Guidance for Industry 
 
 
Oversight of Clinical 
Investigations   
A Risk-Based Approach to 
Monitoring  
 
 
 
 
 
 
 
 
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 Good Clinical Practice (OGCP) 
Office of Regulatory Affairs (ORA) 
 
August 2013 
Procedural 
 
 
OMB Control No. 0910-0014 
Current expiration date available at https://www.reginfo.gov  
(Search ICR and enter OMB control number 0910-0014)    
See additional PRA statement in section VII of this guidance.
10555fnlPRAupdate11-21-22.docx 
   
Guidance for Industry 
 
Oversight of Clinical Investigations  A 
Risk-Based Approach to Monitoring  
 
 
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U.S. Department of Health and Human Services 
Food and Drug Administration 
 
August 2013 
Procedural
  Contains Nonbinding Recommendations 
TABLE OF CONTENTS 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
A.    Current Monitoring Practices and FDA Guidance .................................................................... 3 
B.    FDAs Rationale for Risk-Based Monitoring .............................................................................. 5 
III.  OVERVIEW OF MONITORING METHODS ............................................................. 6 
A.    On-Site and Centralized Monitoring ........................................................................................... 6 
1.  On-Site Monitoring .......................................................................................................................... 6 
2.  Centralized Monitoring .................................................................................................................... 7 
B.    Examples of Alternative Monitoring Techniques ....................................................................... 7 
1.  Communication with Study Site Staff ............................................................................................. 9 
2.  Review of Sites Processes, Procedures, and Records ..................................................................... 9 
3.  Source Data Verification and Corroboration ................................................................................. 10 
IV.  RISK-BASED MONITORING...................................................................................... 10 
A.    Identify Critical Data and Processes to be Monitored .............................................................. 11 
B.    Risk Assessment ........................................................................................................................... 12 
C.    Factors to Consider when Developing a Monitoring Plan ....................................................... 13 
D.    Monitoring Plan ........................................................................................................................... 14 
1.  Description of Monitoring Approaches .......................................................................................... 15 
2.  Communication of Monitoring Results.......................................................................................... 15 
3.  Management of Noncompliance .................................................................................................... 16 
4.  Ensuring Quality Monitoring ......................................................................................................... 16 
5.  Monitoring Plan Amendments ....................................................................................................... 17 
V.  DOCUMENTING MONITORING ACTIVITIES ...................................................... 17 
VI.  ADDITIONAL STRATEGIES TO ENSURE STUDY QUALITY ............................ 17 
A.    Protocol and Case Report Form Design .................................................................................... 17 
B.    Clinical Investigator Training and Communication ................................................................. 18 
C.    Delegation of Monitoring Responsibilities to a CRO ................................................................ 18 
D.    Clinical Investigator and Site Selection and Initiation ............................................................. 19 
VII.  PAPERWORK REDUCTION ACT OF 1995 .............................................................. 19 
 
  Contains Nonbinding Recommendations 
Guidance for Industry1 
Oversight of Clinical Investigations  A Risk-Based  
Approach to Monitoring  
 
 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this topic.  It 
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.  
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance. 
  
 
 
I.  INTRODUCTION  
 
This guidance assists sponsors of clinical investigations in developing risk-based monitoring 
strategies and plans for investigational studies of medical products, including human drug and 
biological products, medical devices, and combinations thereof.  The overarching goal of this 
guidance is to enhance human subject protection and the quality of clinical trial data by focusing 
sponsor oversight on the most important aspects of study conduct and reporting.   
 
This guidance makes clear that sponsors can use a variety of approaches to fulfill their 
responsibilities for monitoring clinical investigator (CI) conduct and performance in 
investigational new drug (IND) studies conducted under 21 CFR part 312 or investigational 
device exemption (IDE) studies conducted under 21 CFR part 812.  The guidance describes 
strategies for monitoring activities that reflect a modern, risk-based approach that focuses on 
critical study parameters and relies on a combination of monitoring activities to oversee a study 
effectively.  For example, the guidance specifically encourages greater use of centralized 
monitoring methods where appropriate. 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Rather, 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 
(CDER) in cooperation with CDERs Office of Scientific Investigations in the Office of Compliance, CBERs 
Office of Compliance and Biologics Quality, CDRHs Office of Compliance, Office of the Commissioners Office 
of Good Clinical Practice, and the Office of Regulatory Affairs (ORA).  
  1  Contains Nonbinding Recommendations 
II.  BACKGROUND 
 
Effective monitoring of clinical investigations by sponsors is critical to the protection of human 
subjects and the conduct of high-quality studies.  Sponsors of clinical investigations involving 
human drugs, biological products, medical devices, and combinations thereof are required to 
provide oversight to ensure adequate protection of the rights, welfare, and safety of human 
subjects and the quality of the clinical trial data submitted to FDA.2  FDAs regulations require 
sponsors to monitor the conduct and progress of their clinical investigations.3,4  The regulations 
are not specific about how sponsors are to conduct such monitoring and are therefore compatible 
with a range of approaches to monitoring (see section III) that will vary depending on multiple 
factors (see section IV.C).   
 
During the past two decades, the number and complexity of clinical trials have grown 
dramatically.  These changes create new challenges to clinical trial oversight, particularly 
increased variability in clinical investigator experience, site infrastructure, treatment choices, and 
standards of health care,5 as well as challenges related to geographic dispersion.  At the same 
time, increasing use of electronic systems and records and improvements in statistical 
assessments, present opportunities for alternative monitoring approaches (e.g., centralized 
monitoring) that can improve the quality and efficiency of sponsor oversight of clinical 
investigations.  FDA encourages sponsors to develop monitoring plans that manage important 
risks to human subjects and data quality and address the challenges of oversight in part by taking 
advantage of the innovations in modern clinical trials.  A risk-based approach to monitoring does 
not suggest any less vigilance in oversight of clinical investigations.  Rather, it focuses sponsor 
oversight activities on preventing or mitigating important and likely risks to data quality and to 
processes critical to human subject protection and trial integrity.  Moreover, a risk-based 
approach is dynamic, more readily facilitating continual improvement in trial conduct and 
oversight.  For example, monitoring findings should be evaluated to determine whether 
additional actions (e.g., training of clinical investigator and site staff, clarification of protocol 
requirements) are necessary to ensure human subject protection and data quality across sites.   
 
This guidance focuses principally on monitoring, which is one aspect of the processes and 
procedures needed to ensure clinical trial quality and subject safety.  Monitoring is a quality 
control tool for determining whether study activities are being carried out as planned, so that 
deficiencies can be identified and corrected.  Monitoring, or oversight, alone cannot ensure 
quality.  Rather, quality is an overarching objective that must be built into the clinical trial 
enterprise.  FDA recommends a quality risk management approach to clinical trials and is 
considering the need for additional guidance describing this approach. 
 
2 21 CFR part 312, subpart D generally (Responsibilities of Sponsors and Investigators) and 21 CFR part 812, 
subpart C generally (Responsibilities of Sponsors). 
3 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, ... 
4 See also 21 CFR 312.53(d), 312.56(a), 812.43(d), and 812.46. 
5 Glickman et al. Ethical and Scientific Implications of the Globalization of Clinical Research. NEJM. 360: 816-823 
(2009).  
  2  Contains Nonbinding Recommendations 
We are aware that the term monitoring is used in different ways in the clinical trial context.  It 
can refer to the assessment of CI conduct, oversight, and reporting of findings of a clinical trial; 
to the ongoing evaluation of safety data and the emerging benefit-risk profile of an 
investigational product; and to the monitoring of internal sponsor and contract research 
organization (CRO) processes and systems integral to proposing, designing, performing, 
recording, supervising, reviewing, or reporting clinical investigations.   
 
For purposes of this guidance, monitoring refers to the methods used by sponsors of 
investigational studies, or CROs delegated responsibilities for the conduct of IND studies, to 
oversee the conduct of, and reporting of data from, clinical investigations, including appropriate 
CI supervision of study site staff and third party contractors.  Monitoring activities include 
communication with the CI and study site staff; review of the study sites processes, procedures, 
and records; and verification of the accuracy of data submitted to the sponsor. 
 
A.  Current Monitoring Practices and FDA Guidance 
 
A survey conducted through the Clinical Trials Transformation Initiative (CTTI)6 indicated that 
a range of practices has been used to monitor the conduct of clinical trials.  These practices vary 
in intensity, focus, and methodology and include centralized monitoring of clinical data by 
statistical and data management personnel; targeted on-site visits to higher risk CIs (e.g., where 
centralized monitoring suggests problems at a site); and frequent, comprehensive on-site visits to 
all CI sites by sponsor personnel or representatives (e.g., clinical monitors or clinical research 
associates).7  See definitions of on-site and centralized monitoring in section III.A. 
 
Although survey participants reported a range of monitoring methods, periodic, frequent visits to 
each CI site to evaluate study conduct and review data for each enrolled subject remain the 
predominant mechanism by which pharmaceutical, biotechnology, and medical device 
companies monitor the progress of clinical investigations.  For major efficacy trials, companies 
typically conduct on-site monitoring visits at approximately 4- to 8-week intervals,8 at least 
partly because of the perception that the frequent on-site monitoring visit model, with 100% 
verification of all data, historically has been FDAs preferred way for sponsors to meet their 
monitoring obligations.  In contrast, academic coordinating centers, cooperative groups, and 
government organizations use on-site monitoring less extensively.  For example, some 
government agencies and oncology cooperative groups typically visit sites only once every 2 or 3 
years to qualify or certify clinical study sites9 to ensure they have the resources, training, and 
safeguards to conduct clinical trials.  FDA also recognizes that regulators and practitioners have 
relied on data from critical outcome studies (e.g., many National Institutes of Health-sponsored 
trials, Medical Research Council-sponsored trials in the United Kingdom, ISIS (International 
 
6 CTTI is a public-private partnership involving FDA, academia, industry representatives, patient and consumer 
representatives, professional societies, investigator groups, and other government agencies, initiated in 2008. CTTIs 
mission is to identify practices that will increase the quality and efficiency of clinical trials.    
7 Morrison et al. Monitoring the Quality of Conduct of Clinical Trials: A Survey of Current Practices. Clin Trials. 8: 
342-349 (2011). 
8 Usher, R. PhRMA BioResearch Monitoring Committee Perspective on Acceptable Approaches for Clinical Trial 
Monitoring. Drug Inf J. 44: 477-483 (2010). 
9 Id. 
  3  Contains Nonbinding Recommendations 
Study of Infarct Survival) trials,10 and GISSI11), which had no regular on-site monitoring and 
used primarily centralized and other alternative monitoring methods.12  These examples suggest 
that use of alternative monitoring approaches should be considered by all sponsors, including 
commercial sponsors, when developing risk-based monitoring strategies and plans.  
 
The 1996 International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) guidance on good clinical practice (ICH 
E6) and the 2011 International Standards Organization (ISO) Clinical investigation of medical 
devices for human subjects  good clinical practice (ISO 14155:2011) address monitoring.  Both 
ICH E6 and ISO 14155:2011 specifically provide for flexibility in how trials are monitored.  ICH 
E6 and ISO 14155:2011 advise sponsors to consider the objective, design, complexity, size, and 
endpoints of a trial in determining the extent and nature of monitoring for a given trial.13,14  The 
ISO standard further states that a sponsors assessment of these factors should be used to develop 
a monitoring plan, a recommendation consistent with FDAs recommendation for monitoring 
plan development in this guidance.  Although the ICH guidance and ISO standard specifically 
provide for the possibility of reduced, or even no, on-site monitoring, they also make clear that it 
would be appropriate to rely entirely on centralized monitoring only in exceptional 
circumstances.   
 
FDA has communicated the goals of, and recommendations for, risk-based monitoring to FDA 
staff in review, inspection, and compliance functions.  FDAs bioresearch monitoring 
compliance program guidance manuals (CPGMs) for sponsors, CROs, and monitors (CPGM 
7348.810)15 and for CIs and sponsor-investigators (CPGM 7348.811)16 are compatible with the 
approaches described in this guidance.  For example, CPGM 7348.810 informs FDA field staff 
that the regulations do not prescribe a specific monitoring technique.  While CPGM 7348.810 
refers to site visits and does not discuss centralized monitoring, the focus is on the review of 
monitoring activities through documentation and whether these activities were carried out in 
accordance with the sponsors (or CROs) monitoring procedures.    
 
 
10 Califf et al. Developing Systems for Cost-Effective Auditing of Clinical Trials. Controlled Clinical Trials. 18: 
651-660 (1997).   
11 Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Italian group for the study of the 
survival of myocardial infarction. 
12 Temple, R. Policy Developments in Regulatory Approval. Statistics in Medicine. 21: 2939-2948 (2002).  
13 Guidance for industry, E6 Good Clinical Practice: Consolidated Guidance, 1996, section 5.18.3. We update 
guidances periodically.  To make sure you have the most recent version of a guidance, check the guidance Web site.  
CDER guidance documents can be found at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
CBER guidance documents can be found at   
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
CDRH guidance documents can be found at 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm. 
14 ISO 14155:2011, Clinical investigation of medical devices for human subjects  Good clinical practice, sections 
5.7 and 6.3.  
15 CPGM 7348.810: Sponsors, Contract Research Organizations and Monitors (March 11, 2011), available at:  
http://www.fda.gov/ICECI/EnforcementActions/BioresearchMonitoring/ucm133777.htm.  
16 CPGM 7348.811: Clinical Investigators and Sponsor-Investigators (December 8, 2008), available at: 
http://www.fda.gov/ICECI/EnforcementActions/BioresearchMonitoring/ucm133562.htm. 
  4  Contains Nonbinding Recommendations 
B.  FDAs Rationale for Risk-Based Monitoring  
 
FDA is issuing this guidance to provide FDAs current recommendations regarding monitoring 
practices and to encourage sponsors to consider a change in approach to monitoring.  FDA 
believes that risk-based monitoring could improve sponsor oversight of clinical investigations.  
This guidance is therefore intended to make it clear that risk-based monitoring, including the 
appropriate use of centralized monitoring (see section III.A.2 for discussion of centralized 
monitoring) and reliance on technological advances (e.g., e-mail, webcasts, online training 
modules), can meet statutory and regulatory requirements under appropriate circumstances. 
 
There is a growing consensus that risk-based approaches to monitoring, focused on risks to the 
most critical data elements and processes necessary to achieve study objectives, are more likely 
than routine visits to all clinical sites and 100% data verification to ensure subject protection and 
overall study quality.17,18,19,20  For example, incorporation of centralized monitoring practices, 
where appropriate, should improve a sponsors ability to ensure the quality of clinical trial data.  
Several publications suggest that certain data anomalies (e.g., fraud, including fabrication of 
data, and other non-random data distributions) may be more readily detected by centralized 
monitoring techniques than by on-site monitoring.21, 22, 23  It has been suggested that a statistical 
approach to central monitoring can help improve the effectiveness of on-site monitoring by 
prioritizing site visits and by guiding site visits with central statistical data checks, an approach 
that is supported by illustrative examples using actual trial datasets.24  A recent review of on-site 
monitoring findings collected during a multi-center international trial also suggests that 
centralized monitoring can identify the great majority of on-site monitoring findings.  The review 
determined that centralized monitoring activities could have identified more than 90% of the 
findings identified during on-site monitoring visits.25   
  
FDA encourages sponsors to tailor monitoring plans to the needs of the trial (see section IV).  
FDA recognizes that this guidance places greater emphasis on centralized monitoring than 
appeared feasible at the time ICH E6 was finalized.  However, FDA considers the approach to 
monitoring described in this guidance to be consistent with ICH E6 and ISO 14155:2011.  FDA 
 
17 Usher, R. PhRMA BioResearch Monitoring Committee Perspective on Acceptable Approaches for Clinical Trial 
Monitoring. Drug Inf J. 44: 477-483 (2010). 
18 FDA, Concept Paper: Quality in FDA-Regulated Clinical Research; Background to HSP/BIMO Workshop 5/10-
5/11/07, (4/26/07). 
19 Brosteanu et al. Risk Analysis and Risk Adapted On-Site Monitoring in Noncommercial Clinical Trials. Clin 
Trials. 6: 585-595 (2009). 
20 Tantsyura et al. Risk-Based Source Data Verification Approaches: Pros and Cons. Drug Inf J. 44: 745-756 (2010). 
21 Usher, R. PhRMA BioResearch Monitoring Committee Perspective on Acceptable Approaches for Clinical Trial 
Monitoring. Drug Inf J. 44: 477-483 (2010). 
22 Baigent et al. Ensuring Trial Validity by Data Quality Assurance and Diversification of Monitoring Methods. Clin 
Trials. 5: 49-55 (2008).   
23 Buyse et al. The Role of Biostatistics in the Prevention, Detection and Treatment of Fraud in Clinical Trials. 
Statistics in Medicine. 18: 3435-51 (1999).   
24 Venet et al. A Statistical Approach to Central Monitoring of Data Quality in Clinical Trials. Clin Trials. 0: 1-9 
(2012). 
25 Bakobaki et al. The Potential for Central Monitoring Techniques to Replace On-Site Monitoring: Findings from 
an International Multi-Centre Clinical Trial. Clin Trials. 9: 257-264 (2012). 
  5  Contains Nonbinding Recommendations 
believes it is reasonable to conclude that the flexibility described in ICH E6 and ISO 14155:2011 
was intended to permit innovative approaches to improve the effectiveness of monitoring.  
Notably, the advancement in electronic systems and increasing use of electronic records (i.e., 
electronic data capture (EDC) systems) facilitate remote access to electronic data and, 
increasingly, to some source data (see section III.B.2.b for further discussion of access to 
electronic source data).  Additionally, statistical assessments using data submitted on paper CRFs 
or via EDC may permit timely identification of clinical sites that require additional training, 
monitoring, or both.  We expect that the pharmaceutical and device industries will, for the 
foreseeable future, continue to use some amount of on-site monitoring, but we anticipate 
decreased use of on-site monitoring with evolving monitoring methods and technological 
capabilities. 
 
The following sections reflect FDAs current thinking on monitoring and include 
recommendations on how to develop and implement a study-specific monitoring plan as well as 
how to document monitoring activities.  FDA acknowledges that there are limited empirical data 
to support the utility of the various methods employed to monitor clinical investigations (e.g., 
superiority of one method versus another), including data to support on-site monitoring.26  As a 
result, the recommendations are based, in part, on FDAs experience from the review of 
protocols during the IND or IDE phase, data submitted in pre-approval applications, results of 
inspections conducted to ensure human subject protection and data integrity, and information 
obtained from public outreach efforts conducted under the auspices of the CTTI. 
 
III.  OVERVIEW OF MONITORING METHODS 
 
A.  On-Site and Centralized Monitoring  
 
This section is intended to assist sponsors in identifying and designing monitoring practices 
appropriate to a given clinical trial.  It describes some of the capabilities of on-site and 
centralized monitoring processes and factors to consider in determining which monitoring 
practices may be appropriate for a given clinical trial.  See section IV.C for a discussion of 
factors to consider when determining the types, frequency, and extent of monitoring activities 
and section IV.D.1 for examples of events or results that would trigger a change in planned 
monitoring activities.   
 
1.  On-Site Monitoring 
 
On-site monitoring is an in-person evaluation carried out by sponsor personnel or representatives 
at the sites at which the clinical investigation is being conducted.  On-site monitoring can 
identify data entry errors (e.g., discrepancies between source records and case report forms 
(CRFs)) and missing data in source records or CRFs; provide assurance that study 
documentation exists; assess the familiarity of the sites study staff with the protocol and 
required procedures; and assess compliance with the protocol and investigational product 
 
26 Two studies are on-going as of June 2013 that compare the effectiveness of on-site to alternative (e.g., centralized) 
monitoring methods (OPTIMON study (https://ssl2.isped.u-bordeaux2.fr/optimon/Default.aspx) and ADAMON 
study (http://ctj.sagepub.com/content/6/6/585.full.pdf+html)). 
  6  Contains Nonbinding Recommendations 
accountability.  On-site monitoring can also provide a sense of the quality of the overall conduct 
of the trial at a site (e.g., attention to detail, thoroughness of study documentation, appropriate 
delegation of study tasks, appropriate CI supervision of site staff performing critical study 
functions).  On-site monitoring can therefore be particularly helpful early in a study, especially if 
the protocol is complex and includes novel procedures with which CIs may be unfamiliar.  
Findings at the site may lead to training efforts at both the site visited and elsewhere (see section 
VI.B).  
 
2.  Centralized Monitoring  
 
Centralized monitoring is a remote evaluation carried out by sponsor personnel or 
representatives (e.g., clinical monitors, data management personnel, or statisticians) at a location 
other than the sites at which the clinical investigation is being conducted.  Centralized 
monitoring processes can provide many of the capabilities of on-site monitoring as well as 
additional capabilities. 
 
FDA encourages greater use of centralized monitoring practices, where appropriate, than has 
been the case historically, with correspondingly less emphasis on on-site monitoring.  The types 
of monitoring activities and the extent to which centralized monitoring practices can be 
employed depend on various factors, including the sponsors use of electronic systems; the 
sponsors access to subjects electronic records, if applicable; the timeliness of data entry from 
paper CRF, if applicable; and communication tools available to the sponsor and study site.  
These may vary by study and by site.  Sponsors who plan to use centralized monitoring 
processes should ensure that the processes and expectations for site record keeping, data entry, 
and reporting are well-defined and ensure timely access to clinical trial data and supporting 
documentation.27  If sponsors intend to rely heavily on centralized monitoring practices, they 
should identify, in the monitoring plan, when one or more on-site monitoring visits would be 
indicated.   
 
B.  Examples of Alternative Monitoring Techniques 
 
As discussed in section II, monitoring activities broadly include communication with the CI and 
study site staff; review of the study sites processes, procedures, and records; and verification of 
the accuracy of data submitted to the sponsor.  This section highlights areas for which centralized 
monitoring techniques could be considered.  For certain monitoring activities, centralized 
monitoring techniques can be considered in place of, or to complement, traditional monitoring 
techniques.  Specific techniques used should be prospectively included in the monitoring plan 
and should be informed by the risk assessment (see section IV.B for discussion of risk 
assessment).   
 
Centralized monitoring techniques should be used to the extent appropriate and feasible to: 
 
27 See guidances for industry: Part 11, Electronic Records; Electronic Signatures  Scope and Application and 
Computerized Systems Used in Clinical Investigations. 
 
  7  Contains Nonbinding Recommendations 
  Supplement or reduce the frequency and extent of on-site monitoring with monitoring 
activities that can be done as well or better remotely or with monitoring activities that can be 
accomplished using centralized processes only.  Examples include: 
  Monitor data quality through routine review of submitted data to identify and 
o
follow-up on missing data, inconsistent data, data outliers, and potential 
protocol deviations that may be indicative of systemic or significant errors in 
data collection and reporting at a site 
  Conduct statistical analyses to identify data trends not easily detected by on-
o
site monitoring, such as 
  Standard checks of range, consistency, and completeness of data 
  Checks for unusual distribution of data within and between study sites, 
such as too little variance28 
  Analyze site characteristics, performance metrics (e.g., high screen failure or 
o
withdrawal rates, high frequency of eligibility violations, delays in reporting 
data), and clinical data to identify trial sites with characteristics correlated 
with poor performance or noncompliance 
  Verify critical source data remotely as described in the monitoring plan, in 
o
cases where such source data are accessible, or where CRF data are, according 
to the protocol, source data 
  Complete administrative and regulatory tasks.  Such tasks include, for 
o
example, verifying continuous institutional review board (IRB) approval by 
reviewing electronic IRB correspondence, if available; performing portions of 
investigational product accountability, such as comparison of randomization 
and CRF data, to preliminarily assess whether the subject was administered or 
dispensed the assigned product and to evaluate consistency between 
investigational product receipt, use, and disposition records; and verifying 
whether previously requested CRF corrections were made. 
Centralized techniques, including routine review of submitted data and statistical and other 
analyses, may also be used to identify significant concerns (e.g., need for clarification of a 
protocol procedure, indications of data fabrication) with non-critical data that may not have 
otherwise been a focus of monitoring (e.g., source document verification). 
  Target on-site monitoring by identifying higher risk clinical sites (e.g., sites with data 
anomalies or a higher frequency of errors, protocol violations, or dropouts relative to other 
sites), through the activities described above.  Such findings, whether related to critical or 
non-critical data, may warrant more intensive and consideration of on-site monitoring. 
The following sections provide additional descriptions of alternative monitoring techniques. 
  
 
28 Collins, Rory. (2010, October) Quality Design of Clinical Trials. Presentation at CTTI work stream 3 expert 
meeting.  Available at: https://www.ctti-clinicaltrials.org/files/monitoring-
collins_quality_design_of_clinical_trials_final.pdf. 
  8  Contains Nonbinding Recommendations 
1.  Communication with Study Site Staff 
 
Communication between the monitor and the study site staff is an essential component of 
monitoring.  Various modes of communication (e.g., teleconferences, videoconferencing, email) 
could be considered for specific study time points (e.g., study initiation) and activities (e.g., to 
discuss findings of a monitors eCRF review, training of new site staff).      
 
2.  Review of Sites Processes, Procedures, and Records 
 
Techniques for monitoring informed consent and site records are included here as examples of 
approaches to monitoring sites processes, procedures, and records. 
  
a.  Informed Consent 
 
Verification of subjects informed consent is a critical activity that should be monitored (see 
section IV.A).  Alternatives to the traditional approach (monitors verifying the original signature 
on the consent form for each subject at the site) may be more effective in identifying 
inadequacies in the consent process and may be more efficient.  For example, the study site 
electronically sends (e.g., fax, e-mail) the signed page(s) of consent forms to the monitor, or the 
monitor performs remote comparison of dates of study procedures and documentation of 
informed consent on CRFs.  An internet portal that enables the site staff to upload signed consent 
forms and enables access by designated monitors is a tool that can be considered.  Use of 
electronic informed consent may also facilitate sponsor oversight of human subject protection.  
We recognize that sponsors must attend to privacy and confidentiality concerns when 
considering techniques for monitoring informed consent remotely. 
 
b.  Sites Records 
 
A growing portion of source documents (e.g., laboratory and radiology reports, source 
documents submitted by the CI for other purposes such as health records documenting serious 
adverse events or adjudicated events) are electronic and may be available to the sponsor 
remotely.  Furthermore, consistent with ICH E6 and ISO 14155:2011, original observations can 
be entered directly into the eCRF or transmitted to the eCRF from various locations, devices, or 
instruments.29  We recognize that sponsors may not have remote access to electronic health 
records maintained by hospitals, universities, and other institutions because of data privacy and 
security concerns as well as technological challenges.  Sponsors should consider risk-based 
approaches to monitoring using the format of study information (i.e., electronic, paper, or 
combination of electronic and paper), tools, and other resources available to them. 
 
As discussed in this guidance, a variety of centralized monitoring techniques can be used to 
replace, supplement, and target on-site monitoring activities.  The majority of these techniques 
 
29 Section 6.4.9 of ICH E6 provides that the trial design description should include The identification of any data to 
be recorded directly on the CRFs (i.e., no prior written or electronic record of data), and to be considered to be 
source data. ISO 14155:2011, section 6.8.2, provides that the clinical investigation plan shall specify which data 
can be recorded directly in the CRFs.  
  9  Contains Nonbinding Recommendations 
(e.g., checks for completeness of data, sites with a higher frequency of protocol violations 
relative to other sites, sites with high screen failure rates) can be performed regardless of the 
extent of use of electronic records in the study.  For example, the majority of these techniques 
can be performed using CRF data collected either using electronic data capture systems or 
entered into a database from a paper CRF collected by the sponsor.  A recent publication 
discusses statistical techniques for identifying various types of data errors.30  We recognize that 
the statistical techniques described in this guidance may not be routinely used by all sponsors 
and may not be appropriate for every trial, but they are included in this guidance as examples of 
monitoring techniques that may be considered by sponsors.   
 
Additional monitoring techniques, such as routine review of data as they are submitted, are 
possible for studies that use electronic CRFs.  Although not a monitoring technique, another 
method of ensuring data quality routinely implemented in eCRFs is the use of electronic prompts 
in the eCRF to minimize errors and omissions at the time of data entry, particularly if data are 
entered directly into the eCRF. 
 
3.  Source Data Verification and Corroboration 
 
The sponsor should consider the quantity and types of source data that need to be verified against 
CRFs or corroborated against other records (e.g., review of medical record to corroborate a 
subjects response of no hospitalizations since the previous visit on a CRF) during the 
sponsors identification of critical data and processes or in the risk assessment, or both.  The 
sponsor should include a description of the quantity and types of source records to verify or 
corroborate in the monitoring plan.  The sponsor should consider which source records are likely 
to provide the most meaningful information about a subjects participation and the CIs conduct 
and oversight.  For example, for a particular study, there may be minimal benefit in comparing 
100% of the source data for each subject to the CRFs for each study visit.  Rather, it may be 
sufficient to compare the most critical data points for a sample of subjects and study visits as an 
indicator of data accuracy.  Similarly, for a particular study, although collection of all 
concomitant medications, body temperature, and body weight are required by the protocol and 
are documented in the medical record and transcribed to a CRF, they may not be identified by 
the sponsor as critical data, because a small error rate in those variables would not affect the 
outcome of the trial.  In the absence of information indicating potential concerns with the data 
(e.g., sites with data anomalies, inconsistent data), source document verification or corroboration 
of these non-critical data may not provide significantly useful information to the sponsor.    
 
                                                                                                                                                                                                                       
IV.  RISK-BASED MONITORING 
 
No single approach to monitoring is appropriate or necessary for every clinical trial.  FDA 
recommends that each sponsor design a monitoring plan that is tailored to the specific human 
subject protection and data integrity risks of the trial.  Ordinarily, such a risk-based plan would 
 
30 Venet et al. A Statistical Approach to Central Monitoring of Data Quality in Clinical Trials. Clin Trials. 0: 1-9 
(2012). 
 
  10  Contains Nonbinding Recommendations 
include a mix of centralized and on-site monitoring practices.  The monitoring plan should 
identify the various methods intended to be used and the rationale for their use (see section IV.D 
for recommendations on the components of a monitoring plan). 
 
Monitoring activities should focus on preventing or mitigating important and likely sources of 
error in the conduct, collection, and reporting of critical data and processes necessary for human 
subject protection and trial integrity.  Sponsors should prospectively identify critical data and 
processes, then perform a risk assessment to identify and understand the risks that could affect 
the collection of critical data or the performance of critical processes, and then develop a 
monitoring plan that focuses on the important and likely risks to critical data and processes.   
 
A.  Identify Critical Data and Processes to be Monitored 
 
Sponsors should prospectively identify critical data and processes that if inaccurate, not 
performed, or performed incorrectly, would threaten the protection of human subjects or the 
integrity of the study results.  As examples, the following types of data and processes should 
ordinarily be identified as critical: 
 
  Verification that informed consent was obtained appropriately 
  Adherence to protocol eligibility criteria designed to exclude individuals for whom the 
investigational product may be less safe than the protocol intended and to include only 
subjects from the targeted study population for whom the test article is most appropriate 
  Procedures for documenting appropriate accountability and administration of the 
investigational product (e.g., ensuring the integrity of randomization at the site level, where 
appropriate) 
  Conduct and documentation of procedures and assessments related to 
  study endpoints 
  protocol-required safety assessments 
  evaluating, documenting, and reporting serious adverse events and unanticipated adverse 
device effects, subject deaths, and withdrawals, especially when a withdrawal may be 
related to an adverse event 
  Conduct and documentation of procedures essential to trial integrity, such as ensuring the 
study blind is maintained, both at the site level and at the sponsor level, as appropriate,  
referring specified events for adjudication, and allocation concealment 
  11  Contains Nonbinding Recommendations 
Other types of data (e.g., covariates such as concomitant treatments or demographic 
characteristics, routine laboratory tests performed as part of subject monitoring that do not 
address protocol specified safety or efficacy endpoints) and processes (e.g., a hospital 
pharmacys storage of an investigational product with no specific critical handling instructions) 
identified by the sponsor as non-critical often may be monitored less intensively.   
 
There is increasing recognition that some types of errors in a clinical trial are more important 
than others.31  For example, a low, but non-zero rate of errors in capturing certain baseline 
characteristics of enrolled subjects (e.g., age, concomitant treatment, or concomitant illness) will 
not, in general, have a significant effect on study results if the errors are distributed randomly.  In 
contrast, a small number of errors related to study endpoints (e.g., not following protocol-
specified definitions) can profoundly affect study results, as could failure to report rare but 
important adverse events.  Based on FDAs inspection and review experience, infrequent errors 
in non-critical data are unlikely to alter FDAs conclusions about whether a product is safe and 
effective and whether participants safety was appropriately monitored.  
 
B.  Risk Assessment 
   
This guidance discusses the risk assessment, a component of risk management, as applied in the 
context of clinical monitoring.  Risk assessment generally involves identifying risks, analyzing 
risks, and then determining whether risks need to be modified by implementing controls (e.g., 
processes, policies, or practices).  The risk assessment recommended in this guidance to inform 
development of a monitoring plan may also support efforts to manage risks across a clinical trial 
(e.g., through modifying the protocol design or implementation) or development program.  This 
guidance does not provide comprehensive detail on how to perform a risk assessment.  There are 
many risk assessment methodologies and tools from a variety of industries that can be applied to 
clinical trials. 32,33    
 
Following the identification of critical data and processes (section IV.A), sponsors should 
perform a risk assessment to identify and understand the nature, sources, and potential causes of 
risks that could affect the collection of critical data or the performance of critical processes.  
Risks to critical data and processes most merit consideration during risk assessment, to ensure 
that monitoring efforts are focused on preventing or mitigating important and likely sources of 
error in their conduct, collection and reporting. 
 
Risk identification for monitoring purposes should generally consider the types of data to be 
collected, the specific activities required to collect these data, and the range of potential safety 
and other human subject protection concerns that are inherent to the clinical investigation (e.g., 
based on trial design or investigational product).   
 
 
31 Baigent et al. Ensuring Trial Validity by Data Quality Assurance and Diversification of Monitoring Methods. Clin 
Trials. 5: 49-55 (2008).   
32 Guidance for industry, Q9 Quality Risk Management, June 2006. 
33 ISO 31010:2009 Risk Management  Risk Assessment Techniques. 
  12  Contains Nonbinding Recommendations 
The identified risks should be assessed and prioritized by considering the following:  
  
  the likelihood of errors occurring 
  the impact of such errors on human subject protection and trial integrity 
  the extent to which such errors would be detectable 
 
Sponsors should use the results of the risk assessment in developing the monitoring plan (e.g., 
determining which risks may be addressed through monitoring, determining the types and 
intensity of monitoring activities best suited to addressing these risks).  Sponsors may also 
determine that some risks are better managed through activities other than monitoring, for 
example, modifying the protocol to remove the source of the risk.  Sponsors should periodically 
evaluate emerging risks and whether monitoring activities require modification to effectively 
oversee the risks.  
 
C.  Factors to Consider when Developing a Monitoring Plan 
 
A monitoring plan ordinarily should focus on preventing or mitigating important and likely risks, 
identified by the risk assessment, to critical data and processes.  The types (e.g., on-site, 
centralized), frequency (e.g., early, for initial assessment and training versus throughout the 
study), and extent (e.g., comprehensive (100% data verification) versus targeted or random 
review of certain data (less than 100% data verification)) of monitoring activities will depend to 
some degree on a range of factors, considered during the risk assessment, including the 
following: 
  Complexity of the study design  
More intensive monitoring (e.g., increased frequency and extent of review) may be necessary as 
study design complexity increases.  Examples may include studies with adaptive designs, 
stratified designs, complex dose titrations, or multiple device placement studies.   
  Types of study endpoints  
Endpoints that are more interpretative or subjective may require on-site visits to assess the 
totality of subject records and to review application of protocol definitions with the CI.  More 
objective endpoints (e.g., death, hospitalization, or clinical laboratory values and standard 
measurements) may be more suitable for remote verification.  Endpoints for which inappropriate 
subject withdrawal or lack of follow-up may impede study evaluation are likely to need more 
intensive monitoring  to identify the reason(s) subjects are withdrawing and to determine 
whether follow-up can be improved. 
  Clinical complexity of the study population 
A study that involves a population that is seriously ill or vulnerable may require more intensive 
monitoring and consideration of on-site monitoring visits to be sure appropriate protection is 
being provided. 
  Geography 
Sites in geographic areas where there are differences in standards of medical practice or subject 
demographics, or where there is a less established clinical trial infrastructure may require more 
intensive monitoring and consideration of on-site monitoring visits.  
  13  Contains Nonbinding Recommendations 
  Relative experience of the CI and of the sponsor with the CI 
CIs who lack significant experience in conducting and overseeing investigations, using a novel 
or innovative medical device, or with the surgical procedure associated with medical device use 
may benefit from more intensive monitoring and frequent communication to ensure CI 
understanding of responsibilities.  In addition, the relative experience of a sponsor with the CI 
may be a factor in determining an appropriate monitoring plan.  
  Electronic data capture 
Use of 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.   
  Relative safety of the investigational product  
A study of a product that has significant safety concerns or for which there is no prior experience 
in human clinical trials (e.g., a phase 1 pharmaceutical investigation or a device feasibility study) 
may require more intensive monitoring and consideration of on-site monitoring visits to ensure 
appropriate CI oversight of subject safety. 
  Stage of the study 
A tapered approach to monitoring may be used where appropriate, with more intensive 
monitoring at initiation and during early stages of a trial.  For example, a tapered approach could 
be used for a complex study where more intensive and on-site monitoring might be required 
early, but where, once procedures are established, less intensive monitoring might suffice.  
Similarly, a tapered approach could be used for relatively inexperienced CIs.         
  Quantity of data 
Some centralized monitoring tools may be more useful as the quantity of data (e.g., size or 
duration of trial, number of sites) collected increases.    
 
D.  Monitoring Plan 
 
For each clinical trial, the sponsor should develop a monitoring plan that describes the 
monitoring methods, responsibilities, and requirements for the trial.  The monitoring plan should 
include a brief description of the study, its objectives, and the critical data and study procedures, 
with particular attention to data and procedures that are unusual in relation to clinical routine and 
require training of study site staff.  The plan should also communicate the specific risks to be 
addressed by monitoring and should provide those involved in monitoring with adequate 
information to effectively carry out their duties.  A monitoring plan may reference existing 
policies and procedures (e.g., standard operating procedure describing general monitoring 
processes or issue investigation and resolution).  All sponsor and CRO personnel involved with 
monitoring, including those who review or determine appropriate action regarding potential 
issues identified through monitoring, should review the monitoring plan and associated 
documents (e.g., standard operating procedures or other documents referenced in the monitoring 
plan).   
 
  14  Contains Nonbinding Recommendations 
Sponsors of device studies wishing to solicit feedback on their monitoring procedures prior to the 
submission of the application may either submit a Pre-Submission,34 or contact CDRHs 
Division of Bioresearch Monitoring.35  
 
Sponsors of drug studies may include specific questions about a monitoring plan in a request for 
a formal meeting with FDA (e.g., end of phase 2 meeting). 
 
The components of a monitoring plan might include the following: 
 
1.  Description of Monitoring Approaches 
 
  A description of each monitoring method to be employed during the study and how it will be 
used to address important risks and ensure the validity of critical data 
  Criteria for determining the timing, frequency, and extent of planned monitoring activities 
  Specific activities required for each monitoring method employed during the study, including 
reference to required tools, logs, or templates 
  Definitions of events or results (e.g., findings from central monitoring activities) that would 
trigger changes in planned monitoring activities for a particular CI   
For example, if it is determined that a CI differs markedly from other CIs in making safety-
related findings or other key safety metrics, in rate of enrollment, in the number of protocol 
deviations, or in the rate of missing CRFs, the CIs site should be considered for targeted on-
site visits.  The establishment of acceptable variation for particular critical data and processes 
would facilitate identification of significant deviations. 
  Identification of possible deviations or failures that would be critical to study integrity and 
how these are to be recorded and reported   
For example, sponsors may wish to establish a specific mechanism for tracking and notifying 
key study personnel of deviations related to collection or reporting of data necessary to 
interpret the primary endpoint, regardless of which monitoring method identified a concern. 
 
The study monitoring plan should also describe how various monitoring activities will be 
documented, regardless of whether they are conducted on-site or centrally (see section V). 
 
2.  Communication of Monitoring Results 
 
  Format, content, timing, and archiving requirements for reports and other documentation of 
monitoring activities (see section V) 
  Process for appropriate communication 
 
34 For more information, see FDAs draft guidance Medical Devices: The Pre-Submission Program and Meetings 
with FDA Staff. When final, this guidance will represent the FDAs current thinking on this topic.  
35 IDE regulations (21 CFR 812.25(e)) require that written monitoring procedures be submitted as part of the IDE 
application. 
  15  Contains Nonbinding Recommendations 
  of routine monitoring results to management and other stakeholders (e.g., CRO, data 
management)  
  of immediate reporting of significant monitoring issues to appropriate parties (e.g., 
sponsor management, CI and site staff, IRB, FDA), as necessary 
  from study management and other stakeholders to monitors   
For example, data management personnel may provide monitors with routine reports of 
outstanding CRFs or of common data queries at or across sites that may enable effective 
targeting of monitoring activities. 
 
3.  Management of Noncompliance 
 
  Processes for addressing unresolved or significant issues (e.g., significant non-compliance 
with the investigational plan, suspected or confirmed data falsification) identified by 
monitoring, whether at a particular site or across study sites   
  Processes to ensure that root cause analyses are conducted where important deviations are 
discovered and that appropriate corrective and preventive actions (e.g., additional training on 
a study or site level) are implemented to address issues identified by monitoring 
  Other quality management practices applicable to the clinical investigation (e.g., reference to 
any other written documents describing appropriate actions regarding non-compliance) 
 
4.  Ensuring Quality Monitoring 
 
  Description of any specific training required for personnel carrying out monitoring activities, 
including personnel conducting internal data monitoring, statistical monitoring, or other 
centralized review activities.  Training should include principles of clinical investigations and 
human subject protection.  In addition, study-specific training should include discussion of 
the trial design, protocol requirements, the study monitoring plan, applicable standard 
operating procedures, appropriate monitoring techniques, and applicable electronic systems. 
  Planned audits of monitoring to ensure that sponsor and CRO staff conduct monitoring 
activities in accordance with the monitoring plan, applicable regulations, guidance, and 
sponsor policies, procedures, templates, and other study plans.  Auditing is a quality 
assurance tool that can be used to evaluate the effectiveness of monitoring to ensure human 
subject protection and data integrity.36  
  Many sponsors have successfully implemented on-site co-monitoring visits (i.e., monitoring 
visits performed by both a study monitor and the monitors supervisor or another evaluator 
designated by the sponsor or CRO) to evaluate whether monitors are effectively carrying out 
visit activities, in compliance with the study monitoring plan.  These visits may be conducted 
either for randomly selected monitors or may be targeted to specific monitors, based upon 
questions arising from review of monitoring visit documentation.   
 
36 See ICH E6, section 5.19 and ISO 14155:2011, section 6.11 for additional information on audits. 
  16  Contains Nonbinding Recommendations 
5.  Monitoring Plan Amendments 
 
Sponsors should consider what events would indicate a need for review and revision of the 
monitoring plan and establish processes to permit timely updates where necessary.  For example, 
a protocol amendment, change in the definition of significant protocol deviations, or 
identification of new risks to study integrity could result in a change to the monitoring plan.  
 
V.  DOCUMENTING MONITORING ACTIVITIES 
 
Documentation of monitoring activities should generally include the following: 
 
  The date of the activity and the individual(s) conducting and participating in it 
  A summary of the data or activities reviewed 
  A description of any noncompliance, potential noncompliance, data irregularities, or other 
deficiencies identified  
  A description of any actions taken, to be taken, or recommended, including the person 
responsible for completing actions and the anticipated date of completion 
Documentation of monitoring should include sufficient detail to allow verification that the 
monitoring plan was followed. 
 
Monitoring documentation should be provided to appropriate management in a timely manner 
for review and follow-up, as indicated. 
 
VI.  ADDITIONAL STRATEGIES TO ENSURE STUDY QUALITY 
 
Although the focus of this guidance is on monitoring the oversight and conduct of, and reporting 
of data from, clinical investigations, FDA considers monitoring to be just one component of a 
multi-factor approach to ensuring the quality of clinical investigations.  Many other factors 
contribute to the quality of a clinical investigation.  This section highlights additional areas that 
complement monitoring and can affect study quality. 
 
A fundamental component of ensuring quality monitoring is a sponsors compliance with 
monitoring plans and any accompanying procedures.   
 
A.  Protocol and Case Report Form Design 
 
The most important tool for ensuring human subject protection and high-quality data is a well-
designed and articulated protocol.  A poorly designed or ambiguous protocol may introduce 
systemic errors that can render a clinical investigation unreliable despite rigorous monitoring.  
Additionally, the complexity of the trial design and the type and amount of data collected may 
influence data quality.37  The CRF, which captures the data required by the protocol, is another 
 
37 Sponsors are encouraged to consult the appropriate review division within FDA's medical product centers with 
questions about quality aspects of clinical trial design. 
  17  Contains Nonbinding Recommendations 
critical tool for which design directly affects the quality of trial data.  Care should be taken to 
ensure that the CRF captures data accurately (e.g., as required by the protocol) and that the CRF 
design and instructions facilitate consistent data collection across CI sites. 
 
B.        Clinical Investigator Training and Communication 
 
Clinical trial monitors conducting on-site visits have historically played an important role in 
training the CI and site staff during a study.  On-site visits also have served as a primary means 
of providing feedback to CIs and study personnel on study conduct.  Without meaningful 
training prior to the conduct of a study and of appropriate instruction during the study (e.g., when 
changes are made to the protocol), CIs and their staff may have difficulty carrying out a trial 
correctly.  Sponsors who plan less frequent or limited on-site monitoring should consider the 
following: 
 
  Monitoring activities should include sufficient time for discussion of CIs and site staffs 
responsibilities, feedback, and additional training, if needed, during the conduct of the study. 
  It may be necessary to implement alternative training (e.g., teleconferences, webcasts, online 
training modules) and communication methods (see section III.B.1) for providing and 
documenting ongoing, timely training and feedback, as well as to provide notification of 
significant changes to study conduct or other important information.   
 
C.  Delegation of Monitoring Responsibilities to a CRO 
 
If a sponsor of an IND study delegates the responsibility for ensuring proper monitoring to a 
CRO, FDA regulations (21 CFR 312.52) require the written transfer of any obligations from a 
sponsor to a CRO and require the CRO to comply with the regulations.38  Although sponsors can 
transfer responsibilities for monitoring to a CRO(s), they retain responsibility for oversight of the 
work completed by the CRO(s) that assume this responsibility.  Sponsors should evaluate CRO 
compliance with regulatory requirements and contractual obligations in an ongoing manner.  For 
example, sponsor oversight of monitoring performed by a CRO may include the sponsors 
periodic review of monitoring reports and vendor performance or quality metrics and 
documented communication between the sponsor and CRO regarding monitoring progress and 
findings.    
 
Sponsors and CROs should consider additional factors when a sponsor transfers responsibilities 
for monitoring to a CRO.  Sponsors and CROs should prospectively establish a clear 
understanding of both parties responsibilities and of the expectations for the conduct of the 
transferred obligations.  Sponsors should share information with a CRO that may inform 
decisions a CRO may make regarding the monitoring practices for a trial (e.g., findings of a risk 
assessment).  Sponsors should prospectively evaluate monitoring procedures and monitoring 
plans developed by a CRO to ensure the monitoring approach is consistent with applicable 
aspects of the trial.  In addition, sponsors and CROs should have processes in place for timely 
 
38 The regulations for investigational device exemptions (21 CFR part 812) do not contain a provision for delegation 
to a contract research organization. 
  18  Contains Nonbinding Recommendations 
exchange of relevant information (e.g., significant monitoring findings, significant changes in 
risk for a trial). 
 
D.  Clinical Investigator and Site Selection and Initiation 
 
In addition to regulatory requirements for CI selection, sponsors should consider factors such as 
sponsors previous experience with the CI or site, workload of the CI and study staff, and 
resource availability at the study site during CI and site selection.   
 
Site initiation is a critical study activity that often involves sponsor personnel from a range of 
disciplines, including monitors.  Key components of site initiation include ensuring the CIs and 
site staff understand their responsibilities, including applicable regulatory requirements as well 
as study processes and procedures, including the sponsors processes for monitoring the 
investigation.  Communication and documentation tools for monitoring discussed in this 
guidance can also be used for site selection and initiation activities.   
 
VII.  PAPERWORK REDUCTION ACT OF 1995 
 
This guidance contains information collection provisions that are subject to review by the Office of 
Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-
3520).  
 
The time required to complete this information collection is estimated to average 4 hours per 
response, including the time to review instructions, search existing data resources, gather the data 
needed, and complete and review the information collection.  Send comments regarding this burden 
estimate or suggestions for reducing this burden to:  
 
Food and Drug Administration  
Center for Drug Evaluation and Research 
Office of Medical Policy 
10903 New Hampshire Avenue, Bldg. 51, rm. 6337 
Silver Spring, MD 20993-0002 
 
This  guidance  also  refers  to  previously  approved  collections  of  information  found  in  FDA 
regulations.  The collections of information in part 312, including certain provisions under subpart D, 
and part 812 have been approved under OMB control numbers 0910-0014 and 0910-0078.   
 
An agency may not conduct or sponsor, and a person is not required to respond to, a collection 
of information unless it displays a currently valid OMB control number.  The OMB control 
number for this information collection is 0910-0014.  The current expiration date is available at 
https://www.reginfo.gov (search ICR and enter OMB control number 0910-0014). 
 
 
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