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 
Current expiration date available at https://www.reginfo.gov 
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 
1.1.  History of DMCs ........................................................................................................... 2 
1.2.  Current Status ............................................................................................................... 3 
2.  DETERMINING NEED FOR A DMC ........................................................................... 3 
2.1.  What is the Risk to Trial Participants? ...................................................................... 4 
2.2.  Is DMC Review Practical? ........................................................................................... 4 
2.3.  Will a DMC Help Assure the Scientific Validity of the Trial? ................................. 5 
3.  DMCs AND OTHER OVERSIGHT GROUPS ............................................................. 5 
3.1.  Institutional Review Boards ......................................................................................... 6 
3.2.  Clinical Trial Steering Committees ............................................................................. 6 
3.3.  Endpoint Assessment/Adjudication Committees ....................................................... 7 
3.4.  Site/Clinical Monitoring ............................................................................................... 7 
3.5.  Others with Monitoring Responsibilities .................................................................... 7 
4.  DMC ESTABLISHMENT AND OPERATION ............................................................ 8 
4.1.  Committee Composition ............................................................................................... 8 
4.2.  Confidentiality of Interim Data and Analyses.......................................................... 10 
4.2.1.  Interim Data .......................................................................................................... 10 
4.2.2.  Interim Reports to the DMC ................................................................................. 11 
4.3.  Establishing a Charter Describing Standard Operating Procedures .................... 12 
4.3.1.  Considerations for Standard Operating Procedures .............................................. 12 
4.3.1.1.  Meeting Schedule and Format ...................................................................... 12 
4.3.1.2.  Meeting Structure.......................................................................................... 13 
4.3.1.3.  Initial Meeting ............................................................................................... 13 
4.3.1.4.  Format of Interim Reports to the DMC and Use of Treatment Codes.......... 14 
4.3.2.  Statistical Methods ................................................................................................ 15 
4.4.  Potential DMC Responsibilities ................................................................................. 16 
4.4.1.  Interim Monitoring................................................................................................ 16 
4.4.1.1.  Monitoring for Effectiveness ........................................................................ 17 
4.4.1.2.  Monitoring for Safety ................................................................................... 17 
4.4.1.3.  Monitoring Study Conduct ........................................................................... 20 
4.4.1.4.  Consideration of External Data ..................................................................... 20 
4.4.1.5.  Studies of Less Serious Outcomes ................................................................ 22 
4.4.2.  Early Studies ......................................................................................................... 23 
4.4.3.  Other Responsibilities ........................................................................................... 24 
4.4.3.1.  Making Recommendations ........................................................................... 24 
4.4.3.2.  Maintaining Meeting Records....................................................................... 24 
5.  DMC RECOMMENDATIONS AND REGULATORY REPORTING 
REQUIREMENTS .......................................................................................................... 25 
6.  INDEPENDENCE OF THE DMC ................................................................................ 26 
6.1.  Desirability of an Independent DMC ........................................................................ 27 
6.2.  Value of Sponsor Interaction with the DMC ............................................................ 27 
6.3.  Risks of Sponsor Exposure to Interim Comparative Data...................................... 28 
6.4.  Statisticians Conducting the Interim Analyses ........................................................ 29 
6.5.  Sponsor Access to Interim Data for Planning Purposes.......................................... 31 
  i    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 
  ii    Contains Nonbinding Recommendations 
 
 
 
Guidance for Clinical Trial Sponsors 
 
Establishment and Operation of Clinical Trial Data Monitoring 
Committees 
 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this 
topic.  It does not create or confer any rights for or on any person and does not operate to bind 
FDA or the public.  You can use an alternative approach if the approach satisfies the 
requirements of the applicable statutes and regulations.  If you want to discuss an alternative 
approach, contact the 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. 
  1    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.   
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe FDAs 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.) 
 
  2    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 
  3    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 IRBs 
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 
  6    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 
  7    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.     
 
  8    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.   
 
  9    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 investigatorsthat 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). 
  10    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 periodthat 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 
  11    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 importantthey document that procedures were pre-
specified 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 
  12    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 DMCs and sponsors 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 DMCs 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 benefitthat is, there is no trend indicating superiority of the new 
productor 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 definitivelyfor 
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 studys 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 re-
consent 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 investigators 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 
  21    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.  
 
  22    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 DMCs 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, 
  23    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 DMCs 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 DMCs 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.  
  24    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 
  25    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 DMCs 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 
  26    Contains Nonbinding Recommendations 
 
 
 
ongoing financial relationship with a trials 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 trials 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 sponsors 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 sponsors 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 
  27    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 
DMCs 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 trials 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 sponsors access to interim data is the diminution of 
the sponsors 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 
  28    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 statisticians 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 sponsors employ possesses information 
  29    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 
  30    Contains Nonbinding Recommendations 
 
 
 
sufficient time and access to the data to provide insightful analyses responsive to the 
DMCs 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 () 
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 
  31    Contains Nonbinding Recommendations 
 
 
 
finding of effectiveness might create an ethical imperative to stop the trial, and it 
would not be possible to quantitate the level of evidence provided by the data if 
the monitoring plan had not been established prior to data review.   
  Determination of the minimum amount of information needed.  For example, to 
assist in defining eligibility criteria for a subsequent trial, the sponsor may wish to 
know only whether estimates of treatment effect in a subgroup are less or greater 
than in the overall data set.  
  Formulation of written questions, preferably with yes/no rather than numerical 
answers, that will elicit only that minimal required information and nothing more.  
  Receiving only written information regarding the requested data (thereby 
documenting what was received and avoiding additional unnecessary 
communications) and abstaining from participation in closed DMC meetings or 
discussions of data with unblinded DMC members (except as otherwise requested 
by the DMC).  
  Identification of those sponsor employees with a critical "need-to-know" and 
restriction of such information to those individuals only.  
  Ensuring that individuals with access to the information avoid any subsequent 
role in the management of the trial and minimize interactions with others in that 
role.  
  Ensuring that individuals who have access to such information make every effort 
to avoid taking actions that will assist others in inferring what the information is.  
  Ensuring that reports of study findings describe any access to interim data by 
individuals involved with study management, and steps taken to prevent such 
access from potentially biasing the study results. 
 
7.  SPONSOR INTERACTION WITH FDA REGARDING USE AND OPERATION 
OF DMCs 
 
There are many situations, several mentioned earlier, in which sponsor consultation with FDA on 
matters regarding a DMC is advisable.   
 
7.1.  Planning the DMC 
 
In planning a clinical trial, a sponsor makes several decisions regarding use, types of 
membership, and operations of a DMC.  Many of these can be critical to the success of 
the trial in meeting regulatory requirements.  This guidance document is intended to 
provide general FDA guidance regarding those decisions, but each set of circumstances 
can raise unique considerations.  Issues regarding use of DMCs are appropriate topics for 
FDA-sponsor meetings (in person or by telephone) at the sponsors 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 
  32    Contains Nonbinding Recommendations 
 
 
 
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 decision-
making.  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 
  33    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 (To find the current expiration date, search for this 
OMB Control No. available at https://www.reginfo.gov).   
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