10555fnlPRAupdate11-21-22.docx

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.
Guidance for Industry

Oversight of Clinical Investigations — A 

Risk-Based Approach to Monitoring 

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or

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http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm

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. FDA’s 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 Site’s 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 

1

Guidance for Industry1

Oversight of Clinical Investigations — A Risk-Based 

Approach to Monitoring 

This guidance represents the Food and Drug Administration’s (FDA’s) 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 activitiesthat 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. 

FDA’s guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Rather, guidances describe the Agency’s 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 CDER’s Office of Scientific Investigations in the Office of Compliance, CBER’s 

Office of Compliance and Biologics Quality, CDRH’s Office of Compliance, Office of the Commissioner’s Office 

of Good Clinical Practice, and the Office of Regulatory Affairs (ORA). 
Contains Nonbinding Recommendations

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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

 FDA’s 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). 
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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 site’s 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 FDA’s 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. CTTI’s 

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.
Contains Nonbinding Recommendations 

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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 sponsor’s assessment of these factors should be used to develop 

a monitoring plan, a recommendation consistent with FDA’s 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. FDA’s 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 sponsor’s (or CRO’s) 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. 
Contains Nonbinding Recommendations

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B. FDA’s Rationale for Risk-Based Monitoring

FDA is issuing this guidance to provide FDA’s 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 sponsor’s 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).
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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 FDA’s 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 FDA’s 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 site’s 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)).
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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 sponsor’s use of electronic systems; the

sponsor’s 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 site’s 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.
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• 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: 

o Monitor data quality through routine review of submitted data to identify and 

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

o Conduct statistical analyses to identify data trends not easily detected by onsite 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

o Analyze site characteristics, performance metrics (e.g., high screen failure or 

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 

o Verify critical source data remotely as described in the monitoring plan, in 

cases where such source data are accessible, or where CRF data are, according 

to the protocol, source data 

o Complete administrative and regulatory tasks. Such tasks include, for 

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/monitoringcollins_quality_design_of_clinical_trials_final.pdf. 
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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 monitor’s eCRF review, training of new site staff). 

2. Review of Site’s Processes, Procedures, and Records

Techniques for monitoring informed consent and site records are included here as examples of 

approaches to monitoring site’s 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. Site’s 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.” 
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(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 

subject’s response of “no hospitalizations” since the previous visit on a CRF) during the 

sponsor’s 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 subject’s participation and the CI’s 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).
Contains Nonbinding Recommendations

11

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
Contains Nonbinding Recommendations

12

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

pharmacy’s 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 protocolspecified definitions) can profoundly affect study results, as could failure to report rare but 

important adverse events. Based on FDA’s inspection and review experience, infrequent errors 

in non-critical data are unlikely to alter FDA’s 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.
Contains Nonbinding Recommendations

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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. 
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14

• 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). 
Contains Nonbinding Recommendations

15

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 CDRH’s 

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 safetyrelated findings or other key safety metrics, in rate of enrollment, in the number of protocol 

deviations, or in the rate of missing CRFs, the CI’s site should be considered for targeted onsite 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 FDA’s draft guidance Medical Devices: The Pre-Submission Program and Meetings 

with FDA Staff. When final, this guidance will represent the FDA’s 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.
Contains Nonbinding Recommendations

16

– 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 monitor’s 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.
Contains Nonbinding Recommendations

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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 sponsor’s 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 welldesigned 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.
Contains Nonbinding Recommendations

18

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 CI’s and site staff’s 

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 sponsor’s 

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.
Contains Nonbinding Recommendations 

19

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 

sponsor’s 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 sponsor’s 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).