.  Prior to approval of an HDE application, any studies using the device 
must be conducted in compliance with the applicable IDE regulations 
(see 21 CFR Part 812). 
a.  Determine if the IRB is reviewing any such studies.  If so, verify that 
the study, if it is considered a significant risk device study, is conducted 
under an approved IDE.  The study must have both IDE approval from FDA 
and IRB approval before the study may begin (21 CFR 812.42).  If it is a 
non-significant risk device study under 21 CFR 812.2(b), or is exempt from 
the IDE requirements under 21 CFR 812.2(c), determine if the study has 
IRB approval. 
ii.  Use of a HUD that has an approved HDE, requires IRB approval before use 
in a facility, with the exception of emergency use (see 21 CFR 814.124).  The 
HDE holder is responsible for maintaining records of the names and 
addresses of the facilities to which the HUD has been shipped, 
correspondence with reviewing IRBs, and any other information requested by 
the reviewing IRB or FDA (21 CFR 814.126(b)(2)). 
 
The IRB should have written procedures addressing the initial and continuing 
review of a HUD used under an HDE.  Written procedures for HUDs may 
include information as to whether the IRB will require an informed consent 
document for the use of a HUD. 
a.  Determine if the IRB reviews the use of HUDs that have an approved HDE. 
If so, determine if the IRB has written procedure(s) for initial and continuing 
review of a HUD.  If the IRB does not have such procedures, FDA 
recommends that the IRB have policies and procedures in place for the 
review and approval, including whether the IRB requires a consent 
document for the use of the HUD. 
 
iii.  An HDE holder may collect safety and effectiveness data in a clinical 
investigation for the HDE-approved indications(s) without an IDE.  IRB approval 
(21 CFR Part 56) and informed consent of the subjects (21 CFR Part 50) are still 
required for the clinical investigations, as defined in these regulations. 
a.  Determine if the IRB approved such a study and verify if it is in compliance 
with the applicable requirements of 21 CFR Parts 50 and 56. 
 
iv.  Clinical investigations of a HUD for an indication different from the HDE- 
approved indication(s) must be conducted in compliance with the applicable 
IDE regulations (21 CFR Part 812), in addition to complying with the applicable 
requirements for IRB approval and informed consent.  If the study is a 
significant risk study, an FDA- approved IDE is required (21 CFR 812.20(a)(1)). 
a.  Determine if the IRB approved a study of a HUD for a different indication 
  Date of Issuance: 09/26/2018  Page 24 of 59   
PROGRAM  7348.809 
 
than the HDE approved indication.  If so, verify that the study is in 
compliance with 21 CFR Parts 812, 50, and 56.  NOTE:  IRBs may 
reference the following link on FDAs Web site for additional guidance on 
IRB review of a HUD. 10 For questions regarding a HUD/HDE, please 
contact the BIMO reviewer or CDRHs, HDE contact at 301-796-5640. 
 
D. IRB responsibilities in making significant risk (SR) and non-significant risk (NSR) 
device determinations 
 
IRB responsibilities for SR/NSR device determinations are found in 21 CFR 
812.66. The IRB serves as FDAs surrogate for NSR investigations, including 
initial and continuing review. 
 
i.  Definition  Under 21 CFR 812.3(m), the definition of a SR device is 
one that is: 
a.  Intended as an implant and presents a potential for serious risk to 
the health, safety, or welfare of a subject; 
b.  Purported or represented for supporting or sustaining human life 
and presents a potential for serious risk to the health, safety, and 
welfare of a subject; 
c.  For a use of substantial importance in diagnosing, curing, mitigating, 
or treating disease and presents a potential for serious risk to the 
health, safety, or welfare of a subject; or 
d.  Otherwise presents a potential for serious risk to the health, safety, 
or welfare of a subject. 
 
Examples of SR devices are dental lasers for hard tissue 
applications, vascular hemostasis devices, biliary stents, and 
collagen and bone replacements. 
 
ii.  NSR devices are devices that do not pose a significant risk to human 
subjects. FDA does not have a specific definition for an NSR device. 
 
NOTE:  NSR should not be confused with minimal risk; a term used to identify 
certain studies that IRBs may approve through an expedited review procedure. 
For a device study to be eligible for expedited review, it must be an NSR study 
AND present no more than minimal risk to the subject (21 CFR 56.110). Minimal 
risk means that the probability and magnitude of harm or discomfort anticipated in 
the research are not greater in and of themselves than those ordinarily 
encountered in daily life or during the performance of routine physical or 
psychological examinations or tests (21 CFR 56.102(i)). 
 
 
 
 
 
10             http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm110194.htm 
  Date of Issuance: 09/26/2018  Page 25 of 59   
PROGRAM  7348.809 
 
Examples of NSR devices are external monitors for glucose monitoring, 
digital mammography, transcutaneous electric nerve stimulators (TENS) 
for treatment of pain (except for chest pain/angina), and conventional 
gastroenterology and urology endoscopes and/or accessories. 
The risk determination is based on the proposed use of a device in an 
investigation, and not the device alone.  SR studies are those that present a 
potential for serious risk to the health, safety, or welfare of a subject.  IRBs should 
consider the potential harm of any associated procedure as well as the potential 
harm caused by the device.  A device may be determined to be NSR in one case, 
while for another indication it may be considered SR. 
 
 
iii.  Risk Determination  The IRB is required to make a risk determination 
when the sponsor or clinical investigator presents a device for 
investigation as NSR.  Unless FDA has already made a risk determination 
for the investigation, the IRB must review the sponsors NSR 
determination for each investigational device study reviewed.  If the IRB 
determines that an investigation involves a significant risk 
device, presented by the sponsor or clinical investigator as NSR, the IRB 
must notify the investigator and where appropriate, the sponsor of the SR 
determination.  (21 CFR 812.66) 
 
a.  Determine whether the IRB has and follows written procedures for 
making the SR/NSR determination for investigational devices.  Although 
not required by the regulations, FDA recommends that IRBs have 
policies and procedures in place that explain how the IRB makes the 
SR/NSR determination and that the decision should be documented. 
b.  Determine if the sponsor made the initial risk determination of NSR and 
presented this information to the IRB. 
c.  Determine if the IRB has made a determination of NSR for any device 
studies. The IRB should make the NSR determination by reviewing 
relevant information at the convened meeting and document the results in 
the meeting minutes. 
d.  Identify if the IRB informed the clinical investigator and/or sponsor when 
the IRB determined the study submitted as NSR has been determined to 
be a SR. 
e.  Determine if the IRB documented in meeting minutes the risk 
determination for each NSR study reviewed. (Note:  21 CFR 
56.115(a)(2) requires a written summary of the discussion of 
controverted issues and their resolution). 
 
 
Where a device study is determined to be SR, the sponsor may not begin the 
investigation except as provided in 21 CFR 812.30(a), requiring approval by 
FDA of an IDE application. 
  Date of Issuance: 09/26/2018  Page 26 of 59   
PROGRAM  7348.809 
 
 
If the IRB agrees with the sponsor that the study is NSR, the IRB reviews the 
study using the criteria in 21 CFR 56.111.  The study may begin without 
submission of an IDE application to FDA and is considered to have an 
approved IDE. 
iv.  Non-Significant Risk (NSR) Device Studies 
Although not required by the regulations, FDA recommends that IRBs have 
written procedures that explain how the IRB makes SR/NSR 
determinations. The IRB should document its SR/NSR determination in the 
IRB meeting minutes. 
a.  Describe the IRBs written procedures that explain how the IRB makes 
the NSR determination. FDA considers this determination to be part of 
the IRBs responsibilities for conducting its initial and continuing review 
of the investigation. 
 
 
Requirements for NSR device studies are located in 21 CFR 812.2(b) -- 
abbreviated requirements, which include labeling (21 CFR 812.2(b)((1)(i)); IRB 
approval (21 CFR 
812.2(b)((1)(ii)); informed consent (21 CFR 812.2(b)((1)(iii)); monitoring (21 CFR 
812.2(b)((1(iv)); record keeping and reports (21 CFR 812.2(b)((1)(v) and (vi)); 
and, prohibitions against promotion and other practices (21 CFR 
812.2(b)((1)(vii)). 
 
Guidance: See Information Sheet Guidance for IRBs, Clinical Investigators, and 
Sponsors: Significant Risk and Non-significant Risk Medical Device Studies. 11 
 
Note:  For additional information on SR or NSR determination, please see  
section 21 of this document. 
 
 Initial IRB Review of Research 
A.  Determine whether the IRB has the authority to approve, modify, or disapprove 
proposed studies, and to modify or suspend or terminate approval of ongoing studies 
B.  Determine whether the IRB provides a system for receiving and distributing the 
materials submitted by the clinical investigators. 
C. Determine whether the IRB ensures that the clinical investigator has the necessary 
experience, research staff, and facility to conduct the clinical investigation. 
D. Determine that each IRB member receives at a minimum, a copy of the consent 
document and a summary of the protocol. 
E.  Determine that all IRB members have access to copies of the complete submission 
to the IRB. 
 
 
11           http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126418.pdf 
  Date of Issuance: 09/26/2018  Page 27 of 59   
PROGRAM  7348.809 
 
 
An acceptable package for initial review would contain the proposed protocol, the 
consent form, and the investigators brochure provided by the sponsor.  When an 
investigators brochure is not available or not required, the protocol should contain 
an appropriate description of the previous animal and human experience 
associated with use of the test article.  Copies of the clinical investigator, sub- 
investigator, and/or any necessary study staff curricula vitae (CVs) should be 
submitted to demonstrate the experience and resources necessary for the IRB to 
assess the study teams qualifications to perform the study.  Any payment 
schedules, information sheets or instruction summaries given to human subjects 
should be included.  When advertising is to be used for recruiting subjects, a copy 
of the advertisement should be submitted for IRB review. 
F.  Determine whether the IRB has reviewed proposed and continuing studies at 
convened meetings.  A majority of the IRB members must be present, including at 
least one member whose primary concerns are in non-scientific areas, except when 
the expedited procedures described in 21 CFR 56.110 apply. 
G. Determine whether IRB-approved research received the approval of a majority of the 
IRB members present at the meeting. 
H. Determine whether the written procedures describe how the IRB ensures that clinical 
investigators make all initially required modifications prior to enrollment of research 
subjects. 
I.  Determine whether the written procedures describe the IRB actions for determining 
when projects require review more often than once a year.  It is recommended that 
the review frequency be recorded in the minutes, and be included in the notice of 
approval sent to the clinical investigator. 
J.  Review whether the IRBs records reflect the IRB determination that risks to subjects 
were minimized in relation to anticipated benefit. 
 
The IRB should ensure that the test article was adequately described and 
appropriate preclinical testing was conducted with the results included in the 
submission.  Typically, a summary and assessment of the preclinical testing (e.g., 
study types, outcomes, and considerations for potential risks, if any, to human 
subjects) to support the investigation phase and duration is included in the 
investigators brochure or study protocol. Without results from preclinical testing, a 
determination of risk to subjects cannot be made. 
 
Note: Please contact the BIMO reviewer for clarification on observations of 
missing or minimal preclinical testing and assessments thereof, as provided by 
the IRB in the submission. 
 
K.  Review the IRBs records regarding the IRB determination that the proposed 
research was acceptable in terms of applicable law, regulations, and standards of 
professional conduct and practices, i.e., an IRB member was assigned the 
responsibility for an in- depth evaluation of the investigational proposal, the consent 
form, and when applicable, the investigators brochure or agreement.  Also, 
  Date of Issuance: 09/26/2018  Page 28 of 59   
PROGRAM  7348.809 
 
determine if the IRB assessed the adequacy of the site facilities for conducting the 
research.  The IRB should evaluate 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 provide the appropriate emergent or 
specialized care, if required). 
 
An IRB should perform an evaluation of the clinical investigator qualifications to 
determine if she/he is qualified by training and experience to oversee and perform 
the research, i.e., curricula vitae, current medical license, if applicable, professional 
references, and/or research training and experience.  For research involving novel 
technologies and/or the potential for increased risk of mortality and/or morbidity, the 
IRB should evaluate any additional information documenting the clinical investigators 
previous specific experience in this field (e.g., as demonstrated by recent 
presentations or publications) and with the test article. Should questions arise 
regarding clinical investigator qualifications during an inspection, please contact the 
BIMO reviewer. 
 
 
 Continuing IRB Review of Research 
When the IRB reviews and approves research at a convened meeting without 
conditions, the effective date of the initial approval is the date of that IRB meeting. 
 
When the IRB reviews and approves research with conditions at a convened meeting 
without requiring further review at a subsequent convened meeting, the effective date 
of the initial approval is the date on which the IRB chairperson (or any other 
individual(s) designated by the IRB) has reviewed and accepted as satisfactory all 
changes to the protocol or informed consent documents, or any other responsive 
materials, required by the IRB. 
 
In either circumstance, the expiration date of the initial approval period, which is the 
date by which the first continuing review must occur, may be as late as one year after 
the effective date of initial IRB approval (see 21 CFR 56.109(f)). 
A.  Determine whether the clinical investigator promptly submits progress reports. 
B.  Determine whether each member has access to progress reports. 
C. Determine whether at least one member is assigned responsibility for appropriate 
review of each progress report. 
D. Determine how progress reports are evaluated to determine whether the study 
should be amended, terminated or allowed to continue as originally approved. 
E.  Determine whether the protocols and consent forms approved by the IRB are those 
used by the clinical investigator. 
F.  Determine whether unanticipated problems involving risk to subjects or others are 
promptly submitted and reviewed by the IRB. 
  Date of Issuance: 09/26/2018  Page 29 of 59   
PROGRAM  7348.809 
 
G. Determine whether the IRB files contain documentation that appropriate continuing 
review procedures were completed and the IRB followed the criteria for approval of 
research as outlined in 21 CFR 56.111. 
H. Determine that the review for ongoing studies is performed by the IRB at the  
assigned frequency and before the approval expiration date. 
 
 Adverse Event Reporting 
FDA regulations use different terms when referring to an adverse event (AE).  For 
example, adverse device effect is used in 21 CFR 812.46; adverse drug event is 
used in 21 CFR 312.32; and unanticipated problems is used in 21 CFR 312.66.  For 
device studies, Part 812 uses the term unanticipated adverse device effect as 
defined in 21 CFR 812.3(s). 
 
In general, an AE observed during the conduct of a study should be considered an 
unanticipated problem involving risk to human subjects, and therefore reported to the 
IRB, only if the AE were unexpected, serious, and would have implications for the 
conduct of the study (e.g., requiring a significant, and usually safety-related change 
in the protocol, such as revising inclusion/exclusion criteria, including a new 
monitoring requirement, or modifying the informed consent or investigators 
brochure). 12 An individual AE ordinarily does not meet these criteria because, as an 
isolated event, its implications for a study cannot be understood. 13 
 
 
 
: 14 
Examples of AEs that FDA considers unanticipated problems include 
  A single occurrence of a serious, unexpected event that is uncommon and 
strongly associated with drug exposure (such as angiodema, agranulocytosis, 
hepatic injury, or Steven-Johnson syndrome). 
  A single occurrence, or more often a small number of occurrences, of a serious, 
unexpected event that is not commonly associated with drug exposure, but 
uncommon in the study population (e.g., tendon rupture, progressive multifocal 
leukoencephalopathy). 
  Multiple occurrences of an AE that, based on an aggregate analysis, is 
determined to be an unanticipated problem.  There should be a determination that 
the series of AEs represents a signal that the AEs were not isolated occurrences 
and involve risk to human subjects (e.g., a comparison of rates across treatment 
groups reveals a higher rate in the drug treatment arm versus a control). 
 
 
 
12           http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126572.pdf 
13 
Guidance for Clinical Investigators, Sponsors, and IRBs, Adverse Event Reporting to IRBs -- Improving 
Human Subject Protection (Jan. 2009) at 3. 
 
14 
Guidance for Clinical Investigators, Sponsors, and IRBs, Adverse Event Reporting to IRBs -- Improving 
Human Subject Protection (Jan. 2009) at 4-5. There are additional examples in this guidance. 
  Date of Issuance: 09/26/2018  Page 30 of 59   
PROGRAM  7348.809 
 
 
A.  Determine if the IRB has written procedures in place for clinical investigator 
reporting of AEs to the IRB (21 CFR 56.108(b)).  The written procedures should 
also address how unanticipated problems are reported to the IRB, appropriate 
institutional officials, and FDA.  The written procedures should include reporting of 
serious AEs observed during the conduct of an in vitro bioavailability or 
bioequivalence study in humans (21 CFR 320.31(d)(3)) that is exempt from the 
IND requirements under Part 312 (21 CFR 320.31(d)). 15 
B.  Determine if the IRB has written procedures for notifying subjects of changes 
in a protocol or informed consent triggered by an adverse event. 
C. For device studies, determine if unanticipated adverse device effect (UADE) 
reports were submitted to the IRB as soon as possible, but in no event later than 
10 working days after the investigator first learned of the event.  (21 CFR 
812.150(a)(1)) 
 
The investigational device exemption (IDE) regulations define an UADE as ... 
any serious adverse effect on health or safety or any life-threatening problem or 
death caused by, or associated with, a device, if that effect, problem, or death 
was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects. (21 CFR 
812.3(s)) 
 
 IRB Reporting to the Clinical Investigator and the Institution 
A.  Determine whether the IRB notifies clinical investigators and the institution in writing 
of the IRB decisions to approve or disapprove a proposed research activity, or of 
modifications required to secure IRB approval of the research activity in accordance 
with 21 CFR 56.109(e). 
B.  Determine whether the IRB notifies clinical investigators of the IRBs continuing 
review and the investigators responsibility to promptly report and obtain IRB approval 
of proposed changes in a research activity, and to report unanticipated problems 
regarding risks to human subjects or others, any instance of serious or continuing 
noncompliance with applicable regulations, and any suspension or termination of IRB 
approval.  (21 CFR 56.108(a) and (b)) 
 
The IRB should ensure that clinical investigators are made aware of their 
responsibilities for complying with the IRB written procedures.  Some methods for 
informing clinical investigators may include, but are not limited to, the following: 
 
 
 
 
 
15 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplic 
  Date of Issuance: 09/26/2018  Page 31 of 59   
PROGRAM  7348.809 
 
i.  Handbooks or Informational Sheets for clinical investigators which describe 
their responsibilities. 
ii.  Letters of approval to clinical investigators which describe their responsibilities. 
For the latter method, a sample copy of the approval letter should be 
referenced in and attached to the written procedures. 
iii.  The IRB procedures given to the clinical investigators or posted electronically 
by the IRB for access by clinical investigators. 
 
Clinical investigators must be provided with an opportunity to respond in person or 
in writing to the IRB for any disapproval of their proposed research (21 CFR 
56.109(e)). IRB files should contain copies of both the IRB notifications and 
subsequent responses from the clinical investigator. 
C. Determine whether the IRB maintains records to document that both the IRB and 
the clinical investigator have met their responsibilities. 
The IRB written procedures should describe how the IRB reports its findings and 
actions to the clinical investigator and the institution.  Notifications of IRB actions are 
to be in writing.  IRB requests for additional information and/or modifications of the 
proposed research should be fully described in the notices to the clinical 
investigators. 
 
 
 Expedited Review 
A.  Determine whether the IRBs use of expedited review procedures meets the 
requirements of 21 CFR 56.110, and that these actions are documented in 
the IRB records. 
 
The list of categories of research that may be approved through expedited review is 
found in the Federal Register Notice published in 1998. 
(http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/Guidanc  
esInformationSheetsandNotices/ucm118099.htm). 
B.  Determine that expedited review procedures are not used for circumventing the 
convened meeting requirements.  Examples of such misuse may be any of the 
following actions: 
i.  Interim approval granted by the chairperson pending review of the proposed 
study at a later convened meeting. 
ii.  Approval granted for the one-patient nonemergency use in a protocol which 
does not meet the requirements of 21 CFR 56.110 
iii.  Expedited approval based on IRB approval of the protocol at another institution 
for which no cooperative agreement exists 
iv. Expedited review of a claimed emergency use when the circumstances do not 
meet the requirements of 21 CFR 56.102(d). 
C. Ensure that the IRB adopted a method for keeping all members advised of research 
proposals which have been approved via expedited review. 
  Date of Issuance: 09/26/2018  Page 32 of 59   
PROGRAM  7348.809 
 
 Exception from Informed Consent 
A.  Exception from general requirements for informed consent (21 CFR 50.23). 
i.  Determine whether all uses of FDA-regulated articles exempted from prior 
IRB review on the basis of emergency use meet the requirements of 21 CFR 
50.23(a) and (b), and 56.102(d) and 56.104(c). 
ii.  Determine whether the clinical investigators documentation of emergency 
use, consistent with 21 CFR 50.23(a) and (b), was submitted to the IRB within 
5 working days after the use of the test article as required by 21 CFR 50.23(c). 
iii.  Determine whether subsequent use is subject to IRB review. 
iv.  Determine if the IRB written procedures contain procedures for emergency 
use and that the IRB followed its procedures. 
 
B.  Exception from informed consent requirements for emergency research (21 CFR 
50.24). 
 
Studies involving an exception from informed consent requirements for 
emergency research under 21 CFR 50.24: 
 
i.  Determine if the IRBs written procedures contain information for 
reviewing clinical investigations with the exception from informed 
consent requirements and that the IRB followed its procedures. 
ii.  Determine if the IRB, with the concurrence of a licensed physician who is a 
member of or consultant to the IRB and who is not otherwise participating in 
the clinical investigation, found and documented whether the investigation 
satisfies the criteria in 21 CFR 50.24(a)(1): 
a.  Determine if the IRBs written procedures contain information for 
reviewing clinical investigations with the exception from informed 
consent requirements and that the IRB followed its procedures. 
b.  Determine if the IRB, with the concurrence of a licensed physician 
who is a member of or consultant to the IRB and who is not 
otherwise participating in the clinical investigation, found and 
documented whether the investigation satisfies the criteria in 21 CFR 
50.24(a)(1): 
i.  The human subjects were in a life-threatening situation that 
necessitated urgent intervention; 
ii.  Available treatments were unproven or unsatisfactory; 
iii.  Collection of valid scientific evidence was necessary to 
determine the safety and effectiveness of the intervention; 
iv.  Obtaining informed consent was not feasible because the 
subjects were not able to give their informed consent as a 
result of their medical condition; 
v.  Participation in the research held out the prospect of direct 
benefit to the subjects; 
vi.  The clinical investigation could not practicably be carried out 
without the waiver; 
  Date of Issuance: 09/26/2018  Page 33 of 59   
PROGRAM  7348.809 
 
vii.  The proposed investigational plan defines the length of the 
potential therapeutic window based on scientific evidence, 
and the investigator has committed to attempting to contact a 
Legally Authorized Representative (LAR) for each subject 
within that window of time and, if feasible, to asking the LAR 
contacted for consent within that window rather than 
proceeding without consent; 
viii.  The IRB has reviewed and approved informed consent 
procedures and an informed consent document consistent 
with 50.25; and 
ix.  Additional protections of the rights and welfare of the subjects will be 
provided (e.g., community consultation and public disclosure). 
c.  Assure that an IRB-approved informed consent was available in the event 
it became possible to obtain informed consent from a prospective subject 
or their legally authorized representative (LAR). 
d.  Determine if the IRB reviewed the proposed plan and procedures for 
attempting to contact the LAR or family member within the therapeutic 
window (protocol-specified period of time during which the test article must 
be administered.) 
Determine if the IRB assured that an independent data monitoring 
committee was established by the sponsor to provide oversight of the 
clinical investigation. Note: Community consultation and public 
disclosure to communities are an additional protection of the rights and 
welfare of the subjects. 
e.  Determine if the IRB: 
i.  Reviewed and requested appropriate modifications in the plans for 
and contents of the community consultation and public disclosure 
prior to initiation of the clinical investigation. 
ii.  Evaluated the adequacy of the community consultation: 
1.  Whether the IRB considered the community concerns and 
incorporated the feedback, as appropriate, into the IRBs 
review of the protocol and informed consent document. 
2.  Whether IRB meeting minutes reflected consideration of the 
community consultation. 
3.  Whether IRB meeting minutes reflected sufficient detail to 
show attendance at the meetings, actions taken by the IRB, 
the vote on these actions, the basis for requiring changes in 
or disapproving research, and a written summary of the 
discussion of controverted issues and their resolution. 
4.  Whether the IRB reviewed plans for and contents of public 
disclosure following completion of the clinical investigation. 
 
 Informed Consent 
The IRB is responsible for ensuring that each consent document provides the required 
information in readily understandable wording (see 21 CFR 50.20 and 50.25). 
  Date of Issuance: 09/26/2018  Page 34 of 59   
PROGRAM  7348.809 
 
A.  Determine whether the consent form contains the required elements in 21 CFR 
50.25(a) and any of the elements of 21 CFR 50.25(b) that are relevant to the study. 
B.  Determine if the IRB reviewed and approved the consent form(s), including changes 
and revisions to the informed consent document. 
C. When the research is expected to involve potential subjects who do not speak 
English, the IRB should review and approve a translated consent form.  Determine 
the IRBs instructions to clinical investigators for obtaining translations of informed 
consent documents. 
D. Determine if the IRB has SOPs for dealing with a change in the protocol or informed 
consent if an interim analysis changes the treatment assignments of the protocol or 
the informed consent.  (21 CFR 50.25(b) requires that significant new findings 
developed during the course of the research which may relate to the subjects 
willingness to continue participation in the research will be provided to the subject.) 
E.  Determine if the IRB has ever waived informed consent requirements for FDA- 
regulated studies, i.e., permitted subjects to participate in a study without obtaining 
informed consent.  FDA regulations only allow the exception from informed consent 
under two circumstances:  21 CFR 50.23 and 21 CFR 50.24, discussed above. 
F.  Determine if the IRB has approved a waiver of the requirement to sign a written 
consent form. Obtain any written procedures and document each instance where 
this occurred. Collect any minutes during which the board approved and granted the 
exception. Include the documents that the IRB reviewed to make its determination. 
As noted in 21 CFR 109(c)(1), the IRB may, for some or all subjects, waive the 
requirement that the subject, or the subjects legally authorized representative, sign 
a written consent form if it finds: 
 
i.  that the research presents no more than minimal risk of harm to subjects, and 
ii.  involves no procedures for which written consent is normally required outside 
the research content. 
If applicable, determine if the IRB waived the requirement that the subject, 
or the subjects legally authorized representative, signed a written consent 
form. 
G. As a result of Public Law 105-115, known as the Food and Drug 
Administration Modernization Act of 1997, the National Library of Medicine 
(NLM) within the National Institutes of Health (NIH) developed an Internet- 
based registry and results data bank for clinical trials of drugs, including 
biological products, for serious or life-threatening conditions. The Food and 
Drug Administration Amendments Act of 2007 (FDAAA) broadened the 
scope of the ClinicalTrials.gov (CT.gov) registry to applicable clinical trials 
(ACTs) for all diseases and conditions and outlined requirements for 
submitting registration, summary results, and adverse events information for 
ACTs of drug products (including biological products) and device products, 
as well as pediatric post market surveillances of device products, to the 
clinical trial databank. FDA published regulations implementing the CT.gov 
submission requirements at 42 CFR Part 11 in the Federal Register (81 FR 
64982) on September 21, 2016.  FDAAA also requires that a certification 
  Date of Issuance: 09/26/2018  Page 35 of 59   
PROGRAM  7348.809 
 
form (Form FDA 3674) accompany certain human drug, biological, and 
device product applications made to FDA. (The certification requirement 
went into effect on December 26, 2007.) 
For additional information regarding the CT.gov registration and reporting 
requirements see the CP 7348.810 for Sponsors, Contract Research Organizations 
and Monitors. 
Applicable clinical trials, as defined in 42 CFR Part 11, are: 
i.  For drugs, including biological products: 
Controlled clinical investigations, other than Phase I clinical investigations, of 
a drug product subject to section 505 of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 355) or a biological product subject to section 351 of 
the Public Health Service Act (42 U.S.C. 262), where clinical investigation 
has the meaning given in 21 CFR 312.3 and phase 1 has the meaning given 
in 21 CFR 312.21. 
A clinical trial of a combination product with a drug primary mode of action 
under 21 CFR Part 3 is also an ACT, provided that it meets all other criteria of 
the definition under this part. 16 
 
ii.  For device products: 
A prospective clinical study of health outcomes comparing an intervention 
with a device product subject to section 510(k), 515, or 520(m) of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 360(k), 21 U.S.C. 360e, 21 U.S.C. 
360j(m)) against a control in human subjects (other than a small clinical trial 
to determine the feasibility of a device product, or a clinical trial to test 
prototype device products where the primary outcome measure relates to 
feasibility and not to health outcomes); 
A pediatric postmarket surveillance of a device product as required under 
section 522 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360l); or 
A clinical trial of a combination product with a device primary mode of action 
under 21 CFR Part 3, is also an ACT, provided that it meets all other criteria 
of the definition under this part. 17 
 
When examining informed consent documents related to an applicable 
clinical trial registered on ClinicalTrials.gov, determine if the appropriate 
required statement referencing ClinicalTrials.gov is included.  21 CFR 
50.25(c). The statement is: 
 
 
 
 
16 See 42 CFR 11.10(a). See also ClinicalTrials.gov Protocol Data Element Definitions for Interventional and   
Observational Studies (February 7, 2017) for a complete list of the required elements for registration. 
17 See footnote 16. 
  Date of Issuance: 09/26/2018  Page 36 of 59   
PROGRAM  7348.809 
 
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. 
 
 
 Pediatric Studies  General 
A.  If a study involves children as subjects, 21 CFR 56.109(h) requires the IRB to 
determine that the research study complies with 21 CFR Part 50 Subpart D  
Additional Safeguards for Children in Clinical Investigations (Subpart D).  Subpart 
D requires that the IRB review each clinical investigation involving children as 
subjects and approve only those investigations that meet the criteria with respect 
to the level of risk posed by the study (see 21 CFR 50.51, 50.52, and 50.53). 
Where parental permission is to be obtained, the IRB may find that the permission 
of one parent is sufficient, if consistent with State law, for clinical investigations 
conducted under 21 CFR 50.51 or 50.52. Where clinical investigations are covered 
by 21 CFR 50.53 or 50.54, permission is to be obtained from both parents unless 
one parent is deceased, unknown, incompetent, or not reasonably available. 
 
 
Additionally, when the IRB determines that assent from the child is required, it must 
also determine whether and how assent must be documented.  The IRB must also 
assure that adequate provision is made to obtain the assent of the children (if in the 
IRBs judgment the children are capable of agreeing to participate in the study) and 
to obtain the permission of the childrens parents or guardians, in order for these 
studies to be approved.  There are also specific requirements if the children are 
wards of the State. See below. 
For research involving children as subjects, the IRB must find and document one 
of the following: 
i.  21 CFR 50.51 -- Clinical investigations not involving greater than minimal risk. 
The IRB may approve a clinical investigation involving pediatric subjects 
provided that the study does not pose more than minimal risk to the children 
and adequate provision is made to solicit the assent of the children and the 
permission of their parents or guardians, as described in 21 CFR 50.55. 
 
Determine if the IRB approved any studies under 50.51 and how 
the board documented its decision. 
ii.  21 CFR 50.52 -- Clinical investigations involving greater than minimal 
risk but presenting the prospect of direct benefit to individual subjects. 
 
The IRB may approve a clinical investigation involving pediatric 
subjects if the study involves more than minimal risk that holds out 
  Date of Issuance: 09/26/2018  Page 37 of 59   
PROGRAM  7348.809 
 
the prospect of direct benefit for the individual subject, or by a 
monitoring procedure that is likely to contribute to the subjects well- 
being, only if the IRB finds and documents that: 
 
1.  The risk is justified by the anticipated benefit to subjects; 
2.  The relation of the anticipated benefit to the risk is at least as 
favorable to the subjects as that presented by available 
alternative approaches; and 
3.  Adequate provisions are made for soliciting the assent of the 
children and permission of their parents or guardians, as 
described in 21 CFR 50.55. 
 
Determine if the IRB approved any studies under 50.52 and how 
the board documented its decision. 
 
 
iii.  21 CFR 50.53 -- Clinical investigations involving greater than 
minimal risk and no prospect of direct benefit to individual subjects, 
but likely to yield generalizable knowledge about the subjects 
disorder or condition. 
The IRB may approve a clinical investigation involving more than 
minimal risk to children by an intervention or procedure that does 
NOT hold out the prospect of direct benefit to the individual subject, 
or by a monitoring procedure that is not likely to contribute to the 
well-being of the subject, only if the IRB finds and documents that: 
1.  The risk represents a minor increase over minimal risk; 
2.  The intervention or procedure presents experiences to subjects 
that are reasonably commensurate with those inherent in their 
actual or expected medical, dental, psychological, social, or 
educational situation; 
3.  The intervention or procedure is likely to yield generalizable 
knowledge about the subjects disorder or condition that is of 
vital importance for the understanding or amelioration of the 
subjects disorder or condition; and 
4.  Adequate provisions are made for soliciting the assent of the 
children and the permission of their parents or guardians, as 
described in 21 CFR 50.55. 
 
Determine if the IRB approved any studies under 50.53 and how the 
board documented is decision. 
 
iv.  21 CFR 50.54 -- Clinical investigations not otherwise approvable that 
present an opportunity to understand, prevent, or alleviate a serious 
problem affecting the health or welfare of children. 
  Date of Issuance: 09/26/2018  Page 38 of 59   
PROGRAM  7348.809 
 
 
Determine if the IRB approved and documented any clinical investigations 
that present a reasonable opportunity to further the understanding, 
prevention, or alleviation of a serious problem affecting the health or welfare 
of children according to 50.54. 
 
Note: Before the IRB could approve a study under this provision, the 
Commissioner of Food and Drugs, after consultation with a panel of experts, 
must have determined either: 
 
1.  That the clinical investigation in fact satisfies the conditions of 21 CFR 
50.51, 50.52, or 50.53 as applicable; or 
 
2.  That the following conditions are met:  (i) the clinical investigation presents 
a reasonable opportunity to further the understanding, prevention, or 
alleviation of a serious problem affecting the health or welfare of children; 
(ii) the clinical investigation will be conducted in accordance with sound 
ethical principles; and (iii) adequate provisions are made for soliciting the 
assent of children and the permission of their parents or guardians as set 
forth in 21 CFR 50.55. 
 
B.  If an IRB regularly reviews research that involves pediatric studies: 
 
i.  Determine if the IRB has written procedures describing how to review a 
pediatric study and how to make the special determinations required by 21 
CFR Part 50 Subpart D. 
 
For meetings at which a pediatric study was reviewed, determine if the IRB 
considered including in the membership ...one or more individuals 
knowledgeable about and experienced in working with [pediatric] subjects. 
(21 CFR 56.107(a))  If the membership of the IRB does not include such 
individuals, determine if the IRB utilized consultants or invited individuals 
with appropriate pediatric expertise to assist the IRB in reviewing the study. 
(21 CFR 56.107(f)) 
ii.  Determine if meeting minutes at which the IRB reviewed a pediatric 
study document the discussion about the level of risk posed by the 
study. 
iii. Determine  if  meeting  minutes  document  the  risk  determination  for  the 
particular type of pediatric study as described in 21 CFR 50.51, 50.52, or 
50.53 made by the IRB and the rationale. 
iv. Determine if the IRB found and documented that the clinical 
investigation presents a reasonable opportunity to further the 
  Date of Issuance: 09/26/2018  Page 39 of 59   
PROGRAM  7348.809 
 
understanding, prevention, or alleviation of the serious problems 
affecting the health, welfare of children. 
 
C. 21 CFR 50.56  Wards 
 
Determine if the IRB approved clinical investigations under 21 CFR 50.53 or 50.54 
that are for children who are wards of the State or any other agency, institution, or 
entity.  If so, determine whether the IRBs actions conformed to 21 CFR 50.56. 
 
 
 Electronic Records and Electronic Signatures 
Computerized systems are more commonly being used by IRBs to collect and 
preserve records as required by 21 CFR 56.115. 
 
Computerized systems range from a desktop or laptop personal computer using an 
internal network to different systems located at multiple sites which use an Internet 
connection (e.g., a Web-based system managed by an independent software vendor 
to which the IRB, the sponsor and clinical sites have controlled access). 
 
Regardless of the type of system used by the IRB, an important principle to 
understand when evaluating IRB records is that the regulatory requirements for 
adequate documentation of IRB activities do not change whether the documentation 
is captured on paper, electronically, or using a hybrid approach. 
 
21 CFR Part 11 (Part 11) describes the technical and procedural requirements that 
must be met if a firm chooses to maintain records electronically and/or use electronic 
signatures. Part 11 is a companion regulation to other FDA regulations and laws.  It is 
within these other regulations and laws, called predicate rules, where specific 
requirements for issues such as recordkeeping, record content, signatures, and record 
retention are addressed. 
A.  Guidance for Industry -- Part 11, Electronic Records; Electronic Signatures  Scope  
and Application 18
 
 
Section III. B. 2 of the Part 11 guidance document 19 states that Part 11 is 
applicable to the following electronic records and electronic signatures: 
i.  Records that are required to be maintained under the predicate rules 
and that are maintained in electronic format in place of paper format. 
ii.  Records that are required to be maintained under the predicate rules, 
that are maintained in electronic format in addition to paper format, and 
 
 
18 
htt ps: / / w w w . f da.gov / dow nloads/ r egulatory i nform ati on/guidances/ ucm 1 25125.pdf   
19 htt ps: / / w w w . f da.gov/ d o w nloads/ r egulatory i nform ati on/guidances/ ucm 1 25125.pdf,   P age  5 
  Date of Issuance: 09/26/2018  Page 40 of 59   
PROGRAM  7348.809 
 
are relied on to perform regulated activities. 
iii.  Records that are required to be submitted to FDA under predicate rules 
and that are in electronic format. 
iv.  Electronic signatures that are intended to be the equivalent of 
handwritten signatures, initials or other general signings that are 
required by the predicate rules and/or the IRBs written procedures. 
 
 
In Section III. C. of the Part 11 guidance document,20 specific requirements for 
which the agency intends to exercise enforcement discretion include the: 
i.  validation of computerized systems; 
ii.  use of computer-generated, time-stamped audit trails; 
iii.  use of legacy systems; 
iv.  generation of copies of records; and 
v.  protection of records (i.e., record retention and availability). 21 
 
B.  Inspectional Guidelines 
 
 
The field investigator should consult with the Center contact and/or the ORA 
national computer expert for guidance on the depth to which Part 11 should be 
covered during an inspection. 
 
 
C. Equipment, Procedures, Processes 
i.  Describe any computerized system(s) used at the IRB site(s) to generate, 
collect, or preserve documented IRB activities (e.g., stand-alone personal 
computer, Web- based system, hand-held computers). 
ii.  Determine whether electronic records or reports are defined in the IRBs 
written procedures. 
iii.  Explain how the IRB determines which records (e.g., meeting minutes, 
voting logs, etc.) are collected and stored in electronic format (i.e., does 
the IRB prescribe any off-the-shelf program or follow any written 
procedures which describe selection of records for electronic formatting). 
iv.  Determine whether electronic records are available for inspection and 
have been retained for the required period of time (i.e., at least 3 years 
after completion of the research) (see 21 CFR 56.115(b)). 
v.  Determine whether the IRBs electronic system has operating instructions, 
user- manuals, access policies and procedures, training policies, or 
management controls to create, modify, maintain, or transmit electronic 
records. 
vi.  Determine whether individuals who develop, maintain or use the 
 
 
20 
htt ps: / / w w w . f da.gov / dow nloads/ r egulatory i nform ati on/guidances/ ucm 1 25125.pdf, page6 
21 htt ps: / / w w w . f da.gov/ d o w nloads/ r egulatory i nform ati on/guidances/ ucm 1 25125.pdf   
  Date of Issuance: 09/26/2018  Page 41 of 59   
PROGRAM  7348.809 
 
computerized systems have the necessary training to perform their 
assigned tasks. 
D. Maintenance of Electronic Records 
i.  Determine whether the IRB is able to ensure adequate electronic and 
human readable copies of electronic records suitable for review and 
copying.  (If you are unable to gain access to records from the 
computerized system following the procedures outlined in IOM 5.3, contact 
the Center immediately). 
 
NOTE:  ORA investigators and the inspection team are not to be 
independently accessing a firms electronic files. 
ii.  Determine whether electronic records and documentation meet the 
requirements applicable to IRB records maintained in paper format. 
iii.  Describe how records, reports, or correspondence are transmitted from the 
IRB to the sponsor, clinical investigator, institutional official, FDA, etc., and 
vice-versa. 
iv. Determine how the computerized system allows changes to be made.  (e.g., 
is it based on individual access privileges?  Are all changes to electronic 
source data accompanied with write-protected audit trails to include the 
name, date, and reason for change?) 
 
 
E.  Security 
i.  Determine who is authorized to access the system. 
ii.  Describe how the computerized systems are accessed (e.g., password 
protected, access privileges, user identification). 
iii.  Determine how information is captured related to the creation, 
modification, or deletion of electronic records (e.g., audit trails, date/time 
stamps). 
iv.  Describe whether there is a backup, disaster recovery, and/or contingency 
plan to protect against record loss. Were there any installed software 
upgrades, security or performance patches, or new instrumentation that 
affected the electronic records? 
v.  Describe how error messages or system failures are reported to the IRB, 
including the corrective actions taken, if any. 
 
 Central IRBs/ Independent IRBs 
Under 21 CFR 56.114, institutions involved in multi-institutional studies may use joint 
review, reliance upon the review of another qualified IRB, or similar arrangements 
aimed at avoidance of duplication of effort. 
 
For multicenter studies, a central IRB may conduct reviews on behalf of all study sites 
that agree to participate in the centralized review process.  For sites at institutions that 
have an IRB that would ordinarily review research conducted at the site, the central IRB 
  Date of Issuance: 09/26/2018  Page 42 of 59   
PROGRAM  7348.809 
 
should institute a written agreement with the individual institutions participating in 
centralized review identifying apportionment of the review responsibilities between local 
IRBs and the central IRB. 
A.  If an institution, its IRB, and a central IRB agree to participate in a centralized IRB 
review process, determine whether the action agreed upon is documented and 
signed by the appropriate parties.  Collect a copy of the agreement. 
 
B.  If the written agreement apportions IRB review responsibilities between a central 
IRB and the institutions IRB, determine whether the agreement delineated the 
specific responsibilities of the central IRB and the institutions IRB for the initial and 
continuing review of the study. 
 
C. When an institution and an institutions IRB rely on review by a central IRB, both 
IRBs must have written procedures in place to implement the centralized IRB review 
process (see 21 CFR 56.108, 56.114).  For example, procedures should address 
the following: 
i.  How the institutions IRB determines that the central IRB is qualified to 
review and approve research conducted at the institution. 
ii.  How the central IRB intends to communicate with the relevant 
institutions, the institutions IRBs, and investigators regarding its review. 
iii.  How the central IRB ensures that it provides meaningful consideration of 
relevant local factors for communities from which research subjects will be 
drawn. 
iv. How the central IRB assesses the ability of a geographically remote site to 
participate in the study (e.g., whether the site has medical services 
appropriate for the complexity of the study.) 
When an institution, an institutions IRB, and a central IRB agree to apportion 
IRB review responsibilities between the two IRBs, each IRB must have written 
procedures describing how it implements its responsibilities under the 
agreement (see 21 CFR 56.108, 56.115(a)(6)).22 
 
 Investigational New Drug (IND) Application / Investigational Device Exemption (IDE) 
Status 
A.  For Investigational Device Studies: 
 
As discussed previously in Section J.4. IRB Responsibilities in Making SR and 
NSR Device Determinations, the IRB is required to make a risk determination 
when the sponsor or clinical investigator presents a device for investigation as 
NSR.  Unless FDA has already made a risk determination for the investigation, the 
IRB must review the sponsors NSR determination for each investigational device 
study reviewed.  If the IRB determines that an investigation involves a significant 
 
 
22         http://www.fda.gov/RegulatoryInformation/Guidances/ucm127004.htm 
  Date of Issuance: 09/26/2018  Page 43 of 59   
PROGRAM  7348.809 
 
risk device, presented by the sponsor or clinical investigator as NSR, the IRB must 
notify the investigator and where appropriate, the sponsor of the SR determination. 
(21 CFR 812.66) 
 
Although not required by the regulations, FDA recommends that the IRB have written 
procedures that explain how the IRB makes SR/NSR determinations. 
 
i.  Determine whether the IRB has and follows written procedures for significant 
risk and non-significant risk determinations for investigational devices. 
ii.  Determine if the sponsor made the initial risk determination of NSR and 
presented this information to the IRB. 
iii.  Determine if the IRB has made a determination of NSR for any device studies. 
The IRB should make the NSR determination by reviewing relevant  
information at the convened meeting and document the results in the 
meeting minutes. 
iv.  Identify if the IRB informed the clinical investigator and/or sponsor when the 
IRB determined the study submitted as NSR has been determined to be a SR. 
v.  Determine if the IRB documented in meeting minutes the risk determination 
for each NSR study reviewed. (Note:  21 CFR 56.115(a)(2) requires a written 
summary of the discussion of controverted issues and their resolution). 
 
B.  For Investigational New Drug Applications: 
 
FDA regulations require sponsors and clinical investigators to determine whether an 
IND is necessary for a particular study (see 21 CFR 312.50, 312.60).  However, 
FDA regulations require that, in order to approve research, an IRB shall determine 
that the risks to subjects are minimized by using procedures which are consistent 
with sound research design and which do not unnecessarily expose subjects to risk, 
and that risks to subjects are reasonable in relation to anticipated benefits, if any, to 
subjects, and the importance of the knowledge that may reasonably be expected to 
result. (21 CFR 56.111(a)(1)) 
 
Prior to research being approved by the IRB, the IRB should obtain (for example): 
 
i.  Published literature about the chemistry, manufacturing, and control of the 
drug substance and product; 
ii.  A summary of previous human experience with the drug product; 
iii.  Sufficient information regarding the source, purity, quality, and method of 
preparation and delivery of the drug used in the research; and 
iv.  Information regarding the pharmacology and toxicity of the drug product in 
animals. 
 
 
Determine if the IRB obtained the information needed to be able to make the 
determinations required under 21 CFR 56.111(a)(1) and questioned, for 
  Date of Issuance: 09/26/2018  Page 44 of 59   
PROGRAM  7348.809 
 
example, the need for an IND for any studies submitted for review and approval. 
 
If, during an IRBs initial review of a study, the IRB questions whether an IND is 
necessary, but is unable to obtain to resolve this issue, the IRB should follow its 
written procedures for resolving controverted issues, e.g., by notifying the CI of 
the IRBs concerns and delaying approval of the study until the matter is resolved. 
  Date of Issuance: 09/26/2018  Page 45 of 59   
PROGRAM  7348.809 
 
PART IV - ANALYTICAL 
 
No analytical activities are planned under this program. 
  Date of Issuance: 09/26/2018  Page 46 of 59   
PROGRAM  7348.809 
 
PART V - REGULATORY/ADMINISTRATIVE STRATEGY 
 
  Administrative Guidance 
A.  ORA BIMO Division EIR Classification Authority 
 
The ORA BIMO Division must follow the procedures for assigning Division 
inspection conclusions and decisions to an Establishment Inspection Report 
(EIR) within established timeframes as defined in Field Management 
Directive #86, Establishment Inspection Report Conclusions and Decisions 
(FMD #86). 
 
B.  Center EIR Classification Authority 
 
 
The Center has final classification authority for all EIRs generated under this 
compliance program.  If the Center is considering a classification that differs from 
the ORA BIMO Divisions recommended classification, the Center will contact the 
ORA BIMO Division to discuss the issues as soon as possible to avoid delays in 
the final classification process.  In addition, the Center will provide the ORA BIMO 
Division with notice of all final classifications, including the rationale for any 
classification that differs from the ORA BIMO Divisions initial classification. 
 
 
C. EIR Classifications 
 
 
The following guidance is to be used in conjunction with the instructions in FMD- 
86 for initial ORA BIMO Division and Center classification of EIRs generated 
under this Compliance Program: 
i.  NAI - No Action Indicated -- No objectionable conditions or practices were 
found during an inspection (or the objectionable conditions found do not 
justify further regulatory action); 
ii.  VAI - Voluntary Action Indicated -- Objectionable conditions or practices 
were found, but the agency is not prepared to take or recommend any 
administrative or regulatory action; and 
iii.  OAI  Official Action Indicated  Regulatory and/or administrative actions will 
be recommended. 
 
D. Administrative/Civil/Criminal Actions will be in accordance with 21 CFR Parts 50, 56, 
312, and 812.  FDA can invoke other legal sanctions under the FD&C Act and/or Title 
18, USC, where appropriate. 
i.  Administrative Actions for noncompliance -- If apparent noncompliance 
with FDA regulations (21 CFR 56.120), the FDA can move forward with 
the following regulatory actions: 
  Date of Issuance: 09/26/2018  Page 47 of 59   
PROGRAM  7348.809 
 
1.  Untitled Letters 
2.  Warning Letters 
3.  Reinspection to verify corrective actions 
4.  Regulatory meetings 
5.  Withhold approval of new studies that are conducted at the institution or 
reviewed by the IRB 
6.  Direct that no new subjects may be recruited for ongoing studies 
7.  Terminate ongoing studies 
8.  Refer pertinent matters, with headquarters concurrence, to other Federal, 
State, or local agencies for such action as that agency deems appropriate 
 
ii.  Disqualification of an IRB or institution (21 CFR 56.121) 
 
If an IRB or the institution has failed to take adequate steps to correct the 
noncompliance stated in the letter sent by the agency under 21 CFR 
56.120(a), FDA may institute proceedings in accordance with the 
requirements for a regulatory hearing set forth in Part 16 (21 CFR 56.121(a)). 
 
Disqualifications may occur if: 
 
1.  the IRB has refused or repeatedly failed to comply with any of the 
regulations set forth in 21 CFR Part 56 (21 CFR 56.121(b)(1)), and 
2.  the noncompliance adversely affects the rights or welfare of the human 
subjects in a clinical investigation (21 CFR 56.121(b)(2)). 
FDA will issue an order that explains the basis for the determination and will 
send a notice of disqualification to the IRB or institution.  FDA will not approve 
an application for a research permit for a clinical investigation that is to be 
under the review of a disqualified IRB or that is to be conducted at a 
disqualified institution, and may refuse to consider in support of a marketing 
permit the data from a clinical investigation that was reviewed by a disqualified 
IRB. 
E.  Communications 
 
The ORA BIMO Division should promptly inform Headquarters/Centers about any 
written or oral communication from the institution following the inspection.  Similarly, 
Headquarters/Centers should promptly inform the ORA BIMO Division of 
communication (including any written correspondence) with the institution following 
the inspection, including any judicial/administrative actions.  Copies of any written 
communications should be shared. 
 
 
    Regulatory Guidance 
The following criteria are relevant to FDAs classification of inspections of IRBs: 
  Date of Issuance: 09/26/2018  Page 48 of 59   
PROGRAM  7348.809 
 
A.  No Action Indicated (NAI): No objectionable conditions or practices (e.g., violations of 
21 CFR Parts 50, 56, 312, and 812) were found during the inspection, or the 
significance of the documented objectionable conditions found does not justify further 
FDA action. 
i.  Any post-inspectional correspondence acknowledges the IRBs basic compliance 
with pertinent regulations. 
 
B.  Voluntary Action Indicated (VAI): Objectionable conditions were found and 
documented, but the Center is not prepared to take or recommend any further 
regulatory (advisory, administrative, or judicial) action because the objectionable 
conditions do not meet the threshold for regulatory action (i.e., regulatory violations 
uncovered during the inspection are few and do not seriously impact subject safety 
or data integrity). 
i.  Post-inspectional correspondence may identify the issues and, when needed, 
state that FDA expects prompt, voluntary corrective action by the IRB. 
 
C: Official Action Indicated (OAI): An OAI recommendation is appropriate when 
regulatory violation(s) uncovered is/are significant/serious and/or numerous, and 
the scope, severity, or pattern of violations(s) support a finding that: 
i.  Subjects participating in studies approved by the IRB would be or have 
been exposed to an unreasonable and significant risk of illness or injury; 
or 
ii.  Subjects rights would be or have been seriously compromised; or 
iii.  Data integrity or reliability is or has been compromised. 
 
 
Once an OAI decision is reached, additional information (e.g., previous 
inspectional findings, correspondence, or other information about the IRB) may 
assist the Center in determining the type of post-inspectional correspondence that 
is appropriate.  If the Center chooses to issue a Warning Letter and allow the IRB 
to submit a detailed corrective action plan or alternate approach that is acceptable 
to FDA, the Center should nevertheless be prepared to initiate disqualification 
proceedings should the IRB not respond appropriately (i.e., fails to respond, fails 
to develop an adequate corrective action plan, or is found, during a subsequent 
inspection, to have failed to comply with a corrective action plan). 
 
A Warning Letter may be considered when the violations can be corrected 
through specific action(s) by the IRB (e.g., preparation of, and compliance with, a 
detailed corrective action plan, that is acceptable to FDA) and adherence to the 
corrective action plan has a high probability of preventing similar or other 
violations from occurring in the future. 
  Date of Issuance: 09/26/2018  Page 49 of 59   
PROGRAM  7348.809 
 
EXAMPLES: 
 
The following are examples of violations that, alone or in combination, would be 
considered significant and may warrant an OAI classification.  This list is not all 
inclusive; other circumstances may also merit an OAI classification. 
 
When applying the classification criteria, Center reviewers will generally evaluate the 
impact of the IRBs actions (number, scope, and severity of the regulatory violations) on 
subjects rights, safety and welfare.  There are gradations in the severity of each 
example, and the specific observation(s) should support the seriousness of the 
violation(s) and the effect(s) on subjects safety and welfare and/or the reliability and 
acceptability of data for FDA decision-making purposes.  The Center should also 
consider whether FDA has cited the IRB for the same or similar violations during a 
previous inspection. 
  Date of Issuance: 09/26/2018  Page 50 of 59   
PROGRAM  7348.809 
 
 
Inadequate Human Subject Protection 
Violation/Related Citation  Examples 
Failure of the IRB to  IRB is not registered on OHRPs Registration Web site. 
register with OHRP    
(http://ohrp.cit.nih.gov/efile)  The initial IRB registration must occur before the IRB 
  begins to review clinical investigations and must be 
21 CFR 56.106  updated as required by the regulation. 
    IRB has fewer than 5 members 
    IRB fails to have an unaffiliated member OR at least 
Failure to conform to  one member whose primary concerns are scientific 
membership criteria listed in  OR at least one member whose primary concerns 
21 CFR 56.107  are non-scientific 
  IRB is composed entirely of one sex or 
members of one profession 
  Conflicted member votes on his/her own study 
  Invited consultant votes on study 
Failure to conform to  IRB has a member participate in the IRBs initial and 
meeting  participation  continuing review of a project in which the member has a 
criteria as listed in 21  conflicting interest 
CFR 56.107(e) 
Failure to follow written  IRB does not follow written procedures that state the IRB 
procedures  will conduct continuing review at least annually. For 
  example, if a clinical investigator failed to submit a 
21 CFR 56.108(a)  periodic report, the IRB did not detect the omission. 
  IRB records of meetings (e.g., minutes) are missing or 
Failure to have minutes of  do not have sufficient detail to show who attended, 
IRB meetings  in sufficient  actions taken, and the votes, including the number of 
detail  to  show  attendance  members for and against, and abstentions. 
at the meetings   
  Note: Please contact the BIMO reviewer for clarification 
21 CFR 56.115(a)(2)  on the frequency of the missing minutes to warrant an 
OAI classification. 
Failure to have records  Records of continuing review activities are missing or 
of continuing review  incomplete. 
activities   
  Note: Please contact the BIMO reviewer for clarification 
21 CFR 56.115(a)(3)  on the frequency of the missing or incomplete records to 
warrant an OAI classification. 
  Date of Issuance: 09/26/2018  Page 51 of 59   
PROGRAM  7348.809 
 
 
Inadequate Human Subject Protection (cont) 
Violation/Related Citation  Examples 
Failure to make a risk   
determination regarding  The IRB failed to determine whether an investigation 
an investigation presented  presented for approval as NSR is a SR or NSR study. 
for approval as NSR 
 
21 CFR 812.66 
Failure to determine that   
the research study is in  The IRB failed to determine at the time of initial review 
compliance with 21 CFR  that studies involving children were in compliance with 21 
Part 50 Subpart D when  CFR Part 50 Subpart D -- Additional Safeguards for 
some or all of the subjects  Children in Clinical Trials 
in a study are children 
 
21 CFR 56.109(h) 
Failure to conduct   
continuing review of   
research at intervals  The IRB failed to conduct continuing review of 
appropriate to the degree  research at intervals of not less than once per year 
of risk 
 
21 CFR 56.109(f) 
  Date of Issuance: 09/26/2018  Page 52 of 59   
PROGRAM  7348.809 
 
 
Inadequate Human Subject Protection (cont) 
Violation/Related Citation  Examples 
  The IRB failed to determine and document that: 
    The human subjects were in a life-threatening 
  situation that necessitated urgent intervention 
    Available treatments were unproven or 
  unsatisfactory 
    Collection of valid scientific evidence was 
  necessary to determine the safety and 
  effectiveness of the intervention 
    Informed consent was not feasible 
Failure to evaluate that all    Participation in research held out the prospect of 
conditions for exception of  direct benefit to the subjects 
informed consent and    The clinical investigation could not practicably be 
requirements for  carried out without a waiver 
emergency research were    The proposed investigational plan defines the length 
satisfied. 
of the potential therapeutic window based on 
 
scientific evidence, and the investigator has 
21 CFR 50.24 
committed to attempting to contact a LAR for each 
subject within that window of time and, if feasible, to 
asking the LAR contacted for consent within that 
window rather than proceeding without consent 
  The IRB has reviewed and approved informed 
consent procedures and an informed consent 
document consistent with 50.25 
  Additional protections of the rights and welfare of the 
subjects will be provided  (e.g., community consultation 
and public disclosure) 
 
    Follow-Up Inspections 
 
 
A. Centers should evaluate whether the violations found indicate systemic problems with 
the conduct of the study or the reliability of the data and whether additional inspection 
assignments should be issued (e.g., sponsor, CRO, monitor, clinical investigator(s)). 
 
 
B.  Following issuance of a Warning Letter, Centers should schedule a follow-up 
inspection to verify if the IRB is fulfilling the terms of any corrective action plan and 
is in compliance with applicable regulations.  Such follow-up inspections should 
take place within one year after the date of the last Warning Letter 
correspondence, depending on the nature of the violations. 
  Date of Issuance: 09/26/2018  Page 53 of 59   
PROGRAM  7348.809 
 
    Post-Inspection Information Sharing 
 
 
Per the April 27, 2015, agreement between the Department of Veterans Affairs (VA) 
and the FDA Office of Regulatory Affairs (ORA) and upon the written request by the 
Office of Research Oversight, VA, the Center contacts are authorized to provide to 
the Office of Research Oversight, VA, and its staff, redacted copies of FDA- 
reviewed EIRs and any post-inspection correspondence issued to VA facilities or 
employees following any inspection (including the 483s). 
 
Post inspection documents should be sent to: 
Executive Director 
Office of Research Oversight 
(10R) Veterans Health 
Administration Department of 
Veterans Affairs 
810 Vermont Avenue, N.W. 
Washington, D.C. 20420 
 
 
Responses are subject to FDA priority and available resources, and are pursuant to 
ORA, VAs June 18, 2010, non-disclosure agreement. 
  Date of Issuance: 09/26/2018  Page 54 of 59   
 
PROGRAM  7348.809 
 
 
PART VI  REFERENCES, ATTACHMENTS, AND PROGRAM CONTACTS 
 
    References 
A.  FDA Laws 
b.  Federal Food, Drug, and Cosmetic Act (FD&C Act) 
 
B.  Most Relevant 21 CFR Regulations 
i.  Part 50  Protection of Human Subjects 
ii.  Part 56  Institutional Review Boards 
iii.  Part 312  Investigational New Drug Application 
iv.  Part 812  Investigational Device Exemptions 
 
C. Other 21 CFR Regulations 
i.  Part 11 - Electronic Records; Electronic Signatures 
ii.  Part 814 - Premarket Approval of Medical Devices (includes HDE Requirements in 
814.100) 
iii.  Part 320  Bioavailability and Bioequivalence Requirements 
 
D. FDA Guidelines, Guidance, and Inspection Guides 
i.  Guidance for Clinical Investigators, Sponsors, and IRBs: Adverse Event Reporting to 
IRBImproving Human Subject Protection 
(http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126572.pdf) 
ii.  Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors: 
Exception from Informed Consent Requirements for Emergency Research 
(http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM249673.pdf) 
iii.  Guidance for Industry: IRB Review of Stand-Alone HIPPA Authorizations Under FDA 
Regulations 
(http://www.fda.gov/downloads/RegulatoryInformation/sGuidances/UCM126952.pdf) 
iv.  FDA Information Sheet Guidance for Institutional Review Boards, Clinical 
Investigators, and Sponsors (http://www.fda.gov/oc/ohrt/irbs/default.htm) 
v.  Guidance for Clinical Investigators, Institutional Review Boards, and Sponsors: 
Process for Handling Referrals to FDA under 21 CFR 50.54  Additional Safeguards 
for Children in Clinical Investigations (Guidances>ProcessforHandlingReferralsto  
FDAUnder21CFR50.54-AdditionalSafeguardsforChildreninClinical Investigations) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date of Issuance: 09/26/2018  Page 55 of 59 
   
PROGRAM  7348.809 
 
 
 
 
vi.  Guidance for Industry: International Conference on Harmonization (ICH) E6, Good 
Clinical Practice:  Consolidated Guidance 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/G  
uidances/UCM073122.pdf) 
vii.  Guidance for Industry: Computerized Systems Used in Clinical Investigations 
(http://www.fda.gov/OHRMS/DOCKETS/98fr/04d-0440-gdl0002.pdf) 
viii.  Guidance for Industry: Part 11: Electronic Records, Electronic Signatures -- Scope 
and Application (http://www.fda.gov/ohrms/dockets/98fr/5667fnl.pdf) 
ix.  Guidance for IRBs, Clinical Investigators, and Sponsors: IRB Continuing Review after 
Clinical Investigation Approval 
(https://www.fda.gov/downloads/regulatoryinformation/guidances/ucm294558.pdf) 
x.  Humanitarian Device Exemption (HDE) Regulation: Questions and Answers; 
Guidance for HDE Holders, Institutional Review Boards (IRBs), Clinical Investigators 
and FDA Staff 
(http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/Guid  
anceDocuments/ucm110203.pdf) 
xi.  Information Sheet Guidance for IRBs, Clinical Investigators, and Sponsors  
Frequently Asked Questions About Medical Devices 
(http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM127067.pdf) 
xii.  Investigations Operational Manual (IOM) 
(http://www.fda.gov/ICECI/Inspections/IOM/default.htm) 
xiii.  General Principles of Software Validation; Final Guidance for Industry and FDA Staff 
(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocu  
ments/ucm085281.htm) 
xiv.  Guidance for Industry:  Protecting the Rights, Safety, and Welfare of Study Subjects 
  Supervisory Responsibilities of Investigators 
(http://www.fda.gov/OHRMS/DOCKETS/98fr/07d-0173-gdl0001.pdf) 
xv.  Guidance for Industry:  Using a Centralized IRB Review Process in Multicenter 
Clinical Trials 
(http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM127013.pdf) 
xvi.  Information Sheet Guidance for IRBs, Clinical Investigators, and Sponsors -- Significant Risk 
and Nonsignificant Risk Medical Device Studies 
(http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126418.pdf) 
 
 
 
    Program Contacts 
When medical, technical or scientific questions or issues arise from a specific assignment or if 
additional information is required about a specific assignment, consult the Center contact identified in 
the assignment. 
A.  For operational questions, contact: 
Office of Regulatory Affairs (ORA) 
  Date of Issuance: 09/26/2018  Page 56 of 59   
PROGRAM  7348.809 
 
Office of Medical Products and Tobacco Operations (OMPTO) 
Office of Bioresearch Monitoring Operations (OBIMO) - ORAHQ BIMO Inspection POC 
 
 
B.  For questions about GCP and Compliance program issues, specific to a Center 
product area, contact: 
 
 
Center for Drug Evaluation and Research (CDER) Office 
of Scientific Investigations: 301-796-3510, FAX 301-847- 
8748 
Center for Biologics Evaluation and Research (CBER) 
Bioresearch Monitoring Staff: 
CBERBIMONotification@fda.hhs.gov; 240-402-9161. 
Center for Devices and Radiological Health (CDRH) 
Division of Bioresearch Monitoring: 301-796-5490, FAX 
301-847-8137 
Center for Food Safety and Applied Nutrition (CFSAN) 
Bioresearch Monitoring Program 
301-402-1757; 
CFSANBIMO@FDA.HHS.GOV 
Center for Tobacco Products (CTP) 
Office of Compliance and Enforcement (OCE) 877-287-1373 
 
 
C. For crosscutting questions about GCP policy and program issues impacting the 
Agencys BIMO Programs, or suggestions to improve this compliance program, contact: 
Office of Good Clinical Practice 
Office of Special Medical Programs 
Office of the Commissioner 
301-796-8340, FAX 301-847-8640 
  Date of Issuance: 09/26/2018  Page 57 of 59   
 
PROGRAM  73000.000 
 
 
PART VII - HEADQUARTERS RESPONSIBILITIES 
 
  Centers 
Each Center: 
 
A.  Identifies Institutional Review Boards to be inspected and forwards inspection 
assignments and background material (e.g., protocols, correspondence, 
complaint, and Center concerns) to the ORAHQ BIMO Inspection POC and enters 
into the appropriate electronic data system such as FACTS or eNSPect. 
 
B.  Reviews and makes final classifications of EIRs, and enters the classification into 
the appropriate electronic data system. 
 
C. Issues correspondence to the inspected institution after EIR review.  This letter 
will typically be addressed to the most responsible individual in the institution 
along with a copy to the IRB chairperson and will state the Centers assessment 
of the IRBs performance.  Copies of letters will be sent to the appropriate ORA 
BIMO Division Office. 
 
D. Conducts follow-up regulatory and/or administrative actions.  Promptly provides 
copies of relevant correspondence between the institution or IRB and FDA to the 
ORA BIMO Division Offices. 
 
E.  Provides expert technical guidance, advice, information, interpretation, analysis, 
and support related to implementation of the clinical BIMO Program for internal 
and external constituents. 
    ORA/OFFICE OF ENFORCEMENT AND IMPORT OPERATIONS (OEIO)/DIVISION OF 
ENFORCEMENT (DE) 
D. Serves as the Agency clearance point and coordinator for inspection warrants. 
 
E.  For disqualification actions, reviews and issues the letter with the signature of the 
Associate Commissioner for Regulatory Affairs (ACRA, and coordinates actions 
related to the IRB or IRBs parent institution initial response. 
 
 
   ORA/OFFICE OF BIORESEARCH MONITORING OPERATIONS (OBIMO) 
A.  Provides inspection quality assurance, training of field personnel, and operational 
guidance. 
 
B.  Maintains liaison with Centers and ORA BIMO Divisions and resolves operational 
questions. 
  Date of Issuance: 09/26/2018  Page 58 of 59   
 
PROGRAM  7348.809 
 
 
 
C. Coordinates and schedules independent and team inspections. 
 
    Office of Good Clinical Practice, Office of the Commissioner 
A.  Coordinates crosscutting clinical BIMO program activities including modifications of 
this compliance program. 
 
B.  Provides expert technical guidance, advice, information, interpretation, and analysis 
relevant to clinical BIMO Program implementation to internal and external program 
constituents to assure program consistency. 
 
 
C. Serves as agency liaison to other Federal Agencies (e.g., OHRP, VA) for 
coordination of clinical BIMO and human subject protection issues. 
  Date of Issuance: 09/26/2018  Page 59 of 59