Guidance for Clinical 

Trial Sponsors 

Establishment and Operation of 

Clinical Trial Data Monitoring 

Committees 

DRAFT GUIDANCE - NOT FOR IMPLEMENTATION 

For questions on the content of this guidance, contact the Office of Communication, Training, 

and Manufacturers Assistance (CBER) at 800-835-4709 or 301-827-1800. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Biologics Evaluation and Research (CBER) 

Center for Drug Evaluation and Research (CDER) 

Center for Devices and Radiological Health (CDRH) 

December 2005 
Contains Nonbinding Recommendations 

Draft – Not for Implementation 

Guidance for Clinical 

Trial Sponsors 

Establishment and Operation of 

Clinical Trial Data Monitoring 

Committees 

Additional copies of this guidance are available from: 

Office of Communication, Training and 

Manufacturers Assistance, HFM-40 

Center for Biologics Evaluation and Research 

Food and Drug Administration 

1401 Rockville Pike, Rockville, MD 20852-1448 

Phone: 800-835-4709 or 301-827-1800 

Internet: http://www.fda.gov/cber/guidelines.htm 

or 

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Food and Drug Administration 

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Phone: 301-827-4573 

Internet: http://www.fda.gov/cder/guidance/index.htm 

or 

The Division of Small Manufacturers, International, and Consumer Assistance (DSMICA) 

Center for Devices and Radiological Health 

Food and Drug Administration 

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Internet: http://www.fda.gov/cdrh 

Email: DSMICA@cdrh.fda.gov 

Facts-on-Demand (faxback): 800-899-0381 or 301-827-0111 
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Table of Contents 

1. INTRODUCTION AND BACKGROUND..................................................................... 1

1.1. History of DMCs ........................................................................................................... 2

1.2. Current Status............................................................................................................... 3

2. DETERMINING NEED FOR A DMC ........................................................................... 3

2.1. What is the Risk to Trial Participants? ...................................................................... 4

2.2. Is DMC Review Practical? ........................................................................................... 4

2.3. Will a DMC Help Assure the Scientific Validity of the Trial? ................................. 5

3. DMCs AND OTHER OVERSIGHT GROUPS ............................................................. 5

3.1. Investigational Review Boards..................................................................................... 6

3.2. Clinical Trial Steering Committees ............................................................................. 6

3.3. Endpoint Assessment/Adjudication Committees ....................................................... 7

3.4. Site/Clinical Monitoring ............................................................................................... 7

3.5. Others with Monitoring Responsibilities .................................................................... 7

4. DMC ESTABLISHMENT AND OPERATION ............................................................ 8

4.1. Committee Composition ............................................................................................... 8

4.2. Confidentiality of Interim Data and Analyses.......................................................... 10

4.2.1. Interim Data .......................................................................................................... 10

4.2.2. Interim Reports to the DMC ................................................................................. 11 

4.3. Establishing a Charter Describing Standard Operating Procedures .................... 12

4.3.1. Considerations for Standard Operating Procedures .............................................. 12 

4.3.1.1. Meeting Schedule and Format ...................................................................... 12 

4.3.1.2. Meeting Structure.......................................................................................... 13 

4.3.1.3. Initial Meeting............................................................................................... 13 

4.3.1.4. Format of Interim Reports to the DMC and Use of Treatment Codes.......... 14 

4.3.2. Statistical Methods................................................................................................ 15 

4.4. Potential DMC Responsibilities ................................................................................. 16

4.4.1. Interim Monitoring................................................................................................ 16 

4.4.1.1. Monitoring for Effectiveness ........................................................................ 17 

4.4.1.2. Monitoring for Safety ................................................................................... 17 

4.4.1.3. Monitoring Study Conduct ........................................................................... 20 

4.4.1.4. Consideration of External Data..................................................................... 20 

4.4.1.5. Studies of Less Serious Outcomes ................................................................ 22 

4.4.2. Early Studies ......................................................................................................... 23

4.4.3. Other Responsibilities........................................................................................... 24 

4.4.3.1. Making Recommendations ........................................................................... 24 

4.4.3.2. Maintaining Meeting Records....................................................................... 24 

5. DMC RECOMMENDATIONS AND REGULATORY REPORTING 

REQUIREMENTS.......................................................................................................... 25

6. INDEPENDENCE OF THE DMC ................................................................................ 26

6.1. Desirability of an Independent DMC........................................................................ 27

6.2. Value of Sponsor Interaction with the DMC............................................................ 27

6.3. Risks of Sponsor Exposure to Interim Comparative Data...................................... 28

6.4. Statisticians Conducting the Interim Analyses ........................................................ 29

6.5. Sponsor Access to Interim Data for Planning Purposes.......................................... 31

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7. SPONSOR INTERACTION WITH FDA REGARDING USE AND OPERATION 

OF DMCs......................................................................................................................... 32

7.1. Planning the DMC ...................................................................................................... 32

7.2. Accessing Interim Data............................................................................................... 32

7.2.1. DMC Recommendations to Terminate the Study................................................. 33 

7.2.2. FDA Interaction with DMCs ................................................................................ 33 

7.3. DMC Recommendations for Protocol Changes ....................................................... 34

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Guidance for Clinical Trial Sponsors 

Establishment and Operation of Clinical Trial Data Monitoring 

Committees 

)

topic. 

FDA or the public. 

approach, contact the appropriate FDA staff. 

This guidance represents the Food and Drug Administration’s (FDA’s current thinking on this 

It does not create or confer any rights for or on any person and does not operate to bind 

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 

If you cannot identify the appropriate FDA staff, 

call the appropriate number listed on the title page of this guidance. 

1. INTRODUCTION AND BACKGROUND 

This guidance discusses the roles, responsibilities and operating procedures of Data Monitoring 

Committees (DMCs) (also known as Data and Safety Monitoring Boards (DSMBs) or Data and 

Safety Monitoring Committees (DSMCs)) that may carry out important aspects of clinical trial 

monitoring. This guidance is intended to assist clinical trial sponsors in determining when a 

DMC may be useful for study monitoring, and how such committees should operate. We 

recognize that in many clinical trials the sponsor delegates some decision-making regarding the 

design and conduct of the trial to some other entity such as a steering committee (see Section 

3.2) or contract research organization (CRO) (see 21 Code of Federal Regulations (CFR) 

312.3(b)). This document, while pertaining primarily to the sponsor with regard to trial 

management and decision-making, may also be relevant to any individual or group to whom the 

sponsor has delegated applicable management responsibilities (see Section 3). This guidance 

finalizes the draft guidance entitled "Guidance for Clinical Trial Sponsors: On the Establishment 

and Operation of Clinical Trial Data Monitoring Committees" dated November 2001. 

Sponsors of studies evaluating new drugs, biologics, and devices are required to monitor these 

studies (see 21 CFR 312.50 and 312.56 for drugs and biologics, and 21 CFR 812.40 and 21 CFR 

812.46 for devices). Various individuals and groups play different roles in clinical trial 

monitoring. One such group is a DMC, appointed by a sponsor to evaluate the accumulating 

outcome data in some trials.1 

A clinical trial DMC is a group of individuals with pertinent expertise that reviews on a regular 

basis accumulating data from one or more ongoing clinical trials. The DMC advises the sponsor 

regarding the continuing safety of trial subjects and those yet to be recruited to the trial, as well 

as the continuing validity and scientific merit of the trial. When a single DMC is responsible for 

monitoring multiple trials, the considerations for establishment and operation of the DMC are 

generally similar to those for a DMC monitoring a single trial, but the logistics may be more 

1 Some government agencies that sponsor clinical research have required the use of DMCs in certain clinical trials. Current FDA 

regulations, however, impose no requirements for the use of DMCs in trials except under 21 CFR 50.24(a)(7)(iv) for research 

studies in emergency settings in which the informed consent requirement is excepted. 

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complex. For example, multiple conflict of interest determinations may be needed for each 

DMC member. 

Many different models have been proposed and used for the operation of DMCs. Although 

different models may be appropriate and acceptable in different situations, experience has shown 

that some approaches have particular advantages or disadvantages. In this document, we 

highlight these advantages and disadvantages, with particular attention to the setting in which 

investigational products are being evaluated for possible marketing approval in well-controlled 

clinical trials. The intent of this guidance document is to ensure wide awareness of acceptable 

practices and of potential concerns regarding operation of DMCs that may arise in specific 

situations. 

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

responsibilities. Instead, guidances describe FDA’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 FDA guidances means that something is suggested or 

recommended, but not required. 

1.1. History of DMCs 

DMCs have been a component of some clinical trials since at least the early 1960's. 

DMCs were initially used primarily in large randomized multicenter trials sponsored by 

federal agencies, such as the National Institutes of Health (NIH) and the Department of 

Veterans Affairs (VA) in the U.S. and similar bodies abroad, that targeted improved 

survival or reduced risk of major morbidity (e.g., acute myocardial infarction) as the 

primary objective. In 1967, an NIH external advisory group first introduced the concept 

of a formal committee charged with reviewing the accumulating data as the trial 

progressed to monitor safety, effectiveness, and trial conduct issues in a set of 

recommendations to the then-National Heart Institute. (Heart Special Project Committee, 

'Organization, Review and Administration of Cooperative Studies (Greenberg Report): A 

Report from the Heart Special Project Committee to the National Advisory Heart 

Council, May 1967;' Controlled Clinical Trials, vol. 9, 137-148, 1988.) The 

recommendation for the establishment of such committees was based on the recognition 

that interim monitoring of accumulating study data was essential to ensure the ongoing 

safety of trial participants, but that individuals closely involved with the design and 

conduct of a trial may not be able to be fully objective in reviewing the interim data for 

any emerging concerns. The involvement of expert advisors external to the trial 

organizers, sponsors, and investigators was intended to ensure that such problems would 

be addressed in an unbiased way by the trial leadership. The operational and functional 

aspects of these committees, based on experience over several decades, were discussed in 

a 1992 NIH workshop (Ellenberg, S., Geller, N., Simon, R. and Yusuf, S. (eds.): 

Practical Issues in Data Monitoring of Clinical Trials (workshop proceedings). Statistics 

in Medicine, 12:415-616, 1993.) 

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Few trials sponsored by the pharmaceutical/medical device industry incorporated DMC 

oversight until relatively recently. The increasing use of DMCs in industry-sponsored 

trials is the result of several factors, including: 

• The growing number of industry-sponsored trials with mortality or major 

morbidity endpoints; 

• The increasing collaboration between industry and government in sponsoring 

major clinical trials, resulting in industry trials performed under the policies of 

government funding agencies, which often require DMCs; 

• Heightened awareness within the scientific community of problems in clinical 

trial conduct and analysis that might lead to inaccurate and/or biased results, 

especially when early termination for efficacy is a possibility, and need for 

approaches to protect against such problems; 

• Concerns of IRBs regarding ongoing trial monitoring and patient safety in 

multicenter trials. 

1.2. Current Status 

DMCs are currently used in a variety of situations, and different models of operation 

have been employed. Although no single model may be optimal for all settings, and 

there is not necessarily consensus about the optimal model in any given setting, there are 

advantages and disadvantages with respect to some of the different approaches that are in 

use. 

As noted above, government agencies that sponsor clinical research, such as the NIH and 

the VA, have required the use of DMCs in certain trials. Current FDA regulations, 

however, impose no requirements for the use of DMCs in trials except under 21 CFR 

50.24(a)(7)(iv) for research studies in emergency settings in which the informed consent 

requirement is excepted. FDA believes that the issues discussed in this document arise in 

trials with both private and public sponsorship. We recognize that the potential conflicts 

of interest faced by government sponsors can be different from those of industry 

sponsors, so that the implications for the approach to monitoring, particularly with regard 

to confidentiality and independence issues (see Section 4.2 and Section 6), may also 

differ to some extent. Nevertheless, we believe that the discussion of advantages and 

disadvantages of various approaches to DMC operation is relevant to all trials in which 

the use of a DMC is appropriate, regardless of the sponsor's funding (i.e., public or 

private sector), the investigational setting of the trial (academic or other), trial size, or the 

phase of development. In general, DMC models used in federally funded trials that are 

established in accordance with policies of the funding agencies are acceptable to FDA. 

2. DETERMINING NEED FOR A DMC 

All clinical trials require safety monitoring, but not all trials require monitoring by a formal 

committee that may be external to the trial organizers, sponsors, and investigators. As noted 

earlier, DMCs have generally been established for large, randomized multisite studies that 

evaluate treatments intended to prolong life or reduce risk of a major adverse health outcome 

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such as a cardiovascular event or recurrence of cancer. DMCs are generally recommended for 

any controlled trial of any size that will compare rates of mortality or major morbidity, but a 

DMC is not required or recommended for most clinical studies. DMCs are generally not needed, 

for example, for trials at early stages of product development. They are also generally not 

needed for trials addressing lesser outcomes, such as relief of symptoms, unless the trial 

population is at elevated risk of more severe outcomes (see Sections 4.4.1.5 and 4.4.2 for further 

discussion). 

Although the value of a DMC is well accepted in settings such as those described above, it is 

important to recognize that DMCs add administrative complexity to a trial and require additional 

resources, so we recommend that sponsors limit the use of a DMC to the circumstances 

described in Section 2.1. There are several factors to consider when determining whether to 

establish a DMC for a particular trial. These factors, discussed below, relate primarily to safety, 

practicality, and scientific validity. 

2.1. What is the Risk to Trial Participants? 

A fundamental reason to establish a DMC is to enhance the safety of trial participants in 

situations in which safety concerns may be unusually high, in order that regular interim 

analyses of the accumulating data are performed. We recommend that sponsors consider 

using a DMC when: 

• The study endpoint is such that a highly favorable or unfavorable result, or even a 

finding of futility, at an interim analysis might ethically require termination of the 

study before its planned completion; 

• There are a priori reasons for a particular safety concern, as, for example, if the 

procedure for administering the treatment is particularly invasive; 

• There is prior information suggesting the possibility of serious toxicity with the 

study treatment; 

• The study is being performed in a potentially fragile population such as children, 

pregnant women or the very elderly, or other vulnerable populations, such as 

those who are terminally ill or of diminished mental capacity; 

• The study is being performed in a population at elevated risk of death or other 

serious outcomes, even when the study objective addresses a lesser endpoint; 

• The study is large, of long duration, and multi-center. 

In studies with one or more of these characteristics, the additional oversight provided by 

a DMC can further protect study participants. In other studies, such as short-term studies 

for relief of symptoms as noted above, such committees are generally not warranted. 

2.2. Is DMC Review Practical? 

A second consideration is whether DMC review is practical. If the trial is likely to be 

completed quickly, the DMC may not have an opportunity to have a meaningful impact. 

In short-term trials with important safety concerns, however, a DMC may still be 

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valuable. In such cases, in order for the DMC to be informed and convened quickly in 

the event of unexpected results that raise concerns, special mechanisms would have to be 

developed to permit DMC evaluation and input. Alternatively, the trial could build in 

"pauses" so that interim data could be reviewed by a DMC before an additional cohort of 

participants would be enrolled. 

2.3. Will a DMC Help Assure the Scientific Validity of the Trial? 

A third consideration in the decision of whether to have a DMC for a trial is whether a 

DMC can help assure scientific validity (and perception of such) of the trial. Trials of 

any appreciable duration can be affected by changes over time in the understanding of the 

disease, the affected population, and the standard treatment used outside the trial. These 

external changes may prompt an interest in modifying some aspects of the trial as it 

progresses. When a DMC is the only group reviewing unblinded interim data, trial 

organizers faced with compelling new information external to the trial may consider 

making changes in the ongoing trial without raising concerns that such changes might 

have been at least partly motivated by knowledge of the interim data and thereby 

endanger trial integrity. Sometimes accumulating data from within the trial (e.g., overall 

event rates) may suggest the need for modifications. Recommendations to change the 

inclusion criteria, the trial endpoints, or the size of the trial are best made by those 

without knowledge of the accumulating data (with the exception of changes the DMC 

might recommend on the basis of emerging safety concerns, as discussed in Section 

4.4.1.2). When the trial organizers are the ones reviewing the interim data, their 

awareness of interim comparative results cannot help but affect their determination as to 

whether such changes should be made. Changes made in such a setting would inevitably 

impair the credibility of the study results. This problem will be addressed more fully in 

Section 6.3. 

3. DMCs AND OTHER OVERSIGHT GROUPS 

Several different groups and individuals may assume or share responsibility for various aspects 

of clinical trial monitoring and oversight, and it is important to recognize the different roles they 

play. These groups are all components of a system that assists sponsors in conducting trials that 

are ethical and that produce valid and credible results. The sponsor of a clinical trial takes 

responsibility for and initiates the investigation (21 CFR 50.3(e); 21 CFR 312.3; 21 CFR 

812.3(n)). Typically, the sponsor holds the Investigational New Drug Application or 

Investigational Device Exemption (IND/IDE) (21 CFR 312.40(a)(1); 21 CFR 812.40).2 

2 This guidance document may also be relevant to parties who participate in leadership roles in a clinical 

investigation other than sponsors, including funding organizations and/or others who share decision-making 

authority for a trial. The sponsor may be an individual, committee, company, university, or government agency, or 

some combination, that holds the IND or IDE and/or has responsibility for designing, initiating, funding, managing, 

coordinating, continuing and/or concluding the clinical trial. If a product manufacturer initiates a trial and delegates 

decision-making authority to a steering committee on which it has a representative, the manufacturer and the 

steering committee may also share certain responsibilities typically held by a sponsor. When the holder of the IND 

or IDE is also a study investigator, that individual is considered a sponsor-investigator (21 CFR 312.3(b); 21 CFR 

812.3(o)). 

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The responsibilities delegated to steering committees or contract research organizations (CROs) 

by a manufacturer and/or funding agency can vary considerably. It is important that the 

responsibilities and authorities of the product manufacturer, the funding organization (if 

different) and any other entity be clearly defined and understood by all parties at the start of the 

endeavor. Potential conflicts of interest of each party, especially sponsors and clinical 

investigators (see 21 CFR Part 54) should be carefully considered when determining roles and 

responsibilities. 

3.1. Institutional Review Boards 

An institutional review board (IRB) is responsible for evaluating a trial to determine, 

among other things, whether "[r]isks to subjects are minimized" and "[r]isks to subjects 

are reasonable in relation to anticipated benefits" (21 CFR 56.111(a)). An IRB’s 

evaluation entails review of the study protocol, relevant background information, the 

informed consent document, proposed plans for informing participants about the trial, 

and any other procedures associated with the trial. To determine whether risks to 

subjects are minimized by "using procedures which are consistent with sound research 

design" (21 CFR 56.111(a)(1)(i)), an IRB may appropriately request information about 

the approach to trial monitoring, including the statistical basis for early termination, when 

relevant, and what steps the sponsor is taking to minimize the risks to patients. As part of 

its oversight, therefore, an IRB may appropriately inquire as to whether a DMC has been 

established and, if so, seek information about its scope and composition. 

For ongoing trials, the IRB is responsible for considering information arising from the 

trial that may bear on the continued acceptability of the trial at the study site(s) it 

oversees (see 21 CFR 56.103). A DMC, on the other hand, generally has access to much 

more data than the IRB during the trial, including interim efficacy and safety outcomes 

by treatment arm, and makes recommendations with regard to the entire trial. Given its 

obligation to minimize the risks to patients, an IRB may take action based on information 

from any appropriate source, including recommendations from a DMC to the sponsor. A 

trial may have multiple IRBs, each responsible for the patients at a single site, but only 

one DMC. Under 21 CFR 56.103, 21 CFR 312.66, 21 CFR 812.40, and 21 CFR 

812.150(a), individual investigators (or the sponsor of investigational devices) are 

responsible for assuring that IRBs are made aware of significant new information that 

arises about a clinical trial. Such information may include DMC recommendations to the 

sponsor that are communicated to IRB(s), either directly or through individual 

investigators or sponsors. Additionally, it may be useful for sponsors to ensure that IRBs 

are informed when DMCs have met, even when no problems have been identified and the 

DMC has recommended continuation of the trial as designed. 

3.2. Clinical Trial Steering Committees 

In some clinical trials the sponsor may choose to appoint a steering committee; this 

committee may include investigators, other experts not otherwise involved in the trial, 

and, usually, representatives of the sponsor. A sponsor may delegate to a steering 

committee the primary responsibility for designing the study, maintaining the quality of 

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study conduct, ongoing monitoring of individual toxicities and adverse events, and, in 

many cases, writing study publications. When there is a steering committee, the sponsor 

may elect to have the DMC communicate with this committee rather than directly with 

the sponsor. Interactions between the steering committee and the DMC consist primarily 

of discussions during "open sessions" (see Section 4.3) of DMC meetings and the 

communication of recommendations following each DMC review of the trial. More 

extensive interactions might occur when early termination is being considered, or when 

external forces (e.g., announcement of results of related studies) impact the ongoing trial. 

3.3. Endpoint Assessment/Adjudication Committees 

Sponsors may also choose to establish an endpoint assessment/adjudication committee 

(these may also be known as clinical events committees) in certain trials to review 

important endpoints reported by trial investigators to determine whether the endpoints 

meet protocol-specified criteria. Information reviewed on each presumptive endpoint 

may include laboratory, pathology and/or imaging data, autopsy reports, physical 

descriptions, and any other data deemed relevant. These committees are typically 

masked to the assigned study arm when performing their assessments regardless of 

whether the trial itself is conducted in a blinded manner. Such committees are 

particularly valuable when endpoints are subjective and/or require the application of a 

complex definition, and when the intervention is not delivered in a blinded fashion. 

Although such committees do not share responsibility with DMCs for evaluating interim 

comparisons, their assessments (if performed at frequent intervals throughout the trial 

with results incorporated into the database in a timely manner) help to ensure that the 

data reviewed by DMCs are as accurate and free of bias as possible. 

3.4. Site/Clinical Monitoring 

The sponsor or a group under contract to the sponsor generally performs site/clinical 

monitoring of a clinical trial to assure high quality trial conduct. They perform "on site" 

monitoring of individual case histories, assess adherence to the protocol, ensure the 

ongoing implementation of appropriate data entry and quality control procedures, and in 

general assess adherence to good clinical practices. In blinded studies, these monitors 

remain blinded to study arm assignment. 

3.5. Others with Monitoring Responsibilities 

In addition to those described above, other groups have important monitoring 

responsibilities. Study investigators, of course, have the front-line responsibility for 

identifying potential adverse effects experienced by study participants, adjusting the 

intervention accordingly and reporting the experience to the sponsor. The sponsor is 

responsible for monitoring and analyzing these investigator reports and relaying them as 

required to FDA, other regulatory authorities (as appropriate) and other investigators (21 

CFR 312.32(c), 21 CFR 812.40). The sponsor and FDA, respectively, also review 

adverse experience reports from all trials of a given product (21 CFR 312.32(c); 21 CFR 

812.150(b)). In addition, for medical device studies, sponsors are responsible for 

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ensuring that FDA and any reviewing IRB(s) are promptly informed of significant new 

information about an investigation (21 CFR 812.40). For drug and biologic studies, 

sponsors must notify IRBs, as well as FDA and other investigators, if the sponsor 

withdraws the IND for a safety reason (21 CFR 312.38(c)). 

4. DMC ESTABLISHMENT AND OPERATION 

4.1. Committee Composition 

The selection of DMC members is extremely important, as DMC responsibilities relate to 

the safety of trial participants. A poorly constituted DMC may fail to note problems that 

should be addressed, or may make recommendations that are unwarranted or whose 

consequences are inadequately considered, thereby undermining the safety of participants 

as well as the value of the trial. The ability of DMCs to provide the anticipated additional 

assurance of patient safety and trial integrity therefore depends on appropriate selection 

of DMC members. 

The sponsor and/or trial steering committee generally appoint members of a DMC. 

Factors to consider in the selection of individuals to serve on a DMC typically include 

relevant expertise, experience in clinical trials and in serving on other DMCs, and 

absence of serious conflicts of interest as discussed below. The objectives and design of 

the trial and the scope of the responsibilities given to the DMC determine the types of 

expertise needed for a particular DMC. 

Most DMCs are composed of clinicians with expertise in relevant clinical specialties and 

at least one biostatistician knowledgeable about statistical methods for clinical trials and 

sequential analysis of trial data. For trials with unusually high risks or with broad public 

health implications, the DMC may include a medical ethicist knowledgeable about the 

design, conduct, and interpretation of clinical trials. Prior DMC experience is important 

when considering the committee as a whole; it is highly desirable that at least some 

members have prior DMC service. Prior DMC experience is particularly important for 

the statistical DMC member if there is only one statistician serving on the DMC. 

Some trials may require participation of other types of scientists. Toxicologists, 

epidemiologists, and clinical pharmacologists, for example, could be included in 

particular cases when such expertise appears important for informed interpretation of 

interim results. 

One or more individuals (often non-scientists) who may help bring to the DMC the 

perspectives of the population under study may be a useful addition in some settings. 

Generally, such a DMC member would not also be a participant in the trial, since 

awareness of the accumulating data could affect compliance or other aspects of trial 

participation. Rather, the member could be someone with the disease or condition under 

study or a close relative of such an individual, for example. 

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Appropriate representation of gender and ethnic groups may be of particular importance 

for some trials. DMCs for international trials will usually include representatives from at 

least a subset of participating countries or regions; however, it is often not feasible to 

have every participating country represented on the DMC. For the reasons discussed at 

the beginning of Section 4.1, we recommend that the primary criterion for selecting all 

appointees should be their respective expertise and experience. An important practical 

consideration would be their ability to commit to attending DMC meetings and to 

maintaining confidentiality of the interim results they have reviewed (see Section 4.2). A 

DMC may have as few as 3 members, but may need to be larger when representation of 

multiple scientific and other disciplines, or a wider range of perspectives generally, is 

desirable. For logistical reasons, sponsors typically wish to keep the DMC as small as 

possible, while still having representation of all needed skills and experience. Some 

redundancy may be desirable, however, in scientifically and/or ethically complex trials, 

trials of long duration in which DMC attrition might be anticipated, or in trials in which 

the DMC must meet fairly frequently so that not all members would likely be able to 

attend all meetings. 

Conflicts of interest deserve special consideration in choosing individuals to serve on a 

DMC. The most obvious conflict is financial interest that could be substantially affected 

by the outcome of the trial. (See Section 6 for further discussion. See also Department 

of Health and Human Services, Financial Relationships and Interests in Research 

Involving Human Subjects: Guidance for Human Subject Protection, available at 

http://www.hhs.gov/ohrp/humansubjects/finreltn/fguid.pdf.) 

Investigators entering subjects into the trial have a different type of conflict of interest— 

their knowledge of interim results could influence their conduct of the trial. An 

investigator who is aware of early trends might change his or her pattern of recruitment, 

or modify his or her usual way of monitoring the status of participants. We therefore 

recommend that DMC members for a given trial not include investigators in that trial. 

Individuals known to have strong views on the relative merits of the interventions under 

study may have an "intellectual" conflict of interest and might not be able to review the 

data in a fully objective manner; such individuals may therefore not be optimal DMC 

members. We recommend that sponsors avoid appointing to a DMC any individuals who 

have relationships with trial investigators or sponsor employees that could be considered 

reasonably likely to affect their objectivity. 

We recommend that sponsors establish procedures to: 

• Assess potential conflicts of interest of proposed DMC members; 

• Ensure that those with serious conflicts of interest are not included on the DMC; 

• Provide disclosure to all DMC members of any potential conflicts that are not 

thought to impede objectivity and thus would not preclude service on the DMC; 

• Identify and disclose any concurrent service of any DMC member on other 

DMCs of the same, related or competing products. 

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The sponsor often appoints the DMC chair, but may seek advice from trial investigators 

or trial steering committee members. Prior DMC experience is more important for the 

chair than for other DMC members, as members will look to the chair for leadership on 

administrative as well as scientific issues. Sponsors will typically want to select a chair 

who is capable of facilitating discussion, integrating differing points of view, and moving 

toward consensus on recommendations to be provided to the sponsors. Sponsors may 

also want to be assured that a potential chair is willing to make a firm commitment to 

participate for the duration of the trial (or for the term of the appointment, for chairs of 

DMCs monitoring multiple trials). 

4.2. Confidentiality of Interim Data and Analyses 

As described in 21 CFR 314.126(b)(5) (drugs) and 21 CFR 860.7(f)(1) (devices), 

sponsors of well-controlled studies should take appropriate measures to minimize bias.3 

Knowledge of unblinded interim comparisons from a clinical trial is generally not 

necessary for those conducting or sponsoring the trial; further, such knowledge can bias 

the outcome of the study by inappropriately influencing its continuing conduct or the plan 

of analyses. Unblinded interim data and the results of comparative interim analyses, 

therefore, should generally not be accessible by anyone other than DMC members or the 

statistician(s) performing these analyses and presenting them to the DMC (see id.). 

Consistent with 21 CFR 314.126(b)(5) (drugs) and 21 CFR 860.7(f)(1) (devices), 

sponsors should establish written procedures, which may be included in the DMC charter, 

to ensure the minimization of bias, such as maintaining confidentiality of the interim data 

(see Section 4.3.1.4). Sponsors may, of course, also address such confidentiality issues in 

written agreements between the sponsor and members of the DMC as well as written 

agreements between the sponsor and investigators. 

Even for trials not conducted in a double-blind fashion, where investigators and patients 

are aware of individual treatment assignment and outcome at their sites, the summary 

evaluations of comparative unblinded treatment results across all participating centers 

would usually not be available to anyone other than the DMC. Section 6 addresses the 

particular confidentiality issues for the statistician/statistical team performing the interim 

analyses. 

4.2.1. Interim Data 

Interim comparative data, whether treatment assignment is revealed or coded, will 

be most securely protected from inadvertent or inappropriate access by the 

sponsor or its project team if the data are prepared for analysis by a statistical 

group that is independent of the sponsor and investigators—that is, the group is 

not otherwise involved in the trial design or conduct and has no financial or other 

important connections to the sponsor or other trial organizers (see Section 6). The 

All discussions in this guidance relating to adoption of procedures for the minimization of bias refer to the 

minimization of bias in adequate and well-controlled clinical trials for drugs, as described in 21 CFR 314.126, and 

well-controlled clinical trials for devices, as described in 21 CFR 860.7(f). 

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lead investigators, the study steering committee, and/or the sponsor generally 

develop the analytical plan (often collaboratively), but problems can arise when 

these same individuals are involved in the actual preparation of the interim 

results, for reasons discussed in Section 6.4. They may, however, work with the 

statistician who will be preparing and presenting the interim analyses prior to the 

first analysis of unblinded data to develop a template for the interim reports. 

Procedures should be established to safeguard confidential interim data from the 

project team, investigators, sponsor representatives, or anyone else outside the 

DMC and the statistician(s) performing the interim analyses (see 21 CFR 

314.126(b)(5) (drugs) and 21 CFR 860.7(f)(1) (devices)). 

Although assigning responsibility for interim analysis to individuals employed by 

the sponsor is generally discouraged, such assignment may be appropriate if 

sufficiently secure procedures are in place to credibly ensure that the results of 

such analyses are not revealed to other sponsor employees or to anyone other than 

DMC members. We recommend that a description of such procedures be included 

in the DMC charter (see Section 4.3). 

4.2.2. Interim Reports to the DMC 

We recommend that any part of the interim report to the DMC that includes 

comparative effectiveness and safety data presented by study group, whether 

coded or completely unblinded, be available only to DMC members during the 

course of the trial, including any follow-up period—that is, until the trial is 

completed and the blind is broken for the sponsor and investigators. If interim 

reports are shared with the sponsor, it may become impossible for the sponsor to 

make potentially warranted changes in the trial design or analysis plan in an 

unbiased manner (see Section 6.3). Even aggregate data on safety and efficacy 

may be informative; these data may be needed for some trial management 

functions (e.g., sample size adjustments, centralized endpoint assessment), but are 

best limited to those who cannot otherwise carry out their trial management 

responsibilities. 

In some cases (for example, in open-label trials with special concerns about 

safety), there may be a rationale for the sponsor and/or investigators to have 

access to the ongoing comparative safety data to ensure continuous monitoring. 

Such access should be specified and justified in the study protocol and understood 

by the DMC (see 21 CFR 314.126(b)(5) (drugs) and 21 CFR 860.7(f)(1) 

(devices)). 

In many cases, the DMC receives reports in two parts: an "open" section, which 

presents data only in aggregate and focuses on trial conduct issues such as accrual 

and dropout rates, timeliness of data submission, eligibility rates and reasons for 

ineligibility; and a "closed" section, in which the comparative outcome data are 

presented. The open section of these reports is usually provided to sponsors, who 

may convey any relevant information in these reports to investigators, IRBs, and 

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other interested parties, as the data presented in the "open" section are not likely 

to bias the future conduct of the trial and are often important for improving trial 

management. 

4.3. Establishing a Charter Describing Standard Operating Procedures 

DMCs typically operate under a written charter that includes well-defined standard 

operating procedures. Such charters are important for the same reason that study 

protocols and analytical plans are important—they document that procedures were prespecified and thereby reduce concerns that operations inappropriately influenced by 

interim data could bias the trial results and interpretation. The sponsor may draft this 

charter and present it to the DMC for agreement, or the DMC may draft the charter with 

subsequent concurrence by the sponsor. Topics to be addressed would normally include a 

schedule and format for meetings, format for presentation of data, specification of who 

will have access to interim data and who may attend all or part of DMC meetings, 

procedures for assessing conflict of interest of potential DMC members, the method and 

timing of providing interim reports to the DMC, and other issues relevant to committee 

operations. FDA may request that the sponsor submit the charter to FDA well in advance 

of the performance of any interim analyses, ideally before the initiation of the trial (see 

21 CFR 312.23(a)(6)(iii)(g); 21 CFR 312.41(a); 21 CFR 812.150(b)(10)). In such cases, 

FDA would usually consider the charter when FDA reviews the study protocol. 

4.3.1. Considerations for Standard Operating Procedures 

4.3.1.1. Meeting Schedule and Format 

The initial frequency of DMC meetings will depend on the expected rate of 

accrual and event occurrence at the time the trial is designed as well as the 

perceived risk of the experimental and/or control interventions. Annual 

meetings may be adequate for some studies; other trials will require more 

frequent review. Occasionally, there may be a need for extra meetings, when, 

for example, there is concern about potentially emerging safety problems, or 

when important new information external to the trial arises. The study 

protocol will generally describe the schedule of interim analyses to be 

considered by the DMC, or the considerations that will determine the timing 

of meetings (e.g., a plan for interim analysis after a certain number of primary 

outcomes have been reported). The study protocol will also typically describe 

the statistical approach to the interim analysis of trial data. To minimize the 

potential for bias, these descriptions should be complete before the conduct of 

any unblinded interim analyses (see 21 CFR 314.126(b)(5) (drugs) and 21 

CFR 860.7(f)(1) (devices)). 

Face-to-face meetings are generally preferable, but telephone meetings may 

be necessary in some situations, particularly when new information must be 

urgently considered. In some settings, when the DMC has already had 

numerous meetings and the committee is very familiar with the trial and the 

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analytical issues, telephone meetings may be sufficient. When telephone 

meetings are held, precautions may be needed to assure the confidentiality of 

the proceedings, and to prevent inadvertent access to conversations. 

4.3.1.2. Meeting Structure 

Attendance at meetings raises the same confidentiality issues as access to 

interim reports provided to the DMC. A central tenet of clinical trials is the 

importance of maintaining confidentiality of interim comparative data (see the 

Guidance for Industry, ICH E9, Statistical Principles for Clinical Trials, 

available at http://www.fda.gov/cder/guidance/ICH_E9-fnl.pdf). Although 

FDA typically expects that confidentiality of the interim data will be 

maintained, the DMC may interact with the sponsor and/or trial lead 

investigators to clarify issues relating to the conduct of the trial, potential 

impact on the trial of external data, or other topics. In order to permit such 

interaction without compromising confidentiality, many DMC meetings 

include an "open" session in which information in the open report is 

discussed. These non-confidential data may include, for example, status of 

recruitment, baseline characteristics, ineligibility rate, accuracy and timeliness 

of data submissions, and other administrative data. Sponsors may also use 

open sessions to provide external data to the DMC that may be relevant to the 

study being monitored. Open session discussions might include 

representatives of the sponsor, steering committee, study investigators, FDA 

representatives, or others with trial responsibilities. There is a benefit to 

having a wider attendance at these sessions, since they provide an opportunity 

for those with the most intimate knowledge of the study to share their insights 

with the DMC and raise issues for the DMC to consider. The DMC generally 

considers the comparative interim data contained in the closed report in a 

"closed" session attended only by the DMC members and the statistician who 

prepared and is presenting the interim analyses to the DMC. Following the 

closed session, the DMC may meet again with the sponsor to relay any 

recommendations the DMC has made. 

Section 6 describes the risks to study integrity when sponsor representatives 

have access to unblinded interim data and attend closed sessions of DMC 

meetings. In settings in which a sponsor chooses to permit its representatives 

or other non-DMC members to attend the closed session despite the risks of 

such arrangements, we recommend that the DMC have the option of 

conducting an "executive" session with no participants other than DMC 

members. 

4.3.1.3. Initial Meeting 

Scheduling the initial meeting of a DMC before the study is initiated has 

many advantages. At this meeting, the DMC can discuss the protocol and 

analytic plan, model informed consent form, data collection instruments and 

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other important trial documents, and present any suggestions for modifications 

to the sponsor and/or steering committee. Regulatory considerations may also 

be discussed. Meeting participants typically discuss and complete plans for 

monitoring the safety and effectiveness data, including: 

• Scheduling of meetings; 

• Format for the interim reports to the DMC; 

• Timing of the delivery of the report to the DMC members prior to the 

meeting; 

• Definition of a "quorum" of DMC members, including representation 

of essential scientific and other disciplines; 

• Handling of meeting minutes; and 

• Other aspects of the process. 

It is particularly important that the sponsor and the DMC agree on the data 

monitoring plan, including the approach to early termination. 

4.3.1.4. Format of Interim Reports to the DMC and Use of Treatment 

Codes 

It is important that the general format and content of interim reports to the 

DMC be acceptable to the DMC. This may be accomplished most efficiently 

if the sponsor proposes a template for these reports at its first meeting, so that 

changes requested by the DMC may be implemented before interim data are 

first presented. However, the templates may change during the course of the 

trial as experience is accrued. Further, the DMC will generally need easy and 

timely access to any additional data and analyses deemed important, and may 

request such additional material when needed. 

We recommend that a DMC have access to the actual treatment assignments 

for each study group. Some have argued that DMCs should be provided only 

coded assignment information that permits the DMC to compare data between 

study arms, but does not reveal which group received which intervention, 

thereby protecting against inadvertent release of unblinded interim data and 

ensuring a greater objectivity of interim review. This approach, however, 

could lead to problems in balancing risks against potential benefits in some 

cases. For example, to maintain blinding of the actual treatment assignments, 

safety outcomes would have to be coded differently from effectiveness 

outcomes when adverse effects would reveal the assigned intervention. This 

would prevent the DMC from evaluating the balance of risks and benefits of 

the active interventions, its most critical responsibility. 

Also, decisions about a trial are often asymmetric with respect to study arms; 

that is, a DMC may recommend termination of a study with a trend toward 

showing harm on the basis of data that, were they in the other direction, would 

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not be considered strong enough to terminate early with a conclusion of 

benefit. Similarly, a trend suggesting a safety concern with a new intervention 

could be sufficient to suggest the need for trial modification, while a similar 

trend in the opposite direction (new intervention looks better than standard) 

might not. 

A common approach is presentation of results in printed copy using codes (for 

example, Group A and Group B) to protect against inadvertent unblinding 

should a report be misplaced, with separate access to the actual study arm 

assignments provided to DMC members by the statistical group responsible 

for preparing DMC reports. To ensure the DMC’s and sponsor’s ability to 

address an emerging safety concern rapidly, they should establish a process to 

unblind treatment codes to DMC members in a timely fashion when needed 

(cf. 21 CFR 312.32(d); 21 CFR 812.46(b)(2)). For example, DMC members 

might routinely receive the unblinded treatment codes in a mailing separate 

from that containing the interim reports. 

4.3.2. Statistical Methods 

Statistical approaches to monitoring trials, and the principles involved in their 

implementation, are addressed in Guidance for Industry, ICH E9, Statistical 

Principles for Clinical Trials, available at 

http://www.fda.gov/cder/guidance/ICH_E9-fnl.pdf 4

. Planners of clinical trials 

most commonly use group sequential methods, in which interim analyses are 

performed at regular intervals based either on chronological time or amount of 

information accrued, but other approaches, such as those based on Bayesian 

methods, have been used as well. Statistical methods are also available to assess 

stopping for futility; that is, when the likelihood that the treatment effect being 

sought, based on the interim data, is very unlikely to be established. Other 

statistical strategies for monitoring may also be appropriate. 

The sponsor or trial steering committee usually proposes the particular statistical 

approach to interim monitoring, but the DMC should generally review it before it 

is made final, to ensure that the DMC agrees to be guided in its actions by the 

planned approach. FDA will typically request that the sponsor submit a final 

monitoring plan once it has been put in place, and before the initiation of interim 

monitoring, as such a plan would typically be considered a critical component of 

the study protocol (see 21 CFR 312.23(a)(6)(iii)(g); 21 CFR 312.41(a); 21 CFR 

812.150(b)(10)). Because statistical approaches based on classical hypothesis 

testing methods are by far the most common, the remaining discussion in this 

section will focus on issues within that framework. As noted earlier, other 

monitoring strategies may also be appropriate. 

Although ICH documents are meant to provide guidance for drug and biologics sponsors, the statistical monitoring 

principles in ICH E9 could be used in the evaluation of medical devices as well. 

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One of the major responsibilities of a DMC is to evaluate the relative treatment 

effects based on protocol-specified endpoints to determine if the trial is meeting 

its objectives. A major concern when data on group differences are assessed 

repeatedly as they accumulate is that the Type I error (false positive) rate may be 

inflated if adjustment is not made for the multiple looks at the data. Typically, the 

monitoring plan will specify a statistical approach that permits multiple interim 

reviews while maintaining the Type I error rate at the desired level. These 

approaches usually generate boundaries for interim estimates of benefit that 

indicate the magnitude of benefit needed to support stopping the trial at interim 

points prior to its planned completion, while maintaining the desired overall 

probability of Type I error. Such boundaries can serve as useful guidelines to the 

DMC in making recommendations regarding continued accrual to and conduct of 

the trial. The DMC will usually recommend termination when these thresholds 

are crossed, but it is not obligated to do so, since other aspects of the interim data 

may complicate the issue. For example, the data on effectiveness may be very 

strong, with a stopping boundary having been crossed, but emerging safety 

concerns may make the benefit-to-risk assessment non-definitive at that interim 

review. FDA expects the sponsor to direct the DMC to exercise its own judgment 

in such circumstances; the DMC can be flexible in assessing the data relative to 

the stopping boundaries. If the DMC recommends early termination for efficacy 

before a boundary is crossed, however, and this recommendation is implemented, 

the Type I error cannot be preserved and the study results may be difficult to 

interpret. 

Statistical assessment may also suggest that early termination of a trial be 

considered on the basis of futility, as defined previously. In this case, a DMC 

may recommend early termination on the grounds that the trial is unlikely to meet 

its objectives and there is therefore no basis for continuing enrollment and/or 

follow-up. Before recommending that a trial be terminated due to futility, a DMC 

will typically consider the Type II error, the chance of making a false negative 

conclusion. Stopping on the basis of futility does not raise concerns about Type I 

error in that trial, since the conclusions of the trial will not be positive. 

Nevertheless, protection of Type I error may be important even when there is a 

stated intention to stop early only for futility reasons since interim review of 

outcome data always raises the possibility that the DMC may find early results so 

persuasive that it would recommend early termination of the trial. 

4.4. Potential DMC Responsibilities 

4.4.1. Interim Monitoring 

Most experience with DMCs has been in the setting of studies that address major 

outcomes such as mortality or serious irreversible morbidity. Although many 

such studies focus on short-term endpoints such as 30-day survival, other studies 

often use endpoints that require a substantial duration of follow-up after the 

intervention delivery has been completed. The need for monitoring in such 

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studies often extends beyond the time when individuals are treated, since trends in 

survival or other serious outcomes may not become evident until some time 

during the follow-up period. Thus, the DMC’s responsibility to monitor the study 

generally continues until the planned completion of follow-up, regardless of the 

duration of treatment. 

4.4.1.1. Monitoring for Effectiveness 

In studies with serious outcomes, all parties would wish that any major 

treatment advance be identified and made available as soon as possible. It is 

critical, however, that the study yield a valid and definitive result. Thus, 

tensions between ethical and scientific considerations may arise. Consider, 

for example, a placebo-controlled trial of a new product for a serious illness or 

condition for which there is no standard treatment. If the emerging data 

suggest that those receiving the treatment are doing better, one might expect 

that a DMC would consider whether the study should be terminated earlier 

than planned. Estimates of treatment effect, however, will be unstable at early 

points in a study, and the chance is substantial of observing a nominally 

statistically significant benefit (e.g., p<0.05) at one of multiple interim 

analyses during a study of an ineffective product (see Section 4.4.2). A DMC, 

guided by a pre-specified statistical monitoring plan acceptable to both the 

DMC and the study leadership, will generally be charged with recommending 

early termination on the basis of a positive result only when the data are truly 

compelling and the risk of a false positive conclusion is acceptably low. 

A second type of consideration is whether the hypothesized benefit is likely 

ultimately to be achieved. If the interim data suggest that the new product is 

of no benefit—that is, there is no trend indicating superiority of the new 

product—or that accrual rates are too low or noncompliance too great to 

provide adequate power for identifying the specified benefit, a DMC may 

consider whether continuation of the study is futile and may recommend early 

termination on this basis. In this case, false negative conclusions are of 

concern; statistical procedures are available to guide such determinations (see 

Section 4.3.2). 

4.4.1.2. Monitoring for Safety 

There are several aspects to safety monitoring in long-term outcome studies. 

First, the primary efficacy endpoint itself often has safety implications. If 

individuals given the investigational intervention are found to be at higher risk 

for the outcome of interest (e.g., mortality, disease progression, loss of organ 

function) sooner than those given the control, the DMC may consider 

recommending early termination on safety grounds. Such assessments have 

potential implications for falsely concluding that there is an adverse effect, 

just as regular assessments of efficacy have the potential to lead to false 

positive conclusions about benefit. Statistical considerations for early 

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stopping when the data are trending in the direction of harm are often different 

from the case of trends in the direction of benefit, however. It is usually 

appropriate to demand less rigorous proof of harm to justify early termination 

than would be appropriate for a finding of benefit. In some cases, however, it 

may be appropriate to establish a harmful effect more definitively—for 

example, if a positive effect on the primary endpoint has been demonstrated or 

appears to be emerging, a precise assessment of a negative trend on a 

potentially important safety endpoint may be required for benefit-to-risk 

considerations. 

A second important aspect of safety monitoring in these trials is comparison 

of adverse event rates in each treatment arm. In some cases adverse events of 

particular concern can be identified in advance of the trial, and particular 

attention will be given to monitoring these events. For example, in a large 

trial of hormone replacement therapy, specific monitoring plans were 

established to detect a possible increase in breast cancer incidence in women 

taking active therapy. Because many types of adverse reactions cannot be 

anticipated prior to a large-scale study, the DMC should generally be provided 

with interim summaries by treatment arm of adverse events observed, not 

limited to those identified in advance. This is particularly important for 

serious events that may result from the disease being treated as well as the 

intervention itself, or occur at an observable background rate in the population 

under study. An effect of the drug on these events can only be detected by 

comparing the rates of the events in treatment and control groups. 

To illustrate the process, consider acute myocardial infarctions (AMIs) 

occurring during a study of an antidiabetic therapy. Diabetics are at increased 

risk of AMI so that a specific AMI in a participant could not be attributed to 

the new drug. A DMC for such a trial, however, would regularly review the 

number of myocardial infarctions observed in each study arm. If an 

imbalance between groups emerges, concerns will arise that some of the 

myocardial infarctions may be due to the intervention rather than the disease 

itself. Since a potentially large number of adverse event categories may be 

observed and compared between the study arms, sensitivity on the part of the 

DMC to the issues of multiplicity, i.e., the elevated probability of "false 

positives" when performing multiple analyses, is warranted. Not all potential 

risks can be identified in advance of the trial, so pre-specifying risks of 

concern cannot always be done. 

A third aspect of safety monitoring is consideration of individual events of 

particular concern. Although a DMC typically reviews summary adverse 

event data as discussed above, it will not usually review in detail every 

adverse event reported, or even every serious adverse event. This 

responsibility generally lies with the sponsor, who must assure review of such 

events promptly (see, e.g., 21 CFR 312.32(b); 21 CFR 812.42(d); 21 CFR 

812.46(b)). The sponsor has the responsibility of reporting to FDA serious, 

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unexpected adverse events in drugs and biologics trials under 21 CFR 312.32 

and unanticipated adverse events in the case of device trials under 21 CFR 

812.150(b)(1). For clinical trials involving drugs and biologics, we 

recommend that sponsors notify DMCs about any waivers granted by FDA for 

expedited reporting of certain serious events. 

The involvement of a DMC in the review of individual adverse event reports 

will vary from case to case. In some studies, it may be important for the DMC 

to see detailed information on all deaths or other specified events, particularly 

events that are likely to have been caused by the product being tested (e.g., 

acute liver failure in a drug study). In other studies, where many deaths or 

other serious events are expected, the DMC may view only the summary 

tabulations and comparative statistics to determine whether there appears to be 

an excess of an important adverse event in one of the study arms. Simple 

listings of adverse outcomes, especially without treatment assignments, are 

rarely useful for DMC discussion. 

The sponsor may ask the DMC to review any individual event thought to be of 

major significance by the study’s medical monitor; such events would 

generally include deaths or other serious outcomes for which a causal 

connection with the intervention is plausible. We recommend that the DMC 

be informed in a timely manner of any cases for which unblinding of 

treatment code at the clinical site or by the treating clinician is thought to be 

necessary to provide an appropriate intervention, so that the DMC can assess 

the potential impact of such actions on the overall study blind. Review of 

individual cases by the DMC does not relieve the sponsor of the regulatory 

responsibilities, discussed above, regarding evaluation of these events and 

reporting as required to FDA. 

Concerns about the extent and type of adverse events observed may lead to 

early termination of the trial when the DMC judges that the potential benefits 

of the intervention are unlikely to outweigh the risks. In other cases, a DMC 

may recommend measures short of termination that might reduce the risk of 

adverse events. For example, the DMC might recommend: 

• Changing the eligibility criteria if the risks of the intervention seem to 

be concentrated in a particular subgroup. 

• Altering the product dosage and/or schedule if the adverse events 

observed appear likely to be reduced by such changes. 

• Instituting screening procedures that could identify those at increased 

risk of a particular adverse event. 

• Informing current and future study participants of newly identified 

risks via changes in the consent form and, in some cases, obtaining reconsent of current participants to continued study participation. 

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4.4.1.3. Monitoring Study Conduct 

The DMC typically shares responsibility for assessment of data related to 

study conduct with the sponsor, the study leadership (such as a steering 

committee), and to some extent with IRBs. A DMC will generally review 

data related to the conduct of the study (that is, the quality of the study and its 

ultimate ability to address the scientific questions of interest), in addition to 

data on effectiveness and safety outcomes. These data may include, among 

other items: 

• Rates of recruitment, ineligibility, noncompliance, protocol violations 

and dropouts, overall and by study site; 

• Completeness and timeliness of data; 

• Degree of concordance between site evaluation of events and 

centralized review; 

• Balance between study arms on important prognostic variables; 

• Accrual within important subsets. 

The DMC may issue recommendations to the sponsor regarding trial conduct 

when concerns arise that some aspects of trial conduct may threaten the safety 

of participants or the integrity of the study. For example, if the data presented 

to the DMC are not current, the DMC will not be able to meet its 

responsibility of ensuring that the study continues to be safe for its current and 

future participants. As another example, an excess of dropouts may endanger 

the ultimate interpretability of the study results. 

4.4.1.4. Consideration of External Data 

A DMC may be asked to consider the impact of external information on the 

study being monitored. Release of results of a related study may have 

implications for the design of the ongoing study, or even its continuation. In 

some cases, particularly when unexpected safety issues arise in related studies, 

the sponsor may bring external data to the attention of the DMC; in other 

cases, the data may be publicly reported. Such data may lead to 

recommendations ranging from termination of the study, termination of one or 

more study arms, changes in target population, dose and/or duration of the 

intervention, or use of concomitant treatments. The DMC may also 

recommend changes to the consent form or investigator’s brochure, and/or 

letters from the sponsor to study participants describing the new results. 

The role of the DMC in considering interim changes to a study protocol or 

other aspects of study conduct in response to external information raises 

additional issues that merit consideration. 

In many cases, access to the unblinded data will be essential to making the 

best decision regarding changes to an ongoing trial that are suggested by 

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external data. For example, if external reports indicate that use of the study 

drug in a different indication raised serious, unexpected safety concerns, a 

decision about continuing the ongoing trial may depend on whether the 

interim data suggest important benefits that may make the newly found risks 

acceptable, or the extent to which the newly identified concerns are evident in 

the ongoing study. In some circumstances, DMCs of separate but closely 

related trials (e.g., trials of the same product in different patient populations) 

may consider sharing confidential interim data when unexpected safety issues 

arise in one trial and information from the two trials together may improve 

decision-making in both trials. Because such sharing limits the extent to 

which the trials can be considered independent, it should be pursued only in 

the rare situations when early stopping might be considered, but the issues 

leading to this consideration are ambiguous, for example, when a safety 

concern arises that appears biologically implausible. Both DMCs would 

typically require the express consent of the respective sponsors prior to 

sharing such information. 

In some cases, however, significant involvement of the DMC in 

considerations of changes based on external data could have undesirable 

consequences precisely because the DMC is aware of the interim study 

results. Many kinds of trial modifications (e.g., changing endpoints, changing 

or adding to prespecified analysis subgroups) could, if made with knowledge 

of trial results, have significant effects on type I error and interpretation of 

final results. If it is perceived that emerging results could have influenced 

these types of interim protocol changes, the credibility of the trial may be 

severely damaged. In general, to minimize the potential for bias, the trial 

leadership, which is insulated from knowledge of the interim data, rather than 

the DMC, should be responsible for proposing potential changes other than 

those driven by safety considerations (cf. 21 CFR 314.126(b)(5), 21 CFR 

860.7(f)(1)). 

The principle that interim protocol changes should not be influenced by 

emerging results has implications for sponsors, who would initiate requests 

for protocol changes, and FDA staff, who would need to evaluate any such 

requests for protocol changes for INDs under 21 CFR 312.30 and for IDEs 

under 21 CFR 812.35. Sponsors who wish to have the ability to request 

interim protocol changes without raising concerns about biasing the study 

should establish procedures to minimize bias, such as ensuring that they are 

completely unaware of unblinded comparative data (see 21 CFR 

314.126(b)(5), 21 CFR 860.7(f)(1)). If the study is performed with blinded 

treatment allocation, and access to unblinded data is limited to the DMC, 

making such changes as requested by the sponsor is straightforward. If 

treatment allocation is not blinded, it is more difficult to maintain 

confidentiality of interim comparative results, as sponsor staff such as medical 

monitors will be reviewing data on each case. In such circumstances it may 

be very advantageous for the sponsor to set up a "firewall" to ensure that those 

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who would be proposing interim protocol changes based on external data are 

insulated from knowledge of interim comparative results. To avoid any 

influence of interim data on consideration of protocol changes, FDA staff will 

also generally remain blinded to the interim results. Under 21 CFR 312.41(a) 

(drugs) or 21 CFR 812.150(b)(10) (devices), we may request additional 

information or data to aid in FDA's review of protocol amendments and other 

aspects of clinical trials under an IND or IDE, respectively. Under these 

authorities, we will typically request that, once interim data have been seen by 

the sponsor, such data should also be available to FDA, provided such data 

form the basis for a request by the sponsor to amend a study protocol. It may 

be necessary for FDA to play a more active role regarding interim results in 

rare cases when there is an immediate need to evaluate a serious safety 

concern, especially when we may have important relevant information that 

may not otherwise be available to the DMC. Even in such cases, however, it 

will generally be preferable for FDA to provide such information to the DMC, 

where possible, rather than taking a direct role in interim evaluations. 

4.4.1.5. Studies of Less Serious Outcomes 

Many clinical trials evaluate interventions to relieve symptoms. These studies 

are generally short-term, evaluating treatment effect over periods of a few 

days to a few months. These studies tend to be smaller than major outcome 

studies and, therefore, are completed more quickly. Because the primary 

endpoints of such studies are not serious irreversible events, as in a major 

outcome study, the ethical issues for monitoring are different. In these 

studies, valuable secondary objectives such as characterization of the effect 

(i.e., magnitude, duration, time to response), assessment of the effect in 

population subsets, comparison of several doses and/or comparison of the new 

product to an active control can be ethically pursued even when the 

conclusion regarding the primary outcome is clear. Early termination for 

effectiveness is rarely appropriate in such studies. First, the study may be 

essentially completed by the time any interim analysis could be undertaken. 

Second, the effectiveness of an intervention to relieve symptoms would not 

generally be so compelling as to override the need to collect the full amount of 

safety data, or to collect other information of interest and importance that 

characterizes the effect, as noted above. 

DMCs have not been commonly established for short-term studies of 

interventions to relieve symptoms. The need for an outside group to monitor 

data regularly to consider questions of early stopping for efficacy or protocol 

modification is usually not compelling in this situation. Such a group is 

probably warranted only when termination of the trial for efficacy, even at the 

expense of obtaining more complete safety information, would be indicated 

for ethical reasons. 

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For products intended solely to relieve symptoms, as opposed to curing or 

delaying progress of a serious disease or medical condition, an expert group to 

oversee all studies at all stages of development, monitor the developing safety 

database and make recommendations for design of successive studies based 

on early results may be useful. The sponsor or investigator could refer an 

unusual safety concern arising in any study to this type of external group for 

review, while maintaining its own primary role in monitoring the 

accumulating results. Such a group may be particularly valuable when the 

patient population is at relatively high risk of serious events; for example, in 

studies of drugs to control symptoms of angina, congestive heart failure, or 

chronic obstructive lung disease. The external group would independently 

evaluate individual events and overall event rates in ongoing studies and 

advise the sponsor about emerging concerns. Clearly, monitoring 

considerations of this type are more clinical than statistical. Sponsors 

frequently constitute internal groups to monitor these types of studies, and 

these may be satisfactory in most cases. Nevertheless, external advisors, who 

will be less committed to the existing development plan, may identify some 

problems more readily than internal reviewers. Thus, sponsors may find it 

valuable to augment such internal groups with one or more external advisors. 

4.4.2. Early Studies 

DMCs are not usually warranted in early studies such as Phase 1 or early Phase 2 

studies, or pilot/feasibility studies, but formal monitoring groups may be useful 

for certain types of early clinical studies. While these formal monitoring groups 

will often consist of individuals internal to the sponsor and/or investigators, a 

DMC overseeing safety may be considered when risk to participants appears 

unusually high, e.g., with particularly novel approaches to treating a disease or 

condition. When the investigator is also the product manufacturer or IND/IDE 

sponsor, and thereby subject to potentially strong influences related to financial 

and/or intellectual incentives, a DMC could provide additional, independent 

oversight that would enhance safety of study participants and the credibility of the 

product development. Sponsors may therefore wish to consider establishing 

DMCs in such settings. 

A DMC’s role in early phase studies would be different from that in late Phase 2 

or Phase 3 studies. Early studies are often exploratory in nature; they are 

frequently not randomized or controlled and therefore accumulating results are 

known to the investigators and sponsor. Issues regarding statistical interpretation 

of interim data, or confidentiality of interim data, are therefore generally less 

relevant in this setting. Nevertheless, for difficult situations in which the potential 

scientific gain from continuing a study must be evaluated in the context of ethical 

considerations for ensuring subjects’ rights and welfare, particularly in settings 

such as those described above, DMCs may be helpful to investigators, sponsors 

and IRBs by providing independent, objective expert counsel. We expect, 

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however, that the need for independent DMCs in early phase studies will be 

infrequent. 

4.4.3. Other Responsibilities 

4.4.3.1. Making Recommendations 

A fundamental responsibility of a DMC is to make recommendations to the 

sponsor (and/or, as noted in the Introduction, a steering committee or other 

group delegated by the sponsor to make decisions about the trial) concerning 

the continuation of the study. Most frequently, a DMC’s recommendation 

after an interim review is for the study to continue as designed. Other 

recommendations that might be made include study termination, study 

continuation with major or minor modifications, or temporary suspension of 

enrollment and/or study intervention until some uncertainty is resolved. 

Because a DMC’s actions potentially impact the safety of trial participants, it 

is important that a DMC express its recommendations very clearly to the 

sponsor. Both a written recommendation and oral communication, with 

opportunity for questions and discussion, can be valuable. Recommendations 

for modifications are best accompanied by the minimum amount of data 

required for the sponsor to make a reasoned decision about the 

recommendation, and the rationale for such recommendations should be as 

clear and precise as possible. Sponsors may wish to develop internal 

procedures to limit the interim data released by a DMC after a 

recommendation until a decision is made regarding acceptance or rejection of 

the recommendation, to facilitate maintaining confidentiality of the interim 

results should the trial continue. We recommend that a DMC document its 

recommendations, and the rationale for such recommendations, in a form that 

can be reviewed by the sponsor and then circulated, if and as appropriate, to 

IRBs, FDA, and/or other interested parties. Sections 5 and 7.2.1 address 

implications for reporting to FDA of DMC recommendations for major study 

changes such as early study termination. 

4.4.3.2. Maintaining Meeting Records 

We recommend that the DMC keep minutes of all meetings (see Guidance for 

Industry, ICH E6, Good Clinical Practice: Consolidated Guidance, Section 5.5 

at 5.5.2, available at http://www.fda.gov/cder/guidance/959fnl.pdf). We also 

recommend that the DMC divide meeting minutes into two parts, according to 

whether they include discussion of confidential data (usually unblinded 

comparative data). The second part of the minutes will typically summarize 

discussion of the comparative unblinded outcome data and provide the 

rationale for the recommendations made to the sponsor. Generally, the DMC 

does not circulate this portion of the minutes or the interim study reports for 

the closed session outside the DMC membership until the trial is terminated. 

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We also recommend that after each meeting, the DMC issue a written report 

to the sponsor based on the meeting minutes. This report does not have to be 

extremely detailed, but should include sufficient information to explain the 

rationale for any recommended changes. Sponsors should establish 

procedures to minimize the potential for bias, such as requiring that reports to 

the sponsor include only those data generally available to the sponsor (e.g., 

number screened, number enrolled at each site) (see 21 CFR 314.126(b)(5) 

(drugs) and 21 CFR 860.7(f)(1) (devices)). If no changes are recommended, 

the report may be as simple as "The DMC recommends that the study 

continue as designed." We further recommend that the report to the sponsor 

include a summary of the discussion in any open session of the meeting and 

document any information provided orally to the sponsor that was not 

included in the written report. The sponsor may convey the relevant 

information in this report to other interested parties such as the study 

investigators, who should provide any such information, as appropriate, to 

participating IRBs. Of course, sponsors and/or investigators must report to 

participating IRBs, as well as to FDA, applicable changes in the protocol or 

study procedures made as a result of DMC recommendations (see 21 CFR 

56.108(a)(3) and (4) and 312.30 and 312.66 for drugs and 21 CFR 812.40 for 

devices). 

We recommend that the DMC or the group preparing the confidential interim 

reports to the DMC maintain all meeting records in order to best ensure 

continued confidentiality of interim data. We may request copies of these 

records when the study is completed (21 CFR 312.58 (drugs); 21 CFR 

812.150(b)(10) (devices)). We may also request access to the electronic data 

sets used for each set of interim analysis. We therefore recommend that 

sponsors arrange for archiving such electronic data sets. 

5. DMC RECOMMENDATIONS AND REGULATORY REPORTING 

REQUIREMENTS 

All clinical trials conducted under an IND or IDE are subject to regulatory safety reporting 

requirements. These requirements include prompt reporting to FDA of certain serious and 

unexpected adverse events (see 21 CFR 312.32(c), 21 CFR 312.52, 21 CFR 812.46(b), 21 CFR 

812.150(b)(1)). In general, for an event that is individually recognizable as a serious event 

potentially related to administration of a medical product (e.g., agranulocytosis, hepatotoxicity 

for drug studies), the sponsor (sometimes through a CRO managing that aspect of the trial, see 

21 CFR 312.52) is responsible for notifying FDA (21 CFR 312.32, 21 CFR 812.150(b)(1)). The 

sponsor may make this notification with or without unblinding the individual case, as 

appropriate. 

As discussed above in Section 4.4.1.2, evidence of a possible relationship between many serious 

adverse events and an investigational drug might be detectable only by comparison of rates in the 

two arms of a controlled trial and not by review of individual cases. For example, in a drug trial 

carried out in patients with coronary artery disease, in whom heart attacks and strokes would be 

expected to occur, an increased heart attack or stroke rate would not be recognized except by 

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comparison to the rate in the control group; if such comparison demonstrated an increase in heart 

attack and stroke rate, it could be presumed that the increase in heart attack and stroke rate was 

drug-related. Such a finding involving a serious adverse event, conveyed to a sponsor by a DMC 

with a recommendation to change the trial (e.g., design, informed consent), could represent, on 

its face, a report of one or more serious unexpected adverse event(s). As required by 21 CFR 

312.32(d)(1), the sponsor would need to investigate a DMC’s recommendation relating to such 

events as potentially reportable to FDA under 21 CFR 312.32. If the sponsor concluded that the 

increased rate of serious unanticipated adverse events was "associated with the use of the drug," 

the finding, and support for it (which could include the DMC report, any analysis, and pertinent 

data) would need to be submitted as a serious unexpected adverse experience. These 

considerations would also apply to unanticipated adverse device effects under 21 CFR 

812.50(b)(1). 

Findings conveyed to a sponsor by a DMC as part of a recommendation to modify the trial could 

therefore mean that serious and unexpected events were occurring, and the sponsor would 

consequently be required to report an analysis of these events to FDA and to all study 

investigators according to 21 CFR 312.32(c)(1)(B)(ii) (drug trials) and 21 CFR 812.150(b)(1) 

(device trials). Study investigators are generally responsible for reporting such findings to their 

IRBs, according to 21 CFR 312.66 (drug trials) and 21 CFR 812.150(a)(1) and 21 CFR 812.40 

(device trials), although direct reporting from sponsors to responsible IRBs may be arranged and 

may be preferable in some situations; for example, when a central IRB has been established. For 

a device trial, however, the sponsor is responsible for notifying all participating IRBs when an 

evaluation of an unanticipated adverse event is conducted (21 CFR 812.150(b)(1)). 

The requirement to report DMC recommendations related to serious adverse events in an 

expedited manner in clinical trials of new drugs (21 CFR 312.32(c)) would not apply when the 

DMC recommendation is related to an excess of events not classifiable as serious. Nevertheless, 

we recommend that sponsors inform FDA about all recommendations related to the safety of the 

investigational product whether or not the adverse event in question meets the definition of 

"serious." Examples might be recommendations to lower the dose of a study agent because of 

excess toxicity, or to inform current and future trial participants of an emerging safety concern 

that had not been recognized at the start of the trial. 

6. INDEPENDENCE OF THE DMC 

Independence of a DMC depends on the relationships of its members to those sponsoring, 

organizing, conducting, and regulating the trial. Independence is greatest when members have 

no involvement in the design and conduct of the trial except through their role on the DMC, and 

have no financial or other important connections to the sponsor (other than their compensation 

for serving on the DMC) or other trial organizers that could influence (or be perceived to 

influence) their objectivity in evaluating trial data. 

Independence is defined on a continuum. DMCs are rarely, if ever, entirely independent of the 

sponsor, as the sponsor generally selects the members, gives the committee its charge, and pays 

committee members for their expenses and services. Aside from being compensated for their 

duties as DMC members, however, we recommend that these members generally have no 

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ongoing financial relationship with a trial’s commercial sponsor and not be involved in the 

conduct of the trial in any role other than that of a DMC member. 

A critical issue in planning and managing operations of a DMC is resolving the tension that can 

arise between having a maximally independent DMC and having a DMC that is well informed 

about the trial: its objectives, its design, and its conduct. To narrowly defining "independence" 

may result in eliminating from consideration the most knowledgeable researchers, who are likely 

to have had some past interaction with others sponsoring or performing research in their area of 

expertise. Additionally, while sponsor involvement in looking at comparative data threatens 

independence, sponsor representatives, study statisticians, and study investigators may contribute 

valuable perspectives regarding the trial that may not be available to the committee from more 

independent sources. With regard to sponsor/investigator involvement with the DMC, this 

tension is best resolved by permitting interaction with the committee in a carefully defined and 

limited manner, as described in Section 4.3.1.2. The involvement of such individuals with the 

DMC will typically be limited in terms of what interim data may be viewed, which sessions may 

be attended, what topics may be discussed, and what roles (e.g., observer, consultant, member), 

may be played. Some of the considerations in addressing these issues are discussed below. 

6.1. Desirability of an Independent DMC 

Independence of the DMC from the sponsor offers the following advantages: 

• Independence from the sponsor helps ensure that sponsor interests do not unduly 

influence the DMC, promoting objectivity that benefits the subjects and the trial. 

• Through enhancement of objectivity and reduction of the possibilities for bias, 

independence of the DMC increases the credibility of the trial’s conclusions. 

• Independence of the DMC and complete blinding of the sponsor to interim 

outcome data preserve the ability of the sponsor to make certain modifications to 

a trial in response to new external information without introducing bias. 

• In a commercially sponsored trial, independence of the DMC may shield the 

sponsor (and thus the trial) from securities issues by maintaining the sponsor in a 

fully blinded situation. 

6.2. Value of Sponsor Interaction with the DMC 

A sponsor’s decision to establish an independent DMC does not preclude interaction of 

the sponsor with the DMC. Sponsor involvement in an open part of the DMC meeting, 

during which data such as enrollment, compliance, and event rates may be viewed in 

aggregate but not separately by study arm, has significant advantages. The sponsor may 

provide important information to the DMC regarding the sponsor’s goals, plans, and 

resources that the DMC can later integrate into its deliberation. Further, the review of 

interim comparative data may raise certain questions that the DMC might want to address 

to the sponsor. These interactions may improve the quality of the monitoring process and 

may also provide the sponsor with information relevant to the costs, timetable, and likely 

interpretability of the study that can be of significant value in planning future studies 

and/or other aspects of product development. The risk to the study of such sponsor 

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involvement can be quite limited provided that (1) appropriate care is taken to ensure that 

the sponsor does not see outcome data separately by study arm and (2) the sponsor does 

not unduly influence the closed deliberations of the committee. 

On the other hand, involvement by sponsor representatives and certain investigators in 

the portion of the DMC meeting where unblinded data are reviewed presents substantial 

disadvantages, as discussed in Sections 6.1 and 6.3. Even so, such involvement is not 

entirely without rationale. When a DMC is facing difficult decisions based on interim 

safety or efficacy data, the sponsor representatives, study statisticians, and study 

investigators may contribute valuable perspectives that may not be available from more 

independent sources. For example, such individuals might point out that unanticipated 

difficulties in collecting certain data may affect their reliability. In addition, such 

individuals might have detailed knowledge of other relevant information about the drug 

(or disease) gained from the trial in question or from other studies that could enhance the 

DMC’s ability to monitor the current trial. To the extent such perspectives can be 

obtained through a combination of having independent DMC members who are very 

familiar with the drug, the disease, and trial and having sponsor involvement in open 

session only, some risks (see Section 6.3) will be minimized. When a trial’s procedures 

are such that sponsor representatives or investigators do see unblinded data with the 

DMC, the DMC may wish to develop its recommendations in an executive session (see 

Section 4.3.1.2). 

6.3. Risks of Sponsor Exposure to Interim Comparative Data 

Sponsor exposure to unblinded interim data, through the DMC or otherwise, can present 

substantial risk to the integrity of the trial. One concern is that unblinding of the sponsor 

increases the risk of further unblinding, e.g., of participants, potential participants, or 

investigators, thereby potentially compromising objective safety monitoring, equipoise, 

recruitment, administration of the intervention, or other aspects of the trial. In some 

cases, this risk may be limited and manageable. However, even when unblinding is 

limited to a small group or a single individual within the sponsoring organization who 

maintains confidentiality of the results, it is possible that an individual with knowledge of 

interim data may reveal, or be perceived to reveal, information inadvertently, e.g., by 

facial expression or body language. 

An additional problem arising from a sponsor’s access to interim data is the diminution of 

the sponsor’s ability to manage the trial without introducing bias. Many trials, 

particularly those with DMCs, take place over several years. During that time, it is not 

uncommon for scientific advancements, e.g., development of new tests, approval of new 

products, announcement of results of other trials, to significantly affect a given trial. 

Such developments may suggest a need for modifications of the experimental protocol, 

e.g., allowing certain concomitant treatments, changing endpoints. Non-scientific 

developments, such as new financial considerations, production problems, enrollment 

problems, and missing data, may also suggest the need for protocol changes. If the 

sponsor has had access to interim data, it may be impossible to avoid allowing that 

knowledge to influence decisions regarding modifications of the trial; it may also be 

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impossible for outside evaluators to assess the impact of that influence. For example, if 

based on external developments, a sponsor were considering terminating accrual in one 

subgroup or changing an endpoint, knowledge of current results in that subgroup or with 

regard to that endpoint would introduce unavoidable, but unmeasurable bias. Thus, the 

sponsor who knows interim data may well find itself in a position where a protocol 

change that appears to be in the interest of the trial or even essential for continuing the 

trial, cannot be made without potentially introducing biases that can be neither quantified 

nor corrected. This may lead to major difficulties in interpreting the results of statistical 

comparisons. 

In certain situations, exceptions to the strict maintenance of confidentiality of interim 

data will be warranted. For example, as noted earlier, in trials in which severe toxicity or 

other severe morbidity is expected and ongoing continual monitoring is required to 

ensure maximal protection of trial participants, the sponsor may need to be more actively 

involved in monitoring unblinded safety data despite the risks to confidentiality of the 

interim results. 

6.4. Statisticians Conducting the Interim Analyses 

As discussed in Section 2.1, DMCs add administrative complexity to a trial, adding 

complexity to the statistician's analyses of the trial. Traditionally, the primary trial 

statistician performs interim analyses and reports to the DMC. "Primary trial statistician" 

may refer to an individual statistician or statistical group responsible for designing the 

trial and managing its conduct in collaboration with the study chair and others in the trial 

leadership. This arrangement can be appealing because the primary trial statistician will 

be extremely knowledgeable about the study and will be able to provide the most 

informative interaction with the DMC. 

Assigning the primary trial statistician the responsibility for interim analysis and 

reporting to the DMC can be problematic, however. When issues arise that might suggest 

changes to the trial design, a statistician performing both the primary collaborative and 

the interim analysis functions including reporting to the DMC, will probably be the only 

member of the trial management team with knowledge of the interim data. In 

considering possible changes, the statistician’s objectivity will inevitably be 

compromised by the knowledge of the potential impact of such changes on the outcome 

of the trial. When statisticians with knowledge of interim data participate in trial 

management meetings in which potential changes to study size, entry criteria, or 

endpoints are discussed, perceptions of biased decision-making could arise. Even if the 

statisticians remain silent about the interim data, it is essentially impossible for any 

opinion they may express not to be influenced by knowledge of these data. When the 

statistician is present for such discussions and knows which of the alternative courses of 

action is more likely to result in the experimental intervention being shown effective, 

even unintentional non-verbal communication may reveal (or may be perceived to reveal) 

some of that knowledge. Furthermore, if the sponsor must make a decision with major 

financial implications and a statistician in the sponsor’s employ possesses information 

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critical to that decision, both may be placed in a very uncomfortable position in which the 

risk is high of verbal or non-verbal transmission of information regarding interim data. 

For this reason, when there is a DMC and a formal mechanism for interim analyses, it is 

advantageous for the statistician performing the interim analysis to be uninvolved in 

managing the conduct of the trial, especially in regard to making decisions about design 

modifications. This could mean that a statistician other than the primary trial statistician 

would take responsibility for the interim analysis and reporting to the DMC. 

Alternatively, the primary statistician could maintain this role, but forego further 

involvement in trial management once interim analysis was undertaken. Sponsors may 

identify and develop other approaches to reduce potential inappropriate influence of 

interim data on trial management. 

Another important issue relating to the role of the statistician arises when the statisticianis 

employed by the sponsor. Elsewhere in this guidance, we have described the concerns 

associated with sponsors being aware of the interim comparative data. For purposes of 

quality assurance, sponsors often wish to maintain control of the data and have their own 

statisticians perform the analyses, including the unblinded analyses for the DMC. 

Typically and appropriately, such statisticians are instructed not to disclose interim data 

to others within the sponsoring organization. Questions can always arise, however, as to 

whether the statisticians are adequately separated from others within the sponsoring 

organization involved in managing the trial. 

For these reasons, the integrity of the trial may be best protected when the statisticians 

preparing unblinded data for the DMC are external to the sponsor and uninvolved in 

discussions regarding potential changes in trial design while the trial is ongoing. This is 

an especially important consideration for critical studies intended to provide definitive 

evidence of effectiveness. Balanced against this concern, however, is the need for the 

statisticians reporting to the DMC to be very familiar with details of the study and have 

ample opportunity to assess the interim data. The primary trial statistician, whether or 

not employed by the sponsor, is usually best situated to play this role. We recognize that 

an external statistician contracted by the sponsor to perform interim analysis may not be 

entirely free from the types of pressures and concerns that may affect a statistician 

employed by the sponsor. 

There has been substantial experience with the model in which the primary trial 

statistician also analyzes interim data and reports to the DMC. This arrangement has 

worked well, for the most part. In the admittedly infrequent situation in which interim 

protocol changes need to be considered, however, participation of statisticians with 

knowledge of interim data could complicate the interpretability of the data. Sponsors 

may wish to take the above considerations into account in establishing procedures for the 

operation of the DMC and the process of interim monitoring. 

If the statistician reporting unblinded data to the DMC is not the primary trial statistician, 

it is particularly important that efforts be made to ensure both that the unblinded 

statistician is very familiar with the design, setting, and objectives of the trial, and has 

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sufficient time and access to the data to provide insightful analyses responsive to the 

DMC’s needs. 

If the primary trial statistician takes on the responsibility for interim analysis and 

reporting to the DMC, we recommend that this statistician have no further responsibility 

for the management of the trial once interim analysis begins and have minimal contact 

with those who have such involvement. In this case, we recommend that sponsors 

establish and document procedures to ensure this separation, and designate a different 

statistician to advise on the management of the trial. 

If the primary trial statistician takes on the responsibility for interim analysis and 

reporting to the DMC, and it appears infeasible or highly impractical for any other 

statistician to take over responsibilities related to trial management, we recommend that 

sponsors consider, develop and document procedures to minimize the risks of bias that 

are associated with such arrangements, as described above. 

If the statistician responsible for interim analysis and reporting to the DMC is employed 

by the sponsor, special care should be taken to minimize the potential for bias, such as 

ensuring that confidential interim data are not revealed to anyone else within the sponsor 

organization (see 21 CFR 314.126(b)(5) (drugs) and 21 CFR 860.7(f)(1) (devices)). 

While the sponsor or the DMC may suggest to the statistician the nature of the analyses 

and tables they wish reported to the DMC, we recommend the statistician also have the 

familiarity with the study and data access necessary to perform additional analyses that 

might be suggested by the accumulating data and/or requested by the DMC. 

6.5. Sponsor Access to Interim Data for Planning Purposes 

Often, sponsors wish to have access to unblinded interim data for the purpose of planning 

product development, e.g., designing/initiating further trials or making decisions 

regarding production facilities. This interest is understandable, but such access is 

problematic for reasons already discussed. In general, sponsors are advised to avoid 

seeking information about unblinded interim data because of the significant possibility 

that they may wind up impairing trial management or even making the trial results 

uninterpretable by doing so. Further, plans or decisions based on statistically imprecise 

interim data may often be suboptimal. Where the sponsor nonetheless has a compelling 

need to review such information, certain approaches may lessen, although they do not 

eliminate, risks to the trial: 

• Discussion of such an action with FDA in advance. This is particularly advisable 

when the sponsor intends to use the study in support of a licensing or marketing 

application. 

• Development of appropriate stopping rules and apportionment of type I error (α) 

before performing any unblinded interim analysis. This is important because any 

viewing of study arm-specific effectiveness data by the DMC and/or sponsor in a 

study of a serious illness raises the possibility that an unanticipated extreme 

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finding of effectiveness might create an ethical imperative to stop the trial, and it 

would not be possible to quantitate the level of evidence provided by the data if 

the monitoring plan had not been established prior to data review. 

• Determination of the minimum amount of information needed. For example, to 

assist in defining eligibility criteria for a subsequent trial, the sponsor may wish to 

know only whether estimates of treatment effect in a subgroup are less or greater 

than in the overall data set. 

• Formulation of written questions, preferably with yes/no rather than numerical 

answers, that will elicit only that minimal required information and nothing more. 

• Receiving only written information regarding the requested data (thereby 

documenting what was received and avoiding additional unnecessary 

communications) and abstaining from participation in closed DMC meetings or 

discussions of data with unblinded DMC members (except as otherwise requested 

by the DMC). 

• Identification of those sponsor employees with a critical "need-to-know" and 

restriction of such information to those individuals only. 

• Ensuring that individuals with access to the information avoid any subsequent 

role in the management of the trial and minimize interactions with others in that 

role. 

• Ensuring that individuals who have access to such information make every effort 

to avoid taking actions that will assist others in inferring what the information is. 

• Ensuring that reports of study findings describe any access to interim data by 

individuals involved with study management, and steps taken to prevent such 

access from potentially biasing the study results. 

7. SPONSOR INTERACTION WITH FDA REGARDING USE AND OPERATION 

OF DMCs 

There are many situations, several mentioned earlier, in which sponsor consultation with FDA on 

matters regarding a DMC is advisable. 

7.1. Planning the DMC 

In planning a clinical trial, a sponsor makes several decisions regarding use, types of 

membership, and operations of a DMC. Many of these can be critical to the success of 

the trial in meeting regulatory requirements. This guidance document is intended to 

provide general FDA guidance regarding those decisions, but each set of circumstances 

can raise unique considerations. Issues regarding use of DMCs are appropriate topics for 

FDA-sponsor meetings (in person or by telephone) at the sponsor’s request. 

7.2. Accessing Interim Data 

As discussed above, accessing interim data by the sponsor carries many risks, not all of 

which may be fully appreciated by the sponsor. We recommend that sponsors contact 

FDA before initiating communication with the DMC regarding access to interim data 

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from a trial likely to be an important part of a regulatory submission. While FDA 

permission is not required, a discussion regarding the potential risks and implications of 

that action and of methods to limit the risks may contribute to informed decision making. 

7.2.1. DMC Recommendations to Terminate the Study 

In almost all cases, a DMC is advisory to the sponsor; the sponsor decides 

whether to accept recommendations to discontinue a trial. FDA will rarely, if 

ever, tell a sponsor which decision to make. For trials that may be terminated 

early because a substantial benefit has been observed, however, consideration 

may still need to be given to the adequacy of data with regard to other issues such 

as safety, duration of benefit, outcomes in important subgroups and important 

secondary endpoints. We recommend that sponsors of trials that could 

potentially be terminated early for efficacy reasons discuss these issues with FDA 

prior to implementing the trial, when the statistical monitoring plan and early 

stopping boundaries are being developed. In these settings, consultation with 

FDA may provide the sponsor with important information regarding the 

regulatory and scientific implications of a decision and may lead to better 

decisions. Sponsors are encouraged to revisit these issues with FDA when 

considering DMC recommendations for early termination if new issues have 

arisen and/or if the regulatory implications of early termination were not 

adequately clarified at the outset of the trial. 

For trials that may be terminated because of safety concerns, timely 

communication with FDA is often required (see, e.g., 21 CFR 312.56(d) (drugs); 

21 CFR 812.150 (devices)). In such cases, we recommend that the sponsor 

initiate discussion as soon as possible about the appropriate course of action, for 

the trial in question as well as any other use of the investigational product. 

We strongly recommend that sponsors initiate discussion with FDA prior to early 

termination of any trial implemented specifically to investigate a potential safety 

concern. 

7.2.2. FDA Interaction with DMCs 

In rare cases, we may wish to interact with a DMC of an ongoing trial to ensure 

that specific issues of urgent concern to FDA are fully considered by the DMC or 

to address questions to the DMC regarding the consistency of the safety data in 

the ongoing trial to that in the earlier trials, to optimize regulatory decisionmaking. An example might be a situation in which FDA is considering a 

marketing application in which a safety issue is of some concern, and the sponsor 

has a second trial of the investigational agent ongoing. In such a situation, we 

might wish to be sure that the DMC for the ongoing trial is aware of the existing 

safety data contained in the application and is taking those data into consideration 

in evaluating the interim safety data from the ongoing trial. In such a case, we 

could request that the sponsor arrange for FDA to communicate with, or even 

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Draft – Not for Implementation 

meet with, the DMC (see 21 CFR 312.41(a); 21 CFR 812.150(b)(10)), and care 

should be taken to minimize the possibility of jeopardizing the integrity of the 

ongoing trial. 

7.3. DMC Recommendations for Protocol Changes 

A DMC may, in some instances, recommend changes to the study protocol, particularly 

in the context of their responsibilities for monitoring patient safety. Many protocol 

changes have little impact on the usefulness of a trial to gain regulatory approval. Certain 

types of changes to the protocol, however, such as changes in the primary endpoints, 

could have substantial impact on the validity of the trial and/or its ability to support the 

desired regulatory decision if they potentially could have been motivated by the interim 

data. We recommend that sponsors discuss proposed changes of the latter type with FDA 

before implementation. 

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