Use of Data Monitoring 
Committees in Clinical Trials 
 
Guidance for Industry 
 
 
 
DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to https://www.regulations.gov.  Submit written 
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061, Rockville, MD  20852.  All comments should be identified with the 
docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact (CDER) Dat Doan, 240-402-8926; (CBER) 
Office of Communication, Outreach and Development, 800-835-4709 or 240-402-8010; or 
(CDRH) Center for Devices and Radiological Health, CDRHClinicalEvidence@fda.hhs.gov.  
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
Center for Devices and Radiological Health (CDRH) 
 
February 2024 
Clinical/Medical 
Revision 1 
 
8204696dftrv1.docx   
Use of Data Monitoring Committees  
in Clinical Trials 
 
Guidance for Industry 
 
Additional copies are available from: 
 
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Center for Drug Evaluation and Research 
Food and Drug Administration 
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and/or 
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 Food and Drug Administration 
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guidances 
and/or 
Office of Policy 
Center for Devices and Radiological Health 
Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 66, Room 5431 
Silver Spring, MD 20993-0002 
Email: CDRH-Guidance@fda.hhs.gov 
https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance/guidance-documents-medical-devices-
and-radiation-emitting-products  
  
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
Center for Devices and Radiological Health (CDRH) 
 
 
February 2024 
Clinical/Medical 
Revision 1 
 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  SCOPE ............................................................................................................................... 3 
III.  BACKGROUND ............................................................................................................... 3 
A.  Evolution of the Role of DMCs ..................................................................................................... 3 
B.  Current Status ................................................................................................................................ 4 
IV.  DETERMINING WHETHER TO USE A DMC ........................................................... 4 
V.  DMCS AND OTHER OVERSIGHT GROUPS ............................................................. 5 
A.  Institutional Review Boards .......................................................................................................... 6 
B.  Clinical Trial Steering Committees .............................................................................................. 6 
C.  Endpoint Assessment/Adjudication Committees ........................................................................ 7 
D.  Clinical Site Monitors and Entities Reviewing Safety Reporting .............................................. 7 
1. Clinical Site Monitors ...................................................................................................................... 7 
2. Entities Reviewing Safety Data ........................................................................................................ 8 
E.  Adaptation Committee .................................................................................................................. 9 
VI.  DMC ESTABLISHMENT AND OPERATION .......................................................... 10 
A.  Committee Composition .............................................................................................................. 10 
1. Membership ................................................................................................................................... 10 
2. Conflict of Interest ......................................................................................................................... 10 
3. Training Considerations ................................................................................................................ 11 
B.  Establishing a Charter Describing DMC Obligations, Responsibilities, and Standard 
Operating Procedures .......................................................................................................................... 11 
C.  DMC Responsibilities .................................................................................................................. 13 
1. Monitoring of Trial Conduct .......................................................................................................... 13 
2. Monitoring of Results of Interim Analysis of Trial Data ............................................................... 13 
3. Consideration of External Data ..................................................................................................... 17 
4. Recommendations and Documentation .......................................................................................... 18 
D.  Interim Data and Analyses .......................................................................................................... 19 
1. Confidentiality of Interim Data ...................................................................................................... 20 
2. Interim Reports to the DMC .......................................................................................................... 21 
3. Analysis Used by the DMC ............................................................................................................ 21 
VII.  INDEPENDENCE OF THE DMC ................................................................................ 22 
VIII.  FDA RECOMMENDATIONS AND REGULATORY REPORTING 
REQUIREMENTS ...................................................................................................................... 23 
REFERENCES ............................................................................................................................ 25 
APPENDIX .................................................................................................................................. 26 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Use of Data Monitoring Committees in Clinical Trials  
2  Guidance for Industry1 
3   
4   
5  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
6  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
7  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
8  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
9  for this guidance as listed on the title page.   
10   
11   
12   
13   
14  I.  INTRODUCTION  
15   
16  This guidance provides recommendations to help sponsors2 of clinical trials3 determine (1) 
17  when a data monitoring committee (DMC) (also known as a data and safety monitoring board 
18  (DSMB) or a data and safety monitoring committee (DSMC) or an independent data monitoring 
19  committee (IDMC)) would be useful for trial monitoring and (2) what procedures and practices 
20  should be considered to guide their operation.4  This guidance revises the guidance for clinical 
21  trial sponsors Establishment and Operation of Clinical Trial Data Monitoring Committees 
22  issued in March 2006 (the 2006 guidance).  When finalized, this guidance will supersede the 
23  2006 guidance.5 
 
1 This guidance has been prepared by the Office of Medical Policy in the Center for Drug Evaluation and Research 
in cooperation with the Center for Biologics Evaluation and Research and the Center for Devices and Radiological 
Health at the Food and Drug Administration.  
 
2 A sponsor of a clinical trial evaluating a new drug or biological product is defined under 21 CFR 312.3(b) as a 
person who takes responsibility for and initiates a clinical investigation. A clinical investigation is defined under 21 
CFR 312.3(b) as any experiment in which a drug is administered or dispensed to, or used involving, one or more 
human subjects.  A sponsor of a clinical trial evaluating a device is defined under 21 CFR 812.3(n) as a person 
who initiates, but who does not actually conduct, the investigation, that is, the investigational device is administered, 
dispensed, or used under the immediate direction of another individual.  
 
3 For the purposes of this guidance, the terms clinical trial and clinical investigation are used interchangeably.  
 
4 Sponsors of clinical investigations evaluating investigational drugs, biological products, and devices may be 
required to monitor these investigations (see 21 CFR 312.50 and 312.56 (for drugs and biological products) and 21 
CFR 812.2(b)(1)(iv), 812.40 and 812.46 (for devices)).  Certain categories of devices are exempt from some 
provisions of 21 CFR part 812 (see 21 CFR 812.2(c)).  This guidance does not pertain to the applicability of part 
812; the language in this guidance discussing the requirements of part 812, including language discussing 
monitoring and reporting requirements, is relevant to a particular investigation only to the extent those requirements 
of part 812 actually apply to such investigation. 
 
5 For the purposes of this guidance, references to drugs includes drugs approved under section 505 of the FD&C Act 
(21 U.S.C. 355) and biological products licensed under 351(a) of the PHS Act (42 U.S.C. 262(a)) that are regulated 
as drugs.  Hereafter, unless otherwise specified, the term drug will be used to refer to all such products. 
 
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24   
25  Significant changes in DMC structure and practice since the 2006 guidance was issued include:  
26   
27    The increased use of DMCs in trials (Califf et al. 2012) of modest size as reflected in the 
28  clinical trials data bank housed at ClinicalTrials.gov6 
29   
30    A trend for DMC charters to become longer and more detailed  
31   
32    An increased use of DMCs to implement certain adaptive clinical trial designs7 
33    
34    An increased use of some DMCs to oversee an entire clinical development program 
35  rather than a single clinical trial8 
36   
37    The potential for expansion of functions of a DMC; for example, for review of 
38  aggregate9 data for safety reporting for trials under an investigational new drug 
39  application (IND) 
40   
41    An increased globalization of medical product development and use of multiregional 
42  trials with DMCs10 
43   
44  For the purposes of this guidance, a clinical trial DMC is a group of individuals with relevant 
45  expertise that reviews accumulating data on a regular basis from one or more clinical trials and 
46  recommends to the sponsor whether to continue, modify, or stop a trial or trials.  A clinical trial 
47  DMC is established by the sponsor but should be independent of the sponsor and the trial 
48  conduct (see section VII of this guidance).  
49   
50  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
51  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
 
6 ClinicalTrials.gov is a database of privately and publicly funded clinical studies conducted around the world and is 
a resource provided by the U.S. National Library of Medicine.  Listing a study does not mean it has been evaluated 
by the U.S. Federal Government; not all listed studies are regulated and/or evaluated by FDA.  Information on 
whether a DMC has been appointed for a registered trial can be provided on ClinicalTrials.gov using the optional 
Data Monitoring Committee data element (Y/N) (https://www.clinicaltrials.gov/prs-info/protocol-definitions#study-
oversight).  
 
7 See the guidance for industry Adaptive Designs for Clinical Trials of Drugs and Biologics (December 2019) and 
the guidance for industry and Food and Drug Administration staff Adaptive Designs for Medical Device Clinical 
Studies (July 2016).  We update guidances periodically.  For the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  
 
8 See Clinical Trials Transformation Initiative (CTTI) Overview:  Data Monitoring Committees, available at 
https://ctti-clinicaltrials.org/our-work/ethics-and-human-research-protection/data-monitoring-committees/. 
 
9 For the purposes of this guidance, the term aggregate refers to data within a treatment arm or across treatment 
arms. 
 
10 See the International Council for Harmonisation (ICH) guidance for industry E17 General Principles for Planning 
and Design of Multiregional Clinical Trials (July 2018).   
 
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52  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
53  the word should in Agency guidances means that something is suggested or recommended, but 
54  not required.  
55   
56   
57  II.  SCOPE 
58   
59  This guidance pertains primarily to the sponsors responsibility for clinical trial management and 
60  decision-making but may also be relevant to any individuals or group to whom the sponsor has 
61  delegated applicable trial management responsibilities (see section V of this guidance).   
62   
63   
64  III.  BACKGROUND 
65   
66  DMCs have a unique role in clinical trial oversight because they are often the only group with 
67  access to accumulating unblinded safety and efficacy data.  In order to adequately assess the 
68  benefits and risks of an intervention, the DMC should evaluate safety data within the context of 
69  the interventions efficacy, such that the DMC should have access to safety results as well as 
70  comparative efficacy results.  Generally, a DMC monitors accumulating safety data and advises 
71  the sponsor regarding the safety of the interventions in trial subjects, monitors interim 
72  effectiveness results to see whether they support benefit (or futility), and helps to ensure the 
73  scientific merit and integrity of the trial.  In most cases, a DMC is responsible for a single trial.  
74  When a single DMC is responsible for monitoring multiple related trials, the considerations for 
75  the establishment and operation of the DMC are generally similar to those for a DMC 
76  monitoring a single trial, but the logistics may be more complex.  
77   
78  Different designs for DMCs may be appropriate in different situations, and experience has shown 
79  that no single design is optimal for all settings.   
80   
81  A.  Evolution of the Role of DMCs 
82   
83  DMCs have been a component of some clinical trials since the early 1960s (see the appendix for 
84  a brief history).   
85   
86  Beginning in the 1990s, the use of DMCs for clinical trials sponsored by the pharmaceutical 
87  industry became more common, especially in clinical trials of conditions associated with 
88  significant morbidity or mortality.  At the same time, more sophisticated statistical methods for 
89  conducting interim analyses of accumulating clinical trial data were being developed.  These 
90  included methods that control the overall false positive rate while allowing for planned interim 
91  assessments, as well as methods for computing predictive probabilities that a trial, if run to 
92  completion, would be successful (Ellenberg et al. 2002; Balakrishnan 2014; DeMets and Lan 
93  2013; Proschan et al. 2006).  With the use of these methods, it became common for industry-
94  sponsored trials to include interim monitoring for administrative purposes (e.g., audits to ensure 
95  the correct data is being collected), and with this practice came an increasing reliance on DMCs 
96  to assist in this monitoring.  The International Council for Harmonisation (ICH) guidance for 
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97  industry E9 Statistical Principles for Clinical Trials11 provides recommendations on the 
98  appropriate conduct of interim analyses, including the establishment and operation of DMCs, in 
99  part because of this increasing use of DMCs in industry-sponsored clinical trials. 
100   
101  Since 2006, there has been an increase in the use of DMCs in many disease areas beyond those 
102  involving serious morbidity or mortality.  For example, DMCs can provide the specialized 
103  expertise to evaluate emerging efficacy and safety data for trials in rare diseases (e.g., certain 
104  genetic disorders), for trials in vulnerable populations (e.g., neonates), and for oncologic 
105  therapies with highly specific targets and potential serious risks (e.g., biological products for 
106  genetic targets, immunotherapies).  They are also being used in early phase trials in serious 
107  diseases or conditions.  With the growth of DMC oversight, a variety of approaches to DMC 
108  operations has been developed.  In some cases, sponsors have engaged a single DMC to oversee 
109  a clinical development program encompassing multiple trials.  
110   
111  B.  Current Status 
112   
113  Under FDA regulations, sponsors are not required to use DMCs in clinical trials except under 21 
114  CFR 50.24(a)(7)(iv), where an institutional review board (IRB) can approve a clinical trial in an 
115  emergency setting without requiring informed consent from all research subjects, provided 
116  certain requirements are met, including the establishment of an independent DMC.   
117   
118   
119  IV.  DETERMINING WHETHER TO USE A DMC  
120   
121  As stated previously, DMCs are established to monitor accumulating data from an ongoing trial 
122  and make recommendations concerning the safety and effectiveness of an investigational 
123  product or the futility of an ongoing trial (see section V1.C of this guidance).  A prominent 
124  responsibility is also to help ensure subject safety.  Although all clinical trials have a plan for 
125  monitoring data and subject safety, not all trials call for involvement or monitoring by a DMC 
126  (see section V of this guidance).   
127   
128  An important consideration in determining whether to use a DMC in a development program is 
129  whether DMC review is practical for the particular clinical trial.  Although the practicality of 
130  having a DMC for long-term trials is well established, it is not as clear for short-term trials.  If 
131  the trial is likely to complete enrollment quickly and the follow-up period is short, convening a 
132  DMC to review interim data to assess continued exposure of subjects to investigational 
133  interventions may be impractical and of little value.  Careful consideration should therefore be 
134  given to whether a DMC could have a meaningful impact on the conduct of the trial.  Where 
135  sponsors consider DMC oversight critical for safety monitoring of short-term trials, specific 
136  mechanisms should be developed to permit timely DMC evaluation (e.g., pauses in advance of 
137  dose escalation) or to conduct data and safety oversight in an expedient manner (e.g., by an 
138  independent monitor(s)).   
139   
 
11 See the ICH guidance for industry E9 Statistical Principles for Clinical Trials (September 1998). 
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140  Other factors can suggest the value of using a DMC, such as a limited experience in a 
141  therapeutic area or participation of subjects from a vulnerable population.  Instances may also 
142  occur in which a DMC can be useful in the context of a single-arm trial (e.g., using historical 
143  control data).  For example, if the single-arm trial has adaptive elements, it may be preferable to 
144  use an independent group to determine if a prespecified adaptation is to be implemented.  
145    
146  FDA strongly recommends establishing a DMC if trial subjects are at risk of serious morbidity or 
147  mortality (e.g., hospitalization, heart attack, stroke, death).  In addition to the effects of the 
148  subjects condition, investigational products may cause serious unexpected adverse eventsan 
149  important reason to consider monitoring interim results using a DMC.  In cases where an 
150  assessment of causality can be made on the basis of a single event (e.g., agranulocytosis, 
151  Stevens-Johnson syndrome), the sponsors internal safety management team or other entity 
152  responsible for reviewing safety data (see section V.E of this guidance) may be able to identify a 
153  potential risk and bring it to the attention of the sponsor and regulators.  In cases where the event 
154  may be anticipated to occur in the population enrolled in the trial regardless of the intervention 
155  (e.g., myocardial infarctions in an older population) or could be related to other treatments being 
156  administered, the relationship between the investigational product and the adverse events will be 
157  less clear.  In these cases it is often critical to conduct an analysis of safety data to determine 
158  whether, for investigational drugs, there is a reasonable possibility that the adverse event was 
159  caused by the investigational drug12 or whether, for investigational devices, it was caused by or 
160  associated with the investigational device.13  In such cases, a DMC or another independent entity 
161  should review aggregate safety reports across study arms.  
162    
163  Sometimes the DMC is used to make recommendations on operational matters based on 
164  accumulating noncomparative14 safety and efficacy data (e.g., fewer than expected outcome 
165  events or a higher than anticipated rate of dropouts).  These findings can also be addressed by 
166  other groups (e.g., clinical trial steering committees).  Changes to the trial design that involve an 
167  analysis of results by study group are best performed by a body independent of the sponsor, the 
168  investigators, and the subjects.   
169   
170   
171  V.  DMCS AND OTHER OVERSIGHT GROUPS 
172   
173  Various parties may have or share responsibility for aspects of clinical trial monitoring and 
174  oversight, and it is important to recognize the roles they play and how responsibilities are 
175  assigned among these entities.  These parties are all part of a system that helps to ensure the 
176  conduct of trials that produce valid, reliable, and credible results.  As noted however, DMCs play 
 
12 See 21 CFR 312.32(c). 
 
13 See 21 CFR 812.3(s), 812.46(b), and 812.150(b)(1). 
 
14 A noncomparative analysis is an examination of accumulating trial data in which the treatment group assignments 
of subjects are not used in any manner in the analysis.  A comparative analysis is an examination of accumulating 
trial data in which treatment groups are identified, either with the actual assigned treatments or with codes (e.g., 
labeled as A and B, without divulging which treatment is investigational).  For more information about comparative 
and noncomparative analysis, see the guidance for industry Adaptive Designs for Clinical Trials of Drugs and 
Biologics.  It should be noted, reporting data with codes can be informative and should be best treated as unblinded. 
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177  a unique role in providing clinical trial oversight, given that they are generally the only oversight 
178  group that has access to accumulating unblinded safety and efficacy data.  The relationship 
179  between the DMC and other groups commonly associated with clinical trials is described in the 
180  following subsections. 
181   
182  A.  Institutional Review Boards 
183   
184  An IRB is responsible for evaluating a trial both before and after it is initiated to determine 
185  whether [r]isks to subjects are minimized and [r]isks to subjects are reasonable in relation to 
186  anticipated benefits, if any, to subjects, and the importance of the knowledge that may be 
187  expected to result, in accordance with 21 CFR 56.111(a)(1) and (2).  An IRB may request more 
188  information be given to subjects when, in the judgment of the IRB, the additional information 
189  would add meaningfully to the protection of the rights, safety, or well-being of the subjects.15   
190   
191  In trials in which there is the possibility of serious morbidity or involvement of vulnerable 
192  populations, an IRB should inquire as to whether a DMC has been established and, if so, seek 
193  information about its scope and composition as part of its oversight. 
194    
195  For ongoing trials, the IRB is responsible for considering information arising from the trial that 
196  may bear on the continued acceptability of the trial at the trial sites it oversees (see 21 CFR 
197  56.103 and 21 CFR 56.109), but it will generally only have access to blinded (i.e., 
198  noncomparative) data and will not see unblinded interim results.  A DMC, on the other hand, has 
199  access to detailed data during the trial, including unblinded interim efficacy and safety outcomes 
200  by treatment arm.  Under 21 CFR 312.66, 812.40, and 812.150, individual investigators or 
201  sponsors are responsible for assuring that IRBs are made aware of significant new information 
202  that arises about a clinical trial (e.g., DMC recommendations) (see section VI.C.4 of this 
203  guidance).  In multi-site studies where a single IRB serves as the IRB of record for research 
204  involving multiple institutions, the individual investigators or sponsors should also report the 
205  collected information to investigators at all sites, as appropriate, in accordance with the single 
206  IRBs communication plan.   
207   
208  B.  Clinical Trial Steering Committees 
209   
210  In some clinical trials, the sponsor may choose to appoint a steering committee; this committee 
211  may include investigators, other experts not otherwise involved in the trial, and, usually, 
212  representatives of the sponsor.  The steering committee may consider many aspects of trial 
213  performance (e.g., rate of recruitment, loss to follow-up, overall event rates, whether prognostic 
214  or predictive enrichment strategies are being implemented, demographic inclusion), but it should 
215  always be blinded to outcomes by study arm.  It may also recommend, based on trial 
216  performance (e.g., recruitment and loss to follow-up), additional measures to identify possible 
217  subjects, elimination of exclusion criteria (e.g., age limitations), and additional efforts to identify 
218  reasons for discontinuation.  Because of the various roles and responsibilities a steering 
219  committee may have, it is important that the responsibilities of the steering committee and the 
 
15 See the ICH guidance for industry E6(R2) Good Clinical Practice:  Integrated Addendum to ICH E6(R1) (March 
2018).   
 
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220  DMC be clearly delineated while the clinical trial is being planned.  When there is a steering 
221  committee, the sponsor may elect to have the DMC communicate with this committee rather than 
222  directly with the sponsor.  Interactions between the steering committee and the DMC should 
223  occur during open sessions (see section VI.C of this guidance) of DMC meetings and when the 
224  recommendations following each DMC review of the trial are communicated, so that the 
225  confidentiality of interim results of unblinded cumulative safety and efficacy data is maintained.  
226  More-frequent interactions may occur when early termination is being considered or when 
227  external events (e.g., announcement of results of related trials) could affect the ongoing trial. 
228   
229  C.  Endpoint Assessment/Adjudication Committees 
230   
231  Given that DMCs have access to unblinded data (e.g., unblinded, comparative data), they should 
232  not adjudicate trial endpoints.  To determine whether the endpoints meet protocol-specified 
233  criteria, sponsors may choose to establish an endpoint assessment/adjudication committee (also 
234  known as a clinical events committee) to review important endpoint data reported by clinical 
235  investigators.16  These committees are expected to be blinded to the assigned intervention when 
236  performing their assessments, regardless of whether the trial itself is conducted in a blinded 
237  manner.  The committees assessments help ensure that the data reviewed by DMCs are as 
238  accurate and free of bias as possible, provided the adjudication results are completed and 
239  transferred in a timely manner to the DMC for its deliberations.   
240   
241  D.  Clinical Site Monitors and Entities Reviewing Safety Reporting 
242   
243  1.  Clinical Site Monitors 
244   
245  The sponsor or a contract research organization17 hired by the sponsor generally performs 
246  clinical site monitoring of a clinical trial to assure high-quality trial conduct.  Clinical site 
247  monitors perform central and/or on-site monitoring of subject-level data to assess protocol 
248  compliance and adherence to good clinical practice.18  They should also review individual case 
249  report forms, with particular attention to adverse events.  These monitors should remain blinded 
250  to treatment assignments and should never review accumulating effectiveness data for trial 
251  decision-making purposes.  
252   
253  All clinical trials conducted under an IND or an investigational device exemption (IDE) are 
254  subject to regulatory safety reporting requirements.  These requirements, for example, include 
255  prompt reporting to FDA of serious and unexpected adverse events when, based on the available 
256  evidence, the sponsor (or, if applicable, the contract research organization, see 21 CFR 312.52) 
 
16 See the guidance for industry Adaptive Designs for Clinical Trials of Drugs and Biologics and the guidance for 
industry and Food and Drug Administration staff Adaptive Designs for Medical Device Clinical Studies.    
 
17 See 21 CFR 312.3(b), defining a contract research organization as a person that assumes, as an independent 
contractor with the sponsor, one or more of the obligations of a sponsor, e.g., design of a protocol, selection or 
monitoring of investigations, evaluation of reports, and preparation of materials to be submitted to the Food and 
Drug Administration.  
 
18 See ICH E6(R2). 
 
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257  concludes that there is reasonable possibility the investigational product caused the event (i.e., it 
258  is a serious and unexpected suspected adverse reaction (see 21 CFR 312.32(c)) or when the 
259  event is an unanticipated adverse device effect (see 21 CFR 812.46(b), and 812.150(b)(1)).  
260  Safety monitoring should generally be assigned to individuals or entities that review adverse 
261  events for safety reporting.   
262   
263  2.  Entities Reviewing Safety Data 
264   
265  When the potential relationship between a serious and unexpected adverse event and the 
266  investigational product can be assessed only by comparing event rates in treated and control 
267  groups, an entity (either a DMC or an independent safety team) that can potentially review 
268  unblinded safety data reporting will be critical to evaluate the adverse events, looking for 
269  evidence of emerging safety signals.19  If the entity that reviews safety data is unblinded to 
270  information regarding the subjects experiencing the adverse event, it should be blinded to 
271  efficacy data.  
272   
273  An entity that reviews aggregate data for safety reporting should review unblinded accumulating 
274  safety data across multiple trials in a product development program.  Whether those entities are 
275  managed by contract research organizations or are internal to the sponsor, the role of an entity 
276  that reviews safety data is distinct from how a traditional DMC operates.  Such entities can have 
277  different operational practices, but there should be separation between individuals reviewing 
278  unblinded safety data and those involved in the conduct of a trial.   
279   
280  Based on its review of unblinded safety and effectiveness data, a traditional DMC can recommend 
281  that the sponsor modify or stop the trial because the investigational product (1) is not effective; 
282  (2) has caused an unexpected adverse event in a drug or biological product trial under 21 CFR 
283  312.32 or an unanticipated adverse device effect that presents an unreasonable risk to subjects in 
284  the case of a device trial under 21 CFR 812.46(b) and 812.150(b)(1); or (3) has clearly been 
285  shown to be effective, generally using planned interim analysis procedures.  By contrast, the role 
286  of an entity that reviews accumulating safety data would generally be to determine whether to 
287  recommend that the sponsor submit an IND or IDE report to FDA and all participating 
288  investigators.20  It will usually be critical to unblind the interventions assigned to subjects who 
289  have serious adverse events of interest to make this determination, but the entity that reviews 
290  aggregate data for safety purposes should not have access to data on effectiveness.  
291   
292  The threshold that a DMC would use for reporting safety concerns to the sponsor and 
293  recommending termination or significant modification to the trial may be higher than the 
294  threshold for reporting potential serious risks obtained from aggregate data in an IND or IDE 
 
19 See the guidance for industry Safety Reporting Requirements for INDs and BA/BE Studies (December 2012).  
 
20 For example, see the draft guidance for industry Safety Assessment for IND Safety Reporting (December 2015).  
When final, this guidance will represent FDAs current thinking on this topic.  For trials conducted under an IDE, 
sponsors must also report the results of the evaluation of an unanticipated adverse device effect to all reviewing 
IRBs within 10 working days after the sponsor first receives notice of the effect (21 CFR 812.2(b)(1)(iv), 812.46(b), 
and 812.150(b)(1)).   
 
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295  report to FDA.21  Although DMCs and entities that review accumulating safety data have distinct 
296  roles in characterizing safety, it may be possible in some settings to have the DMC conduct these 
297  safety evaluations and provide recommendations to sponsors about whether a difference in the 
298  occurrence of safety events in the investigational arm compared to the control arm suggests a 
299  causal relationship between the investigational product and the adverse event.  Even if a causal 
300  relationship is suspected for a particular type of serious adverse event, it may still be appropriate 
301  to continue the trial (Bhattarcharya et al. 2018).  
302   
303  E.  Adaptation Committee 
304   
305  For trials utilizing an adaptive design,22 a dedicated independent adaptation body could be 
306  established that is distinct from a DMC.  Alternatively, the adaptive decision-making role could 
307  be assigned to the DMC, although its primary responsibility should remain subject safety and 
308  trial integrity.  Using a DMC to support adaptive trials might best be reserved for group 
309  sequential designs and other relatively straight forward adaptive designs with simple adaptation 
310  algorithms.  Depending on the specific trial design, either approach may be appropriate.  Use of 
311  separate bodies might facilitate the inclusion of more-relevant expertise on each committee and 
312  allow the DMC to focus most effectively on its primary responsibilities.  Alternatively, use of a 
313  single bodysuch as a DMCfor both purposes avoids the logistical challenges of information 
314  sharing with, and interactions between, multiple monitoring groups.   
315   
316  The committee tasked with making adaptation recommendations should include appropriate 
317  expertise, including a statistician or statisticians knowledgeable about the adaptation 
318  methodology, monitoring plan, and decision rules.  Furthermore, the responsibility of this 
319  committee should be to make adaptation recommendations or decisions based on appropriately 
320  implementing a carefully designed and prespecified adaptation plannot to identify potential 
321  design aspects to adapt after reviewing comparative interim results.  Therefore, it is important 
322  that the DMC or adaptation committee be involved at the trial design stage in detailed 
323  discussions with the sponsor about hypothetical scenarios.  The DMC or adaptation committee 
324  should also determine whether actions dictated by the adaptation plan are considered reasonable 
325  by all parties involved.  
326     
 
21 See the draft guidance for industry Safety Assessment for IND Safety Reporting.   
 
22 The term adaptive design means a clinical trial design that allows for prospectively planned modifications to one 
or more aspects of the design based on accumulating data from subjects in the trial.  See the guidance for industry 
Adaptive Designs for Clinical Trials of Drugs and Biologics and the guidance for industry and Food and Drug 
Administration staff Adaptive Designs for Medical Device Clinical Studies. 
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327  VI.  DMC ESTABLISHMENT AND OPERATION 
328   
329  A.  Committee Composition 
330   
331  1.  Membership 
332   
333  The sponsor or trial steering committee, or both, generally appoint members of a DMC.  Most 
334  DMCs are composed of individuals with expertise in current clinical trial conduct and clinicians 
335  with expertise in relevant clinical specialties.  DMCs should also include one biostatistician 
336  knowledgeable about statistical methods for clinical trials (including the methods anticipated for 
337  the trial under its oversight) and sequential analysis of trial data, if applicable.  The importance 
338  for including individuals on the DMC with expertise in informatics and technology should also 
339  be assessed.  It is generally important to have some members with experience in serving on 
340  DMCs and some members familiar with FDA regulatory requirements for clinical trials.  Both 
341  types of experience are typically critical for the DMC chair.  All DMC members should be 
342  screened for conflicts of interest (see sections V1.A.2 and VII of this guidance). 
343   
344  A well-constructed DMC should be equipped to identify unexpected issues and mitigate 
345  problems that could otherwise cause risk to subjects or could adversely affect the quality of the 
346  data and integrity of the trial.  The objectives and design of the trial and the scope of the 
347  responsibilities given to the DMC should determine the types of expertise needed for a particular 
348  trial.  For example, for trials with unusually high risks to subject safety or with broad public 
349  health implications, the DMC should consider including a medical ethicist knowledgeable about 
350  the design, conduct, and interpretation of clinical trials.   
351   
352  DMCs will often be supported by an independent statistician or statistical group that is 
353  responsible for providing and presenting statistical analyses and reports to the DMC during 
354  closed sessionsthey are not considered part of the DMC.  This role is distinct from the DMC 
355  statistician (or statisticians), who is a voting member.  The independent statistician or statistical 
356  group, as well as an adaptation committee (should one exist), should have access to unblinded 
357  data and ensure they are familiar with the design, setting, and objectives of the trial and should 
358  have sufficient time and access to the data to provide insightful analyses responsive to the needs 
359  of the DMC. 
360   
361  2.  Conflict of Interest 
362   
363  Conflicts of interest should be evaluated when choosing individuals to serve on a DMC.  One 
364  potential conflict is a financial interest that could be substantially affected by the outcome of the 
365  trial.23  Aside from being compensated for their duties on the committee, DMC members should 
366  have no ongoing financial relationship with a trials commercial sponsor (or its direct 
 
23 See section VIII of this guidance for further discussion.  See also the HHS Guidance on Financial Conflicts of 
Interest (2004), available at https://www.hhs.gov/ohrp/regulations-and-policy/guidance/financial-conflict-of-
interest/index.html, which provides points to consider in determining whether specific financial interests in research 
affect the rights and welfare of human subjects and what actions could be considered to protect those subjects. 
 
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367  competitors24) and should not be involved in the conduct of the trial in any role other than that of 
368  a DMC member.  
369      
370  Persons known to have strong views on the relative merits of the intervention(s) under 
371  evaluation in the clinical trial may have an intellectual conflict of interest or bias and may not be 
372  able to review the data in a fully objective manner; such individuals are therefore usually not 
373  appropriate DMC members.  Each potential DMC candidate should be well vetted by sponsors 
374  for financial as well as intellectual conflicts of interest. 
375   
376  3.  Training Considerations 
377   
378  Adequate preparation for the role as a DMC member is integral to the DMCs mission.  DMC 
379  members should understand that the roles and responsibilities of DMC membership differ from 
380  participation in a clinical trial as an investigator.  Sponsors are therefore strongly encouraged to 
381  consider the learning and training requisites of members selected to serve on a DMC before 
382  involvement in their first DMC meeting25 and perhaps again later, if needed.   
383   
384  B.  Establishing a Charter Describing DMC Obligations, Responsibilities, and 
385  Standard Operating Procedures 
386   
387  All DMCs should operate under a written charter that clearly states the purpose of the DMC, the 
388  specific questions it is expected to address, and the possible recommendations it can make to the 
389  sponsor during the trial.  DMC charters should prespecify the meeting schedule and the types of 
390  data that will be available for review so that all members have a good understanding of 
391  responsibilities associated with their DMC membership.  The charter should outline the 
392  operating procedures governing the DMC deliberations to reduce concerns that changes made 
393  with knowledge of interim unblinded data might bias the trial results and interpretation.  The 
394  charter should note that DMCs should not have a role in redesigning the trial after reviewing 
395  unblinded data.  It is critical that during DMC deliberations there is no introduction of bias by 
396  investigators or sponsors and that all proceedings involving data analysis and availability, and/or 
397  any potential changes to the protocol during the trial26 be carried out with appropriate attention 
398  to maintenance of confidentiality of unblinded interim results in order to maintain trial 
399  credibility.  To maintain confidentiality of unblinded information, DMC members should be 
400  aware of all stipulations under the charter related to meeting formats (i.e., who should be present 
401  during sessions), confidentiality, and data handling.  The charter can be prepared by the sponsor 
402  and presented to the DMC for discussion and agreement or be prepared by the DMC itself with 
403  presentation to the sponsor for concurrence.  
404   
 
24 For the purposes of this guidance, direct competitor refers to the commercial sponsor of a trial for a product that is 
or would be competitive with that being evaluated. 
 
25 See the guidance for industry Adaptive Designs for Clinical Trials of Drugs and Biologics and the guidance for 
industry and Food and Drug Administration staff Adaptive Designs for Medical Device Clinical Studies.  
 
26 Potential changes in protocol may include those involving safety, such as restricting eligibility or dropping a trial 
arm. 
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405  The DMC charter and documented concurrence with the charter by all DMC members should be 
406  in place in advance of performing any interim analyses and ideally before the initiation of the 
407  trial and any subject enrollment.  FDA may request that the sponsor submit the charter to FDA 
408  well in advance of the performance of any interim analyses, ideally before the initiation of the 
409  trial (see 21 CFR 312.23(a)(6)(iii)(g); 312.41(a); 812.150(b)(10)).  In such cases, FDA would 
410  usually consider the charter when FDA reviews the study protocol.  At a minimum, we 
411  recommend that the DMC charter include the following elements.  
412   
413  1.  Composition of Committee: 
414   
415    Criteria and rationale for selection of committee members 
416   
417    Outline and clarification of roles of committee members including voting and 
418  nonvoting members  
419   
420    Procedures for assessing financial and intellectual conflict of interests for potential 
421  DMC members, including procedures for identifying and considering concurrent 
422  service of any DMC member on other DMCs for trials of the same, related, or 
423  competing product  
424    Procedures for adding or removing members when appropriate or for disbanding the 
425  DMC, including procedures for informing FDA and disclosing to FDA the rationale 
426  for these changes  
427   
428  2.  Meeting Information, Schedule, and Format: 
429   
430    Planned frequency of meetings, when additional meetings might be scheduled, and 
431  preferred platform (e.g., email, video, phone, in person) for communications and 
432  conditions for convening ad hoc meetings  
433   
434    Who may attend open and closed portions27 of DMC meetings and whether any 
435  members will not attend full meetings  
436   
437    Who will create specific reports and have access to them, where reports will be 
438  stored, what reports will be generated in the course of the clinical trial (e.g., 
439  prespecified statistical monitoring plan, statistical analysis plan) and how they will be 
440  transmitted within and outside of the DMC 
441   
442    Handling of meeting minutes for open and closed portions 
443   
444    Definition of a quorum of DMC members, including representation of scientific and 
445  other disciplines 
446   
 
27 See section VI.D.1 of this guidance. 
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447  3.  Planned Analyses by Committee and Protection of Data, if applicable, including: 
448   
449    Schedule and basis of planned interim analyses identified in the protocol and/or 
450  statistical analysis plan 
451   
452    Analyses associated with prespecified safety considerations  
453   
454  4.  Maintaining Confidentiality of Data: 
455   
456    How unblinded analyses will be prepared (e.g., by an independent statistician) for the 
457  DMC and at what frequency 
458   
459    How blinding of the trial will be maintained for sponsors, investigators, and subjects 
460   
461    What procedures will be followed to maintain confidentiality of interim comparative 
462  data in communications between the DMC, the sponsor, and outside parties 
463   
464    What strategies will be used for maintaining blinding and confidentiality when 
465  preparing reports for the DMC open sessions 
466   
467    Who, besides the DMC and the independent unblinded statistician, will have access 
468  to interim data and reports to the DMC chair 
469   
470  C.  DMC Responsibilities 
471   
472   1.  Monitoring of Trial Conduct 
473   
474  The DMC considers various matters related to trial conduct.  The sponsor, the trial leadership 
475  (such as a steering committee), and to some extent IRBs also have responsibilities for ongoing 
476  assessment of data regarding the trial conduct.  Such matters related to trial conduct can include: 
477   
478    Rates of recruitment, ineligibility, noncompliance, protocol violations, and 
479  dropoutsoverall and by trial site 
480   
481    Completeness and timeliness of data 
482   
483    Degree of concordance between site evaluation of events and centralized review 
484   
485    Balance between trial arms on important prognostic variables 
486   
487    Accrual within important trial subject subsets 
488   
489  2.  Monitoring of Results of Interim Analysis of Trial Data  
490   
491  Interim analyses are generally conducted for one or more of the following purposes:  
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492   
493    Safety  to determine if there is a credibly increased risk of a serious adverse 
494  outcome in subjects receiving the investigational product, indicating that enrollment 
495  should be stopped.  To determine a safety risk, review of unblinded efficacy data 
496  should also be conducted by the DMC as they evaluate a benefit-risk assessment. 
497    
498    Implementing a predefined adaptive feature:28 
499   
500    Efficacy  to determine if there is statistically strong evidence of efficacy such 
501  that enrollment should be stopped.29 
502   
503    Futility  to determine if there is no longer a reasonable likelihood that the trial 
504  will reach a conclusion of effectiveness, so that enrollment should be stopped to 
505  protect subjects from further exposure to a potentially ineffective investigational 
506  product and to conserve resources. 
507   
508    Other adaptations  a DMC or a separate adaptation committee should determine 
509  if a prespecified adaptive aspect of the trial design is to be implemented.  This can 
510  include modifying the sample size, changing a randomization ratio, or restricting 
511  future enrollment to a prespecified subgroup (adaptive enrichment).   
512   
513  a.  Monitoring for Safety 
514   
515  The most common and most recognized purpose of a DMC is to monitor clinical trials for safety.  
516  First, in studies where the investigational product is intended to prevent significant morbidity or 
517  mortality, the effect on the primary effectiveness endpoint itself would almost always have safety 
518  implications if the group receiving the investigational product had a lower response than the 
519  control.  If subjects given the investigational product are found to be at higher risk for mortality, 
520  disease progression, or loss of organ function than those given the control, the DMC may 
521  recommend early termination on safety grounds.  However, such assessments carry the risk of 
522  falsely concluding that there is an adverse effect, just as repeated assessments of effectiveness 
523  endpoints have the potential to lead to false positive conclusions about benefit.   
524   
525  Statistical considerations for early stopping when the data are trending in the direction of harm 
526  are usually less rigorous (i.e., have a lower threshold for stopping the investigational product) 
527  than those applied to early stopping for benefit, because it is usually appropriate to demand less 
 
28 ClinicalTrials.gov is a database of privately and publicly funded clinical studies conducted around the world and 
is a resource provided by the U.S. National Library of Medicine.  Listing a study does not mean it has been 
evaluated by the U.S. Federal Government; not all listed studies are regulated and/or evaluated by FDA.  
Information on whether a DMC has been appointed for a registered trial can be provided on ClinicalTrials.gov using 
the optional Data Monitoring Committee data element (Y/N) (https://www.clinicaltrials.gov/prs-info/protocol-
definitions#study-oversight). 
 
 
 
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528  proof of harm to justify early termination than would be appropriate for a finding of benefit.  In 
529  some cases, however, it may be appropriate to establish a harmful effect more definitivelyfor 
530  example, if a positive effect on the primary effectiveness endpoint appears to be emerging, a 
531  precise assessment of a negative trend on a potentially important safety endpoint may be 
532  appropriate for benefit-risk considerations.   
533   
534  For trials that are terminated because of safety concerns, timely communication with FDA is 
535  required (see, e.g., 21 CFR 312.56(d) (drugs); 21 CFR 812.40, 812.46(b)(2), and 812.150(b) 
536  (devices)).  For trials where there is a potential safety concern, the sponsor should take 
537  immediate action, as warranted, in the interest of patient safety and initiate discussion with FDA 
538  as soon as possible about the appropriate course of action, both for the trial in question and any 
539  other use of the investigational product, before suspending or terminating a trial.    
540   
541  A second important aspect of safety monitoring is comparison of adverse event rates (other than 
542  trial endpoints) in each treatment arm.  In some cases, adverse events of particular concern can 
543  be identified in advance of the trial, and particular attention will be given to monitoring these 
544  events.  For example, in a large trial of hormone replacement therapy, specific monitoring plans 
545  were established to detect a possible increase in breast cancer incidence in women taking active 
546  therapy (Wittes et al. 2007).  The DMC should generally be provided with interim summaries of 
547  serious adverse events by treatment arm.  This approach is particularly important to identify and 
548  distinguish serious events that typically occur in the disease being treated, as well as the 
549  intervention itself, or for events that can be anticipated to occur at an observable background rate 
550  in the population under investigation.  An effect of the investigational product on these events 
551  can only be detected by comparing the rates of the events in treatment and control groups.   
552   
553  A third aspect of safety monitoring is consideration of serious individual events.  Although a 
554  DMC typically reviews adverse event data, as discussed previously, the committee may elect to 
555  review all or just certain serious adverse events.  It is recommended that DMCs not routinely 
556  review all adverse events individually.30  If the DMC sees trends or identifies an unanticipated 
557  serious safety concern, it should provide feedback to the sponsor or trial steering committee so 
558  that the sponsor can take appropriate action to address potential safety concerns. 
559   
560  Concerns about the extent and type of adverse events observed can lead to early termination of 
561  the trial when the DMC decides that the potential benefits of the intervention are unlikely to 
562  outweigh the risks.  In other cases, a DMC should recommend measures short of termination that 
563  may reduce the risk of adverse events.  For example, the DMC may recommend: 
564   
565    Changing the eligibility criteria or screening procedures if the risks of the 
566  intervention seem to be concentrated in a particular subgroup. 
567   
568    Altering the product dosage and/or schedule if the adverse events observed 
569  appear likely to be reduced by such changes.  This alteration could entail 
570  dropping a particular arm in studies with more than two arms. 
571    
 
30 See 21 CFR 312.32(c). 
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572    Informing current and future trial subjects of newly identified risks through 
573  changes in the consent form, and in some cases reconsenting current subjects for 
574  continued trial participation.  
575   
576  It is important to note that trial monitoring of interim data for safety purposes does not imply 
577  that only safety data should be reviewed by a DMC.  In determining whether the potential for 
578  safety risks is such that trial modification or early termination is warranted, a DMC should 
579  consider the potential for benefit in its deliberations.  For this reason, sponsors should plan to 
580  provide to DMCs the data and analyses sufficient for benefit-risk determinations while taking 
581  the appropriate steps to ensure integrity of trial results (see section VI.D.3 of this guidance). 
582   
583  b.  Monitoring for Effectiveness 
584   
585  Another common purpose of a DMC is to monitor trial data for effectiveness.  Particularly in 
586  trials of investigational products where effectiveness would have important implications for 
587  treating a serious condition, including for subjects in the trial, it is desirable that clear evidence 
588  of effectiveness be identified as soon as possible.  In these instances, it is imperative to consider 
589  the importance for prespecification and appropriate methods to avoid inflating the chance of 
590  obtaining an erroneous result by repeated looks at the accruing comparative data.  Estimates of 
591  treatment effect should be unstable at early points in a trial, and there is a substantial chance of 
592  observing a nominally statistically significant but false benefit at one of multiple interim 
593  analyses during a trial of an ineffective product (Pocock and Hughes 1989) (see section VI.D.2 
594  of this guidance).  A DMC, guided by a prespecified statistical monitoring plan acceptable to 
595  both the DMC and the trial leadership, will generally be charged with recommending early 
596  termination on the basis of a positive result only when the data are compelling and the risk of a 
597  false positive conclusion is acceptably low.  The statistical monitoring plan should describe the 
598  criteria for early termination and should be included in the DMC charter, as well as the statistical 
599  analysis plan, and should describe the criteria for early termination.  
600   
601  c.  Monitoring for Futility 
602   
603  A related purpose of a DMC is to determine trial futility.  If the interim data suggest that the new 
604  product is of no benefit, a DMC may consider whether continuation of the trial would be futile 
605  (that is, the trial is highly unlikely to be successful if run to completion) and may recommend 
606  early termination on this basis.  In this case, false negative conclusions are of concern; available 
607  statistical procedures should be used to guide such determinations (see section VI.D.3 of this 
608  guidance). 
609   
610  d.  Monitoring to Make Other Types of Adaptations to the Trial Design 
611   
612  An adaptive design is defined as a clinical trial design that allows for prospectively planned 
613  modifications to one or more aspects of the design based on accumulating data from subjects in 
614  the trial.31  This may include interim analyses with prespecified criteria for stopping the trial for 
 
31 See the guidance for industry Adaptive Designs for Clinical Trials of Drugs and Biologics and the guidance for 
industry and Food and Drug Administration staff Adaptive Designs for Medical Device Clinical Studies.    
 
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615  efficacy or futility (see sections VI.C.2.b and c above).  Other aspects of the design that might 
616  be modified include the sample size, study arms (e.g., elimination of a particular dose or doses), 
617  randomization ratio, and trial population.  Some adaptations can be based on blinded or 
618  noncomparative data accumulated in the trial.  For example, if the overall event rate in a trial is 
619  low, a decision could be reached to increase trial size or to introduce prognostic enrichment.  
620  Such adaptations should either be prespecified in the protocol or done by an entity without 
621  access to comparative data; they do not threaten trial integrity because they do not involve 
622  unblinding of interim results.  These adaptations could reasonably be made by a steering 
623  committee or the sponsor, assuming they are blinded to the comparative data.32  If the 
624  adaptations are unblinded (including those instances in which the treatment arms are labeled as 
625  A and B rather than as treatment and control), it is particularly important that the opportunities 
626  for adapting not only be prespecified but that they also be conducted in a manner designed to 
627  preserve trial integrity.   
628   
629  A DMC could have the responsibility of recommending to the sponsor that a specific adaptive 
630  design element be implemented.  If so, this responsibility should be explicitly stated in the DMC 
631  charter, recognizing that the main priority of a DMC is both to ensure subject safety and to 
632  preserve trial integrity.   
633   
634  3.  Consideration of External Data 
635   
636  The DMC, the sponsor, or the trial steering committee may consider the impact of external 
637  information on the trial being monitored when appropriate.  In these instances, protocol changes 
638  based on consideration of external data should be proposed by the sponsor or steering committee 
639  to minimize influence/bias from knowledge of internal comparative results.  The release of 
640  results of a related trial (e.g., a trial of a pharmacologically related drug or comparable device) 
641  may have implications for the design of the ongoing trial, or even its continuation.  In some 
642  cases, particularly when unexpected safety issues arise in related trials, the sponsor may bring 
643  external data to the attention of the DMC; in other cases, the data may be publicly reported.  
644  Such data may lead to a wide range of recommendations, such as (1) termination of the trial, (2) 
645  termination of one or more trial arms, (3) changes in target population, dose, and/or duration of 
646  the intervention, (4) changes in monitoring, or (5) use of concomitant treatments.  The DMC may 
647  also recommend changes to the consent form, investigators brochure, and/or letters from the 
648  sponsor to trial subjects describing the external results. 
649   
650  When FDA has critical safety information regarding another trial of the investigational product 
651  or a trial of a related product from the same sponsor that is relevant and important for a DMC to 
652  consider, FDA may request that the sponsor confirm that the DMC for the ongoing trial is aware 
653  of the existing safety data and is taking that data into consideration in evaluating the interim 
654  safety data from the ongoing trial.  An example would be a situation in which FDA is 
655  considering a marketing application in which a safety issue is of concern and the sponsor has a 
656  second, ongoing trial of the investigational product.  In such situations and as appropriate, FDA 
657  may request that the sponsor arrange for FDA to communicate with, or even meet with, the 
658  DMC.  
 
32 Ibid.   
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659   
660  In some circumstances, program-wide DMCs could be helpful.  These are DMCs of separate but 
661  closely related trials (e.g., trials of the same product in different subject populations) that may 
662  consider sharing confidential interim data when unexpected safety issues arise in one trial and 
663  information from the two trials together may improve decision-making for both trials.  Sharing 
664  the results of trials of related investigational products poses potential confidentiality problems, 
665  and the DMC charter should address how information can be shared when the DMC members 
666  are not exactly the same across trials within the program.  From an ethical perspective, it is 
667  important to consider safety-related issues in both trials when considering appropriate trial 
668  changes and to institute similar safety changes in both trials.  
669   
670  The role of the DMC in considering interim changes to a trial protocol or other aspects of trial 
671  conduct in response to external information raises additional issues that merit consideration.  In 
672  many cases, a DMCs knowledge of both the interim trial results and external data can have 
673  undesirable consequences.  For instance, various types of trial modifications (e.g., changing 
674  endpoints, changing or adding to prespecified analysis subgroups) could have significant effects 
675  on statistical inferences (e.g., Type I error probability) if made with knowledge of interim results.  
676  If it is perceived that emerging results could influence these types of interim protocol changes, 
677  the credibility of the trial can be severely damaged.  It should be understood that an unplanned 
678  change in trial design that may have been informed by unblinded interim analyses is discouraged 
679  without first discussing with FDA.   
680   
681  4.  Recommendations and Documentation 
682   
683  a.  Making Recommendations 
684   
685  A fundamental responsibility of a DMC is to make recommendations to the sponsor concerning 
686  the continuation of the trial.  Most frequently, a DMCs recommendation after an interim review 
687  is for the trial to continue as designed.  Other less frequent but possible recommendations, 
688  however, as discussed previously, include trial termination, trial continuation with major or 
689  minor modifications (such as implementation of prespecified adaptive elements), or temporary 
690  suspension of enrollment and/or trial intervention until an identified uncertainty is resolved. 
691   
692  A DMC should express its recommendations clearly to the sponsor because a DMCs actions 
693  potentially affect the safety of trial subjects.  Both a written recommendation and an oral 
694  communication, with opportunity for questions and discussion, can be valuable.  
695  Recommendations for modifications are best accompanied by the minimum amount of data 
696  critical for the sponsor to make a reasonable decision about the recommendation, and the 
697  rationale for such recommendations should be as clear and precise as possible.  Sponsors may 
698  wish to develop internal procedures to limit the interim data released by a DMC after a 
699  recommendation and until a decision is made regarding acceptance or rejection of the 
700  recommendation in order to help maintain confidentiality of the interim results should the trial 
701  continue.  We recommend that a DMC document its recommendations and rationale in a manner 
702  that can be reviewed by the sponsor and then circulated, as appropriate, to IRBs, FDA, and/or 
703  other interested parties, when based on interim data.  Major trial changessuch as early trial 
704  termination, change in population or entry criteria, or change in trial endpointscan have 
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705  substantial impact on the validity of the trial and/or its ability to support the desired regulatory 
706  decision.  Sponsors should discuss with FDA any proposed protocol changes based on review of 
707  interim data that were not planned for, before implementation, and submit such changes to FDA 
708  in accordance with 21 CFR 312.30 and 812.35.  However, if the sponsor learns of information 
709  that presents an imminent safety hazard to trial participants, sponsors should implement the 
710  necessary changes as quickly as possible to ensure the safety and welfare of study subjects (see 
711  21 CFR 312.30(b)(2)(ii) and 812.35(a)(2)). 
712   
713  b.  Maintaining Meeting Records 
714   
715  FDA recommends that the DMC keep minutes of all meetings but use separate minutes for open 
716  and closed sessions.33  We also recommend that after each meeting the DMC issue a written 
717  report to the sponsor based on the meeting minutes.  This report should include sufficient 
718  information to explain the rationale for any recommended changes.  Sponsors, as discussed 
719  previously in this section, should establish procedures to minimize bias, such as requiring that 
720  reports to the sponsor include only those data generally available to the sponsor (e.g., number 
721  screened, number enrolled at each site) (see 21 CFR 314.126(b)(5) and 21 CFR 860.7(f)(1)).  If 
722  no changes are recommended, the report may be as simple as The DMC recommends that the 
723  trial continue as designed.  We further recommend that the report to the sponsor include a 
724  summary of discussions in any open session of the meeting.  The sponsor may convey the 
725  relevant information in this report to other interested parties, such as the trial investigators or, as 
726  appropriate, to reviewing IRBs.  Sponsors and/or investigators must report to and obtain prior 
727  approval from reviewing IRBs and/or FDA, as appropriate, for protocol changes made as a result 
728  of DMC recommendations, in accordance with applicable FDA regulations (see 21 CFR 
729  56.108(a)(3) and (4); 21 CFR 312.30 and 312.66 (for drugs); 21 CFR 812.35 and 812.40 (for 
730  devices)). 
731   
732  FDA recommends that the DMC or the group preparing the confidential interim reports to the 
733  DMC maintain all meeting records to promote continued confidentiality of interim data.  FDA 
734  may request copies of these records when the trial is completed (21 CFR 312.58; 21 CFR 
735  812.150(b)(10)), and we may also request access to the electronic data sets used for each set of 
736  interim analysis.  FDA therefore recommends that sponsors arrange for archiving such electronic 
737  data sets. 
738   
739  D.  Interim Data and Analyses 
740   
741  As described in 21 CFR 314.126(b)(5) and 21 CFR 860.7(f)(1), sponsors of controlled studies 
  
742  should take appropriate measures to minimize bias.34 Knowledge of unblinded interim 
 
33 See section 5.5.2 in the ICH guidance for industry ICH E6(R2) Good Clinical Practice:  Integrated Addendum to 
E6(R1).  See Guidelines for establishing and operating a Data and Safety Monitoring Board (DSMB) at 
https://www.niaaa.nih.gov/research/guidelines-and-resources/guidelines-establishing-and-operating-data-and-safety-
monitoring. 
 
34 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 investigations for devices (as described in 21 CFR 860.7(f)). 
 
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743  comparisons from a clinical trial is rarely critical for those conducting or sponsoring the trial.  
744  Such knowledge can bias the outcome of the trial by inappropriately influencing trial conduct or 
745  the approach to analyses.  Unblinded interim data and the results of comparative interim analyses 
746  therefore should generally not be accessible by anyone other than DMC members or the 
747  statisticians performing these analyses and presenting them to the DMC.  Consistent with 21 
748  CFR 314.126(b)(5) (drugs) and 21 CFR 860.7(f)(1) (devices), sponsors should establish written 
749  procedures, which should be included in the DMC charter, to ensure minimization of the 
750  potential for bias, such as maintaining confidentiality of the interim data (see section VI.C.1.d of 
751  this guidance).  Before initiation of the clinical trial, sponsors should consider addressing such 
752  confidentiality issues in written agreements between the sponsor and members of the DMC, as 
753  well as written agreements between the sponsor and investigators.  Trial design modifications 
754  that involve examination of comparative analyses include discontinuation of treatment arms or 
755  adjustments to sample-size based on estimated treatment effects observed during a trial.  A DMC 
756  can be involved in making recommendations about planned (prespecified) adaptations based on 
757  their review of interim results.  
758   
759  Even for trials not conducted in a double-blind fashion, where investigators and subjects are 
760  aware of individual treatment assignment and outcome at their sites, the summary evaluations of 
761  comparative unblinded treatment results across all participating centers would usually not be 
762  available to anyone other than the DMC or the independent statistician performing the analyses.  
763   
764  1.  Confidentiality of Interim Data 
765   
766  As emphasized, access to the accumulating comparative effectiveness data should be limited to 
767  the DMC and any statistical personnel involved in generating the interim analysis results for 
768  DMC review.  Broader access unblinds the trial and could lead to bias.  Of note, FDA considers 
769  the data to be unblinded when they are reviewed by treatment group (e.g., A versus B), whether 
770  or not the groups are identifiable.  As with the review of any unblinded safety and effectiveness 
771  data, this function should be reserved for the DMC.  However, an entity that reviews safety 
772  reporting may review unblinded datausually data only for particular adverse events of interest 
773  and subjects with those eventswith the awareness that confidentiality regarding unblinded 
774  data should be maintained to preserve trial integrity.  One helpful approach that could be 
775  considered is maintaining appropriate firewalls between such safety review entities and those 
776  directly involved in the conduct of the trial, especially if the safety review entity is also tasked 
777  with performing aggregate analyses of adverse events across treatment arms.   
778   
779  As noted, the DMC will usually be provided with unblinded data to make its assessments.  It is 
780  usual to have an independent statistician perform those analyses and for that statistician to be 
781  clearly firewalled and have no role in modifications of the trial conduct.  Trial integrity will be 
782  best protected when the statisticians preparing unblinded data are external and independent from 
783  the sponsor and DMC and are uninvolved in discussions regarding potential changes in trial 
784  design while the trial is ongoing.  Balanced against this concern, however, is the importance for 
785  the statisticians reporting to the DMC to be very familiar with details of the trial and to have 
786  ample opportunity to assess the interim data.   
787   
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788  Attendance at meetings raises the same confidentiality issues as does access to interim reports 
789  provided to the DMC.  FDA fully expects confidentiality of the interim data during interactions 
790  with clinical trial stakeholders, including the sponsor and/or trial investigators.  To facilitate this 
791  interaction without compromising confidentiality, many DMC meetings include an open session 
792  where non-confidential data are discussed, such as status of recruitment, baseline characteristics, 
793  ineligibility rate, accuracy and timeliness of data submissions, and other administrative data.  
794  Sponsors may also use open sessions to provide external data to the DMC that may be relevant to 
795  the trial being monitored.  Open session discussions might include representatives of the sponsor, 
796  steering committee, trial investigators, FDA representatives, or others with trial responsibilities, 
797  and benefits exist to having a wider attendance at these sessions.  These subjects provide an 
798  opportunity for those with relevant knowledge of the trial to share their insights with the DMC 
799  and raise issues for the DMC to consider.   
800   
801  The DMC should discuss the comparative interim data in a closed session attended only by the 
802  DMC members and the statistician who prepared the data and is presenting the interim analyses 
803  to the DMC.  Following the closed session, the DMC may meet again with the sponsor to relay 
804  any recommendations the DMC has made.   
805   
806  2.  Interim Reports to the DMC 
807   
808  In many cases, the DMC receives reports in two parts:  (1) an open section, which presents data 
809  only in aggregate and focuses on trial conduct issues such as accrual and dropout rates, 
810  timeliness of data submission, eligibility rates, and reasons for ineligibility and (2) a closed 
811  section, in which the comparative outcome data are presented.  The open section of these reports 
812  should be provided to sponsors, who should convey any relevant information in this section to 
813  investigators, IRBs, and other interested parties, because the data presented in the open section 
814  should not bias the future conduct of the trial and are often important for improving trial 
815  management. 
816   
817  3.  Analysis Used by the DMC 
818   
819  The typical statistical analysis plan (SAP) submitted to FDA focuses on defining the principal 
820  features of the statistical analyses of the primary and secondary variables associated with the trial 
821  objectives.  DMCs may review additional exploratory analyses that are distinct from those in the 
822  formal SAP submitted to FDA.  The SAP details the (pre-specified) statistical methods and also 
823  provides a basis for the sample sizes anticipated for the trial.  It should also provide for pre-
824  specified interim analyses to determine early success or to stop for futility (i.e., the overall trial 
825  appears unlikely to succeed).  However, the DMC may perform or request additional statistical 
826  analyses outside the SAP that look at the accumulated data to date and decide, for example, that 
827  the chances for meeting the success criteria at the end of the trial are low.  They may also 
828  consider sensitivity analyses that can be used to challenge that decision.  The DMC would then 
829  convey their recommendation to the trial sponsor or steering committee.  A DMC may also 
830  conduct or request unblinded analyses by considering both the primary endpoint of interest and 
831  imbalances in serious adverse events among the trial arms.  Therefore, these statistical analyses 
832  may also differ from those in the SAP.  
833   
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834  For those trials in which another group makes decisions that impact trial design and/or conduct, 
835  it is important to convey those changes to the DMC when they occur.  For example, an 
836  adaptation committee may recommend adding or dropping an arm, or an entity that reviews 
837  safety reporting may identify a new safety concern.  These decisions may affect the statistical 
838  considerations of the DMC.   
839   
840  Finally, as noted earlier, the DMC may serve as the entity that reviews safety data for 
841  recommending when an IND or IDE safety report should be sent to FDA35 or may serve as a 
842  program-wide safety assessment group involving multiple trials.  The statistical analyses used to 
843  review safety data may vary accordingly but are unlikely to be part of the SAP submitted to 
844  FDA. 
845   
846   
847  VII.  INDEPENDENCE OF THE DMC 
848   
849  The independence of a DMC depends on the relationships of its members to those sponsoring, 
850  organizing, conducting, and regulating the trial (Ellenberg 2012).  Independence is established 
851  when members have no involvement in the design or conduct of the trial or in the endpoint 
852  determination except through their role on the DMC or the adjudication committee.  In addition, 
853  no significant financial or other important connections should exist between the DMC members 
854  and the sponsor (other than their compensation for serving on the DMC), or other trial 
855  organizers, nor should there be other professional or financial relationships that could influence 
856  or be perceived to influence the members objectivity in evaluating trial data (see section VI.A.2 
857  of this guidance).  
858   
859  A critical issue in planning and managing the operations of a DMC is resolving the tension that 
860  can arise between having a maximally independent DMC and having a DMC that is well 
861  informed about the trial objectives, design, and conduct.  Defining independence too narrowly 
862  and rigidly may eliminate from consideration the most knowledgeable researchers, who are 
863  likely to have had some past interaction with others sponsoring or performing research in their 
864  area of expertise.  Moreover, although sponsors should not examine unblinded comparative data 
865  of an ongoing trial, sponsor representatives, trial statisticians, and trial investigators may 
866  contribute valuable perspectives regarding the trial that may not be available to the committee 
867  from more independent sources.  With regard to sponsor/investigator involvement with the    
868  DMC, this tension is best resolved by permitting interaction with the committee in a carefully 
869  defined and limited manner, as described in section VI.C.1.b of this guidance.  The involvement 
870  of such persons with the DMC should be limited in terms of what interim data may be viewed, 
871  which sessions may be attended, what topics may be discussed, and what roles (e.g., observer, 
872  consultant, member) may be played.   
873   
874  Independence of the DMC from the sponsor is critical, because it (1) ensures that sponsor 
875  interests do not influence the DMC, (2) enhances the DMCs objectivity and reduces the 
876  possibilities for bias, increasing the validity of the trials conclusions, (3) preserves the ability of 
 
35 See section V.D of this guidance and see the draft guidance for industry Safety Assessment for IND Safety 
Reporting.  
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877  the sponsor to make appropriate modifications to a trial in response to new external information 
878  on trial conduct problems without introducing bias, and (4) may shield the sponsor (and thus the 
879  trial) from conflict of interest by maintaining the sponsor in a fully blinded state. 
880   
881   
882  VIII.  FDA RECOMMENDATIONS AND REGULATORY REPORTING 
883  REQUIREMENTS 
884   
885  As discussed in section VI.C.1.a. of this guidance, evidence of a possible relationship between 
886  many serious adverse events, especially those that occur spontaneously in the population, and an 
887  investigational product may be detectable only by comparison of rates in the two arms of a 
888  controlled trial and not by review of individual cases.  Consistent with 21 CFR 312.32(d)(1), the 
889  sponsor must investigate a DMCs recommendation relating to such safety events as potentially 
890  reportable to FDA under 21 CFR 312.32.  If the sponsor concludes that there is a reasonable 
891  possibility that the increased rate of serious unanticipated adverse events was associated with use 
892  of the drug, the finding, and support for it (which could include the DMC report, any analyses, 
893  and pertinent data) must be submitted to FDA as a serious unexpected suspected adverse 
894  reaction.  Similar considerations would also apply if the sponsor concludes that an increased rate 
895  of adverse events constitutes an unanticipated adverse device effect under 21 CFR 812.46(b) and 
896  812.150(b)(1). 
897   
898  Findings conveyed to a sponsor by a DMC as part of a recommendation to modify the trial could 
899  be based on a finding that there was an increased rate of serious and unexpected adverse events 
900  in the investigational product arm, and the sponsor may accordingly be required to report an 
901  analysis or evaluation of these events to FDA and to all trial investigators according to 21 CFR 
902  312.32(c)(1)(i)(B)(ii) (drug trials) and 21 CFR 812.150(b)(1) (device trials).  In clinical trials for 
903  investigational products, the requirement to expediently report unexpected serious adverse events 
904  for which there is a reasonable possibility that the drug caused the adverse event (21 CFR 
905  312.32(c)) or unanticipated serious adverse effect on health or safety or any life-threatening 
906  problem or death caused by, or associated with, a device (21 CFR 812.3 and 812.150(b)(1)) 
907  would not apply when the DMC recommendation is related to an excess of events not 
908  classifiable as serious.  Nevertheless, we recommend that sponsors inform FDA about all DMC 
909  recommendations related to the safety of the investigational product, whether or not the adverse 
910  events that led to the recommendation meet the definition of serious.  Examples include 
911  recommendations to lower the dose of an investigational drug because of excess toxicity or to 
912  inform current and future trial subjects of an emerging safety concern with the investigational 
913  product that had not been recognized at the start of the trial.36 
914   
915  A DMC recommends to the sponsor whether to continue, modify, or stop a trial or trials; the 
916  sponsor decides whether to accept recommendations to discontinue a trial.  The final decision on 
 
36 A noncomparative analysis is an examination of accumulating trial data in which the treatment group assignments 
of subjects are not used in any manner in the analysis.  A comparative analysis is an examination of accumulating 
trial data in which treatment groups are identified, either with the actual assigned treatments or with codes (e.g., 
labeled as A and B, without divulging which treatment is investigational).  For more information about comparative 
and noncomparative analysis, see the guidance for industry Adaptive Designs for Clinical Trials of Drugs and 
Biologics.  It should be noted, reporting data with codes can be informative and should be best treated as unblinded. 
 
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917  whether to discontinue the trial based on a DMCs recommendation is the sponsors.  For trials 
918  that may be terminated early because a substantial benefit has been observed, DMCs and 
919  sponsors should consider the adequacy of data with regard to other issues such as safety, 
920  duration of benefit, outcomes in important subgroups, and important secondary endpoints.  
921  Sponsors may discuss with FDA the DMCs recommendations for early termination based on 
922  evidence of effectiveness, because the regulatory implications of early termination should be 
923  considered.      
924   
925  Note that for trials that fall under the jurisdiction of more than one regulatory body, reporting 
926  requirements during a trial may vary.37  It is important for sponsors and DMC members to be 
927  aware of and comply with relevant jurisdictional reporting requirements.     
 
37 For the purposes of this guidance, the term aggregate refers to data within a treatment arm or across treatment 
arms.  
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928  REFERENCES 
929   
930  Balakrishnan, N, editor, 2014, Methods and Applications of Statistics in Clinical Trials:  
931  Concepts, Principles, Trials, and Design, Volume 1, John Wiley & Sons, Inc., Hoboken, New 
932  Jersey, https://onlinelibrary.wiley.com/doi/book/10.1002/9781118596005.  
933   
934  Bhattarcharya, A, P Gallo, A Crisp, L LaVange, G Molenberghs, F Petavy, J Seltzer, 2018, The 
935  Changing Landscape of Data Monitoring CommitteesPerspectives From Regulators, 
936  Members, and Sponsors, Biometric Journal, https://doi.org/10.1002/bimj.201700307. 
937   
938  Califf, RM, DA Zarin, JM Kramer, RE Sherman, LH Aberle, and A Tasneem, 2012, 
939  Characteristics of Clinical Trials Registered in ClinicalTrials.gov, 2007-2010, JAMA, May 
940  2;307(17):1838-1847, https://doi.org/10.1001/jama.2012.3424. 
941   
942  DeMets, DL, and KK Lan, 2013, Alpha-Spending Function, In Encyclopedia of Statistical 
943  Sciences, S Kotz, CB Read, N Balakrishnan, B Vidakovic, and NL Johnson, editors, 
944  https://doi.org/10.1002/0471667196.ess7157.  
945   
946  Ellenberg, S, TR Fleming, and DL DeMets, 2002, Data Monitoring Committees in Clinical 
947  Trials:  A Practical Perspective, John Wiley & Sons, Ltd., Print ISBN:  0-471-48986-7. 
948   
949  Ellenberg, SS, 2012, Protecting Clinical Trial Participants and Protecting Data Integrity:  Are We 
950  Meeting the Challenges?, PLOS Medicine 9(6): e1001234, 
951  https://doi.org/10.1371/journal.pmed.1001234. 
952   
953  Pocock, SJ, and MD Hughes, 1989, Practical Problems in Interim Analyses, With Particular 
954  Regard to Estimation, Control Clin Trials, 10(4 Suppl): 209S221S. 
955     
956  Proschan, MA, KKG Lan, and JT Wittes, 2006, Statistical Monitoring of Clinical Trials:  A 
957  Unified Approach, Springer.com.  
958   
959  Wittes, J, E Barrett-Connor, E Braunwald, M Chesney, HJ Cohen, D DeMets, L Dunn, J Dwyer, 
960  RP Heaney, V Vogel, L Walters, S Yusuf, 2007, Monitoring the Randomized Trials of the 
961  Women's Health Initiative:  The Experience of the Data and Safety Monitoring Board, Clin 
962  Trials, 4(3):218234, https://doi.org/10.1177/1740774507079439. 
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963   
964  APPENDIX   
965   
966  Data Monitoring Committees (DMCs) were initially used in large randomized multicenter trials 
967  sponsored by Federal Agenciessuch as the National Institutes of Health (NIH) and the 
968  Department of Veterans Affairs (VA) in the United States (and similar bodies abroad)that 
969  targeted improved survival or reduced risk of major morbidity (e.g., acute myocardial infarction) 
970  as the primary objective.  In a set of recommendations to the National Heart Institute in 1967,1 an 
971  NIH external advisory group first introduced the concept of a formal committee charged with 
972  reviewing the accumulating data as the trial progressed in order to monitor safety, effectiveness, 
973  and trial conduct issues.   
974   
975  The recommendation for the establishment of such committees was based on the recognition that 
976  interim monitoring of accumulating trial data was essential to ensure the ongoing safety of trial 
977  subjects but that individuals closely involved with the design and conduct of a trial could not be 
978  expected to be fully objective in reviewing the interim data for any emerging concerns and 
979  should not see unblinded data.  The involvement of expert advisors external to the trial 
980  organizers, sponsors, and investigators was intended to ensure that issues would be addressed in 
981  an unbiased way.  The operational and functional aspects of these committees, based on 
982  experience over several decades, were discussed in a 1992 NIH workshop.2
983   
984   
 
1  Heart Special Project Committee, 1988, 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, 9(2):137148. 
 
2  Ellenberg, S, N Geller, R Simon, and S Yusuf, editors, 1993, Proceedings of Practical Issues in Data Monitoring 
of Clinical Trials, Bethesda, MD, January 2728, 1992, Statistics in Medicine, 12:415616. 
26