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Strategies for Designing and Implementing a Successful Independent Imaging Review
By Stephen W. Bates, Program Director and Nicholas R. Enus, Senior Project Manager, Medical Imaging & Diagnostics, Perceptive Informatics Inc., MA, USA
Medical
imaging related endpoints in clinical trials are becoming
increasingly important in supporting trial outcomes.
Additionally, regulatory agencies seem to be increasing their
acceptance of, and ultimately their absolute requirement for
independent assessment of these imaging endpoints. However, many
pharmaceutical companies and the CROs they employ are unfamiliar
with the processes and procedures that must be implemented to
support this new type of analysis. A successful independent
imaging review requires proper planning and implementation all
the way from protocol design to drug submission. This article
will present a basic strategy that should be employed to help
ensure that clinical trials are designed and conducted in such a
way as to minimize cost yet maximize the speed, accuracy, and
ultimately regulatory acceptance of an independent imaging
review.
The planning and design of independent medical imaging within a
clinical trial should begin during study protocol design. It is
important for the study protocol to reflect the needs and
requirements of the independent imaging review. For example, the
collection of clinical and imaging data and case report form
design should be done in such a way as to facilitate the
independent review, minimize discrepancies between the
investigator and the independent review and ease the overall
comparison of data.
Once finalized, the study protocol will serve as a guiding
resource for various independent medical imaging specific
documentation and procedures, which will be developed and
implemented over the course of a typical project lifecycle by
the contracted independent medical imaging vendor. The following
tasks and deliverables pertaining to independent medical imaging
should be developed in partnership between the sponsor and
independent medical imaging vendor and should include, but not
be limited to, the following:
1. Independent medical imaging vendor contract/exhibit
2. Project Plan
3. Imaging standardization protocol
4. Investigator site imaging qualification and start-up
5. Investigator site manual
6. Image tracking software
7. Independent endpoint review committee imaging charter
8. Image analysis software
9. Independent reviewer manual
10. Image data reconciliation
11. Independent central reviewer selection/approval
12. Image analysis data export
13. Study progress/metric reporting
Independent Medical Imaging Vendor Contract/Exhibit
This is perhaps one of the most important medical imaging
documents that is developed and should be given as much planning
and thought as any of the other Independent Imaging Vendor (IIV)
documentation. Although it is not always feasible, it is most
efficient to engage an IIV prior to study enrollment and
subsequent baseline imaging. At the very least, IIV
participation should be finalized prior to any review activities
to avoid costly delays due to lack of imaging standardization
and re-review of data.
Although the contract/exhibit should be based upon the study
proposal sent and agreed to by the sponsor, the proposal may not
be all-inclusive of all necessary imaging services. At the early
stages of a project, budgetary and timeline concerns often
supersede scientific rigor, and important imaging-related
details can be sidelined for later discussion. For example,
optimistic patient enrollment calculations can result in
under-estimation in study duration. Additionally, details of the
review criteria are commonly modified late in the process after
work has already begun in support of the originally planned
methodology. In this case, a scope change and re-work on the
sponsor’s and IIV’s behalf is typically necessary.
It is important that the sponsor involve all internal parties
when making decisions (e.g. Data Mgmt, Clinical Team, Medical
Team, etc.), even if it is not readily apparent that involving
all parties is necessary. Doing so will help ensure the study
stays within budget and original scope. It seems clear that the
amount of forethought and investment in the independent review
process early on will pay dividends in decreased costs, time and
re-work through the study’s lifecycle.
Project Plan
The Project Plan is a critical document and should be drafted
and sent to the sponsor as soon as possible upon project award.
This document should contain items such as team contact
information, escalation procedure, critical path documents, a
project timeline, and medical imaging risk identification and
mitigation/prevention. It should be developed in partnership
with the IIV and used as a guidance document for the project’s
conduct and life cycle.
Imaging Standardization Protocol (ISP)
This document should be one of the first IIV documents generated
as it is absolutely critical early in the process (prior to
baseline imaging) and throughout the study’s lifecycle. One of
the main factors that highlight this importance is the fact that
study protocols habitually lack the specific detail necessary to
ensure imaging standardization. Often study protocols simply
leave too much to interpretation and Investigator’s will often
fill in the details using standard hospital protocols, which can
vary widely. A well-written ISP, that gives detailed
instructions as to how and which medical imaging should be
acquired for a clinical trial, will help to mitigate this risk.
The ISP should be sent to the Investigator sites during the
study start-up/investigator site qualification period (see
below). It is important that review and approval of this
document be completed expeditiously by the sponsor, as delays in
finalizing this document will result in obvious delays of the
investigator site qualification process. Lastly, sponsor and IIV
should avoid the temptation to create lengthy and verbose ISP
documents. The ISP should not attempt to supplant or justify the
study protocol nor should it attempt to contain encyclopedic
instruction regarding the independent review process. Quite
frankly, imaging technicians have little time and interest in
such matters and generally respond better to abbreviated ISP
documents that provide instruction in a clear and concise
manner.
Investigator Site Imaging Qualification and Start-up
An investment in this process should be made early in the trial
and the expected duration should be from one to 12 months or
more. Total duration will depend on the number and composition
of the investigator sites, imaging complexity, and the amount of
emphasis on imaging-related endpoints that the sponsor demands.
At this point, the sponsor should make some firm decisions
regarding patient enrollment and the qualification process. A
more stringent policy (i.e. no enrollment prior to qualification
completion) will most likely delay enrollment and increase costs
but also improve imaging compliance and ultimate data integrity.
It is also important to budget for ongoing re-qualification due
to new investigator site initiations and/or staffing turnover.
Site imaging qualification should typically consist of two parts
– the first is collecting information (additional site/imaging
facility contact and scanner information via survey as well as
an agreement from the site to comply with the ISP for all trial
imaging). The second part should be requiring investigator sites
to submit a test image to the IIV. The request and collection of
this test image should be directly managed by the IIV. In many
cases, assistance from the clinical monitors and/or sponsors
will be necessary to collect these items from unresponsive or
ill-trained investigator sites. There should be a firm
escalation plan in place to guide the imaging qualification
process.
Investigator Site Manual (ISM)
This document should be developed by the IIV and approved by the
sponsor. The ISM should be distributed to each site along with
all necessary study materials (Image Transmittal Forms, Shipping
Supplies, Digital Media, etc.) upon completion of the site’s
medical imaging qualification. This document will serve as an
informational and procedural source for the investigator site.
It should contain all the necessary instructions and study
procedures the investigator sites will need to follow in order
to acquire and submit medical imaging successfully to the IIV.
Image Tracking Software
It is important for the sponsor and IIV to agree upon a
standardized imaging tracking and query management process.
Often this includes study-specific tracking software. Prior to
the development of tracking software such as this, high-level
requirement specifications should be finalized to identify and
list the fields/data necessary to capture. These fields/data,
along with the medical imaging received will be used not only
for the independent analysis performed by the IIV, but also will
eventually be reported to the sponsor (or sponsor’s designated
data mgmt. CRO). It is critical that there should be absolute
agreement on all data to be tracked prior to patient enrollment.
Independent Endpoint Review Committee Imaging Charter
This is one of the most important and influential documents that
will be developed for a study. This document should identify and
contain all of the requirements specific to the study’s
independent medical imaging review. Items such as which
modalities will be reviewed by the independent reviewers, what
analysis criteria (i.e. RECIST) will be used, what types of
reviews will be performed (i.e. single vs. double), and how the
analysis criteria will be applied during the independent medical
imaging review. The implications of this document are
far-reaching and touch many of the other study documents and
procedures. It is recommended that this document be sent to a
regulatory agency for review and approval (i.e. Special Protocol
Assessment).
The development of this document should be a true collaboration
of efforts between the sponsor and IIV. It is critical that the
sponsor involve all internal departments during the charter
development. It is not adequate to have only the sponsor’s
clinical and medical teams review and agree to this document.
Other groups, such as the sponsor’s data management department
should also review and approve this document, as it will govern
what type of analysis is done and how that analysis data will be
captured. Lastly, any delays in the review and approval of this
document would possibly result in the delays in many of the
other study activities such as the tracking software, the
analysis software, and the image data transfer to the sponsor
(see below). Thus, it is crucial that this document not only be
completed on schedule, but also as accurately as possible.
Changes to the charter typically involve significant CISs and
re-work for the sponsor and IIV.
Image Analysis Software
Similar to the tracking software, the analysis software is a
study-specific database developed and used by the IIV. Prior to
development of the analysis software, the IIV should draft a
high-level requirement specifications document to identify and
list the fields/data necessary to capture during the independent
review. As could be expected, the charter must be finalized
prior to the development of this database and usually plays an
influential role in the development of the high-level
requirement specifications and analysis database. This database
is used by the independent imaging reviewers of the IIV to
perform the independent medical imaging review. The data
captured by the analysis software during the independent review
is the very data that will eventually be transferred to the
sponsor on a pre-determined schedule (see below). Any delays in
the high-level requirement specifications or the analysis
software would result in delays in the completion of the
independent image review by the IIV independent reviewers.
Data Reconciliation
Before a subject’s images can be centrally reviewed by the IIV,
the sponsor and IIV should work together to determine all images
acquired by the investigator site, have actually been received
by the IIV. In many cases, it is possible for the investigator
site to have not sent in one or more of the subject’s images.
This situation would obviously result in inconsistencies between
the clinical database and the IIV database and should be avoided
if at all possible. The most effective means by which to ensure
each of the databases are consistent is to perform image data
reconciliation for each subject. This entails comparing the two
databases manually or electronically via reports run from the
IIV database of all images received and reports run by the
sponsors data management CRO of all images recorded in the
patient’s clinical CRF. Whether this is done manually or
electronically should depend on study size/complexity and/or
sponsor preference (financial and resourcing issues may play a
role in the decision making). It is important to note that
discrepancies noted between the two databases should be
immediately queried for and followed up for resolution by the
IIV and/or sponsor/monitors, as a discrepant subject typically
should not be centrally reviewed until its discrepancies are
resolved.
Independent Central Reviewer (ICR) Selection/Approval
Independent central reviewer selection should typically be
managed by the IIV. The IIV should identify and propose the ICR
to the sponsor for CV review and approval. Once the sponsor has
approved the proposed ICR(s), the IIV should then proceed to
train the ICR per the charter training requirements.
Image Analysis Data Export
This is the data that will be sent to the sponsor and/or
sponsor’s data management CRO as captured in the analysis
database during the independent imaging review. The IIV should
draft a detailed Data Export Specifications document to list and
describe exactly how and what data will be transfered to the
sponsor and/or sponsor’s data management CRO. The specifications
document should be drafted and sent to the sponsor and/or
sponsor’s data management CRO at the same time or shortly after
the analysis software requirements document is completed.
Obviously if something is not captured in the analysis software,
it cannot be transferred in the image analysis data export.
Thus, it is critical that the charter is written correctly and
accurately, that the analysis software is developed correctly
and accurately (captures the necessary and required analysis
data as required per charter), and finally that the data export
specifications are written correctly and accurately so as to
ensure that not only is the correct data being transferred to
the sponsor/data mgmt. CRO, but that it is being transferred
accurately and in the correct format (as per the data export
specifications). Typically the image analysis data export is
sent to the sponsor and/or data management CRO during the
critical and time-sensitive periods in the study. For this
reason, any delays or issues with the content or accuracy of the
data export can be largely detrimental for the sponsor and
should be avoided. Proper involvement of all applicable parties
and a timely and accurate review of all study documents,
especially the charter, analysis software specifications, and
data export specifications can typically avoid these issues.
Query Management & Study Progress/Metric Reporting
The quality and completeness of the medical imaging being
submitted to the IIV by the investigator sites is just as
important as completing the independent medical imaging review,
as issues with image quality or completeness will obviously
decrease the integrity of the analysis data being captured and
sent to the sponsor. Thus, it becomes crucial for the IIV and
sponsor to manage and monitor IIV queries and study
progress/metrics. Regarding query management, the IIV should
send updated query reports to the sponsor on a weekly basis.
These reports should be inclusive of all open queries at the
time and should be filterable and have the ability to be sorted
by site, patient, country, and so on. These reports should be
sent to the sponsor and clinical monitoring CRO and should be
utilized by the clinical monitors as a means to manage queries
at their assigned investigator sites. Proper query management
involves diligence and site follow-up by not only the IIV, but
also by the clinical monitors and even sponsor in the case of
query escalations. The sponsor and IIV should plan and agree to
a query escalation process and document this process within the
Project Plan.
Regarding study progress and metric reporting, the IIV should
have a means to report all relevant study metrics and progress
throughout the study’s life cycle. Metrics to be reported should
include, but not be limited to, medical imaging received,
subjects queried, patient review status (interim review
complete, final review complete etc.), total patients reviewed,
total patient left to review and so on. It is important that the
IIV and sponsor have awareness and a sense of urgency in making
sure that the study’s metrics and progress are aligned with the
sponsor’s targeted timelines. Proper visibility and management
of these metrics will help mitigate and possibly avoid hiccups
in the study’s progress.
As has been repeated throughout this article, delays in many of
the study’s activities and deliverables have a cascading effect
into many of the other seemingly unrelated study deliverables.
There are many moving parts to the independent medical imaging
review portion of a trial and any one of them impact the entire
machine, ultimately affecting the end and most critical product
being sent to the sponsor; the image analysis data export. At
the end of the day, this is the product that the sponsor is
contracting the IIV to provide. It should now be clear how each
of the critical IIV deliverables and activities impact each
other and the final product of the study. It is an understanding
and attention to each of these moving parts that will lead to
the proper design and implementation of a successful independent
medical imaging review.
Stephen W. Bates is Program Director of the Oncology/Cardiology Group at Perceptive Informatics, Medical Imaging. He joined Perceptive in 2001. Stephen has had extensive experience in a wide range of clinical trials and imaging techniques, including the performance of both oncology (RECIST/Cheson) and CNS volume measurement in the past six years. Prior to joining Perceptive, he was a U.S. Navy and Nationally Certified Orthopaedic Technician. Stephen managed the largest U.S. Military orthopaedic surgical clinic in Asia, where his responsibilities included JCAHO compliance and mass casualty preparedness. He graduated summa cum laude with a Bachelor of Science degree in Cell/Molecular Biology from Bridgewater State College and is currently pursuing a Masters Degree in Technology Management. For article feedback, contact Stephen at
stephen.bates@perceptive.com
Nicholas R. Enus is Senior Project Manager of the Oncology/Cardiology Group at Perceptive Informatics, Medical Imaging. He had joined Perceptive in 2003. Nicholas has had extensive experience in a wide range of clinical trials and imaging techniques, including oncology, cardiovascular and CNS in the past four-and-a-half years. He graduated cum laude with a Bachelor of Science degree in Exercise Physiology from the University of Massachusetts, with a double Minor in Clinical Lab Sciences and Psychology. For article feedback, contact Nicholas at
nicholas.enus@perceptive.com
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