Donelle Bussom RN, MSN

Maintaining health and safety of patients is a primary objective when conducting any form of research. With the research arena becoming increasingly complicated, maintaining oversight over patients' safety is more critical than ever. In order to assist in this effort, data monitoring committees (DMCs) have been created in order to monitor data in an independent, organized, unbiased, and real-time manner.  

A data monitoring committee (also known as a data safety monitoring board, or DSMB) is a committee comprised of independent experts who are gathered to advise a research organization during the conduct of a clinical trial or trials. DMCs were created in the 1960s, to evaluate the patient and community impact of marketed products in longer running government trials. The use of such committees made its way to the private, mainstream pharmaceutical industry about a decade later. Throughout the 2000s, with economic markets as well as patient populations changing, drug companies began to produce more targeted trial designs, many of which had special or higher-risk patient populations targeted to obtain more rapid product approval. As part of this evolution, DMCs have not only become a more regular part of clinical programs, but their use is also in earlier phases of clinical development.  

While all global regulations require the ongoing safety monitoring of clinical trials, currently, no concise guidance exists describing how, when, and why to use a DMC. The emphasis on appropriately incorporating DMCs into a clinical program often leaves sponsors with questions concerning creation and implementation of these committees, therefore expertise (internal or consultant) is crucial for success. 

The recommendations within the industry on when to use a DMC includes research studies where: 					

There is a randomized trial (or set of trials) with a large study population conducted over a relatively long period of time

The trial is intended to provide definitive information about effectiveness and/or safety of a medical intervention

Prior data suggests that the intervention being studied has potential to induce potentially unacceptable toxicity

The trial is evaluating mortality or another major endpoint, such that inferiority of one treatment arm has safety and effectiveness implications

It would be ethically important for the trial to stop early if the primary question addressed has been answered, even if secondary questions or complete safety data were not yet fully addressed

If two or more of these questions are noted to be applicable, a DMC is indicated. If fewer than two apply, a DMC may not be indicated; however, there is nothing to contraindicate implementation of a committee under any circumstances.  

When implemented, the DMC has three fundamental priorities: protecting and ensuring the safety of study participants, preserving the integrity and credibility of the trial and its results, and also facilitating the timely dissemination of reliable clinical findings to the broader community. 

A committee is composed of a panel of three to nine independent experts (key opinion leaders, statisticians, scientific experts, etc.), with expertise relevant to the product and drug indication. An uneven number of committee members should always be maintained so that a clear decision is made when voting occurs. Globally conducted trials should ensure that member selection allows for appropriate regional representation.  

For any sized pharmaceutical company, navigating the processes of the DMC meetings can be deceivingly difficult and costly, as all conflicts of interest and biases must be avoided with a complete appearance of transparency maintained. The operational process of a DMC is fairly standard and includes the following activities (listed in approximate order of completion): 

Selection of members requires execution of confidentiality agreements, review of medical or other qualifications, collection of active medical licenses, absence of sanctions and debarment, and anti-bribery and corruption checks, review of conflict of interest declarations, and if the previously noted checks are in favor of committee inclusion—implementation of consulting agreements. This process takes an average of about four months.  

Approximately two to three weeks prior to first patient initiation, an organization meeting is held, where key documents are reviewed, the draft DMC charter is reviewed and ratified, and the data shells and sample formats for data presentation are agreed-upon. Following the organizational meeting, final minutes are prepared, circulated, and approved. After the minutes are finalized and approved, the DMC charter is also updated, finalized, and distributed to all committee members. Once these organizational processes are complete, data review meetings are held over the course of the project according to the finalized DMC charter with all findings and recommendation documented and distributed. The flowchart in Figure 1 outlines this process for a typical DMC requiring three members.  

Three models are reviewed ahead, including the "DIY" model, and two different models of outsourcing (partial and full). With any of these models, careful consideration needs to be made to ensure the unblinded statistical team has no direct contact regarding the unblinded data with any member of the working project/blinded team. This philosophy needs to also be applied to manage the documentation of the meeting minutes for closed sessions as well as any recommendations. 

Do It Yourself (DIY) model/In-sourcing model 

In the "DIY" model, the sponsor provides all services, including locating and contracting committee members, drafting and finalizing committee charter, meeting logistics and preparation, statistical analysis, meeting moderation, and all applicable documentation. This model gives sponsors full control over timelines and provision of data, and allows them complete oversight over staff and costs. When using this model, sponsors must take extra care to ensure that no bias or conflict of interest is introduced.  

In a partial outsourced model, the sponsors can internally handle all activities that would not come under scrutiny for transparency or bias issues. This includes completion of all of the member locations and on-boarding processes, including consulting agreements, drafting of charter, meeting logistics and preparation, open-meeting moderation, and provision of blinded statistical activities. All other activities, such as the unblinded statistical support activities and closed meeting moderation/documentation, would then be outsourced to a third-party vendor, such as with consultants or a CRO. With this partial outsourcing, the sponsor is less involved overall, which can produce some anxiety on the sponsor's side, especially when the sponsor is a small biotech company, for example. However, outsourcing is an ideal solution for medium-sized sponsors, because they may have difficulty providing sufficient resources to adequately staff separate blinded/unblinded and other support-team members required to avoid the potential bias and transparency issues. Larger sponsors may also benefit from an outsourced model, as it is financially beneficial to outsource a few resources when they are needed, reducing time and recruitment costs versus hiring and maintaining the full staff required for specialized committee support over longer periods of time.  

Fully outsourced models are typically handled by a CRO. This model can be practical and cost-effective; however, it does remove some of the control away from the sponsor. The CRO will provide a service, which includes providing the experienced, appropriate staff required to create and support a DMC for staff acquisition, meeting logistics, moderation, and documentation.  

When done internally, companies often use highly paid staff (i.e., statisticians) to do non-scientific work, such as member onboarding, contracts, meeting logistics/preparation, and various documentation. The CRO has the ability to use more appropriate level staff (i.e., a nurse or high-level administrative support) for these tasks that not only ensures quality, but also cost-effectiveness. This model is ideal for any sized sponsor because it is able to easily avoid any appearance of bias or non-transparency, as well as being assured that the sponsor can review and provide input at any stage of the project or be guided by the CRO experts on the regulations, processes, and requirements. Care does need to be taken when selecting whom or where to outsource, as a team with experience is needed not only for efficiency gains, but also avoidance of errors—which are always costly at some level. If the wrong outsourced team is consulted, miscommunication and bias can be accidentally introduced, or an improperly assembled DMC could be put in place.  

For the average pharmaceutical company, each DMC managed would require a minimum of six staff members, plus committee members. The six staff members include: one member of procurement/contracts to perform the location of members and onboarding/qualification process; two statisticians (one blinded, one unblinded); two programmers (one blinded, one unblinded); and one for administrative support. Based on average internal cost for these resources, combined with DMC member fees and travel and logistical costs, the average DMC using these staff members could cost about $800,000. Considering these assumptions, outsourcing DMC services can create a significant cost savings based on the following: 					

Each internal member only provides work for the amount of meetings required—there is no fear of conflict of interest

Sponsors pay only for the work required—which means only portions of staff are used and billed for the project—versus having to hire and train an entire team of resources internally

Outsourcing allows the use of the appropriate level of staff 

There are three sourcing options to be considered when implementing a DSM: full in-sourcing, partial outsourcing, and complete outsourcing of work. There can be incremental level of cost savings with the various levels of outsourcing. It may also be possible that additional savings can be made for any model with the use of the same committee (and management teams) during programs (eliminating many onboarding or other start-up processes). These three models will, therefore, provide sponsors with viable options for implementing DMCs on any project, thus enhancing the monitoring of patient safety during their trials. 

, RN, MSN, is Director, Drug Safety, ICON Clinical Research, email: 

, RN, BSN,  is Senior Drug Safety Manager, ICON Clinical Research, email: 

Ellenbeg, S, Fleming T, DeMets D. "Data Monitoring Committees in Clinical Trials, A Practical Perspective." West Sussex, England: Wiley; 200. 

Herson, J. "Data and Safety Monitoring Committees in Clinical Trials." Boca Raton, FL: Chapman and Hall; 2009.  

Slutsky, A.S. and J.V. Lavery (2004). "Data Safety and Monitoring Boards." 

Institute of Translation Health Sciences. Data Safety Monitoring Boards (DSMBs). Web site. 

National Institute of Dental and Craniofacial Research. "Data and Safety Monitoring Board (DSMB) Guidelines." Web site. 

http://www.nidcr.nih.gov/Research/ToolsforResearchers/Toolkit/DSMBGuidelines.htm

NIH Guide: NIH Policy for Data and Safety Monitoring. NIH Web site/ 

http://grants.nih.gov/grants/guide/notice-files/not98-084.html

The Research Subject Advocate (RSA) Program. A Guide to Data and Safety Monitoring Boards (DSMB). Web site. 

http://www.utmb.edu/gcrc/aboutus/RAS/RSA.dsmb.htm

Articles

Exploring sourcing model options for appropriate incorporation of DMCs into a clinical program.

Implementation and Usage of Data Monitoring Committees

Maintaining health and safety of patients is a primary objective when conducting any form of research. With the research arena becoming increasingly complicated, maintaining oversight over patient’s safety is more critical than ever. In order to assist in this effort, Data Monitoring Committees (DMCs) have been created in order to monitor data in an independent, organized, unbiased, and real-time manner. 

A Data Monitoring Committee (also known as Data Safety Monitoring Board, or DSMB) is a committee comprised of independent experts who are gathered to advise a research organization during the conduct of a clinical trial or trials. DMCs were created in the 1960s, to evaluate the patient and community impact of marketed products in longer running government trials. The use of such committees made its way to the private, mainstream pharmaceutical industry about a decade later. Throughout the 2000s, with economic markets as well as patient populations changing, pharmaceutical companies began to produce more targeted trial designs, many of which had special or higher-risk patient populations targeted to obtain more rapid product approval. As part of this evolution, DMCs have not only become a more regular part of clinical programs, but their use is also in earlier phases of clinical development. 

While all global regulations require the on-going safety monitoring of clinical trials, currently, no concise guidance exists describing how, when, and why to use a DMC. The emphasis on appropriately incorporating DMCs into a clinical program often leaves sponsors with questions concerning creation and implementation of these committees, therefore expertise (internal or consultant) is crucial for success.

The recommendations within the industry on when to use a DMC includes research studies where:

The trial is evaluating mortality or another major endpoint, such that inferiority of one treatment arm has safety as well as effectiveness implications

It would be ethically important for the trial to stop early if the primary question addressed has been definitively answered, even if secondary questions or complete safety information were not yet fully addressed

If two or more of these questions are noted to be applicable, a DMC is indicated. If fewer than two apply, a DMC may not be indicated; however, there is nothing to contraindicate implementation of a committee under any circumstances.

When implemented, the DMC has three fundamental priorities: protecting and ensuring the safety of study participants, preserving the integrity and credibility of the trial and its’ results, and also facilitating the timely dissemination of reliable clinical findings to the broader community.

A committee is composed of a panel of three-to-nine independent experts (key opinion leaders, statisticians, scientific experts, etc.), with expertise relevant to the product and therapeutic indication. An uneven number of committee members should always be maintained so that a clear decision is made when voting occurs.

Globally conducted clinical trials should ensure that member selection allows for appropriate regional representation. This is determined by assessing which regions provide the majority of enrolled patients and then selecting appropriate panel members. 

For any sized pharmaceutical company, navigating the processes of the DMC meetings can be deceivingly difficult and costly, as all conflicts of interest and biases must be avoided with a complete appearance of transparency maintained (the complete, accurate, and timely disclosure of all information).

The operational process of a DMC is fairly standard and includes the following activities (listed in approximate order of completion):

Selection of committee members requires execution of confidentiality agreements, review of medical or other qualifications, collection of active medical licenses (as applicable), absence of sanctions and debarment, and anti-bribery and corruption checks, review of conflict of interest declarations, and if the previously noted checks are in favor of committee inclusion--implementation of consulting agreements. This process takes an average of approximately four months. 

Approximately two-to-three weeks prior to first patient initiation, an organization meeting is held, where key documents are reviewed, the draft DMC charter is reviewed and ratified, and the data shells and sample formats for data presentation are agreed-upon. Following the organizational meeting, final minutes are prepared, circulated, and approved. After the minutes are finalized and approved, the DMC Charter is also updated, finalized, and distributed to all committee members. Once these organizational processes are complete, Data Review meetings are held over the course of the project according to the finalized DMC Charter with all findings and recommendation documented and distributed. The following flowchart outlines this process for a typical DMC requiring three members. Four data review meetings have been included, as this is a fairly common number of meetings for many clinical trials lasting 18 months to two years in duration; however, data review meetings will occur as needed until project completion.

Figure 1. DMC process flowchart (click to enlarge)

Three models are reviewed below including the “DIY” model, and two different models of outsourcing (partial and full). With any of these models, careful consideration needs to be made to ensure the unblinded statistical team has no direct contact regarding the unblinded data with any member of the working project/blinded team. This philosophy needs to also be applied to manage the documentation of the meeting minutes for closed sessions as well as any recommendations, as these may be completed by statisticians attending the meetings.

In the “DIY” model, the sponsor provides all services include locating and contracting committee members, drafting and finalizing committee charter, meeting logistics and preparation, statistical analysis, meeting moderation, and all applicable documentation (minutes and recommendations). This can be a standard model for larger sponsor companies with many resources and multiple on-going programs. This model gives sponsors full control over timelines and provision of data, and also allows them complete oversight over staff and costs. When using this model, sponsors must take extra care to ensure that no bias or conflict of interest is introduced at any point during the project. 

In a partial outsourced model, the sponsors can internally handle all activities that would not come under scrutiny for transparency or bias issues. This includes completion of all of the member locations and on-boarding processes including consulting agreements, drafting of charter, meeting logistics and preparation, open meeting moderation and provision of blinded statistical activities. All other activities, such as the unblinded statistical support activities and closed meeting moderation/documentation would then be outsourced to a third party vendor, such as with consultants or a CRO. With this partial outsourcing, the sponsor is less involved overall, which can produce some anxiety on the sponsor’s side, especially when the sponsor is a small or biotech company.

However, outsourcing is an ideal solution for medium-sized sponsors because they may have difficulty providing sufficient resources to adequately staff separate blinded/unblinded and other support team members required to avoid the potential bias and transparency issues. Additionally, DMC expert staff may not be available to the small to mid-sized company. 

Larger sponsors may also benefit from an outsourced model as it is financially beneficial to outsource a few resources when they are needed, reducing time and recruitment costs vs. hiring and maintaining the full staff required for specialized committee support over longer periods of time. 

Fully outsourced models are typically handled by a CRO. This model can be practical and cost effective; however it does remove some of the control away from the sponsor. The CRO will provide a service, which includes providing the experienced, appropriate staff required to create and support a DMC for staff acquisition, meeting logistics, moderation, and documentation. 

When done internally, companies often use highly paid staff (such as statisticians) to do non-scientific work such as member onboarding, contracts, meeting logistics/preparation, and various documentation (minutes, etc.). The CRO has the ability to use more appropriate level staff (for example, a nurse or high-level administrative support) for these tasks that not only ensures quality, but also cost effectiveness. This model is ideal for any sized sponsor because they are able to easily avoid any appearance of bias or non-transparency, as well as being assured that they can review and provide input at any stage of the project or be guided by the CRO experts on the regulations, processes, and requirements. Care does need to be taken when selecting whom or where to outsource, as a team with experience is needed not only for efficiency gains, but also avoidance of errors—which are always costly at some level (time or money). If the wrong outsourced team is consulted, miscommunication and bias can be accidentally introduced, or an improperly assembled DMC could be put in place. Therefore a qualified vendor or consultant should always be used.

For the average pharmaceutical company, each DMC managed would require a minimum of six staff members, plus committee members. The six staff members include:

One member of procurement/contracts to perform the location of members and onboarding/qualification process.

Two statisticians (one blinded and one unblinded) 

Two programmers (one blinded and one unblinded) 

One administrative support (minutes, files, distributions, etc.) 

Based upon average internal cost for these resources, in combination with DMC member fees and travel and logistical costs; the average DMC utilizing these staff members could cost in the ballpark of $800,000. Based on these assumptions, outsourcing DMC services can create a significant cost savings based on the following:

Each internal team member only provides work for the amount of meetings required – there is no fear of conflict of interest

Sponsors pay only for the work required – which means only portions of staff are used and billed for the project – vs. having to hire and train an entire team of resources internally.

Outsourcing allows the use of the appropriate level of staff for the task. 
  

As previously stated, there are three options to be considered: full in-sourcing (DIY/doing all the work in-house); partial outsourcing (doing part of the work such as locating and assembling the DMC in-house and outsourcing tasks such as meeting planning, moderation, and documentation); and finally complete outsourcing of work. Costs were based on the full-time salaries for regular, permanent staff to complete all DMC tasks (by noted six staff above) plus the typical honoraria of the DMC members. This was compared against the typical CRO hourly charges for outsourced models using safety coordinators/managers and administrative support plus the same honoraria fees to complete the same tasks. Please see Table 1 below for cost comparison models:

Table 1. Comparison of souring model costs for Data Monitoring Committee costs. Costs estimates are based on the use of a 3 DMC member committee with 4 meetings over a typical 18-month project

As can be seen in Table 1, there can be incremental level of cost savings with the various levels of outsourcing. It may also be possible that additional savings can be made for any model with the use of the same committee (and management teams) during programs (eliminating many onboarding or other start-up processes). These three models will therefore provide sponsors with viable options for implementing DMCs on any project, thus enhancing the monitoring of patient safety during their trials.

 Data Monitoring Committees in Clinical Trials, A Practical Perspective. 

Data and Safety Monitoring Committees in Clinical Trials

. Boca Raton, FL: Chapman and Hall; 2009. 

National Institute of Dental and Craniofacial Research. Data and Safety Monitoring Board (DSMB) Guidelines. Web site. 

Maintaining health and safety of patients is a primary objective when conducting any form of research.

Donelle Bussom RN, MSN

Articles

Implementation and Usage of Data Monitoring Committees

Data Monitoring Committees: Implementation and Sourcing Model Options