Guidance for Clinical 

Trial Sponsors

On the Establishment and Operation 

of Clinical Trial Data Monitoring 

Committees

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be submitted by the date 

provided in the Federal Register notice announcing the availability of the draft guidance. 

Submit comments to Docket Management Branch (HFA-305), Food and Drug Administration, 

5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with 

the docket number listed in the notice of availability that published in the Federal Register.

For questions on the content of this draft document contact Mary Foulkes (CBER), 301-827-

3034, Robert Temple (CDER), 301-594-6758, or Joanne Less (CDRH), 301-594-1190.

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)

November 2001
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Guidance for Clinical 

Trial Sponsors

 On the Establishment and Operation 

of Clinical Trial Data Monitoring 

Committees

Copies of this Draft Guidance are available from: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

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

Fax: 1-888-CBERFAX or 301-827-3844

Voice information System: 800-835-4709 or 301-827-1800

or

Office of Training and Communications

Division of Communications Management

Drug Information Branch, HFD-210

Center for Drug Evaluation and Research

Food and Drug Administration

5600 Fishers Lane, Rock ville, MD 20857

(Phone 301-827-4573)

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

or

The Division of Small Manufacturers Assistance (DSMA), HFZ-220

Center for Devices and Radiological Health

Food and Drug Administration

1350 Piccard Drive, Rockville, MD 20850

800-638-2041 or 301-443-6597

Internet: DSMA@CDRH.FDA.GOV

Fax: 1-301-443-8818

Facts-On-Demand (FAX) at 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 ....................................................................................................... 2

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

2.1. Risk to Trial Participants..................................................................................... 3

2.2. Practicality of DMC Review................................................................................. 3

2.3. Assurance of Scientific Validity........................................................................... 4

3. DMCS AND OTHER OVERSIGHT GROUPS ............................................................. 4

3.1. IRBs........................................................................................................................ 4

3.2. Clinical Trial Steering Committees..................................................................... 4

3.3. Endpoint Assessment/Adjudication Committees............................................... 5

3.4. Site/Clinical monitoring........................................................................................ 5

3.5. Others with Monitoring Responsibilities............................................................ 5

4. DMC ESTABLISHMENT AND OPERATION ............................................................ 5

4.1. Committee Composition....................................................................................... 5

4.2. Confidentiality of Interim Data and Analyses.................................................... 7

4.2.1. Interim Data ................................................................................................ 7

4.2.2. Interim Reports to the DMC ....................................................................... 7

4.3. Establishing Standard Operating Procedures.................................................... 8

4.3.1. Considerations for Standard Operating Procedures.................................... 8

4.3.1.1 Meeting Schedule and Format ........................................................ 8

4.3.1.2 Meeting Structure............................................................................ 8

4.3.1.3 Initial Meeting................................................................................. 9

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

Codes............................................................................................... 9

4.3.2. Statistical Methods.................................................................................... 10

4.4. Potential DMC Responsibilities......................................................................... 11

4.4.1. Interim Monitoring.................................................................................... 11

4.4.1.1 Monitoring for Effectiveness......................................................... 11

4.4.1.2 Monitoring for Safety.................................................................... 12

4.4.1.3 Monitoring Study Conduct............................................................ 13

4.4.1.4 Consideration of External Data.................................................... 14

4.4.1.5 Studies of Less Serious Outcomes................................................. 15

4.4.2. Early Studies............................................................................................. 16

4.4.3. Other Responsibilities............................................................................... 16

4.4.3.1 Making Recommendations............................................................ 16

4.4.3.2 Maintaining Meeting Records....................................................... 17

5. DMCS AND REGULATORY REPORTING REQUIREMENTS ............................ 17

5.1. Safety Reporting.................................................................................................. 17

5.2. Expedited Development ...................................................................................... 18

6. INDEPENDENCE OF THE DMC................................................................................ 18

6.1. Desirability of an Independent DMC................................................................ 19
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6.2. Value of Sponsor Interaction with the DMC.................................................... 19

6.3. Risks of Sponsor Exposure to Interim Comparative Data.............................. 20

6.4. Conduct of the Interim Analyses....................................................................... 20

6.5. Sponsor Access to Interim Data for Planning Purposes.................................. 21

6.6. Use of Interim Data in Regulatory Submissions.............................................. 22

7. SPONSOR INTERACTION WITH FDA REGARDING USE AND OPERATION 

OF DMCS ........................................................................................................................ 22

7.1. Planning the DMC.............................................................................................. 22

7.2. Accessing Interim Data....................................................................................... 22

7.2.1. DMC Recommendations to Terminate the Study..................................... 23

7.3. DMC Recommendations for Protocol Changes............................................... 23
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GUIDANCE FOR CLINICAL TRIAL SPONSORS

 On the Establishment and Operation of Clinical Trial Data 

Monitoring Committees

This guidance document represents the Agency’s current thinking on this topic. It does not 

create or confer any rights, privileges, or benefits on or for any person and does not operate to 

bind FDA or the public. An alternative approach may be used if such approach satisfies the 

requirements of the applicable statutes and regulations.

1. INTRODUCTION AND BACKGROUND

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

Committees (DMCs) that carry out important aspects of clinical trial monitoring. The document 

is intended to assist sponsors of clinical trials in determining when a DMC is needed for optimal 

study monitoring, and how such committees should operate. We recognize that in many clinical 

trials the sponsor delegates much 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 CFR 312.3(b)). In this document, references to the sponsor with 

regard to trial management and decision-making should be understood to refer also to any 

individual or group to which the sponsor has delegated the relevant management responsibilities.

Sponsors are required to monitor studies evaluating new drugs, biologics, and devices (see 21 

CFR 312.50 and 312.56 for drugs and biologics, as well as 21 CFR 600.80, and 21 CFR 812.40 

and 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. 

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

accumulating data from an ongoing clinical trial. The DMC advises the sponsor regarding the 

continuing safety of current participants and those yet to be recruited, as well as the continuing 

validity and scientific merit of the trial.

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

shown that some of these 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. 

The intent of the document is not to dictate the use of any particular approach but rather to 

ensure wide awareness of potential concerns that may arise in specific situations.
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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 and the Veterans Administration 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. The 

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

interim monitoring of study data was essential to ensure the 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. 

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 due to 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 demand for approaches to protect 

against such problems. 

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, advantages and 

disadvantages can be described for some of the different approaches that have been taken. 

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

Institutes of Health and the Veterans Administration, have required the use of DMCs in 

certain trials. Current FDA regulations impose no requirements for the use of DMCs in trials 

except for research studies in emergency settings conducted under 21 CFR 50.24(a)(7)(iv), in 

which the informed consent requirement may be waived. FDA believes that the issues 

discussed in this document arise in both industry- and government-sponsored trials, and 

therefore has not differentiated between them. We recognize that the potential conflicts of 

interest faced by government sponsors are somewhat 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 
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some extent. Nevertheless, we believe that the discussion of advantages and disadvantages 

of various approaches to DMC operation is relevant to all trials, regardless of the sector of 

the sponsor. 

2. DETERMINING NEED FOR A DMC

All clinical trials require safety monitoring (21 CFR 312.32(c)), but not all trials require 

monitoring by a formal committee external to the trial organizers and investigators. As noted 

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

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

such as a cardiovascular event or recurrence of cancer. Because monitoring of accumulating 

results is almost always essential in such trials, DMCs should be established for controlled trials 

with mortality or major morbidity as a primary or secondary endpoint. They may also be helpful 

in settings where trial participants may be at elevated risk of such outcomes even if the study 

intervention addresses lesser outcomes such as relief of symptoms. Although DMCs may prove 

valuable in other settings as well, a DMC is not needed or advised for every clinical study. 

Several factors are relevant to determining whether or not to establish a DMC for a particular 

trial. These relate primarily to safety, practicality, and scientific validity.

2.1. Risk to Trial Participants

A fundamental consideration is the safety of those who would be at potential risk due to their 

participation in the trial. Is the study endpoint one for which a favorable or unfavorable early 

result might ethically require termination of the study before its planned completion? Is there 

reason for a particular safety concern (for example, if the method of administering the test 

treatment involves unusually high risk)? Is the treatment to be tested novel, so that there is 

little prior information on clinical safety, or is there specific prior information that raises 

concerns about the potential for serious toxicity? Safety concerns are usually heightened in 

studies performed in potentially fragile populations such as children or the very elderly, or in 

any group at relatively high risk of death or morbid events in whom a medical intervention 

might increase such risk or cause unanticipated adverse events. The oversight of a DMC in 

addition to typical sponsor-conducted safety monitoring can provide further protection of 

study participants. A trial that is large, of long duration, and multi-center raises more 

possibilities of safety concerns because of the greater overall exposure and because 

prolonged exposure may cause adverse effects not readily recognized as such. DMCs may 

be more important in these trials. 

2.2. Practicality of DMC Review

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

quickly, a DMC might not have an adequate opportunity to contribute. In short-term trials 

with important safety concerns that may warrant a DMC, sponsors need mechanisms to 

permit the DMC to be informed and convened quickly in the event of unexpected results that 

raise concerns.
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2.3. Assurance of Scientific Validity

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

can help assure the scientific validity 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, the trial organizers are free to make changes in the 

ongoing trial that may be motivated by newly available data outside the trial or by 

accumulating data from within the trial (e.g., overall event rates). In general, 

recommendations to change the inclusion criteria, the trial endpoints, or the size of the trial 

are most credibly made by those without knowledge of the accumulating data. 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 these changes should be 

made. Such changes would inevitably impair the credibility of the study results. We will 

address this problem 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.

3.1. IRBs 

An Institutional Review Board (IRB) is responsible for evaluating a trial to determine, among 

other things, whether "risks to subjects are minimized" and "risks to subjects are reasonable 

in relation to anticipated benefits" (21 CFR 56.111(a)(1) and (3)). An IRB’s evaluation 

entails review of the trial protocol, relevant background information, the informed consent 

document, proposed plans for informing participants about the trial, and any other procedures 

associated with the trial. For ongoing trials, the IRB is responsible for considering available 

information arising from the trial that may bear on the continued acceptability of the trial at 

that site. Unlike a DMC, an IRB generally does not review unblinded summaries of interim 

safety and effectiveness data, but the IRB may take action based on recommendations from a 

DMC to the trial sponsor.

3.2. Clinical Trial Steering Committees

A Steering Committee, when it exists, has primary responsibility for designing the study, 

maintaining the quality of study conduct, and writing the final study report. It is appointed 

by the sponsor and is comprised of investigators, possibly other experts not otherwise 

involved in the trial, and, usually, representatives of the sponsor. When there is a Steering 

Committee, the sponsor may elect to have the DMC communicate with this committee rather 

than directly to the sponsor.
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3.3. Endpoint Assessment/Adjudication Committees

Endpoint Assessment/Adjudication Committees review important endpoints reported by trial 

investigators to determine whether they 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. The 

committee should be masked to assigned study arm when performing its assessments, 

whether or not 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 clearly 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 

Staff internal to the sponsor or a group under contract to the sponsor generally perform 

site/clinical monitoring. 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 the groups defined above, other trial components 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 tracking these investigator reports and relaying them as required to FDA, 

IRBs (medical devices only), and other investigators (21 CFR 312.32(c)). FDA, in turn, is 

responsible for ongoing consideration of adverse experience reports from all trials of a given 

product.

4. DMC ESTABLISHMENT AND OPERATION

4.1. Committee Composition 

The selection of DMC members is extremely important as the DMC is assigned critical 

responsibilities. A DMC that fails to note problems that should be addressed, or that makes 

recommendations that are unwarranted or whose consequences are inadequately considered, 

can undermine the safety of participants as well as the value of the trial. Thus, the ability of 

DMCs to provide the anticipated additional assurance of patient safety and trial integrity 

depends on appropriate selection of DMC members. 

The trial sponsor and/or trial Steering Committee generally appoints a DMC. Factors to 

consider in the selection of individuals to serve on a DMC should include relevant expertise, 
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experience in clinical trials and in serving on other DMCs, and a lack 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. Some DMCs may include a medical ethicist knowledgeable 

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

helpful, but not essential, although it is desirable that at least some members have prior DMC 

service. Some trials may require participation of other types of scientists; for example, a 

study in which the investigational drug has variable absorption or excretion might include a 

clinical pharmacologist on the DMC; toxicologists, epidemiologists, and laboratory scientists 

could be included in particular cases. 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. That individual should not be participating in the trial, but could 

be someone with the disease under study or a close relative of such an individual, for 

example. DMCs for international trials should have representation from participating 

countries or regions to the extent practical. Appropriate representation of gender and ethnic 

groups may be of particular importance for some trials. All appointees should be prepared to 

maintain 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 it is sensible 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. Potential DMC members should be free of financial interests that could be 

substantially affected by the outcome of the trial. Investigators entering subjects into the trial 

should not be members of the DMC for that trial to avoid any possible influence of 

knowledge of interim results on 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. Also, 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. Ideally, DMC members 

should not have relationships with those in trial leadership positions that could be considered 

reasonably likely to affect their objectivity. Sponsors should have their own established 

procedures in place to assess potential conflicts of interest of proposed DMC members, to 

ensure that those with serious conflicts of interest are not included on the DMC, and to 

provide disclosure to all DMC members of any minor conflicts that are not thought to impede 

objectivity. 
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The study sponsor usually appoints the DMC chair. 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. (If the DMC includes only one 

statistician, however, it is desirable for the statistician to have had prior DMC experience as 

well.) The chair should be capable of facilitating discussion, integrating differing points of 

view and moving toward consensus on recommendations to be provided to the trial sponsors. 

It is particularly important for the chair to make a firm commitment to participate for the 

duration of the trial. 

4.2. Confidentiality of Interim Data and Analyses

Knowledge of unblinded interim comparisons from a clinical trial is not necessary for those 

conducting or those sponsoring the trial; further, such knowledge can bias the outcome of the 

study by inappropriately influencing its continuing conduct or the plan of analyses. 

Therefore, interim data and the results of interim analyses should generally not be accessible 

by anyone other than DMC members. Sponsors should establish procedures to ensure the 

confidentiality of the interim data (see Section 4.3.1.4.).

4.2.1. Interim Data

The interim unblinded data will be most securely protected from inadvertent or 

inappropriate access by the sponsor if it is prepared for analysis by an entity independent 

of the sponsor and investigators (see Section 6.4). The lead investigators, the study 

Steering Committee, or the sponsor generally develops the analytical plan, but these 

individuals should generally not be involved in the actual preparation of the interim 

results, for reasons discussed in Section 6.4. They should, 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.

4.2.2. Interim Reports to the DMC

Any part of the interim report to the DMC that includes comparative effectiveness and 

safety data presented by study group, whether coded or uncoded, should generally be 

available only to DMC members during the course of the trial, including any follow-up 

period—that is, until the blind is broken. If such 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). 

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 DMC may 

share the open section of these reports with sponsors, who may convey any relevant 

information in these reports to investigators, IRBs, and 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.
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4.3. Establishing Standard Operating Procedures

All DMCs should have well-defined standard operating procedures (SOPs). The sponsor 

may draft these SOPs and present them to the DMC for agreement, or the DMC may draft the 

SOPs 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, and the method and 

timing of providing interim reports to the DMC. The sponsor should submit a description of 

the SOPs to FDA well in advance of the performance of any interim analyses, optimally 

before the initiation of the trial.

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; many (perhaps most) trials will require more 

frequent review. The study protocol should describe the schedule of interim 

analyses to be considered by the DMC, or the considerations that will determine 

the timing of meetings. The study protocol should also clearly describe the 

statistical approach to the sequential analysis of trial data, which may be 

addressed in greater detail in an analytical plan. These descriptions should be 

complete before the conduct of any interim analyses. 

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 analytical issues, 

telephone meetings may be sufficient.

4.3.1.2 Meeting Structure

Attendance at meetings raises the same confidentiality issues as access to interim 

reports to the DMC. Although confidentiality of the interim data should be 

maintained, the DMC may interact with the study 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 nonconfidential data may include, for example, status of recruitment, baseline 

characteristics, ineligibility rate, accuracy and timeliness of data submissions, and 

aggregated safety and outcome data. Open session discussions might include 

representatives of the study sponsor, Steering Committee, study investigators, and 

FDA. There is a benefit to having a wider attendance at these sessions, since they 
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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 then 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 Committee. Following the 

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

recommendations the Committee 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 sponsors choose to permit its representatives or other non-DMC 

members to attend the closed session despite the risks of such arrangements, the 

DMC should have the option of conducting an “executive” closed session with no 

participants other than DMC members.

4.3.1.3 Initial Meeting

The initial meeting of a DMC should occur before the start of the study if at all 

possible. At this meeting, the DMC should discuss the protocol and analytic plan, 

model informed consent form, data collection instruments and other important 

trial documents, and present any suggestions for modifications to the sponsor 

and/or Steering Committee. Meeting participants should 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 approach to early termination when multiple primary 

endpoints or important secondary endpoints, or composite endpoints with multiple 

components (for example, death and relapse) are to be evaluated. 

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

The sponsor should ensure that the general format and content of reports to the 

DMC are acceptable to the DMC. At its first meeting, as noted above, the 

sponsor should propose a template for these reports, so that changes requested by 

the DMC may be implemented before the time when interim data will actually be 

presented. The statistician preparing the reports to the DMC should ideally be 

independent of the sponsor and clinical investigators (and a Steering Committee if 

there is one) to avoid inadvertent influence of data trends on the conduct of the 

trial (see Section 6.3 and Section 6.4).
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A DMC should generally 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. To maintain 

blinding of the actual study arm 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 balancing risks and 

benefits of the active interventions, its most critical responsibility. Also, 

decisions about a trial are often asymmetric with respect to study arm. 

Additionally, 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. 

The statistical group responsible for preparing the reports to the DMC should 

present results in printed copy using codes (for example, Group A and Group B) 

to protect against inadvertent unblinding should a report be misplaced, and 

provide separate access to the actual study arm assignments for DMC members. 

A process should be in place to ensure rapid unblinding of treatment codes to 

DMC members when needed. 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

The International Conference on Harmonization guidance document, “Statistical 

Principles in Clinical Trials” (ICH E9), addresses the statistical monitoring of trials, 

describes available statistical approaches, and presents the principles involved in their 

implementation. 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 and may be used as well. Statistical methods are 

also available to support 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. The sponsor and/or trial Steering Committee usually proposes the particular 

statistical approach, but the DMC should generally review it before being made final, to 

ensure that the DMC agrees to be guided in its actions by the planned approach. Once a 

final plan has been put in place, the sponsor should submit it to FDA before the initiation 

of interim monitoring. 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. 

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 
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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, procedures should specify a 

statistical approach in advance of the trial’s initiation 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 being exceeded, but 

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

interim review. The sponsor should expect the DMC to exercise its own judgment in 

such circumstances. If the DMC recommends early termination for efficacy before a 

boundary is crossed, 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 should be 

considered on the basis of futility—that is, when the probability, given the interim results, 

that the trial will ultimately be able to demonstrate the effectiveness of the investigational 

product is very low. 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. 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 is 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. In all studies, it is essential that the DMC carefully monitor the 

interim data throughout the duration of the study, regardless of the duration of treatment.

4.4.1.1 Monitoring for Effectiveness

In studies with serious outcomes, all 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 placebocontrolled trial of a new product for a serious illness or condition for which there 
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is no standard treatment. If the emerging data suggest that those receiving the 

treatment are doing better, one might 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 of observing a nominally 

statistically significant benefit (e.g., p<0.05) at some point during a study of an 

ineffective product is substantial (see Section 4.4.2). A DMC, guided by a prespecified statistical monitoring plan, will 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 those 

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 the re 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 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 aspect of safety monitoring in these trials is the interim review of 

adverse events observed in each study arm. In some cases, one can predict 

adverse events of concern in advance of the study, but the sponsor should provide 

the DMC with summaries of the adverse events observed. This is particularly 

important when the event may result from the disease being treated as well as the 

intervention itself. For example, individuals with diabetes are at elevated risk of 

myocardial infarction. Thus, a specific case of myocardial infarction in a 

participant in a trial of a new antidiabetic therapy cannot be readily attributed to 
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the new therapy. A DMC, however, will 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, the interpretation of safety findings by the DMC must be sensitive to 

the issues of multiplicity.

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. 

The DMC might recommend an alteration of the product dosage and/or schedule 

if the adverse events observed appear likely to be reduced by such changes. It 

might recommend that screening procedures be instituted that could identify those 

at increasing risk of adverse events. The DMC could also recommend that current 

and future study participants be informed of newly identified risks via changes in 

the consent form and that, in some cases, re-consent of current participants to 

continued study participation be obtained. 

Although a DMC should always review summary adverse event data, 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 reviews 

such events promptly, usually blinded to study arm assignment, and has the 

responsibility of reporting serious, unexpected adverse events in drugs and 

biologics trials to FDA under 21 CFR 312.32 and unanticipated adverse events in 

the case of device trials under 21 CFR 812.150(b)(1). 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. In other studies, where many such 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. The DMC should always be prepared 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. The 

DMC should learn 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. 

4.4.1.3 Monitoring Study Conduct

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
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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.

Assessment of conduct-related data is a responsibility shared with the sponsor, the 

study leadership (such as a Steering Committee), and to some extent with IRBs. 

The DMC may issue recommendations 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 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, the study 

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, use of concomitant 

treatments, etc. 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 raises some issues that merit further discussion.

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

decision regarding changes to an ongoing trial. 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 cases, however, significant involvement of the DMC in considerations of 

changes based on external data could have undesirable consequences. Many trial 
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modifications (e.g., changing endpoints, changing or adding to prespecified 

analysis subgroups) could have a different impact on type 1 error and 

interpretation of final results depending on whether the modifications were based 

solely on external data or based in part on knowledge of the interim efficacy data. 

In general, the trial leadership, rather than the DMC, should be addressing 

potential changes other than those driven by safety considerations.

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 regularly 

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

modification is certainly less compelling in this situation. For such products, 

however, 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 many cases; nevertheless, external advisors, who will be less 

committed to the existing development plan, may identify problems more readily 

than internal reviewers.
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4.4.2. Early Studies

DMCs may be useful for certain types of early clinical studies such as Phase 1 or early 

Phase 2 studies in special circumstances. An external group overseeing safety may be 

valuable 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 should therefore seriously 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 not randomized or controlled, accumulating results are 

known to the investigators and sponsor, and information about previous and ongoing 

trials of the product play a greater role in the monitoring of an individual trial. 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 ethical considerations must be evaluated in the context of the potential scientific 

gain from continuing a study, 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 that such situations will be infrequent.

4.4.3. Other Responsibilities

4.4.3.1 Making Recommendations

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

sponsor 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. 

The DMC should express its recommendations very clearly to the sponsor. Both 

a written recommendation and oral communication, with opportunity for 

questions and discussion, are valuable. Recommendations for modifications other 

than termination should be 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. 

The DMC should document its recommendations and their rationale in a form that 

can be reviewed by the sponsor, IRBs, regula tory agency, or other interested 

parties as appropriate (see section 5). 
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4.4.3.2 Maintaining Meeting Records

As noted in the ICH E6 (Good Clinical Practices) document, the DMC should 

keep minutes of all meetings. After each meeting, the DMC should 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. The DMC should divide meeting 

minutes into two parts, according to whether or not they include discussion of 

confidential data (usually unblinded comparative data). Reports to the sponsor 

should include only those data generally available to the sponsor (e.g., number 

screened, number enrolled at each site). The report should include a summary of 

the discussion in any open session of the meeting and should document any 

information provided verbally 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, any changes in the 

protocol or study procedures made as a result of DMC recommendations must go 

to study investigators and participating IRBs, as well as to FDA (see 21 CFR 

56.108(a)(3) and (4) and 312.30 for drugs and biologics, and 812.40 for devices). 

The second part of the minutes should summarize discussion of the comparative 

unblinded outcome data and provide the rationale for the recommendations made 

to the sponsor. Generally, the DMC will not circulate this portion of the minutes 

outside the DMC membership until the trial is terminated. 

The DMC or the group preparing the confidential interim reports to the DMC 

should maintain all meeting records. The sponsor should submit to FDA all 

meeting records, including the non-confidential and confidential interim reports to 

the DMC, with the clinical study report (see 21 CFR 314.50(d)(5)(ii)). The 

sponsor should arrange for archival of electronic data sets used for each set of 

interim analyses; these data sets should be available on request from FDA after 

the study is completed.

5. DMCs AND REGULATORY REPORTING REQUIREMENTS

5.1. Safety Reporting

All clinical trials conducted under an IND or IDE are subject to regulatory safety reporting 

requirements. These requirements include prompt reporting to FDA of 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 events that are individually recognizable as a serious unexpected event (e.g., 

agranulocytosis, hepatotoxicity), the sponsor (sometimes through a CRO running the trial) 

will retain responsibility for notifying FDA (see 21 CFR 312.52). The sponsor may make the 

report with or without unblinding the case, as appropriate.
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A causal relationship between some serious adverse events and an investigational 

intervention might, however, be detectable only by comparison of rates in the two arms of a 

controlled trial, i.e., would not be recognizable as an intervention-related event except by 

greater frequency (see Section 4.4.1.2). Such findings conveyed to a sponsor by a DMC as 

part of a recommendation to modify the trial would invariably be considered serious and 

unexpected, and the sponsor would be required to report them to FDA and to all study 

investigators according to 21 CFR 312.32 (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) (device trials), 

although direct reporting from sponsors to responsible IRBs may be arranged and may be 

preferable in some situations, e.g., when a central IRB has been established. For a device 

trial, however, the sponsor is clearly responsible for notifying all participating IRBs of 

unanticipated adverse events (21 CFR 812.150(b)(1)). 

Sponsors should notify FDA and the responsible IRBs of any recommendations or requests 

made by a DMC to the sponsor that address safety of participants—for example, 

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. Such recommendations would always be presumptively 

based on findings that would meet the definition of a serious and unexpected adverse event. 

When mutually agreed to by the sponsor and the DMC, a DMC may be delegated 

responsibility for reporting directly to FDA, although in most cases the sponsor will make 

such reports.

5.2. Expedited Development

New therapies intended to treat persons with life-threatening and severely debilitating 

diseases are in some cases developed with particular attention to expediting their evaluation 

and marketing. For such products, FDA may be more actively involved in reviewing and 

facilitating the progress of clinical trials and may need on occasion to interact with a DMC of 

an ongoing trial. In this setting, the sponsor should consider the possibility of such 

interactions prior to the initiation of the trial, and establish procedures under which such 

interactions would take place. The sponsor should construct such procedures to maintain the 

integrity of the trial while providing flexibility for sharing of interim data in the unusual 

circumstances when such data are considered essential for regulatory decision-making.

6. INDEPENDENCE OF THE DMC

An independent DMC is a committee whose members are considered to be independent of those 

sponsoring, organizing, and conducting the trial. That is, they have had no previous involvement 

in the design of the trial, are not involved in its conduct except through the ir role on the DMC, 

and have no financial or other important connections to the study sponsor or other trial 

organizers. 

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 
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services. Furthermore, the DMC generally conveys its recommendations to the sponsor or to a 

Steering Committee in which the sponsor is nearly always represented and the DMC is usually 

not empowered to stop or change a trial on its own. 

Sponsors have taken various roles with respect to the DMC, with varying levels of access to 

interim data. It is important to consider the potential implications of various arrangements in this 

regard.

Arrangements have included:

• Sponsor representative as voting member

• Sponsor representative as non-voting member

• Sponsor representative only in open meeting; may see enrollment, compliance and 

event rates but no study arm specific data.

• No sponsor representation

The committee is considered independent only in the latter 2 cases.

6.1. Desirability of an Independent DMC

Independence of the DMC from the sponsor offers several advantages.

1. The principal responsibilities of the DMC are first, to ensure protection of study 

participants and second, to protect the scientific validity of the trial. Independence 

from the sponsor helps ensure that the DMC is not unduly influenced by sponsor 

interests. In this manner, independence promotes objectivity that benefits not only 

the participants and the trial but the sponsor as well, in that the credibility of the 

trial’s conclusions is enhanced. 

2. 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.

3. Independence of the DMC, by maintaining the sponsor in a fully blinded situation, 

protects the sponsor (and thus the trial) from pressures toward premature disclosure of 

results due to SEC requirements, fiduciary responsibility, or other business 

considerations.

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 committee. Sponsor involvement in an open part of the DMC meeting, at 

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 committee regarding the sponsor’s goals, plans, and resources that the 

committee can later integrate into its deliberation. These interactions may 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 
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product development. The risk to the study of such sponsor 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.

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 potentia lly 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 do maintain 

confidentiality of the results, it should be appreciated that an individual with knowledge of 

interim data may reveal, or be perceived to reveal, information even 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 developments, 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 impossible for outside evaluators to assess 

the impact of that influence. For example, if a sponsor is considering, based on external 

developments, 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 that 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. 

6.4. Conduct of the Interim Analyses

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. FDA has been aware of several cases in which statisticians with knowledge of 

interim data have been at meetings in which potential changes to study size, entry criteria, or 
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endpoints are discussed. Even if the statistician remains quiet about the interim data, it is 

essentially impossible for any opinion he or she may express not to be influenced by 

knowledge of these data. When the statistician is present for such discussions and knows 

which course of action is more likely to result in the experimental intervention being shown 

effective, even unintentional non-verbal communication (e.g., nervousness, smiling) may 

reveal some of that knowledge. Furthermore, if an executive officer of the sponsor must 

make a decision with major financial implications and knows a statistician in the sponsor’s 

employ possesses information 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 all these reasons, the integrity of the trial is best 

protected when the statistician preparing unblinded data for the DMC is external to the 

sponsor, especially for critical studies intended to provide definitive evidence of 

effectiveness. In any case, the statistician should have no responsibility for the management 

of the trial and should have minimal contact with those who have such involvement.

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 should avoid seeking information about 

unblinded interim data and should consider the significant possibility that they may wind up 

impairing trial management or even making the trial results uninterpretable by doing so. 

Where the sponsor nonetheless has a compelling need to review such information, the 

sponsor should follow certain approaches that may lessen, though by no means eliminate, 

risks to the trial:

• The sponsor should consider discussing 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. 

• 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 finding of 

effectiveness might create an ethical imperative to stop the trial. Such a possibility 

should be considered before performing any unblinded interim analysis. The sponsor 

should develop appropriate stopping rules and apportionment of type I error (α) before 

examining the data.

• The sponsor should determine the minimum amount of information needed. For 

example, rather than viewing all outcome data or all primary endpoint data, the sponsor 

may just need to know whether the conditional probability of success on the primary 

endpoint is more or less than a specified magnitude. 

• The sponsor should formulate written questions, preferably with yes/no rather than 

numerical answers, that will elicit only that minimal required information and nothing 

more.

• The sponsor should receive only written information regarding the requested data 

(thereby documenting what was received and avoiding additional unnecessary 
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communications) and should not participate in closed DMC meetings or discussions of 

data with unblinded DMC members (except as otherwise requested by the DMC).

• The SOP should identify individuals with a critical “need-to-know” and SOPs should 

ensure that no one else has access to such information. 

• Individuals with access to the information should avoid any further role in the 

management of the trial and should minimize interactions with others in that role. 

• Where possible, individuals who have access to such information should avoid taking 

actions that will assist others in inferring what the information is.

6.6. Use of Interim Data in Regulatory Submissions

A special circumstance is the case in which the sponsor wishes to use interim data in support 

of a regulatory submission, with the intent to continue the trial to its conclusion. Because of 

the risks to the trial’s credibility, analysis and use of interim data for this purpose is often ill 

advised. Exceptional circumstances may arise, however, in which such use could be 

appropriate. Before accessing and using interim data for this purpose, sponsors should 

confer with FDA and the DMC (or DMC chair) and consider all potential implications of 

such actions. 

7. SPONSOR INTERACTION WITH FDA REGARDING USE AND OPERATION OF 

DMCs

There are many situations, several mentioned earlier, in which a sponsor should consult with 

FDA on matters regarding a DMC. 

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. The present 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 FDAsponsor 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. The sponsor should contact FDA before 

initiating communication with the DMC regarding access to interim data 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.
Draft – Not for Implementation

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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. In certain settings, however, consultation with the FDA before 

making a decision may provide the sponsor with important information regarding the 

regulatory and scientific implications of a decision and may lead to better decisions. For 

trials that may be terminated early because a substantial benefit has been observed, 

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. For trials that may be terminated because of safety concerns, 

timely communication with FDA is required (21 CFR 312.56(d)). In such cases, the 

sponsor should 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.

7.3. DMC Recommendations for Protocol Changes

A DMC may in some instances recommend changes to the study protocol. Many protocol 

changes have little impact on the usefulness of a trial to gain regulatory approval. Certain 

types of changes to the protocol—e.g., changes in the endpoints, changes in permissible 

concomitant medications or in dose/schedule of study medication—could, however, have 

substantial impact on the validity of the trial and/or its ability to support the desired 

regulatory decision. Sponsors should discuss changes of the latter type with FDA before 

implementation.