Department of Health and Human Services 
OFFICE OF 
 
INSPECTOR GENERAL 
 
 
 
 
 
 
D   S M
ATA AND  AFETY  ONITORING 
 
B NIH C
  OARDS IN    LINICAL 
 
T :  M G , 
RIALS    EETING  UIDANCE  
 
 
B F S I  
UT  ACING  OME  SSUES 
 
 
 
 
 
   
 
 
Daniel R. Levinson   
Inspector General  
 
June 2013 
OEI-12-11-00070   
   
EXECUTIVE SUMMARY:  DATA AND SAFETY MONITORING BOARDS IN 
NIH CLINICAL TRIALS:  MEETING GUIDANCE, BUT FACING SOME ISSUES   
OEI-12-11-00070 
 
WHY WE DID THIS STUDY 
 
A Data and Safety Monitoring Board (DSMB) is a committee of experts responsible for 
reviewing clinical trial data on an ongoing basis to ensure the safety of study subjects and 
validity and integrity of the data. Members should be independent, with no vested 
interest in a specific treatment.  A DSMB reviews evidence of adverse events and interim  
treatment outcomes to recommend whether trials should be continued, altered, or 
terminated.  To do so, a DSMB must have access to unmasked data during the course 
of a trial, meaning that members know which subjects are in which treatment group.  This 
study seeks to determine the extent to which DSMBs met National Institutes of Health 
(NIH) guidance, identify any challenges to DSMB effectiveness, and contribute to the 
Office of Inspector Generals body of work concerning clinical trials and human subject 
protections. 
 
HOW WE DID THIS STUDY 
 
We reviewed the extent to which DSMBs met NIH guidance and identified any 
challenges to their effectiveness. According to general NIH guidance, DSMBs (which 
are composed of relevant experts) should meet regularly to review interim trial data and  
make recommendations concerning the trials continuation or termination.  Our findings 
are based on the population of 44 NIH-funded Phase III multi-site clinical trials 
completed in 2009 and 2010 that entailed potential risk.  We reviewed NIH guidance and 
DSMB policies; documentation regarding DSMB meetings, including membership 
rosters and recommendations; surveyed DSMB members and principal investigators; and 
interviewed NIH staff and DSMB stakeholders. 
 
WHAT WE FOUND 
 
DSMBs met general NIH guidance.  They met regularly, and 91 percent of meetings 
resulted in a recommendation to NIH.  DSMB members represented multiple disciplines 
and had significant experience. Most DSMB members identified themselves as either 
clinicians or as clinical trial experts.  However, DSMBs face some issues.  NIH 
participation in closed DSMB meetings diminishes the appearance of independence; not 
all Institutes and Centers (IC) policies reference DSMB access to unmasked data; and 
NIH faces challenges in recruiting and training DSMB members.  
 
WHAT WE RECOMMEND 
 
NIH should (1) direct ICs to articulate the circumstances in which IC staff should 
participate in DSMB meetings, (2) direct ICs to explicitly reference DSMB access to 
unmasked data in their DSMB policies, and (3) identify ways to recruit and train new 
DSMB members.  NIH concurred with all three recommendations. 
 
   
   
TABLE OF CONTENTS 
 
Objectives ....................................................................................................1 

Background..................................................................................................1 

Methodology................................................................................................4 

Findings........................................................................................................7 

DSMBs are meeting NIH guidance in their roles as trial                 
monitors ...........................................................................................7 

DSMBs face some issues that may affect their ability to fulfill    
their roles .........................................................................................9 

Conclusion and Recommendations ............................................................12 

Agency Comments and Office of Inspector General Response .....13 

Appendix: Agency Comments ..................................................................14 

Acknowledgments......................................................................................17 

   
 
   
   
OBJECTIVES  
1. 	  To determine the extent to which Data and Safety Monitoring Boards 
(DSMBs) met National Institutes of Health (NIH) guidance in carrying 
out their responsibilities to monitor trials.  
2. 	  To identify any challenges to DSMB effectiveness.  
BACKGROUND 
Clinical trials test experimental drugs, devices, and treatments to 
determine whether they are safe and effective.  DSMBs are advisory 
committees of experts responsible for reviewing ongoing trial data.  They 
play a unique role in ensuring the safety of human subjects enrolled in 
trials. They also play a critical role in ensuring the merit of these trials.1   
To carry out these functions, DSMBs must have direct access to 
unmasked data during the course of a trial, meaning that members know 
which subjects are in which treatment groupsomething the researchers 
and subjects themselves do not generally know.  NIH requires DSMBs to 
monitor all Phase III multi-site trials that entail potential risk.2     
DSMBs serve as independent bodies of experts that have no vested 
interest in a specific treatment.  DSMBs approach trial monitoring with 
uncertainty regarding whether the intervention or drug being tested will be 
superior to existing treatments or at all effective until proven otherwise.3   
DSMBs review evidence of study-related adverse events and interim  
treatment outcomes to recommend whether trials should be continued, 
altered, or terminated.  This study seeks to explain the important role that 
DSMBs play in NIH-sponsored research involving human subjects, and to 
contribute to the Office of Inspector Generals (OIG) significant body of 
work concerning clinical trials and human subject protections. 
NIH 
NIH is the largest source of funding for medical research in the world; it 
had a budget of $30.9 billion in fiscal year (FY) 2012.4  NIH comprises 
the Office of the Director and 27 Institutes and Centers (IC), each with a 
specific research agenda.    
 
 
 
1 NIH,   Policy for Data  and Safety Monitoring, 1998.  Accessed  at http://grants.nih.gov 
 
on January 15,  2013. 
 
2 Ibid. 

3 This approach is known as practicing clinical equipoise.  

4 NIH,   Operating Plan-Budget Mechanism.  Accessed at 

http://officeofbudget.od.nih.gov on December 18, 2012.  

Data and Safety  Monitoring Boards in NIH Clinical Trials (OEI-12-11-00070)                            1  
   
   
Clinical Trials 
A clinical trial is a controlled study to determine whether an experimental 
drug, treatment, or device is safe and effective.  Drugs, treatments, and 
devices generally undergo three phases of clinical trials. Phase III trials 
typically involve several hundred to several thousand human subjects.  
These trials are used to confirm the effectiveness of a treatment, monitor 
its side effects, compare it to commonly used treatments, and collect 
information on safe usage.  Phase III clinical trials also typically involve 
multiple trial sites where human subjects receive an experimental 
intervention.5  All multi-site clinical trials involving interventions that 
pose potential risk to the participants require a DSMB.6  
 
Grantees, principal investigators, and DSMBs are involved in Phase III 
NIH clinical trials.  A grantee is an organization or individual awarded a 
grant or cooperative agreement by NIH.  The grantee is accountable for 
the use of funds and for the performance of the clinical trial.  Grantees 
typically include academic centers or pharmaceutical and device 
companies.  To direct the trial, a grantee designates a principal investigator 
who is accountable to the grantee and NIH for the trials proper conduct.7  
A DSMB is a group of individuals with pertinent expertise that regularly 
reviews accumulating data from one or more ongoing clinical trials.  A  
DSMB functions as a monitor of the trial to ensure the safety of study 
subjects and validity and integrity of the data.  Independence is critical for 
DSMBs. Without independence, their recommendations could be biased, 
and the ability of the DSMB to fulfill its mission would be compromised.  
DSMBs make recommendations to NIH, Institutional Review Boards 
(IRBs), and/or the principal investigator regarding continuing, altering, 
suspending, or terminating a trial. 8,  9  For instance, a DSMB may 
recommend terminating a trial if  the results are so overwhelmingly 
positive or negative that the ultimate conclusion can be readily predicted 
or if the trial appears futile (e.g., no difference emerged between the 
treatment groups).    
DSMBs meet in open and closed sessions.  They generally first meet in an 
open session attended by voting DSMB members, IC staff, principal 
 
5 NIH,  Glossary. Accessed at http://grants.nih.gov  on January 15, 2013. 
6 NIH,  Policy for Data and Safety Monitoring, 1998. Accessed at http://grants.nih.gov on 

January 15, 2013. 
 
7 NIH,  Glossary. Accessed at http://grants.nih.gov  on January 15, 2013. 

8 An IRB is a committee set up to ensure the protection of the rights and welfare of 

human subjects.  Each clinical trial  must be covered by  an IRB.  IRBs are typically               
site-specific. 

9 NIH,  Policy for Data and Safety Monitoring, 1998. Accessed at http://grants.nih.gov on 

January 15, 2013. 
 
Data and Safety  Monitoring Boards in NIH Clinical Trials (OEI-12-11-00070)                            2  
   
   
investigators, and industry representatives.10  During an open session, 
principal investigators or their designee(s) typically provide an update on 
trial progress and answer questions.  Following the open session, the 
DSMB convenes a closed session to review emerging trial data (including 
potentially unmasked data).  Closed sessions are attended by voting 
DSMB members and sometimes by study statisticians and other IC staff.11   
These closed meetings also include a review and discussions of adverse 
events, participant risk versus benefits, and trial sites.  
NIH DSMBs 
Potential grantees who apply for funding must submit a clinical trial 
protocol, which is a detailed study plan that includes the objectives, 
methodology, and statistical plan for the trial.  The protocol must include a 
data and safety monitoring plan (DSM plan).  For multi-site Phase III 
clinical trials that involve risk to participants, the plan must involve a 
DSMB.12    
 
NIH allows ICs flexibility in implementing the DSMB guidance for data 
and safety monitoring. Each IC should have its own DSMB policy.   
However, NIH does specify responsibilities related to DSMB composition, 
reporting, and conflict of interest.13    
Composition.   DSMBs should consist of experts in all scientific disciplines  
needed to interpret the trial data and ensure patient safety.  They may 
include clinical trial experts, biostatisticians, bioethicists, and clinicians  
knowledgeable about the disease and treatment under study.14  ICs are 
responsible for ensuring that DSMB members have the appropriate 
expertise required for each specific trial.15  
Reporting Recommendations. A DSMB must make recommendations to 
the IC after each meeting concerning  the continuation or conclusion of the 
trial. The IC should review all recommendations and ensure that they are 
addressed and shared with the principal investigator and the IRB.16    
Conflict of Interest. To preserve the groups independence, individual 
DSMB members should not be associated with the trial, meaning that they 
should have no financial or professional interests in the trial.  ICs should 
 
10 NIH,  Policy for Data and Safety Monitoring, 1998.   Open sessions can be public or 
 
private, as decided by  the IC. Accessed  at http://grants.nih.gov on  January 15, 2013.  

11 Ibid. 

12 Ibid. 

13 NIH,  Glossary. Accessed at http://grants.nih.gov  on January 15, 2013. 

14 NIH,  Policy for Data and Safety Monitoring, 1998. Accessed at http://grants.nih.gov 

on January 15,  2013. 
 
15 Ibid. 

16 Ibid. 

Data and Safety  Monitoring Boards in NIH Clinical Trials (OEI-12-11-00070)                            3  
   
   
evaluate whether the potential DSMB members have conflicts of interest 
with or financial stakes in the research outcomes; when conflicts exist, ICs 
must have policies for managing them in a reasonable manner.17  Although 
it is not explicitly required, ICs may require that DSMB members disclose 
a conflict or sign a document maintaining that they are free of any conflict 
of interest.  
Related Reports 
In 1998, OIG issued a series of reports on IRBs.18  This report is a follow-
up on the recommendations from that series regarding the use of DSMBs.  
OIG recommended that NIH and the Food and Drug Administration 
(FDA) define the types of trials for which DSMBs would be required and 
set forth requirements for the composition of DSMBs.19  In response, NIH 
required DSMBs for all Phase III multi-site trials and published guidance 
about their composition.20  FDA released nonbinding recommendations 
regarding the use of DSMBs. Like NIH, FDA defines a DSMB as a group 
of individuals with pertinent experience that reviews accumulating data 
from one or more ongoing clinical trials.  FDA allows trial sponsors to 
determine when a DSMB may be useful for study monitoring.21     
METHODOLOGY 
This study reviewed the extent to which DSMBs for NIH-funded Phase III 
multi-site clinical trials met NIH guidance.  The findings are based on data 
collected on the population of Phase III multi-site clinical trials completed 
in 2009 and 2010 that entailed potential risk.  NIH identified a total of 44 
trials funded by 10 ICs that met these criteria.   
We used several data sources to answer our study objectives:  (1) NIH 
guidance and IC DSMB policies; (2) DSM plans; (3) documentation 
regarding DSMB meetings, including membership rosters and 
recommendations; (4) a survey of DSMB members, (5) a survey of 
principal investigators; (6) structured interviews with staff from the         
10 ICs; and (7) interviews with DSMB stakeholders.  These sources are 
described below.  
 
17 Ibid. 

18 OIG,  Institutional  Review Boards:  Their Role in Approved  Research, OEI-01-97-
00190, June 1998;  Institutional Review Boards:  Promising  Approaches, OEI-01-97-
00191, June 1998;  Institutional Review Boards:  The Emergence of Independent Boards, 

OEI-01-97-00193, June 1998;  Institutional Review Boards:  A Time for Reform, OEI-01-
97-00193, June 1998. 

19 OIG,  Institutional  Review Boards:  A Time for Reform, OEI-01-97-00193, June 1998. 

20 NIH,  Policy for Data and Safety Monitoring, 1998. Accessed at http://grants.nih.gov 

on January 15,  2013. 
 
21 FDA,  Guidance for Clinical  Trial Sponsors:  Establishment and  Operation of Clinical 
 
Trial Monitoring Committees, 2006. Accessed at www.fda.gov on March 7, 2013. 

Data and Safety  Monitoring Boards in NIH Clinical Trials (OEI-12-11-00070)                            4  
   
   
NIH Guidance and IC Policies  
We reviewed NIHs 1998 Policy for Data and Safety Monitoring to assess 
NIH guidance on DSMBs. Because each IC has flexibility in 
implementing this guidance as appropriate for its specific clinical research  
activities, we also reviewed the 10 ICs DSMB policies.   
DSM Plans 
We collected DSM plans from ICs for each of the 44 clinical trials.  From  
these we gathered information about the DSMBs composition and the 
frequency of their meetings.  
Documentation Regarding DSMB Meetings 
We received documentation regarding closed DSMB meetings for 39 of 
the 44 trials in our population (a total of 399 meetings).22  For each closed 
meeting, we received meeting attendance records, a summary of the 
meeting (including any minutes), and DSMB recommendations.   
Survey of DSMB Members 
In April 2012, we surveyed DSMB members about their experiences on 
DSMBs and whether they had enough information to make 
recommendations.  We identified 322 DSMB members through the DSMB 
membership rosters provided by NIH for our population of 44 studies.  Of 
the 322, we ultimately surveyed 251.23   We made up to three attempts to 
elicit responses and ultimately received 180, 72-percent response rate.  
Survey of Principal Investigators 
In November 2012, we surveyed principal investigators about their 
perceptions regarding the representation of scientific disciplines on 
DSMBs and their overall experiences with DSMBs.  NIH provided us a 
list of all 91 principal investigators associated with our population of  
44 trials (some trials had multiple investigators).  Of the 91, we ultimately 
surveyed 69 principal investigators.24   We made up to three attempts to 
elicit responses and ultimately received 30, 43-percent response rate.  
Given this response rate, our results may not reflect the opinions of all the 
principal investigators associated with the 44 clinical trials in our 
population. 
 
 
 
 
 
22 One IC accounted for the five trials for which we did not receive meeting minutes.  
This IC stated that it does not receive DSMB meeting documentation.  

23 Thirty-five email addresses were no longer active; 21 DSMB members were listed 
 
more than once; 5 DSMB members were deceased; and 3 individuals stated that they did 

not  serve on a DSMB and were incorrectly identified.  

24 Seventeen email addresses were no longer active; four individuals confirmed they were 

not the principal investigator for the trial; and one principal investigator was deceased. 

Data and Safety  Monitoring Boards in NIH Clinical Trials (OEI-12-11-00070)                            5  
   
   
 
Structured Interviews With NIH Staff  
We interviewed staff from the 10 ICs associated with 2009 and 2010 trials.  
We asked IC staff about their oversight of DSMBs, including any training 
provided to members and the recruitment process.  We also asked about 
the IC staffs review of DSM plans and DSMB recommendations.   
Interviews With Stakeholders 
We interviewed 11 experts with DSMB experience either as DSMB 
members (e.g., biostatistician, clinician) or a principal investigator.  These 
experts were not directly associated with any trials in our population and 
were identified through research and individual recommendations.  
Conversations focused on the independence of DSMBs, DSMB members  
access to unmasked data, and recruitment and training of DSMB members. 
Limitations 
Given our response rates and the possibility that nonresponding DSMB 
members or principal investigators may have responded differently to our 
questions than responders, our results may not reflect the opinions of all 
DSMB members or principal investigators associated with the 44 clinical 
trials in our population. Also, given that responses were anonymous, we 
are unable to determine the specific trials with which respondents are 
associated.  
Standards 
This study was conducted in accordance with the Quality Standards for 
Inspection and Evaluation issued by the Council of the Inspectors General 
on Integrity and Efficiency.   
Data and Safety  Monitoring Boards in NIH Clinical Trials (OEI-12-11-00070)                            6  
   
   
FINDINGS 
DSMBs are meeting NIH guidance in their roles as 
trial monitors 
According to NIH guidance, DSMBs should meet regularly to review 
interim trial data and make recommendations to ICs concerning the 
continuation or conclusion of the trial.  DSMBs should be composed of 
experts in all scientific disciplines needed to interpret the data and ensure 
patient safety.  For NIH trials completed in 2009 and 2010, we found that 
DSMBs met this general guidance.   
DSMBs met regularly and made recommendations about the 
continuation of the trials 
Clinical trials span many years; therefore the DSMBs must meet over 
many years.  The 39 trials for which we had meeting records met for             
4.5 years on average, ranging from 21 months to 8.5 years.  Almost all 
members reported that their DSMBs met frequently enough to fulfill their 
mission.  Most DSMBs met semiannually (45 percent) or annually (42 
percent). The remainder met quarterly. 
DSMBs initial meetings were usually in person, but over half of the 
subsequent 360 meetings were by teleconference.  IC staff reported that 
meeting via teleconference reduced the burdens of time and travel.   
At the conclusion of closed sessions, DSMB members vote on  
recommendations regarding trial continuation.  Making such 
recommendations is a primary responsibility of the DSMB.  The great 
majority of meetings (91 percent, 365 of 399) resulted in 
recommendations.25  According to meeting records we reviewed, the 
DSMBs recommended stopping seven trials.  Four of these 
recommendations were based on findings that the treatments under study 
were ineffective; the other three were based on findings that the trials 
could not accrue enough subjects in the allotted time to yield useful 
results. All seven trials were subsequently terminated.   
The great majority of DSMB recommendations were to continue the 
studies with no changes; 20 percent of the recommendations were to 
continue the studies with changes.  Recommended changes included 
pretrial changes to the protocol, altering the informed consent form or 
process, changing enrollment, or changing treatment. 
 
 
25 Those that did not were often the final meetings at the close of  the trial or a specific 
meeting solely  on enrollment updates or a protocol modification.  
Data and Safety  Monitoring Boards in NIH Clinical Trials (OEI-12-11-00070)                            7  
   
   
DSMB members represented multiple disciplines and have 
significant experience with DSMBs  
The effectiveness of a DSMB depends in large part on the strengths of its 
members.  Members volunteer their expertise and time to ensure trial 
integrity and patient safety.  According to IC staff and DSMB 
stakeholders, DSMB members are experienced professionals respected in 
their scientific fields.   
The DSM plans and DSMB policies we reviewed generally called for 
members from the disciplines necessary to carry out the task of a DSMB.  
On the basis of our review of the DSMB rosters, DSMBs met this general 
requirement.  DSMBs were composed of clinicians, clinical trial experts, 
biostatisticians, bioethicists, and patient advocates.  On average, each 
DSMB had seven members.  Membership ranged from 4 to 11 per trial.  
More than two-thirds of DSMB members identified themselves as either  
clinicians knowledgeable about the disease and/or treatment relevant to 
the trial or as clinical trial experts.  The vast majority of DSMB members 
and principal investigators reported that these disciplines were adequately 
represented on DSMBs.  DSMB members and principal investigators also 
reported that biostatisticians were adequately represented. 
Bioethicists may be warranted on some DSMBs to provide bioethical 
perspectives on the progress of trials.  However, one-third of DSMB 
members and principal investigators reported that bioethicists were 
underrepresented. Bioethicists were the least represented discipline of 
those members we surveyed (15 of 180).  Staff from two ICs said that 
bioethicists are especially difficult to recruit to DSMBs given their limited 
experience with clinical trials.   
Seventy-five percent of DSMB members reported that they had served on 
more than one DSMB.  On average, they reported serving on five DSMBs 
throughout their careers. Twenty-six of thirty principal investigators 
surveyed reported that the DSMB members had enough experience to 
fulfill their roles.   
Standing DSMBs may account for the large percentage of individuals 
serving on multiple DSMBs.  A standing DSMB is one that meets for a 
number of different trials within the same IC in which the same disease or 
treatment is being studied.  Eight of the ten ICs use standing DSMBs for 
some or all of their trials.  Staff stated that the main advantage to using 
standing DSMBs is having a ready-made, experienced pool of members 
familiar with the roles and responsibilities of a DSMB. 
 
Data and Safety  Monitoring Boards in NIH Clinical Trials (OEI-12-11-00070)                            8  
   
   
DSMBs face some issues that may affect their ability 
to fulfill their roles 
DSMBs met NIHs general guidance by having relevant experts who met 
regularly to offer recommendations to NIH.  To fulfill their roles, however, 
DSMBs must also maintain their independence, be assured access to 
unmasked data, and have a qualified pool of experts from  which to recruit 
DSMB members.  DSMBs face issues in all three of these areas.   
IC participation in closed DSMB meetings diminishes the 
appearance of independence 
According to NIH, ideally, individuals are in no way associated with the 
trials they monitor.26   Association with a trial could take many forms.  For 
instance, DSMB members could have conflicts of interest, meaning 
personal or financial stakes in the outcome of a trial.  However, we found 
that conflict-of-interest paperwork was generally submitted to ICs, as 
required. 
Additionally, IC staff have interests in the trials because the ICs fund the 
trials.  Staff from 9 of the 10 ICs attended closed DSMB meetings at 
which interim data were reviewed.  DSMBs generate recommendations 
regarding trial continuation from the interim data review.   
We did not assess whether any DSMB recommendations were subject to 
bias. However, the extent to which IC staff participated in closed 
meetings diminishes the appearance of independence.  Half (15 of 30) of 
principal investigators responded that IC staff should not participate in 
closed DSMB meetings.  Six of the eleven expert stakeholders expressed 
concern about the extent to which ICs participate in closed DSMB 
meetings.  One stakeholder said that such participation hindered 
independence. Another referred to IC participation as a delicate balance  
between the IC obtaining information and the DSMB maintaining 
independence. 
A few DSMB members and principal investigators did not agree that their 
DSMBs maintained their independence from NIH.  Specifically, 14 (of 
180) DSMB members and 3 (of 30) principal investigators did not believe 
that DSMBs maintained their independence.   
On the other hand, IC staff, most DSMB members, and most principal 
investigators agreed that DSMBs maintained their independence from  
NIH.  In fact, one DSMB member noted that the ICs participation in the 
DSMB was important to help the DSMB make informed decisions; a 
 
26 NIH,  Policy for Data  and Safety Monitoring, 1998.  Accessed  at http://grants.nih.gov   
on January 15,  2013.  
Data and Safety  Monitoring Boards in NIH Clinical Trials (OEI-12-11-00070)                            9  
   
   
stakeholder noted that the DSMBs benefit from the closer relationship the 
ICs have with the principal investigators.  Others also cited the importance 
of having an IC staff attend closed meetings to serve as an executive 
secretary, thereby facilitating note taking, scheduling, and other related 
functions. 
IC staff involvement in DSMB meetings is addressed in each ICs DSMB 
policy.  However, the policies did not always clearly restrict participation 
in closed meetings or define the role of IC staff in closed meetings.  For 
example, one IC policy appears to include no restrictions, stating that 
during closed sessions of the DSMB meetings only DSMB members and 
IC program staff may attend.  Another policy states that closed sessions 
will be restricted to voting and ad hoc members ... and IC staff as 
appropriate. In a third example, the policy is clearer, restricting IC staff 
participation in closed session (when unmasked data would be discussed) 
to the IC executive secretary and statistician.   
Not all IC policies reference DSMB access to unmasked data  
DSMBs are typically the only clinical  trial oversight entity with direct 
access to unmasked data during the course of the trial, meaning that 
members know who is in the control group versus the treatment group.  
Many experts and almost all principal investigators agreed that to fulfill 
their roles, DSMB members must have access to these data if they request 
them.27    
Only 4 of 10 IC policies referenced DSMB access to unmasked data.  One 
IC policy makes clear that members should review masked or unmasked 
data as needed and appropriate. In another example, the policy is very 
clear regarding members access to unmasked data and states that the 
DSMB decides in their first meeting if DSMB members will be unmasked.  
If the DSMB decides to remain masked, they should consider assigning 
one DSMB member to be unmasked to treatment assignment.  The 
remaining six IC policies were silent on the issue of DSMB member 
access to unmasked data. 
A small number of DSMB members (17 of 180) did not believe they had 
access to unmasked data.  Additionally, DSMBs for 14 of 39 trials 
reviewed only masked data at each meeting.28   We do not know whether 
they requested unmasked data. 
 
27 One expert argues that monitoring a trial without access to  unmasked data denies the 
monitors the key information they need to  perform in a competent fashion, and  
incompetent monitoring  poses a risk to research subjects. (Curtis Meinert , Masked 
Monitoring  In Clinical Trials:  Blind Stupidity?  The New England Journal of  Medicine. 
338, 19. May 7, 1998.) 
28 This analysis is based  on the 39 trials for which we have meeting minutes. 
Data and Safety  Monitoring Boards in NIH Clinical Trials (OEI-12-11-00070)                            10  
   
   
ICs face challenges in recruiting and training DSMB members 
The participation of experienced professionals is essential to ensure that 
DSMBs are effective, and ICs must maintain a pool of qualified 
individuals from which to recruit and train new members.  According to 
staff from all 10 ICs, however, recruiting is a challenge.  Membership in a 
DSMB is a voluntary commitment that lasts many years, with little 
reimbursement.  Some DSMB members noted the onerous nature of the 
conflict-of-interest disclosures. For example, former collaborations with 
the study sponsor can be considered a disqualifying conflict.  Furthermore, 
the ICs noted that bioethicists can be challenging to recruit, especially 
because they lack clinical trial experience.  
The ICs reported facing challenges in recruiting DSMB members despite 
the prestige associated with serving on an NIH-sponsored trial DSMB.  
The ICs touted the qualifications of their DSMB members as representing  
the best of the best, and the DSMB members cited their DSMB service as 
not only professionally satisfying but also as an important way to 
contribute to scientific advancement.   
ICs benefit from the depth of experience of their DSMB members.  
However, sustaining that level of experience is a challenge for the ICs 
because those with the most experience eventually retire.  We found that 9  
of 10 ICs do not offer any formal training to DSMB members and, in fact, 
ICs and stakeholders noted that the best form of training is on-the-job 
experience. ICs offer informal training such as online reading materials 
and a review of the DSM plan during the first meeting.  Many DSMB 
members responding to our survey noted that formal training would have 
benefitted them most only at the outset of their DSMB experiences to 
create a common understanding of the role of a DSMB.  
Data and Safety  Monitoring Boards in NIH Clinical Trials (OEI-12-11-00070)                            11  
   
   
CONCLUSION AND RECOMMENDATIONS 
DSMBs play a critical role in ensuring the safety of human subjects and the 
merit of clinical trials.  They fulfill their mission to monitor trials by making 
use of the significant strengths of their members experience.  However,  
DSMBs face three issues that could compromise their effectiveness.  The first 
lies in ensuring their independenceand appearance of independence.  The 
second lies in ensuring their access to unmasked data.  The third lies in 
maintaining a pool of qualified individuals to serve on DSMBs.  We  
recommend that NIH: 
Direct ICs To  Articulate the Circumstances Under Which IC Staff 
Participate in Closed Meetings   
The extent of IC staff involvement in closed DSMB meetings and the lack of 
clarity concerning the ICs expected roles in meetings could diminish the 
appearance of independence.  ICs should clearly describe the circumstances in 
which it is appropriate for specified IC staff to attend closed DSMB meetings, 
and the role of these staff during the meetings.  For instance, IC policies could 
outline that IC executive secretaries will attend closed meetings to take  
minutes and provide appropriate followup. IC policies provide an appropriate 
platform to set these expectations.     
Direct ICs To Explicitly Reference DSMB Access to Unmasked  
Data in Their DSMB Policies 
DSMB members may not always have access to unmasked trial data.  The 
ability of DSMBs to monitor trial progress and ensure the safety of patients 
may be compromised without access to unmasked data.  ICs should ensure that 
DSMB members have access by directing ICs to reference this access in their 
DSMB policies. 
Identify Ways To Recruit and Train New DSMB Members 
According to staff from all 10 ICs, recruiting is a challenge. In addition, 9 of 
10 ICs do not offer any formal training to DSMB members.  Experienced 
professionals are essential to ensure that DSMBs are effective. 
To help recruit and train new DSMB members, NIH could create a forum for 
DSMB issues to be shared and discussed across ICs.  A forum in which IC staff 
can discuss challenges and solutionssuch as how to address recruitment 
issues, including the underrepresentation of bioethicistscould be highly 
beneficial for the effective use of DSMBs.  An online forum is one option for 
ICs to share information and network.  NIH could also sponsor an in-person or 
Webinar conference.  
Data and Safety  Monitoring Boards in NIH Clinical Trials (OEI-12-11-00070)         12  
   
   
In addition, NIH could create a pool of potential DSMB members by  
expanding each DSMBs membership to include one nonvoting member who 
has not previously (or recently) served on a DSMB.    
AGENCY COMMENTS AND OFFICE OF INSPECTOR GENERAL  
RESPONSE 
NIH concurred with all three of OIGs recommendations.  NIH stated that it is 
organizing a trans-NIH working group to review the report and to ensure that 
ICs DSMB policies and practices are optimal.   
Although NIH agreed with our first recommendation, it did not find that the 
presence of IC staff constituted a conflict of interest.  However, we found that 
the presence of IC staff at closed DSMB meetings did create the appearance of 
a conflict of interest for at least some  DSMB members, principal investigators, 
and stakeholders. NIH did state that IC policies should make staff roles and 
responsibilities transparent; clarify why their participation does not affect the 
independence of DSMB-decision making; and delineate instances in which the 
program staff take on additional roles that would constitute a conflict of  
interest.   
In response to our second recommendation, NIH specified that all IC policies 
should state that DSMBs have access to unmasked data.   
In response to our third recommendation, NIH stated that ICs are actively 
exploring ways to enlarge their pools of experts and ensuring that DSMB 
service is appropriately credited and recognized.   
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APPENDIX A 
Agency Comments  
            
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APPENDIX A 

Agency Comments (cont.) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
   
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APPENDIX A 

Agency Comments (cont.) 
 
   
Data and Safety  Monitoring Boards in NIH Clinical Trials (OEI-12-11-00070)         16
  
   
   
ACKNOWLEDGMENTS  
This report was prepared under the direction of Joyce Greenleaf, Regional Inspector 
General for Evaluation and Inspections in the Boston regional office and Russell 
Hereford, Deputy Regional Inspector General. 
Anne Gavin served as the team leader for this study.   Amy Glynn served as the lead 
analyst. Other principal Office of Evaluation and Inspections staff from the Boston 
regional office who contributed to the report include Shreya Patel; central office staff 
who contributed include Debra Roush, Talisha Searcy, Jacquelyn Towns, and Sherri 
Weinstein.  
 
Data and Safety  Monitoring Boards in NIH Clinical Trials (OEI-12-11-00070)         17  
   
Office of Inspector General
http://oig.hhs.gov  
 
The mission of the Office of Inspector General (OIG), as mandated by Public Law 95-452, as  
amended, is  to protect the integrity of the Department of  Health and Human Services  
(HHS)  programs, as well as the health and welfare of beneficiaries  served by those 
programs.  This statutory mission  is  carried  out through  a nationwide network  of  audits, 
investigations, and inspections conducted by the  following operating components: 
Office of Audit Services 
The Office  of  Audit Services  (OAS) provides auditing services  for HHS, either by  conducting  
audits  with its own audit resources or by  overseeing  audit work done by others.  Audits  
examine the performance of HHS programs and/or its grantees and contractors in carrying  
out their respective responsibilities and are intended  to provide independent assessments of 
HHS programs and operations.  These assessments help reduce waste, abuse, and  
mismanagement and promote economy and efficiency  throughout  HHS. 
Office of Evaluation and Inspections 
The Office  of  Evaluation and Inspections (OEI)  conducts national evaluations to  provide 
HHS, Congress, and the public with timely, useful, and reliable information on significant 
issues.  These evaluations focus on preventing fraud,  waste, or abuse  and promoting  
economy, efficiency, and effectiveness of departmental programs.  To promote impact, OEI 
reports also present practical recommendations for improving program operations.  
Office of Investigations 
The Office of Investigations (OI) conducts criminal, civil, and administrative investigations  
of  fraud and misconduct  related to HHS programs, operations, and beneficiaries.  With 
investigators working in all 50 States and the District of Columbia, OI  utilizes its resources 
by actively  coordinating with the Department  of Justice  and other Federal, State, and local 
law enforcement authorities.  The investigative efforts of OI often lead to  criminal 
convictions, administrative sanctions,  and/or  civil monetary  penalties.  
Office of Counsel to the Inspector General 
The Office of Counsel to the  Inspector  General (OCIG) provides general legal services to 
OIG, rendering  advice and opinions on HHS programs and operations and  providing all  
legal support for OIGs  internal operations.  OCIG represents  OIG in all civil and 
administrative fraud and abuse cases involving HHS programs,  including False Claims Act, 
program exclusion, and civil monetary penalty cases.  In  connection with these cases, OCIG 
also negotiates and monitors corporate integrity agreements.  OCIG renders advisory 
opinions, issues compliance program  guidance, publishes fraud alerts, and provides other  
guidance  to  the health care industry concerning the anti-kickback statute and other  OIG  
enforcement authorities.