Sponsor notification to the DMC regarding waivers

Guidance for Clinical

Trial Sponsors

Establishment and Operation of

Clinical Trial Data Monitoring

Committees

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)
March 2006

OMB Control No. 0910-0581
Expiration Date: 10/31/2015
See additional PRA statement in Section 8 of this guidance

Contains Nonbinding Recommendations

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
Office of Training and Communication
Division of Communications Management
Drug Information Branch, HFD-210
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane, Rockville, MD 20857
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
1350 Piccard Drive, Rockville, MD 20850
Phone: 800-638-2041 or 301-443-6597
Internet: http://www.fda.gov/cdrh
Email: DSMICA@cdrh.fda.gov
Facts-on-Demand (faxback): 800-899-0381 or 301-827-0111

Contains Nonbinding Recommendations

Table of Contents
1.

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

History ofDMCs ........................................................................................................... 2

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

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

2.
What is the Risk to Trial Participants? ...................................................................... 4

2.1.
Is DMC Review Practical? ........................................................................................... 4

2.2.
2.3.
Will a DMC Help Assure the Scientific Validity ofthe Trial? ................................. 5

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

3.
3.1.
Institutional Review Boards......................................................................................... 6

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

3.2.
3.3.
Endpoint Assessment/Adjudication Committees ....................................................... 7

3.4.
Site/Clinical Monito1ing ............................................................................................... 7

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

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

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

Confidentiality of Inte1im Data and Analyses.......................................................... 10

4.2.
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 oflnterim 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 ofLess 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

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

6.4.
6.5.
Sponsor Access to Interim Data for Planning Purposes.......................................... 31

1.1.
1.2.

Contains Nonbinding Recommendations

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

8.
PAPERWORK REDUCTION ACT OF 1995.............................................................. 34

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Contains Nonbinding Recommendations

Guidance for Clinical Trial Sponsors

Establishment and Operation of Clinical Trial Data Monitoring

Committees

This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this
topic. It does not create or confer any rights for or on any person and does not operate to bind
FDA or the public. You can use an alternative approach if the approach satisfies the
requirements of the applicable statutes and regulations. If you want to discuss an alternative
approach, contact the appropriate FDA staff. 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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Contains Nonbinding Recommendations

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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Contains Nonbinding Recommendations

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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Contains Nonbinding Recommendations

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

4

Contains Nonbinding Recommendations

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)).

5

Contains Nonbinding Recommendations

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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Contains Nonbinding Recommendations

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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Contains Nonbinding Recommendations

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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Contains Nonbinding Recommendations

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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Contains Nonbinding Recommendations

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
3

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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Contains Nonbinding Recommendations

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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Contains Nonbinding Recommendations

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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Contains Nonbinding Recommendations

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
13

Contains Nonbinding Recommendations

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

14

Contains Nonbinding Recommendations

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.
4

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.

15

Contains Nonbinding Recommendations

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
16

Contains Nonbinding Recommendations

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
17

Contains Nonbinding Recommendations

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,
18

Contains Nonbinding Recommendations

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.

19

Contains Nonbinding Recommendations

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
20

Contains Nonbinding Recommendations

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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Contains Nonbinding Recommendations

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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Contains Nonbinding Recommendations

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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Contains Nonbinding Recommendations

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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Contains Nonbinding Recommendations

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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Contains Nonbinding Recommendations

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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Contains Nonbinding Recommendations

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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Contains Nonbinding Recommendations

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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Contains Nonbinding Recommendations

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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Contains Nonbinding Recommendations

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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Contains Nonbinding Recommendations

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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Contains Nonbinding Recommendations

•

•
•

•
•
•
•

7.

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.

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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Contains Nonbinding Recommendations

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.

8.

PAPERWORK REDUCTION ACT OF 1995

This guidance contains information collection provisions that are subject to review by the Office
of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C.
3501-3520).
The time required to complete this information collection is estimated to average 11.75 hours per
response, including the time to review instructions, search existing data resources, gather the data
needed, and complete and review the information collection. Send comments regarding this
burden estimate or suggestions for reducing this burden to:
Food and Drug Administration
Center for Biologics Evaluation and Research (HFM-99)
1401 Rockville Pike, Suite 200N
Rockville, MD 20852-1448
This guidance also refers to previously approved collections of information fund in FDA
regulations. The collections of information in §§ 312.30, 312.32, 312.38, 312.55, and 312.56
have been approved under OMB Control No. 0910-0014; the collections of information in §
314.50 have been approved under OMB Control No. 0910-0001; and the collections of
information in §§ 812.35 and 812.150 have been approved under OMB Control No. 0190-0078.
An agency may not conduct or sponsor, and a person is not required to respond to, a collection
of information unless it displays a currently valid OMB Control No. The OMB Control No. for
this information collection is 0910-0581 (Expires 10/31/2015).

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