A Risk-Based Approach to 
Monitoring of Clinical 
Investigations 
 
Questions and Answers
Guidance for Industry 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
Center for Devices and Radiological Health (CDRH) 
Office of Clinical Policy (OCLiP)  
Office of Regulatory Affairs (ORA) 
 
April 2023 
Procedural 
 
35086309fnl04-07-23.docx   
A Risk-Based Approach to Monitoring 
of Clinical Investigations 
Questions and Answers  
  
Guidance for Industry
 
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and-radiation-emitting-products 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
Center for Devices and Radiological Health (CDRH) 
Office of Clinical Policy (OCLiP) 
Office of Regulatory Affairs (ORA) 
 
 
April 2023 
Procedural 
 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  QUESTIONS AND ANSWERS ....................................................................................... 4 
A.  Monitoring Approach .................................................................................................................... 4 
B.  Monitoring Plan Content .............................................................................................................. 8 
C.  Follow-Up and Communication of Monitoring Results ............................................................. 9 
  Contains Nonbinding Recommendations 
 
A Risk-Based Approach to Monitoring of Clinical Investigations 
Questions and Answers 
Guidance for Industry1 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
 
I.  INTRODUCTION  
 
This guidance provides information on risk-based approaches to monitoring the conduct of 
clinical investigations2 of human drug and biological products, medical devices, and 
combination products.3  Clinical investigation monitoring is a quality control tool for 
determining whether investigation activities are being carried out as planned.  This guidance 
contains recommendations on planning a monitoring approach, developing the content of a 
monitoring plan, and addressing and communicating monitoring results.  This guidance expands 
on the guidance for industry Oversight of Clinical Investigations  A Risk-Based Approach to 
Monitoring (August 2013) (the 2013 RBM guidance)4 by providing additional information to 
facilitate sponsors implementation of risk-based monitoring.   
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required. 
 
 
1 This guidance has been prepared by the Office of Medical Policy in the Center for Drug Evaluation and Research 
in cooperation with the Center for Biologics Evaluation and Research, the Center for Devices and Radiological 
Health, the Office of Clinical Policy, the Office of Combination Products, and the Office of Regulatory Affairs at 
the Food and Drug Administration.  
 
2 For FDAs regulatory definitions of clinical investigation or investigation, see 21 CFR 50.3(c), 56.102(c), 312.3(b) 
and 812.3(h).  For the purposes of this guidance, we use the terms clinical investigation, investigation, trial or trials, 
and study or studies interchangeably consistent with how these terms are used in the guidance for industry Oversight 
of Clinical Investigations  A Risk-Based Approach to Monitoring (August 2013) (the 2013 RBM guidance). 
 
3 For the definition of combination product, see 21 CFR 3.2(e). 
 
4 We update guidances periodically.  For the most recent version of a guidance, check the FDA guidance web page 
at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 
 
  1  Contains Nonbinding Recommendations 
 
II.  BACKGROUND 
 
Sponsors of clinical investigations involving human drugs, biological products, medical devices, 
and combination products are required to provide oversight, including ensuring proper 
monitoring of the investigation.5  Such oversight helps to ensure adequate protection of the 
rights, safety, and welfare of participants in the clinical investigation and the integrity of the data 
submitted to FDA.  Therefore, sponsors should implement a system to manage, throughout all 
stages of the clinical investigation, both risks to participants (e.g., a safety problem) and to data 
integrity (e.g., incomplete and/or inaccurate data).  
 
This system to manage the quality of the investigation should help ensure data integrity while 
safeguarding the rights, safety, and welfare of trial participants,6 for example, by focusing on the 
design of efficient clinical trial protocols, tools for identifying and tracking potential risks, and 
procedures for data collection and processing.  This system should include a risk-based approach 
to monitoring tailored to the potential risks for the specific clinical investigation.  Effective 
implementation of risk-based monitoring, including the prioritization of monitoring and other 
oversight activities directed at processes and procedures critical for human subject protection and 
maintaining data integrity, should help maximize the quality of a clinical investigation.  
 
Although FDAs regulations require sponsors to monitor the conduct and progress of their 
clinical investigations,7, 8  FDA regulations are not specific about how sponsors are to conduct 
monitoring.  FDA recommends that sponsors use a risk-based approach to develop their 
monitoring plans and to revise their monitoring plans, if needed, as the clinical investigation 
proceeds.  This risk-based approach should be informed by the sponsors overarching quality 
management activities undertaken in the development of the protocol and associated 
investigational plans and should be adjusted throughout the conduct of the investigation as 
needed.   
 
As described in the 2013 RBM guidance, FDA recommends that at the protocol design stage, 
sponsors identify the critical data and processes necessary for human subject protection and 
maintaining data integrity for the investigation.  Once these are identified, sponsors should 
perform a risk assessment and determine whether risks to critical data and processes may be 
 
5 21 CFR part 312, subpart D, generally (Responsibilities of Sponsors and Investigators) and 21 CFR part 812, 
subpart C, generally (Responsibilities of Sponsors). 
 
6 For FDAs regulatory definitions of human subject and subject, see 21 CFR 50.3(g), 56.102(e), 312.3(b) and 
812.3(p).  For the purposes of this guidance, the terms human subject and participant are used interchangeably.  
 
7 21 CFR 312.50 requires a sponsor to, among other things, ensure proper monitoring of the investigation(s) and 
that the investigation(s) is conducted in accordance with the general investigational plan and protocols contained in 
the IND.  21 CFR 812.40 states that sponsors are responsible for, among other things, ensuring proper monitoring 
of the investigation, and 21 CFR 812.46 requires, among other things, that sponsors take certain actions when they 
discover that an investigator is not complying with the signed agreement, the investigational plan, the requirements 
of 21 CFR part 812 or other applicable FDA regulations, or any conditions of approval imposed by the reviewing 
institutional review board or FDA. 
 
8 See also 21 CFR 312.53(d), 312.56(a), 812.43(d), and 812.46.   
 
  2  Contains Nonbinding Recommendations 
 
mitigated through revisions to the protocol and investigational plans.  When risks cannot be 
resolved through such revisions, sponsors should determine how remaining critical risks will be 
identified, tracked, and managed via the sponsors monitoring plan or related study oversight 
plans during the conduct of the investigation.  Such efforts to build quality into the design and 
execution of clinical investigations should be informed by representative study team members9 
involved with conduct, monitoring, and/or reporting of the investigation.  Perspectives from 
patients within the target population to be recruited for a clinical investigation would also be 
valuable.  
 
Monitoring should be conducted per the pre-established monitoring plan, and important issues 
identified through monitoring should be addressed as they are identified.  Monitoring plans 
should also include directions for when and to whom important issues identified during 
monitoring should be escalated.  In addition, FDA recommends that monitoring plans provide 
guidance on when and how to adjust monitoring activities based on observed monitoring 
findings.  For example, when important issues are identified during monitoring of a clinical site, 
there may be a need to increase the duration or frequency of on-site visits at that site.   
 
Sponsors risk management processes should continue throughout the conduct of the 
investigation.  FDA also encourages sponsors to use the information gained from each 
investigation, including the monitoring experience, to inform, as appropriate, the conduct of 
other ongoing investigations, future clinical investigations, risk assessments, and monitoring 
plans. 
 
The study-level monitoring plan and associated monitoring activities are among the elements 
utilized by sponsors in their overall risk-based quality management approach to product 
development; they are important tools to facilitate sponsors identifying and addressing issues 
during the conduct of clinical investigations.  The 2013 RBM guidance outlines factors that 
sponsors should consider in developing a monitoring plan and tailoring monitoring plans to the 
needs of the investigation and provides examples of monitoring methods and techniques.  Since 
finalizing the 2013 RBM guidance, FDA has concluded that additional guidance may be 
beneficial regarding its recommendations for planning a monitoring approach, developing the 
content of monitoring plans, and addressing and communicating monitoring results.  The 
following questions and answers are intended to assist sponsors in planning and conducting risk-
based approaches to monitoring.   
 
 
9 For example, clinical investigator, research nurse, project managers, study physician/medical monitor, data 
managers/data scientists, statisticians, monitoring staff, quality assurance personnel, and contracted service 
providers tasked with critical study functions.  
  3  Contains Nonbinding Recommendations 
 
III.  QUESTIONS AND ANSWERS       
 
A.  Monitoring Approach 
 
Q1.  What is the purpose of the risk assessment and should sponsors document their 
methodologies and activities for assessing risk?    
 
The purpose of the risk assessment is to optimize the study quality in terms of eliminating or 
mitigating important risks to both human subject protection and data integrity.  Therefore, 
consistent with the 2013 RBM guidance, during the protocol design phase, sponsors should 
identify risks, including to protocol-driven processes, that could affect human subject protection 
and data integrity.  The risk assessment should include an evaluation of the potential causes, 
likelihood of detection, and severity of the consequences of risks to critical data or human 
subject protections.  There are various risk assessment methodologies and tools that can be 
applied to clinical trials.10,11 
 
The risk assessment should inform the development of the clinical trial protocol and associated 
investigational plans, including the monitoring plan, and may also support efforts to manage 
risks during the conduct of a clinical investigation or across a products development program.  
Therefore, sponsors should document their risk assessment, including methodologies used for the 
risk assessment, conclusions from the risk assessment, and how the assessment was used to make 
decisions on the management of the risks identified.  Sponsors should reevaluate their risk 
assessment and management processes throughout the conduct of the investigation as issues are 
identified, and monitoring plans (and if necessary, protocol design) should be revised when 
needed to continue to protect the rights, safety, and welfare of participants in the clinical 
investigation and the integrity of data generated during the investigation.  When new risks are 
identified, their potential impact across that product development program, as well as on the 
sponsors other product development programs, as appropriate, should be considered.  If a risk-
based monitoring approach is being used, FDA may request, during inspection, documentation of 
the sponsors initial risk assessment, and any relevant updated risk assessments.  
 
The monitoring plan should include information regarding the identified risks and how the 
monitoring methods will address those risks.  (See Q6 for further details.)  The inclusion of these 
components in the monitoring plan will enhance the utility of the plan by providing a clear 
explanation of the identified risks and how they will be monitored, managed, and mitigated or 
eliminated. 
 
Q2.  Should sponsors monitor only risks that are important and identified during their 
initial risk assessment as likely to occur? 
 
No.  Sponsors should monitor the important and likely risks identified during their initial risk 
assessment, and they should also monitor for additional risks detected during the conduct of the 
clinical investigation that were not identified before the investigation began.  For example, if an 
 
10 See the ICH guidance for industry Q9 Quality Risk Management (June 2006). 
 
11 IEC 31010:2019 Risk Management  Risk Assessment Techniques. 
  4  Contains Nonbinding Recommendations 
 
additional risk is detected during the investigation that was not anticipated and that risk could 
impact the conduct, collection, or reporting of critical processes, procedures, or data, that risk 
should be addressed.   
 
Sponsors should also monitor risks that are less likely to occur, but that could have a significant 
impact on the quality of the investigation including on the rights, safety, and welfare of trial 
participants.   
 
Monitoring plans should consider important risks and should be sufficiently comprehensive so 
that risks that arise during the investigation that were not anticipated can be identified and 
addressed.  
 
Monitoring plans should take into account important risks identified in the initial risk assessment 
while also enabling sponsors to identify and address risks that arise during the investigation that 
were not anticipated.  Monitoring plans should therefore be revised, as needed, if new 
information about risks becomes available.  
 
Q3.  What factors should sponsors consider when determining the timing, types, 
frequency, and extent of monitoring activities?  
 
As described in detail in the 2013 RBM guidance, during the risk assessment, sponsors should 
consider a range of factors to inform the development of the monitoring plan.  While some 
factors described below (see bulleted factors) relate to the investigation overall, other factors 
relate to specific clinical sites; therefore, FDA recommends that the monitoring plan be 
organized to account for both the overall investigation and site-specific risks, recognizing that 
some mitigating activities may not be relevant for all sites. 
 
Sponsors should consider: 
 
  How well established the clinical investigation infrastructures are at different clinical 
sites 
 
  Relative experience of the clinical investigator and of the sponsor with the clinical 
investigator 
 
  Electronic data capture to be utilized12   
 
  Use of electronic data capture (EDC) systems with the capability to assess quality 
metrics (e.g., missing data, data error rates, protocol violations) in real time could 
help identify potentially higher risk sites for the purpose of targeting sites in need 
of more intensive monitoring. 
 
12 See the guidance for industry Electronic Source Data in Clinical Investigations (September 2013) and the revised 
draft guidance for industry Electronic Systems, Electronic Records, and Electronic Signatures in Clinical 
Investigations:  Questions and Answers (March 2023).  When final, this guidance will represent FDAs current 
thinking on this topic.  
  5  Contains Nonbinding Recommendations 
 
 
  Stage of the study (e.g., for a complex study, more intensive and on-site monitoring 
might be warranted early, but once procedures are established, less intensive monitoring 
might suffice)  
 
  Quantity, extent, complexity, and criticality of data to be collected 
 
When developing the monitoring plan, sponsors should determine the types and intensity of 
monitoring activities best suited to address the identified risks while also facilitating 
identification of unanticipated risks.  When suitable, statistical and analytical methods to monitor 
critical data in a centralized manner may be particularly advantageous.  Monitoring activities 
should evolve based on additional issues and risks that may be identified during the conduct of 
the investigation.  The types and intensity of monitoring activities also should be proportionate to 
the risks to participants rights, safety, and welfare and to data integrity inherent in the 
investigation.   
 
While source data verification (SDV)13 may be a part of a risk-based monitoring approach, the 
extent to which SDV is used should be guided by the sponsors risk assessment process and 
focused on critical study data and processes.  Focusing more monitoring activities on risks to the 
most critical data elements and processes should enable sponsors to achieve the objective of 
conducting a quality clinical investigation, including human subject protection and data integrity, 
without necessarily having to conduct frequent routine visits to all clinical sites and extensive 
SDV. 
 
FDA also recommends that sponsors consider the following additional factors:   
 
  Adequate staffing to support the clinical investigation.  Specific considerations include 
relevant study-specific trainings of site staff, the experience and qualifications of the 
research coordinator and specialized research professionals working with and under the 
direction of the clinical investigator, and turnover of personnel at the investigational site 
or among monitoring staff.  
 
  Location where participants will be seen and whether they will be seen at more than one 
location to complete investigation procedures (for example, data collection at the imaging 
center, at a local physicians office, or at the participants home), including when all 
activities take place at locations remote from the investigator without the need for a 
physical clinical site. 
 
  When designing the monitoring plan, sponsors should take into consideration where 
and how the data are going to be collected in the investigation relative to where the 
sponsor oversight activities will be conducted (for example, to confirm that 
appropriate controls, instructions, and training tools are in place). 
 
 
13 For the purposes of this guidance, SDV refers to the process of confirming that study data included in 
efficacy/effectiveness and safety analyses reflect source data obtained during the clinical investigation. 
  6  Contains Nonbinding Recommendations 
 
  Benefit of an early monitoring visit or other early monitoring activities 
 
  By scheduling an early monitoring visit (for example, soon after the first few trial 
participants enroll in the investigation) or by carrying out other early monitoring 
activities, sponsors can help ensure early in the investigation that the protocol is being 
followed and procedures are being performed correctly at clinical sites.  Additionally, 
if early monitoring identifies issues, such as a number of protocol deviations, 
corrective actions can be implemented sooner.  For complex studies, early and more 
intensive on-site monitoring might be warranted. 
 
Q4.  How can a risk-based approach to monitoring that includes centralized monitoring 
help minimize missing data or protocol deviations? 
 
Centralized monitoring is a systematic analytical evaluation of study conduct across multiple 
clinical sites, carried out by sponsor personnel or representatives (e.g., clinical monitors, data 
management personnel, or statisticians).  Centralized monitoring may allow sponsors to (1) 
review study-wide data for inconsistencies or omissions; (2) perform activities such as data 
checks, for completeness and consistency; (3) verify source data; (4) ensure that institutional 
review board and informed consent documents are current; and (5) determine which clinical sites 
need on-site review.  
 
Depending on how centralized monitoring is used, incorporating centralized monitoring as a part 
of a risk-based approach to monitoring may help ensure the quality of a clinical investigation by 
allowing sponsors to aggregate and compare site data and detect potential anomalies more 
quickly.  By reviewing study data and metadata14 in real time across clinical sites, sponsors may 
be able to identify quality issues, such as delays in entering data or incomplete entries, earlier 
than when relying on on-site monitoring alone.  Sites with multiple issues detected through 
centralized monitoring, such as delays in assessments or missing assessments, may also provide 
an early signal that the sponsor should promptly determine whether there is a need for a site visit 
and corrective actions to minimize the likelihood of similar issues occurring during the 
remainder of the clinical investigation. 
 
Q5.  Should the risk-based monitoring approach include processes to ensure that 
appropriate blinding is maintained?  
 
Yes.  As identified in the 2013 RBM guidance, for investigations that include blinding of 
interventions and/or outcome assessments, ensuring that the blinding of the investigation is 
maintained is a critical process that sponsors should consider in their risk assessment. 
 
Specific risks to the maintenance of the blinding that are identified during the risk assessment 
should be mitigated in advance of investigation initiation, when feasible.  In addition, identifying 
and tracking deviations during the conduct of the investigation that could result in unintentional 
 
14 For the purposes of this guidance, metadata is structured information that describes, explains, or otherwise makes 
it easier to retrieve, use, or manage data.  Metadata provides the contextual information required to understand data.  
See the guidance for industry Data Integrity and Compliance with Drug CGMP:  Questions and Answers 
(December 2018).  
  7  Contains Nonbinding Recommendations 
 
unblinding of treatment assignment should be considered as a part of the monitoring plan, to 
ensure that appropriate blinding is maintained at clinical sites and by the sponsor, organizations 
such as contract research organizations and other vendors.  For example, in a blinded 
investigation that requires the site staff personnel dispensing the test article to know whether the 
test article is the investigational product or the placebo, the adequacy of maintaining the blinding 
for the remainder of the site staff should be monitored.   
 
FDA recognizes that Data Monitoring Committees (DMC) may access unblinded data as 
described in the DMC Charter.  (For additional information about DMCs, see the guidance for 
clinical trial sponsors Establishment and Operation of Clinical Trial Data Monitoring 
Committees (March 2006).) 
 
B.  Monitoring Plan Content  
 
Q6.  What elements should sponsors include in monitoring plans?  
 
Monitoring plans should be developed for each investigation based on the risk assessment for 
that investigation.  Monitoring plans should address both study-specific and site-specific risks.  
Monitoring plans also should be designed to enable the management of anticipated and 
unanticipated risks.  As stated earlier, sponsors are encouraged to develop risk-based monitoring 
plans that emphasize critical risks with the greatest potential to adversely affect investigation 
quality, including (1) the rights, safety, and welfare of participants in a clinical investigation; and 
(2) the collection or analysis of critical clinical data such as safety and efficacy/effectiveness 
endpoints.  Section IV.D of the 2013 RBM guidance discusses in detail the recommended 
components of a monitoring plan.  Sponsors also may reference in the monitoring plan other 
clinical trial management plans used for risk management (e.g., a data management plan) that 
address the components recommended in the 2013 RBM guidance rather than repeat the same 
information in the monitoring plan.   
 
In addition to the components recommended in the 2013 RBM guidance, FDA recommends that 
monitoring plans also include the following components, which will help explain how the 
sponsor intends to address the risks that could affect the clinical investigation:  
 
  A description of the investigation design, including the blinding and randomization 
procedures, if applicable 
 
  Processes for confirming that randomization is performed according to the protocol and 
investigational plan or plans  
 
  The sampling plan or plans that will be used to identify the specific records and data that 
will be monitored, including (1) the rationale for how the sampling plan provides a 
representative picture of the overall information and (2) how the sampling plan will be 
implemented 
  
  A description of the types of issues identified through monitoring that would trigger 
immediate issue escalation 
  8  Contains Nonbinding Recommendations 
 
 
  An approach for determining whether (1) an important issue that is detected at a clinical 
site may also be present at other clinical sites; and (2) the finding suggests a systemic 
problem with the protocol or associated investigational plans that requires remediation 
 
C.  Follow-Up and Communication of Monitoring Results 
 
Q7.  How should sponsors follow up on significant issues identified through monitoring, 
including communication of such issues?   
 
Significant issues should be thoroughly evaluated in a timely manner at the appropriate levels 
(for example, sponsor, clinical sites) as described in the monitoring plan.  A root cause analysis 
followed by appropriate corrective and preventive actions should be undertaken promptly to 
reduce the impact of the identified issue on the rights, safety, and welfare of participants in the 
clinical investigation and/or the integrity of the data.  Additionally, the risk assessment and 
monitoring plan should be reviewed and revised, as needed, to help ensure the risk of recurrence 
is decreased, or if possible, eliminated.  In instances in which corrective actions modify study 
processes, the protocol and/or associated investigational plans should be amended to reflect 
changed processes.  Related systemic issues should be identified and resolved promptly to help 
ensure that investigation quality, including the rights, safety, and welfare of investigation 
participants and data integrity, is maintained.   
 
Examples of preventive and corrective actions that may be warranted include but are not limited 
to (1) improved training for the clinical investigator and site staff; (2) halting enrollment at a 
clinical site pending resolution of identified issues; (3) clarifying or revising the protocol and/or 
other related investigational plans and documents; and/or (4) modifying vendor service 
agreements to ensure adequate trial support.   
 
Significant issues identified through monitoring and oversight activities and the actions to be 
taken should be documented and communicated to the appropriate parties, which may include, 
but are not limited to (1) sponsor management; (2) sponsor teams; (3) clinical sites; (4) 
institutional review boards; (5) other relevant parties (for example, DMCs and relevant contract 
research organizations); and (6) applicable regulatory agencies, including FDA, when 
appropriate. 
 
See the 2013 RBM guidance for additional recommendations regarding follow-up and 
communication of significant issues identified via monitoring. 
 
Q8.  How should monitoring activities and the results of these activities be documented 
and shared with those involved in the investigation?  
 
As described in the 2013 RBM guidance, documentation of monitoring activities should 
generally include the following:  (1) the date of the activity; (2) the individuals conducting and 
participating in the activity; (3) a summary of the data or activities reviewed; (4) a description of 
any noncompliance, potential noncompliance, data irregularities, and/or other deficiencies 
identified; and (5) a description of any actions taken, to be taken, or recommended (see section V 
  9  Contains Nonbinding Recommendations 
 
of the 2013 RBM guidance for additional information).  Such documentation should include the 
results of monitoring activities in sufficient detail to allow verification of adherence to the 
monitoring plan describing those activities.  Monitoring activities to be documented should 
include on-site and remote monitoring of clinical sites and centralized monitoring across clinical 
sites.  
 
Reports of monitoring activities should be provided to appropriate management (including 
sponsor staff responsible for the conduct and oversight of the clinical investigation) in a timely 
manner for review and follow-up.  In addition, sponsors should inform the clinical investigator of 
monitoring findings from monitoring activities that are relevant to the clinical investigators 
activities.  
  10