REMOTE SOURCE DOCUMENT

VERIFICATION (rSDV)
The Cost Effective Alternative to Traditional Trial
Monitoring
GLOSSARY OF TERMS

AE Adverse Event
CBER Center for Biologics Evaluation and Research
CDER Center for Drug Evaluation and Research
CDRH Center for Devices and Radiological Health
CMP Clinical Monitoring Plan
CPDI Cost Per Data Item
CRF Case Report Form
CTM Clinical Trial Management
CTTI Clinical Trials Transformation Initiative
EC Ethics Committees
eCRF Electronic Case Report Form
EDC Electronic Data Capture
EMA European Medicines Agency
EMR Electronic Medical Records
eTMF Electronic Trial Master File
FDA US Food and Drug Administration
GCP Good Clinical Practice
HIPPA Health Insurance Portability and Accountability Act
ICH International Conference for the Harmonisation of Good Clinical Practice
IMP Investigation Medicinal Product
IRB Institutional Review Boards
MHRA Medicines & Healthcare Products Regulatory Agency
NBE New Biological Entity
NCE New Chemical Entity
RBM Risk Based Monitoring
rSDV Remote Source Document Verification
SAE Serious Adverse Event
SDV Source Document Verification
TMF Trial Master File
Onsite monitoring within clinical trial development remains one of the largest cost drivers of clinical
monitoring, and the single largest cost line item that Sponsors face. As such, the cost associated with
clinical monitoring is under continuous scrutiny by Sponsors, whilst the integrity of clinical data is under
even greater scrutiny by regulators. Source Document Verification (SDV) is, however, a fundamentally
non-value added activity. It is a quality control step that fails to produce quality but seeks to test the
quality of the data, an approach widely recognized as being inefficient and ineffective. As a non-value
added activity, it should be a prime target for cost reduction while at the same time sustaining and
increasing the integrity of clinical data with the source records on site.

Recently, the pendulum has swung from 100% non-discriminating SDV to extremely low levels. An
example of a Sponsor’s reduced algorithm for a post-marketing study significantly reduced the amount of
data items under review and focused primarily on data items considered critical to the submission. The
Sponsor set monitoring guidelines at 10% of sites and 28% of data points at sites (= 2.8% of all data
review). Not because statistical or “reduced” Source Document Verification was better practice or science,
or because a magic algorithm was found that could assure quality of data points not verified, but
primarily to reduce cost and reduce the occurrence and duration of monitoring visits.

Remote Source Document Verification (rSDV) is a well-defined task within our industry by Sponsors,
vendors and sites, but is a relatively new practice that due to its infancy has a multitude of definitions and
applications. The practices proposed, explored and piloted, range from reviewing fax transmitted source
documents to video recording and the archiving of patient visits. The term remote Source Document
Verification needs to be both defined and standardized across the industry to create a common and
targeted dialog that explores the impact of different practices and technologies on both cost and
achievable data integrity. This white paper frames the issue of remote Source Document Verification and
its role moving forward within the industry to provide a foundation for such dialog.

The FDA in their document ‘Oversight of Clinical Investigations - A risk based approach to Monitoring’,
stress that remote monitoring can provide all of the benefits of onsite monitoring as well as additional
capabilities that will further ensure the integrity of the trial data and the safety of the trial participants.
The FDA are categorically encouraging the use of centralized remote monitoring at locations other than
at trial sites. Various factors will influence the type and extent to which centralized monitoring can be
used, the risk factors as stipulated by TransCelerate Biopharma Inc. can be integral in assigning a risk score
to each trial location. If centralized monitoring is to be used, the sponsor should ensure that the processes
and expectations for site record keeping, data entry, and reporting are well-defined and ensure timely
access to clinical trial data and supporting documentation.(1)

If Sponsors intend to rely heavily on centralized monitoring practices, they should identify, in the monitor-
ing plan, when one or more on-site monitoring visits would be undertaken.

BACKGROUND
Clinical research is funded by numerous organizations, including commercial, academic, government, and
charitable organizations. All organizations are expected to conduct their research to the standards of
Good Clinical Practice (International Council of Harmonization’s E6 Good Clinical Practice Guidelines(2) to
assure there is appropriate human subject protection. Clinical research for products that will be marketed
to the public are held to additional standards such as the Code of Federal Regulations (21 CFR 312 (drugs
and biologics))(3) and 21 CFR 812 (devices)(4) and Regulatory Guidance documents.

To ensure compliance to these guidelines and standards, Clinical Monitors oversee the research at the
investigative site on behalf of Sponsors. The purposes of trial monitoring are to verify that:
• The rights and well-being of human subjects are protected; this is the focus of the latest FDA draft
guidance.
• The reported trial data is accurate, complete, and verifiable from source or certified source
documents.
• The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with
GCP, and with the applicable regulatory requirement(s). This includes review of the control and
management of the investigational product or Clinical Trial Material (CTM).

The monitoring process starts as early as the feasibility assessments, however, the majority of the
Monitor’s workload is performed during trial conduct. Traditionally, the entire monitoring process is
performed by a single individual visiting the site periodically (defined in the clinical monitoring plan or by
necessity) to compare the data collected in the study records or Case Report Forms with the source
documents (primary data source or the first place the data were collected). Components of the review are
as follows:

Maintaining Human Subject Protection entails the following activities:

• Assure that the proper approvals have been received from Institutional Review Boards or Ethics
Committees (ex-US).
• Confirm that informed consent was obtained (proper version approved by the IRB or EC, correct
pages, correct signatures and timing of signatures, correct person obtaining informed consent).
• Ensure that notification of subjects and the IRB has occurred if new data pertaining to the safety of the
study treatments have been identified.

Assuring that the studies are performed to protocol specifications, regulations, and ICH Guidelines which
entails the following activities:

• Adequate training of the investigative team to assure they understand the protocol and can
perform the assessments.
• Qualification of sites.
• Site training.
• Proper selection of subjects (review of deviations).
• Protocol adherence.
• GCP adherence.
• AE/SAE reporting.

Assuring that data collected is accurate to ensure outcomes reported are valid:

• Confirming proper randomization and maintenance of subject blind.

• Simple verification that the data collected matches the data in the primary or certified source.
• A more complex scientific review of the medical record and the entire data collected to assure that
the proper subjects were enrolled and the assessments were done according to the protocol.
• Cross subject reporting to confirm scientific integrity.

Assuring adequate control of investigational product entails the following activities:

• Review of the documentation assuring all approvals have been received prior to shipment of the
investigational product.
• Management of the shipment, storage, and dispensing of investigational product.
• Oversight of the return or destruction of unused investigational product(5).
THE GOLD STANDARD IS NOT GOOD ENOUGH

The Clinical Trials Transformation Initiative (CTTI) surveyed academic/government/collaborative groups,

CROs, Device and Pharmaceutical Companies to better understand current monitoring practices in
October 2009. They found that the frequency of onsite monitoring visits varies across the various groups
conducting clinical research. Academic and Device organizations were less likely to perform onsite
monitoring visits. Only 46% of Academic, Government and Cooperative groups visited a site more than
once a year and only 63% of the Device organizations visited a site more than once a year. More than 80%
of the Pharmaceutical and CRO responders reported performing onsite monitoring visits more than once
a year. A small percentage of the responders in all groups reported using a centralized monitoring process
to guide, target, or supplement site visits (23‐33%).(6)

These organizations all report that more than 50% of the trials they manage are pivotal registration trials
(Phase I, II, III) and the majority have more than 50 sites (with the exception of Device organizations,
where >90% of the studies have <50 sites). Interestingly, the most common factor for determining
monitoring frequency was listed as study design for all groups. Academic groups also reported usual
practice as an equally common factor in determining frequency of onsite monitoring trips. Therefore, it
can be concluded that a large number of trials that are critical registration trials are not thoroughly
monitored and the welfare of subjects is not listed as a top reason for the determination of monitoring
frequency. Budget and study populations were the least common factor in determining the frequency of
onsite monitoring visits.

CTTI reviewed all FDA Warning Letters issued from December 1997-April 2009 for findings related to
monitoring of clinical trials for Center for Drug Evaluation and Research (CDER), Center for Biologics
Evaluation and Research (CBER), and Center for Devices and Radiological Health (CDRH). There were 271
warning letters issued related to the monitoring of clinical trials. Many warning letters cited violations of
more than one area and covered more than one research subject. There were 465 violations cited, with
General Responsibilities of Investigator 21 CFR Part 812.1 (Devices) and Part 312.6 (Drugs and Biologics)
representing 41% of the findings. The most frequently cited violations identified during the Warning
Letter review and the number of times each was cited is shown below (Table 1).(7)

Regulation Regulation Classification Number of Times

Cited

812.100 General responsibilities of investigators (devices) 109

312.60 General responsibilities of investigators (drugs, biologics) 83

Investigator records of each subject’s case history and exposure to

812.140(a)(3) 78
the device

312.62(b) Investigator recordkeeping and record retention: Case Histories 69

812.110(b) Specific responsibilities of investigators: Compliance 65

812.140(a)(2) Investigator records of receipt, use, or disposition of a device 61

Table 1. Most Frequently Cited Violations Identified During FDA Warning Letter
Performing onsite monitoring visits does not assure Sponsors that their studies are being reviewed
completely and appropriately. In 2010, a major pharmaceutical company received a warning letter stating
that despite visits from the Monitors on nine different days, it was not recognized that paediatric patients
had been overdosed. Even after retraining the Monitors, they missed additional overdoses of subjects at
further sites.

A major player in the pharmaceutical industry and the CRO it had employed to oversee a pivotal trial
received warning letters in 2009 relating to its conduct. The pharmaceutical company was cited because
of its overall responsibility to oversee the study conduct. In their warning letter, they were both cited for
not identifying that multiple subjects were dosed at the same site at exactly the same time by the same
person.

In 2010, Catherine Lee presented data at the APEC Harmonization Multi-Regional Clinical Trial Conference
in Seoul on an internal effort that a prominent pharmaceuticals company under took to perform 678 site
audits across four different regions. They identified the reasons for the findings. Of note, 92% of the US
sites and 95% of the European sites had more than five findings at site audit.(8)

92% of US Sites and 95% of European Sites had at least 5 Observations at Site Audit

Percentage - groups by numbers of observations

70
66
58
60

47
50
43

40
Percent

0 - 4 observations
34 34 35
5 - 8 observations
29
30 > 8 observations
23
18
20

0
10
5

0
N. America Europe RoW East Europe
Region

Figure 1. 92% of US Sites and 95% of European Sites had at least 5 Observations at Site Audit(8)
It can be concluded that the current process of clinical trial oversight is not adequate despite significant
costs to Sponsors and significant disruption at the sites. The clinical research community has been
exploring how best to achieve optimum oversight of trial conduct to assure subject safety and obtaining
quality data for answering the research questions from the trial. Research studies are designed to test a
hypothesis and are reviewed by an Institutional Review Board or Ethics Committee to assure that human
subjects are protected based on the specific research protocol. When this process is not conducted
appropriately, subjects can be at risk.

MONITORING ALTERNATIVES
100% SDV Review

Many Sponsors in the Pharmaceutical industry have traditionally carried out 100% Source Document
Verification to ensure that the data collected on the case report forms is the same as that in the primary
source documents. The verification process can be divided into two components:

• A simple verification activity to assure the data is 100% accurate.

• A more complex scientific review of the medical record and the entire data collected to assure that the
proper subjects were enrolled and the assessments were executed according to the protocol.

There are many challenges to this approach. Firstly, there is only one person conducting the site review;
therefore, the Sponsor has a single point of failure identified within the process. Traditionally, there is little
to no oversight of the Monitor’s work and the Sponsor is completely exposed if the quality of the
Monitor’s work is inadequate. As outsourcing and cost pressures increase, managerial oversight will
correspondingly diminish further increasing the Sponsor’s exposure and risk profile.

Monitor turnover rate is a well known issue, but exact rates of turnover on a trial basis are seldom if ever
published. Industry experts quote an annual turnover rate in the range of 10-20% within a company, but
the turnover rate within a clinical trial is usually higher. Sponsors report that Monitor turnover during a
trial is a common occurrence, particularly in multi-year studies. Vacancy rates within outsourcing
organizations are now a more important metric to understand than turnover rate, as this adds to the
pressure on the industry. The risk of errors in reviewing site performance or inadequate review of human
subject protection is greater when there is a transition of monitoring staff. As outsourcing continues to
increase, Sponsor exposure to process compliance will correspondingly increase. Sponsor/Vendor SOPs,
Work Instructions and monitoring escalation procedures will become more difficult to maintain
consistently, as well as train and track. Process compliance will increasingly become an issue that
Sponsors will have to address and compensate for within their programs.

With current budget constraints, increased pressure on the time a Monitor has onsite and additional
non-GCP requirements that a Monitor must perform, the Monitor may not have sufficient time to perform
all activities that are expected. The activities include a full review of all the data being collected and
comparison to source documents, review of all informed consents, review of enrolment, training, CTM
oversight, and investigator conferences.(9)
There is no way, currently, to identify what the Monitor has missed or to have any type of oversight unless
audits are done during trial conduct because all the source data and documents remain solely at the site.
Monitoring contracts need to be linked to monitoring report outcomes to ensure process compliance.

Statistical Sampling

Several methods of more efficient or cost effective monitoring of clinical trials are being explored. One
approach entails using mathematical sampling to determine which subjects and which data should be
reviewed. In some cases, only critical data items undergo onsite review and comparison with source data.

Sampling is done over the entire duration of the trial. This may be reasonable from a data quality
approach but there are significant limitations with implementation.

• This approach is problematic for smaller studies. There needs to be significant numbers of subjects
across the study for this method to be valid.
• The approach may not include the variability of multiple study coordinators. A statistical model
cannot assume that the same study coordinator performs all assessments on all subjects and this
variability must be included in the modeling approach.
• The sampling occurs throughout the duration of the trial: therefore, the opportunity to find problems
fast and remediate those problems is missed, putting more subjects at risk.
• Focuses only on the data quality and not the other key components of monitoring: review of informed
consent, clinical trial material accountability and the importance of following the protocol as
designed and approved by the Institutional Review Board or Ethics Committee.
• Should irregularities be identified on the subset of subjects or data fields that are reviewed, an
escalation process must be clearly defined. This process must be included in the training for all
Monitors that conduct onsite monitoring visits. The process must define how many subjects must be
monitored, what data must not be monitored, how long the enhanced monitoring must be
maintained and whether previous subjects should undergo the more intensive monitoring.
• There are significant challenges in resource planning. When studies are resourced for a decreased %
SDV (subjects or data items) and findings result in escalation, there will be cost overages and there
may be insufficient staff assigned to the trials to address issues.

This approach has the same limitations that are seen with standard onsite monitoring. There is only one
person that reviews all the documents at the site and there is no opportunity for central oversight to
review the quality of the onsite monitoring. The audits that occur to determine the quality of the work at
the site and the quality of the monitoring are not conducted until the end of the study or prior to
marketing approval of a product. With this approach, many of the findings that have been identified in
Investigator Warning Letters and Sponsor Warning Letters will not be identified.
Reduced % SDV

This approach entails performing SDV on only certain data points within the CRF. In this approach, for
example, only critical data items and Adverse Events may be reviewed. This approach may make sense
from an efficacy standpoint, but the Monitor’s responsibilities are greater. Reduced % SDV has the same
limitations as Statistical Sampling:

• The approach may not include the variability of multiple study coordinators. For example, when 10%
of the subjects undergo 100% SDV review, does this include 10% for each study coordinator? Does the
Monitor revert to 100% SDV when a new coordinator starts? What is the training process? How is this
tracked and/or budgeted?
• Should irregularities be identified on the subset of subjects or data fields that are reviewed, an
escalation process must be clearly defined and managed. This process must be included in the
training for all Monitors that conduct onsite monitoring visits. The process must define how many
subjects must be monitored, what data must not be monitored, how long the enhanced monitoring
must be maintained and whether previous subjects should undergo the more intensive monitoring. It
needs to include an oversight process.
• There are significant challenges in resource planning. When studies are resourced for a decreased %
SDV (subjects or data items) and findings result in escalation, there will be cost overages and there
may be insufficient staff assigned to the trials to address issues.

This approach has the same limitations that are seen with standard onsite monitoring and the last three
points of statistical sampling mentioned earlier. There is only one person that reviews all the documents
at the site and there is no opportunity for central oversight to review the quality of the onsite monitoring.
The audits that occur to determine the quality of the work at the site and the quality of the monitoring are
not conducted until the end of the study or prior to marketing approval of a product.

Central Monitoring – Traditional Methodology

With traditional central monitoring, the Monitors fax documents to the Sponsor or CRO for review against
the eCRF or CRF. This approach is usually used only for key data and not for the entire study process and
all documents. Privacy protection is an issue with this methodology (faxes).

The problem with this approach is that there is no archiving system with full audit trail that confirms who
faxed the document, when documents were faxed and a way to maintain the documents in an organized
system. The documents are usually reviewed and the only version of the source remains at the site.
Furthermore the documents are not currently certified as electronic source.

During the conduct of the trial, the Sponsor is still at risk if the documents are not able to be produced at
the time of a site audit. The limitations of not having anyone review the activities at the site include the
potential that there may be missing data that has not been sent for central review. If informed consents
are faxed, there are significant issues with subject confidentiality because there is no control of access to
the subject’s name and personal identifying information, leaving Sponsors exposed to liability and HIPPA
violations.
Remote Source Data Verification

To address the limitations of current approaches to clinical trial oversight and research subject protection,
remote Source Document Verification provides a different approach using technology to improve clinical
trial oversight and eliminate much of the onsite monitoring needed for a trial. The approach is designed
to enable the rapid verification of trial data remotely using staff specifically trained to review the accuracy
(not content) of the trial data. The goal is to enable rapid, cost effective review within days, rather than the
weeks or months that are associated with the standard monitoring approaches. It is designed to enhance
the activities of the onsite Monitor by providing much better visibility into all documents, including
source documents through a 21 CFR Part 11 Compliant system. Radovich and Frick reported using this
approach for a pivotal Phase III trial and compared the results from remote SDV with one of their similar
trials conducted with traditional onsite monitoring, the benefits of this approach are apparent in the case
studies included which will be presented later in this article.(10)

SOURCE DOCUMENTS
Source Document Worksheets and Certified Electronic Source

A significant but not entire component of the Monitor’s role onsite is a comparison of data in the CRF to
the data in the source documents. Certain components of the source data reside in the medical records
and certain data is collected solely for the clinical trial on a source worksheet. Therefore, for the protocol
prescribed data that is collected directly on the worksheet at the time of assessment, the source
worksheet is the Primary Source (identified as certified source).

The source worksheets can then be scanned into an electronic document management system, which will
record who scanned the document and the date and time of the scan with a full audit trail. The source
worksheet can then be reviewed and electronically certified as electronic source. This certified electronic
source can then be used to conduct the SDV remotely.

Medical Record Source Documents

Some data supporting the trial will be found in the Medical Record as the primary source. The SDV review
of this data can be performed by the Monitor at onsite visits. Some Sponsors that are using remote SDV
have the pages of the medical record pertaining to assessments (Med Hx, Lab Reports, and Surgical
Records) scanned into the electronic system and certified as electronic source.

The certification process includes an electronic signature attesting to the fact that the person doing the
scanning has confirmed that the two documents are exactly the same in content, the only difference
being the format of the document. Of course, the certified electronic source is then stored in an
unalterable format with the subject’s personal identifying information removed or redacted.

This approach is particularly beneficial for electronic medical records (EMR) which do not have an audit
trail or EMRs that do not have adequate role-based access to protect other patients’ data within the
system from being viewed by the Monitor. The EMA recognized these concerns in their recent Opinion for
Sponsor. With remote SDV, these documents are further protected because there is now an audit trail
documenting exactly who scanned in the documents and when. There is also a certification process to
certify the source as electronic source.
They have further recommended that the specific documents or sections of the EMR that will be used for
Source Document support are identified and listed in the Protocol and Monitoring plan. Below is a
document matrix that would identify the documents, source, location, and type.

Study Prescribed Study Source Primary Location of Study Documentation

Assessments Data
Informed Informed Consent Research Files Certified electronic source in
Consent eTMF

Medical Progress Notes, Labs Medical Record, EMR Scanned source from
History Medical Record, and
certified as electronic source

Demographics Study Source Study Source Certified electronic source

Worksheet Worksheet in eTMF

Safety Labs Central Lab; Central Labs Imported into EDC (direct
Documentation of source). Documentation of
draw in Study import stored within eTMF
Source Worksheet
Physical Study Source Study Source Certified electronic source
Examination Worksheet Worksheet in eTMF

Subject Direct entry by subjects Study Source Direct Data entry with audit
Questionnaires Worksheet trail showing subject entry.
No other documentation
Clinical Trial Study Source Study Source Certified electronic source
Material Worksheet Worksheet in eTMF
Administration

Vital Signs Study Source Study Source Certified electronic source

Worksheet Worksheet in eTMF
Primary Efficacy Study Source Study Source Certified electronic source
Assessment Worksheet Worksheet in eTMF

ECG ECG performed by site Research Files or EMR Copy of ECG report certified
as electronic source

Images Image and reading by Transcription of Image stored in eTMF.

Site Radiologist or Radiologist review into Original reading by
Central Reader EDC by site onto Radiologist stored if
Worksheet or Direct read at the site
entry into EDC by Third
party Image Central
Reader
Adverse Events Progress Notes, Labs Medical Record, EMR Scanned source from
Medical Record, and certified
as electronic source
Concomitant Medical Record Medical Record, EMR Scanned source from
Medication Medical Record, and certified
as electronic source

Surgical Record Surgical Record; Medical Record, EMR Scanned source from
(if applicable) Surgeon Notes; Medical Record, and certified
Anesthesia Record; as electronic source
Recovery Room or ICU
Record
End of Study Study Source Study Source Certified electronic source
Worksheet Worksheet in eTMF

Table 2. Example of Documentation of Source Locations for a Study using Remote

Division of Monitor Responsibilities

The goal of remote SDV is to enable the medically trained Monitor to spend more time on scientific and
content review within subjects and across subjects at a site. The Monitor still visits the sites to assure that
there are no missing records—that everything has been scanned into the electronic TMF and certified as
e-Source. They meet with the Investigator and Coordinator and perform any training that is needed based
on the results of the remote SDV. They also confirm that the electronic records for Drug/Device
accountability are correct. There are significantly fewer monitoring visits with Monitors visiting sites about
half as frequently as standard monitoring plans. When the Monitors go to the sites, the visits can be
accomplished in one day rather than requiring multi-day visits.

The Monitor’s role with remote SDV is now focused on higher order and more complex review. This results
in better utilization of resources and enables the Monitors to spend time on critical issues such as cross
subject review, safety review, site training and recruiting and retaining subjects for the trial. While there is
some variability across trials, the usual breakdown of data review is shown in Table 3 below.

Primary Data Source is Medical Record (SDV Review Primary Data Source is Source Worksheet designed
performed by the Monitor; data extraction to source for Trial (SDV Review performed by the Remote SDV
worksheets by site) Specialist and Safety oversight performed by the
Monitor)
Informed Consent (remote review) Physical Exam
Inclusion/Exclusion Criteria Vital Signs
Medical History Lab Collection Data (for central labs)
Adverse Events ECG Collection Data
Concomitant Medications CTM Dosing and Compliance
Local Labs (to rule out adverse events) Study Assessments

Overall Safety/Deviation review of data Subject Questionnaires (if not directly entered into the
Subject Portal on the EDC)

Table 3. Breakdown of responsibilities for Monitors and remote SDV Specialists for different data
sources within a trial

While Sponsors and CROs have had pages of the data faxed to them for review against the CRF in the past,
the rSDV approach is very different.

1. The forms are scanned into a 21 CFR Part 11 Compliant system with full audit trail to confirm who
scanned the documents and the date and time that they are scanned.
2. Each set of source documents is certified as electronic source by the person scanning in the
documents, in full compliance with ICH GCP and FDA Guidance on Computerized systems for Clinical
Investigations.
3. The scanned source worksheets are unalterable PDFs.
4. The source documents are stored by subject and visit providing a full accounting of all data for that
subject.
5. If new or revised source documents are required, these are updated using good documentation
practices, scanned and certified as revised source - assuring that there is full congruence between
the source documents and the eCRF.
6. Subject confidentiality is maintained using role-based access and/or redaction in the eTMF system.
Working Practices/Monitor Plan/SOPs

Most of the Monitors who have worked with remote SDV appreciate the approach because it allows them
to perform the most complex review. They do not have to travel as much, they can be well prepared for
the site visits that occur, and they can prioritize visits based on the quality of the work the site performs. In
our experience, only a small subset (approximately 8‐10%) of Monitors do not prefer the approach. If they
are not willing to give up the SDV activity after receiving training, they might not be suited to the higher
level thinking and scientific review that is required of Monitors for the remote SDV process.

The Monitoring Plan must be revised to include information on the source locations and to include a
remote SDV plan. The remote SDV plan includes details of the remote SDV process. This includes SDV
modifications relating to site feasibility, protocol and informed consent and identifies the forms and visits
that will be reviewed by the remote SDV specialist. There is an escalation plan and a communication plan.
The Monitoring Plan specifies activities to be conducted by the remote Monitor as well as those to be
conducted by the onsite Monitors. The addition of the remote SDV also enables the Monitor to complete
cross subject review.

SOPs can be modified to allow electronic signatures and to recognize electronic source, eliminating the
need to maintain paper source documents.

Some EDC systems are designed to enable only the appropriate staff with the appropriate role to do SDV
on a form. For instance, if an rSDV specialist is required to do SDV on a form then a Monitor is not able to
SDV that form within the system. The Monitor is able to acknowledge their scientific oversight with a
different system acknowledgement.

The Regulators Stance

Movement to switch to rSDV within the clinical trials landscape is currently slow, with many members of
the industry being accustomed to the perceived regulatory security of 100% on-site SDV. Some would
liken the current inertia to the paradigm shift that the industry was reluctant to make with the onset of
EDC systems. Despite the FDA positively encouraging it’s use, with the emphasis on trial data integrity and
more productive use of the Monitor’s and trial site’s time, it is still seen as a mode of operation that is well
positioned for future use but not quite suitable for the present. Many large, top tier organisations have
already seized this opportunity and have incorporated it into their internationally unifying digital systems,
allowing the timelines to submission to be reduced by a third. The industry has all but adopted RBM with
the appropriate trial type, however RBM, coupled with the risk factors prescribed by Trans Celerate
Biopharam Inc. and rSDV will potentially possess the ability to revolutionise the conduct of clinical trials.
This will see trials being concluded more quickly, more successfully, under budget and with fewer regula-
tory concerns. It is well understood that procedures in place in many organizations have occurred by
expending a huge investment in both time and effort, therefore the transition to rSDV should potentially
be made in a stepwise manner, for those who require a point of reference, with appropriate amendments
being made to both the protocol and the CMP (Clinical Monitoring Plan). This will allow any sponsor the
luxury of being able to run in parallel a more traditional on site monitoring approach with the
contemporary rSDV model.

The motivation for a more efficient means of monitoring certainly exists, it requires Sponsors to be
forward thinking, willing to initiate change with an input of initial effort and the ability to visualize new,
more streamlined and lean working practices. Given this motivation, the entire industry and ultimately
the patients we seek to assist will benefit.

View appendix for more information on regulatory requirements.

BENEFITS OF REMOTE SDV
The benefits for remote SDV can be classified into four basic areas: Quality, Speed, Cost, and Site
Interactions.

Quality

Remote SDV provides the most comprehensive view of study conduct. The organization sponsoring the
trial has full visibility into what is happening at the site; it is not dependent on a single staff member to
complete all the oversight and review. This enables the Sponsor to perform remote Compliance and
Process Reviews.

All of the study documents are available and visible with remote SDV. When integrated with an electronic
trial management system, additional oversight of Clinical Trial Material is also included. Site issues are
identified within days or weeks rather than months.(11) This protects research subjects as the Sponsor is
able to see issues and institute remediation plans immediately, retrain as necessary or close sites that do
not follow protocol or make serious errors. This is a significant advantage to Sponsors and to their
research subjects.

Speed

Remote SDV provides the fastest approach to review and management of Clinical Trial conduct. With the
Data Entry Process and Data review, the entire data access and review process for a visit can be complete
within one week after a subject is seen. We have also evaluated the duration of the rest of the study
cleaning process. To minimize variability, we compared two studies initiated by the same Sponsor—one
with a traditional CRO approach using EDC and one with remote SDV.(11) The remote SDV trial was the
Phase III trial while the traditional trial was a Phase II—both with the same drug and same patient popula-
tion.

Type of Mean Query Mean Time (d)

Monitoring Resolution Rate from SDV to
(d) Completion
Phase II Traditional 6.2 24.7
Phase III Remote SDV 4.2 9.8
Total Savings 2 14.9

Table 4. Comparison of Time to perform various Data Cleaning Activities between two studies for
the same Sponsor: One with remote SDV and one with traditional monitoring.

This translates into savings of more than three weeks in study conduct by using remote SDV. When one
adds the time savings from data entry (assume 5 working days) and the time savings for SDV (assume 25
working days –going from rSDV to monitoring visits every 6 weeks), then the total savings can be 46.9
days or more than 9 weeks. We also compared two Phase I studies done at the same Phase I unit, one
done with remote SDV and one done using traditional monitoring. The benefits achieved are not limited
to Phase II-‐IV trials. The benefits are also seen with Phase I trials. Sponsors were able to save nearly two
weeks using remote SDV.
 Type of Mean Query Mean Time (d)
Monitoring Resolution Rate from SDV to
(d) Completion
Phase I Traditional 2.2 10.1
Phase I Remote SDV 0.9 1.5
Total Savings 1.3 8.6
Table 5. Comparison of Time to perform various Data Cleaning Activities between two studies at
the same Phase I site: One with remote SDV and one with traditional monitoring.

Cost

Remote SDV saves cost in many areas. The first and most obvious cost savings are in the frequency and
duration of monitoring visits. Data we have collected across the industry indicates that monitoring visits
entail about 21 hours of time for an 8 hour visit. This includes scheduling, preparation, travel, visit, report
and follow up. At a cost of $125/hour for a Monitor, the cost of an 8 hour visit is $2,625. The cost of travel
for a visit is estimated at $1,000/visit. Therefore, the number of eliminated monitoring visits can be
calculated as follows for a study that will have monitoring visits changed from every 6 weeks to every 12
weeks:

• # weeks for interim monitoring visits (FPI-‐LPO)/12*# sites * $3,625.

For example, a two year study (FPI-‐LPO) at 35 sites with every other visit eliminated (q6weeks to q12
weeks) would have the following cost savings for eliminated visits:

104/12*35*$3625=$1,099,583

Additional cost savings are realized when Monitors can cover twice as many sites and when the visits that
they do make to the site are shorter.

Additional cost savings are recognized by remotely and electronically managing the eTMF. No documents
are shipped to the site and with the site facing approach each site is able to upload or scan all documents,
eliminating the need for someone to manage this centrally. Sponsors need to better understand the true
cost of monitoring in order to perform a proper comparison. There are many components that add up to
the total cost of monitoring and some are not easily tracked and accessible for proper calculation (such as
project management time). One approach is to determine the Sponsor’s monitoring cost per data item
(CPDI). The Sponsor should calculate the total identifiable line items associated with monitoring, inclusive
of project contingency and divide by the variables associated with the trial.

For example:

Total Monitoring Costs (line items)/ # of subject / # data items to monitored = Cost per data item

$250,000 /300 subjects/ 600 data items (40 CRF’s x 15 items per page) = $ 1.39 per data item

The Sponsor will still have to review additional variables and ensure definition concerning query
resolution is understood and accounted for; however, CPDI is a critical variable that all Sponsors/vendors
should be able to openly discuss.
Site Interactions

A survey of 115 sites that had completed a Phase III study with remote SDV(7) revealed that the sites were
very accepting of remote SDV (See Figure 4). When asked about their favourite feature of remote SDV,
many cited that they preferred the rapid feedback on their activities. It enables them to “close out” a
subject’s visit when it is still fresh in their minds. We hypothesize that this is the reason that the query
process is much faster with remote SDV. When data entry is included, sites appreciate having this
additional work removed so they can focus their attention elsewhere.

Sites also like the eliminated monitoring visits, which are highly disruptive to the study coordinator (See
Figure 2). Sponsors have reported that they now have to pay extra for onsite monitoring visits. This will
only drive up monitoring costs in the future. When the SDV is complete, Monitor’s focus on sites’ needs
and sites are more receptive to Monitors (See Figure 3).

When sites are able to use a fully integrated suite of software that covers all of their clinical trial needs,
sites gain added efficiency in managing the entire trial process with one login at one place for everything.
In addition to the benefits from the eTMF, they are able to have a single location for everything they do,
including randomization, CTM accountability, reporting of SAEs, and managing documents. Site
payments are also integrated with the EDC, so paying sites rapidly can be accomplished with minimal
staff time. If the Sponsor’s strategy is to build the most positive relationship with the site and to become
the “Sponsor of Choice”, this is the best solution to accomplish this goal.

rSDV Reduced the Degree of Disruption for SDV

5
• Rating:
0=Can’t Tell
4
1=Strongly Agree
3=Neutral
Response

5=Strongly Disagree 3

• Mean = 2.22
- 87% rated answer 1-3 1
- 13% somewhat or strongly
disagreed 0
- 1.4% could not tell 1 4 7 1013161922252631343740434649525556661646770

Site

Figure 2. Site Responses show 87% of Sites found that remote SDV reduced the degree of
disruption for Source Document Verification.
 rSDV enabled Onsite Monitor to Focus on Issues
Important to Me
5
• Rating:
0=Can’t Tell
4
1=Strongly Agree
3=Neutral

Response
5=Strongly Disagree 3

• Mean = 2
- 90% rated answer 1-3 1
- 10% somewhat or strongly
disagreed 0
- 4.3% could not tell 1 4 7 1013161922252631343740434649525556661646770

Site

Figure 3. 90% of site responders found that remote SDV enabled onsite Monitors to focus on issues
important to the Study Coordinator.

I would do another study that used rSDV

5
• Rating:
0=Can’t Tell
4
1=Strongly Agree
3=Neutral
Response

5=Strongly Disagree 3

• Mean = 1.9
- 93% rated answer 1-3 1
- 7% somewhat or strongly
disagreed 0
- 3% could not tell 1 4 7 1013161922252631343740434649525556661646770

Site

Figure 4. 93% of the Sites said they would do another study that used rSDV.
THE IDEAL TRIAL SITUATION

In time and with the authorship of an appropriate CMP and Protocol, rSDV can be used with any clinical
trial providing an appropriate risk has been assigned in line with the specifics of the trial.

At this preliminary stage, with rSDV in the adoption phase, the type of trial that is deemed the most
suitable, fall into these parameters:

1. Post-marketing safety studies, where the focus is the collection of data, for the composition of
FDA/EMA/MHRA reports.
2. Those trials where there is a low emphasis on IMP accountability.
3. Large multi-centre, international phase III/IV trials where CRA travel could potentially contribute up to
50% of trial budgets.
4. Those Sponsors wishing to extend an NCE/NBE to a new indication.
5. Protocols that are not complex and do not involve sub-studies or procedures beyond the normal
standard of care.
6. Trials that do not involve vulnerable populations.
7. Trials being conducted by sites with organizational experience of trials.
8. Those protocols that do not involve up or down titration of the IMP.
9. Trials where the IMP is being administered as normal standard of care, thus not involving a logistical
chain.
10. Protocols with a low chance of unblinding.

SUMMARY
The issue of enhancing clinical trial monitoring is critical to all Sponsors, Investigators and research
subjects. Remote Source Document Verification offers the best alternative to assure both the quality of
the data and the appropriate oversight of trial conduct to assure human subject protection (See Table 6).
Remote SDV provides enhanced monitoring, compliance oversight and faster identification of site issues
at a significantly lower cost than traditional monitoring.

With remote SDV, there is a focus on having the right person with the right skills to do the right job.
Simple verification is done remotely with trained staff that do not have the scientific training that
Monitors are given. This enables the highly skilled Monitors to focus on the higher order thinking and
review, providing a more efficient and cost effective approach. Therefore, Monitors are not eliminated;
they have a more focused job, assuring that subject safety and study conduct are performed correctly.

By using technology specifically designed to assure that regulatory requirements are met (such as
certification of electronic source and protection of subject’s personal identifying information), much of
the process can be done remotely, assuring improved oversight of site performance and minimizing the
time and cost of travel to the sites. This facilitates Sponsor compliance and simplifies the review by
regulatory agencies.

Remote SDV can be used with any type of medical record, including electronic medical records. It offers
an advantage when EMRs have to be printed because of inadequate access control of the EMR for Monitor
access. With remote SDV there is a full audit trail of all the source documents and appropriate access
control can be maintained.
There will need to be minor changes to SOPs, such as including the remote SDV plan as a component of
the Monitoring plan, division of responsibilities for a trial between the Monitor and the rSDV Specialist
and enhancing communication among team members. These are easily achievable and because each of
the team members work within the same system, the interactions are more efficient.

Standard Practice Reduced SDV Mathematical Remote SDV

(Source at site) (Source at site) Sampling (Source (Certified e-Source
at site) available via Web)

Quality: Site/Document NONE NONE NONE 100%

Compliance/Visibility

Speed: Time to SDV Weeks to months Weeks to months N/A Days

Cost +++ ++ ++ +

Cost Control Time & Materials Time & Materials Time & Materials Fixed Price
Training &
Implementation DIFFICULT VERY DIFFICULT NEUTRAL EASY

Site Acceptance POOR NEUTRAL NEUTRAL GOOD

Table 6. Summary of attributes of different monitoring approaches showing the superiority of

remote SDV in providing clinical trial oversight.

Remote SDV provides the best alternative to 100% site monitoring in the industry. The approach enables
100% visibility into site performance and provides the fastest and most responsible approach to
protecting subject safety. With the combination of remote SDV and focused site visits, Sponsors are able
to conduct studies more efficiently and cost effectively while achieving superior quality. The solution
meets the requirements of the sites, Sponsors, and regulators and should be adopted as the new Gold
Standard for Clinical Trial oversight.
ABOUT QUANTICATE
Quanticate is a leading global biometrics focused Clinical Research Organization (CRO) primarily focused
on the management, analysis and reporting of data from clinical trials and post-marketing surveillance. As
Experts in Clinical Data, Quanticate provides high quality teams that offer efficient outsourcing solutions
for clinical data management, biostatistics, SAS programming, source data verification, medical writing
and pharmacovigilance. Quanticate can offer study level support, functional service provision (FSP),
strategic full data-services solutions or technical consultancy to meet the needs of pharmaceutical,
biotechnology and device companies across the globe. Quanticate’s focus on expertise was demonstrated
when it was recognized as a four category winner in the 2015 CRO Leadership Awards for Quality,
Productivity, Regulatory and Innovation. By offering high quality, value-add client specific solutions to
meet current and future development needs, Quanticate has become the supplier of choice for many
companies from top tier pharmaceutical giants through to niche biotechnology and device companies.
Please visit the website at www.quanticate.com for further information and access to white papers.

ABOUT THE AUTHOR

Dr Gavin Boodoo joined Quanticate in 2016 as Manager of Remote Source Document Verification (rSDV)
bringing more than 17 years of experience in clinical trials to the company. He leads Quanticate’s global
rSDV group, providing leadership and support to group operations within the rSDV area. Prior to joining
Quanticate Gavin held senior clinical project managerial positions in medium sized and large publicly
traded companies within the pharmaceutical and CRO service industries.

At Quanticate, Gavin oversees our global rSDV network, ensuring that rSDV practices and operating
processes are of a high quality. As such, he has gained extensive international clinical trials expertise
across developed and emerging markets, and across several different reporting standards.

He brings extensive drug development experience having previously managed programs in over 18
countries, from North America through to Australia. His extensive experience includes management of
clinical operations and medical writing and training across these geographies. He has also had extensive
involvement in training and development and has worked within 2 academic institutions in North
America and The Caribbean to develop a curriculum for Masters programs.

Gavin has a PhD from The Massachusetts Institute of Technology and an MBA from The Tuck Business
School at Dartmouth.
APPENDIX: SUPPLEMENTAL INFORMATION
Informed Consents

Errors in informed consents are a leading cause of findings at site audits. With remote SDV the informed
consent can be scanned into an eTMF system and all informed consents can be reviewed remotely,
assuring that every page is present, the correct version is used and the dates are consistent with
regulation and what is reported in the EDC. It is helpful if the eTMF and EDC systems are integrated.

Access to personal identifying information is controlled by a user’s role within the system, so only those
with permission can access source data (site personnel, Monitors, FDA, company-Sponsored auditors). The
archive for the site will include all informed consents (as separate PDFs for each version for each subject).
The Sponsor’s archive version will not contain the informed consents. The Trusted Third Party Provider
maintains an archive version for the Site and the Sponsor. The Trusted Third Party Provider’s role in
protecting subject confidential information will also be covered in the Informed Consent and the
Protocol. A PDF version of the informed consents can be downloaded and added to the subject’s
electronic medical record. This assures that all data for a subject are available in the EMR.

A second alternative is that the subject’s personal identifying information can be redacted. The Sponsor is
able to see that the document is present, but they cannot access it until the document has been redacted.
Redaction is role based, so those that are able to see personal identifying information can see the
subject’s name and personal information. Once redaction has been completed, the document is released
to the Sponsor for review. Archives of the documents with redaction are included in the Sponsor’s archive
while unredacted Source Documents are provided to the Site for their complete records.

Regulatory Requirements and certified Electronic Source Documents

Remote SDV enables Sponsors to assure studies are conducted to GCP and Federal regulations. It also
meets the following regulations:

• 21 CFR Part 11 (Regulations for Computerized systems)(12)

o The electronic document collection, storage, and review system with customizable
electronic signatures is the basis for remote SDV. It must meet all the requirements
defined by 21 CFR Part 11.

• ICH, GCP, and FDA Guidance for Industry on Electronic Source

o Computerized Systems Used in Clinical Investigations allows for the use of certified
copies. The technology for remote SDV must meet these requirements. First, the
documents are scanned and maintained as unalterable PDFs. There is a full audit trail
showing when the documents were scanned into the system and who scanned
them. There is an electronic signature certifying the source as certified electronic
source. The site staff is trained to use the system and to understand that the source
provided within the system is the “same” as the original paper source.
The system is also designed so that the Sites have control of their Source Documents and can access them
at any time and from any location.

Certifying documents as electronic source is acceptable to the FDA. Both the general guidance on good
clinical practice ICH E6 and the guidance on computerized system in clinical investigations(12) allows for
the use of “certified copies”.(5) A certified copy is defined as a copy of original information that has been
verified, as indicated by dated signature, as an exact copy having all of the same attributes and
information as the original. Of course, the sites must be trained to understand that they are certifying that
the source is exactly the same as the electronic copy. The electronic archiving system must have specific
wording for certification of electronic source.

Scanning

We recommend that Sponsors provide high speed desktop scanners for each site. This is the most cost
effective path for both the site and the Sponsor. At the conclusion of the trial, the scanner is left at the site
or returned. In some instances, third parties provide the scanners to the sites. These assure that scanning
all worksheets for an entire visit can be scanned in as little as a minute. Each subject’s worksheets are filed
by subject and visit in the electronic TMF. The EDC is integrated with the eTMF and a subject placeholder
is generated for all visits within the eTMF as soon as a subject is generated within the EDC.

After the worksheets are scanned the person that scans the worksheet is trained to check that the scan is
complete and includes all the data that is on the original worksheet. They then electronically sign the
worksheet to certify that it is an exact replica of the source. The person that does the scanning does not
have to be the person that sees the subject. For larger trials/programs, a batch uploader/parser can be
deployed. This enables the sites/CRO to upload large volumes of documents/images, without having to
parse them into the correct file. This eliminates site errors/workload.

Some Sponsors pay for the time required to do the scanning while others do not because there are fewer
site visits and fewer hours that the coordinator has to be available to the Monitors. Furthermore, although
the eTMF software can work with any scanner, having a scanner at the desk of the person doing the
scanning is the most efficient and accepted approach for the site. As there are multiple pages for each
visit, we do not recommend a flatbed scanner.
REFERENCES

1. U.S. Food and Drug Administration

http://www.fda.gov/downloads/Drugs/.../Guidances/UCM269919.pdf

2. Morrison BW, Cochran CJ, et al. A CTTI Survey of Current Monitoring Practices-‐ A Clinical
Trials Transformation Initiative. .Society for Clinical Trials, May 17, 2010

3. U.S. Food and Drug Administration, Title 21 Part 312, Investigational New Drug:
www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312

4. U.S. Food and Drug Administration, Title 21 Part 812, Investigational Device Exemptions:
www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=812

5. International Council for Harmonization Guidance for Industry E6 Good Clinical Practice:
Consolidated Guidance, April 1996;
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM073122.pdf

6. Clinical Trials Transformation Initiative; Effective and Efficient Monitoring as a Component of

Quality: Final Report for Work stream 2:
https://www.trialstransformation.org/projects/effeCtive-and-efficient-monitoring/monitoring-project-work stream-2-define-
key-objectives-of-monitoring

7. Lee, Catherine; Quality and GCP Compliance in Multi-Regional Clinical Trials;

http://www.apec-ahc.org/files/tp201002/Session2_CatherineLee.pdf

8. O’Neill, S, Lewis, A, Sorgi-Gendreau, J, Blumenfeld, T; CRAs and Site Performance in the U.S:
Expectations vs. Reality. Monitor. September 2009. P.49-54.

9. Radovich C, Frick J, Remote Source Document Verification: A Sponsor Perspective and Results
of Implementation. Monitor December 2009. P 39-43

10. Nahm ML, Pieper CF, Cunningham MM, 2008 Quantifying Data Quality for Clinical Trials
Using Electronic Data Capture. PLoS ONE 3(8):e3049. doi:10.1371/journal.pone.0003049

11. Reflection paper on expectations for electronic source data and data transcribed to
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12. Guidance for Industry: Computerized Systems Used in Clinical Investigations. US Department
of Health and Human Services, Food and Drug Administration, Office of the Commissioner.
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