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What Do the Sites Want? The Trial Master File
CHAPTER 23
What Do the Sites Want? The Trial Master File Andrew Mitchell, Jochen Tannemann, Kevin McNulty Contents 1. The Need 2. The Solution 3. SWOT 4. Take Home Message 5. Applicable Regulations
257 258 263 264 264
1. THE NEED In today’s clinical development environment, it has become increasingly difficult to find sites that can successfully meet patient enrollment guidelines and adhere to complex study protocols. Data from Tufts Center for the Study of Drug Development underscores this trend, finding that between 1995 and 2005, there were 21% fewer volunteers being admitted into trials and a 30% increase in patient dropouts.1 This same research also found that the number of routine tasks per trial increased by 65% and the average clinical trial staff work burden increased by 67%.2 Top-performing sites are well-sought after and are often working on multiple studies with multiple sponsors simultaneously. Approximately a third of sites are working on more than 20 studies in a year (Figure 23.1). Given these facts, finding these top-performing sites and then maintaining a strong and collaborative relationship is a high priority for sponsors and contract research organizations.Yet, the complexity of clinical research and the increasingly stringent regulatory oversight can make this difficult to accomplish. Sponsors often throw technology at challenges (Figure 23.2) to improve efficiency without carefully thinking through all the business processes from the site perspective, and sites are often reluctant to embrace change and tend to adhere to paper-based solutions (Figure 23.3). 1 Tufts
CSDD Impact Report.
2 Ibid.
Re-Engineering Clinical Trials http://dx.doi.org/10.1016/B978-0-12-420246-7.00023-2
© 2015 Elsevier Inc. All rights reserved.
257
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Re-Engineering Clinical Trials
Figure 23.1 Number of clinical studies sites conducted on an annual basis.3 3 CenterWatch-Intralinks
2013 Site Survey.
Figure 23.2 Number of online clinical systems typically accesses during a study.4 4 Ibid.
2. THE SOLUTION Technology applied correctly, however, does offer a means to streamline procedures, reduce workloads, improve collaboration, and increase audit readiness, while still maintaining regulatory compliance. Considering the
What Do The Sites Want?
259
Figure 23.3 Type of storage for investigator site files.5 5 Ibid.
Figure 23.4 Number of organizations sites typically work with on a clinical trial.
number of parties (Figure 23.4) involved in a trial, automating complete business processes through technology offers the ideal solution. There has been a large industry focus on the trial master file (TMF), and yet almost all commercial solutions do not address the full scope of the TMF. Most electronic (e)TMF solutions focus on the interaction between the
260
Re-Engineering Clinical Trials
Figure 23.5 TMF, ISFs.
TMF and the sponsor, but neglect the interaction with the sites.Yet, international regulation define the full scope of the TMF as both the sponsor file and the investigator site file (ISF) (Figure 23.5): The TMF is normally composed of a sponsor file, held by the sponsor organization and an investigator site file, held by the investigator. These files together are regarded as comprising the entire TMF for the trial and should be established at the beginning of the trial.6 The challenges in implementing this specific solution are driven by privacy and data ownership requirements. Both areas of the TMF (sponsor and ISF) include records that are private to the respective organizations. By using private data rooms for the sponsor TMF and ISF, and additionally controlling the interaction of documents originating from the sponsor (such as protocol and investigator brochure) and those originating from the investigator (such as financial disclosure, medical license), information can be protected at each area that is not to be disclosed to the respective other party. The sponsor and investigator should also be able to grant access to private files to relevant parties in relation to specific tasks and surveillance activities. These tasks include inspections by health authorities and remote monitoring activities through the clinical research associate (CRA). During the past few years, a wide consensus in the commercial community has been reached to organize TMFs in accordance to the Drug Information Association TMF reference model (Figure 23.6).The TMF should reflect this structure. The TMF reference model organizes artifacts in zones and sections. Additionally, for each document a level (study, country, site) and the ownership (sponsor, investigator) can be defined. 6 MHRA, The
Gray Book, p. 330.
What Do The Sites Want?
eTMF
Zone
Section
Artifact
Trial Master File Plan Trial Oversight
Trial Management Plan
... Trial Management
Trial Team Details Trial Team
...
... IB Trial Documents
Protocol
... Central Trial Documents
Subject Documents
...
eTMF
S. Diary
... Submission
Trial Approval
Approval
...
Regulatory
IMP/Export IMP
... ...
...
...
Figure 23.6 TMF organization.
...
261
262
Re-Engineering Clinical Trials
The full TMF will be the final and only resource for study documents. The source of documents can be an individual person providing a document (the originator) or a feeding eClinical system. An artifact stored in the TMF has to be trustworthy and final. Each document entering the TMF undergoes a default filing process. This default process can be shortened for specific document related workflows if the different roles are taken by the same person. Differing from the sponsor TMF, the investigator will usually not have specialist staff for filing and will maintain the ISF in avocation. Therefore, there are some essential requirements for the ISF solution: • Clear integration with eTMF • Temporary permission to be able to see document or download for a short term • Sponsor sees metadata to know what is in the file • Principle investigators need to see and access files in ISF all the time • Should be a repository • Hide tasks that are not pertinent or timely • Table of contents to know where things are • Improved user experience Artifacts may be pushed into the TMF from different originating feeding systems. Because systems used in clinical trials are validated, the respective interfaces also need to be validated. Systems without a validated interface are classified as “nonqualified feeding systems.” A qualified feeding system will push data into the TMF, and document metadata from the feeding system are persistent throughout the feeding process: This includes eSignature status, revision and version history, and document ownership. Nonqualified feeding systems will not be able to push data directly into the TMF, but they will feed documents into the inbox of the TMF.They will trigger the review process and act as the originator of a new artifact. Depending on the risk assessment the default filing process might be shortened for nonqualified feeding systems. The eTMF defines the documentation status of a clinical trial. At different time points, different requirements for the status of documents apply. Study phases such as preparation, start-up, conduct, close-out, and reporting define a different volume and amount of artifacts stored in the TMF. The TMF responsible person should at any time be informed on the quality and completeness of the TMF.
What Do The Sites Want?
263
The TMF receives external information to measure the completeness of a TMF at a given time point. Usually, this information is kept in a clinical trial management system of the sponsor. However, this information is not standardized.The eTMF should not take over trial management functionality but can provide an interface to receive the required information either manually or as an automatic upload. Focusing on the entire business process and then applying technology offers the most complete and efficient solution for the TMF. Implementing a solution that focuses solely on sponsor–TMF interaction is incomplete and does little to improve sponsor relationships with sites.
3. SWOT Strengths: • Improved compliance and efficiency at site—all documents in one place while ensuring that control is always retained by the site • Improved compliance and efficiency at sponsor—enablement of remote monitoring visits • Allows for more efficient use of monitor time to focus on protocolrelated issues versus documentation • Reduce risk to the sponsor: • Increased visibility into the site • Reduce reliance on individual CRAs • Improve consistency across sites • Site inspection readiness • Reduce use and storage of paper Weaknesses: • More complicated to implement than paper systems • More initial training needed • Internet access needed • Higher up-front investment and system costs Opportunities: • Remote source data verification for paper-based studies • Reduced distribution costs versus manual processes • Improve eTMF filing by categorizing and prioritized assignment of content received from the sites • Higher quality of documents from sites in sponsor TMF • Eliminate manual reconciliation of the ISF and TMF (always in synch)
264
Re-Engineering Clinical Trials
• Real-time access to documents as appropriate Threats: • Site may not make full use of the system due to lack of training • Understanding or interest and potentially higher workaround at the site level
4. TAKE HOME MESSAGE Information at each area that is not to be disclosed to the respective other party can dramatically improve document management efficiency and quality. An independent, site-controlled electronic investigator site file would 1. Support ISF filing at each site 2. Manage distribution and collection of content between ISF and sponsor TMF systems 3. Enable remote monitoring and review of a sites paperwork as part of sponsor risk-based monitoring strategy 4. Enable archiving ISF information at end of trial, with ongoing access for authorized personnel
5. APPLICABLE REGULATIONS 21 CFR 11; European data privacy laws.
What Do the Sites Want? The Trial Master File Andrew Mitchell, Jochen Tannemann, Kevin McNulty Contents 1. The Need 2. The Solution 3. SWOT 4. Take Home Message 5. Applicable Regulations
257 258 263 264 264
1. THE NEED In today’s clinical development environment, it has become increasingly difficult to find sites that can successfully meet patient enrollment guidelines and adhere to complex study protocols. Data from Tufts Center for the Study of Drug Development underscores this trend, finding that between 1995 and 2005, there were 21% fewer volunteers being admitted into trials and a 30% increase in patient dropouts.1 This same research also found that the number of routine tasks per trial increased by 65% and the average clinical trial staff work burden increased by 67%.2 Top-performing sites are well-sought after and are often working on multiple studies with multiple sponsors simultaneously. Approximately a third of sites are working on more than 20 studies in a year (Figure 23.1). Given these facts, finding these top-performing sites and then maintaining a strong and collaborative relationship is a high priority for sponsors and contract research organizations.Yet, the complexity of clinical research and the increasingly stringent regulatory oversight can make this difficult to accomplish. Sponsors often throw technology at challenges (Figure 23.2) to improve efficiency without carefully thinking through all the business processes from the site perspective, and sites are often reluctant to embrace change and tend to adhere to paper-based solutions (Figure 23.3). 1 Tufts
CSDD Impact Report.
2 Ibid.
Re-Engineering Clinical Trials http://dx.doi.org/10.1016/B978-0-12-420246-7.00023-2
© 2015 Elsevier Inc. All rights reserved.
257
258
Re-Engineering Clinical Trials
Figure 23.1 Number of clinical studies sites conducted on an annual basis.3 3 CenterWatch-Intralinks
2013 Site Survey.
Figure 23.2 Number of online clinical systems typically accesses during a study.4 4 Ibid.
2. THE SOLUTION Technology applied correctly, however, does offer a means to streamline procedures, reduce workloads, improve collaboration, and increase audit readiness, while still maintaining regulatory compliance. Considering the
What Do The Sites Want?
259
Figure 23.3 Type of storage for investigator site files.5 5 Ibid.
Figure 23.4 Number of organizations sites typically work with on a clinical trial.
number of parties (Figure 23.4) involved in a trial, automating complete business processes through technology offers the ideal solution. There has been a large industry focus on the trial master file (TMF), and yet almost all commercial solutions do not address the full scope of the TMF. Most electronic (e)TMF solutions focus on the interaction between the
260
Re-Engineering Clinical Trials
Figure 23.5 TMF, ISFs.
TMF and the sponsor, but neglect the interaction with the sites.Yet, international regulation define the full scope of the TMF as both the sponsor file and the investigator site file (ISF) (Figure 23.5): The TMF is normally composed of a sponsor file, held by the sponsor organization and an investigator site file, held by the investigator. These files together are regarded as comprising the entire TMF for the trial and should be established at the beginning of the trial.6 The challenges in implementing this specific solution are driven by privacy and data ownership requirements. Both areas of the TMF (sponsor and ISF) include records that are private to the respective organizations. By using private data rooms for the sponsor TMF and ISF, and additionally controlling the interaction of documents originating from the sponsor (such as protocol and investigator brochure) and those originating from the investigator (such as financial disclosure, medical license), information can be protected at each area that is not to be disclosed to the respective other party. The sponsor and investigator should also be able to grant access to private files to relevant parties in relation to specific tasks and surveillance activities. These tasks include inspections by health authorities and remote monitoring activities through the clinical research associate (CRA). During the past few years, a wide consensus in the commercial community has been reached to organize TMFs in accordance to the Drug Information Association TMF reference model (Figure 23.6).The TMF should reflect this structure. The TMF reference model organizes artifacts in zones and sections. Additionally, for each document a level (study, country, site) and the ownership (sponsor, investigator) can be defined. 6 MHRA, The
Gray Book, p. 330.
What Do The Sites Want?
eTMF
Zone
Section
Artifact
Trial Master File Plan Trial Oversight
Trial Management Plan
... Trial Management
Trial Team Details Trial Team
...
... IB Trial Documents
Protocol
... Central Trial Documents
Subject Documents
...
eTMF
S. Diary
... Submission
Trial Approval
Approval
...
Regulatory
IMP/Export IMP
... ...
...
...
Figure 23.6 TMF organization.
...
261
262
Re-Engineering Clinical Trials
The full TMF will be the final and only resource for study documents. The source of documents can be an individual person providing a document (the originator) or a feeding eClinical system. An artifact stored in the TMF has to be trustworthy and final. Each document entering the TMF undergoes a default filing process. This default process can be shortened for specific document related workflows if the different roles are taken by the same person. Differing from the sponsor TMF, the investigator will usually not have specialist staff for filing and will maintain the ISF in avocation. Therefore, there are some essential requirements for the ISF solution: • Clear integration with eTMF • Temporary permission to be able to see document or download for a short term • Sponsor sees metadata to know what is in the file • Principle investigators need to see and access files in ISF all the time • Should be a repository • Hide tasks that are not pertinent or timely • Table of contents to know where things are • Improved user experience Artifacts may be pushed into the TMF from different originating feeding systems. Because systems used in clinical trials are validated, the respective interfaces also need to be validated. Systems without a validated interface are classified as “nonqualified feeding systems.” A qualified feeding system will push data into the TMF, and document metadata from the feeding system are persistent throughout the feeding process: This includes eSignature status, revision and version history, and document ownership. Nonqualified feeding systems will not be able to push data directly into the TMF, but they will feed documents into the inbox of the TMF.They will trigger the review process and act as the originator of a new artifact. Depending on the risk assessment the default filing process might be shortened for nonqualified feeding systems. The eTMF defines the documentation status of a clinical trial. At different time points, different requirements for the status of documents apply. Study phases such as preparation, start-up, conduct, close-out, and reporting define a different volume and amount of artifacts stored in the TMF. The TMF responsible person should at any time be informed on the quality and completeness of the TMF.
What Do The Sites Want?
263
The TMF receives external information to measure the completeness of a TMF at a given time point. Usually, this information is kept in a clinical trial management system of the sponsor. However, this information is not standardized.The eTMF should not take over trial management functionality but can provide an interface to receive the required information either manually or as an automatic upload. Focusing on the entire business process and then applying technology offers the most complete and efficient solution for the TMF. Implementing a solution that focuses solely on sponsor–TMF interaction is incomplete and does little to improve sponsor relationships with sites.
3. SWOT Strengths: • Improved compliance and efficiency at site—all documents in one place while ensuring that control is always retained by the site • Improved compliance and efficiency at sponsor—enablement of remote monitoring visits • Allows for more efficient use of monitor time to focus on protocolrelated issues versus documentation • Reduce risk to the sponsor: • Increased visibility into the site • Reduce reliance on individual CRAs • Improve consistency across sites • Site inspection readiness • Reduce use and storage of paper Weaknesses: • More complicated to implement than paper systems • More initial training needed • Internet access needed • Higher up-front investment and system costs Opportunities: • Remote source data verification for paper-based studies • Reduced distribution costs versus manual processes • Improve eTMF filing by categorizing and prioritized assignment of content received from the sites • Higher quality of documents from sites in sponsor TMF • Eliminate manual reconciliation of the ISF and TMF (always in synch)
264
Re-Engineering Clinical Trials
• Real-time access to documents as appropriate Threats: • Site may not make full use of the system due to lack of training • Understanding or interest and potentially higher workaround at the site level
4. TAKE HOME MESSAGE Information at each area that is not to be disclosed to the respective other party can dramatically improve document management efficiency and quality. An independent, site-controlled electronic investigator site file would 1. Support ISF filing at each site 2. Manage distribution and collection of content between ISF and sponsor TMF systems 3. Enable remote monitoring and review of a sites paperwork as part of sponsor risk-based monitoring strategy 4. Enable archiving ISF information at end of trial, with ongoing access for authorized personnel
5. APPLICABLE REGULATIONS 21 CFR 11; European data privacy laws.