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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Clin Transl Sci. Author manuscript; available in PMC 2010 May 27.
Published in final edited form as:
PMCID: PMC2877373
NIHMSID: NIHMS201839

An Operational Perspective of Challenging Statistical Dogma while Establishing a Modern, Secure Distributed Data Management and Imaging Transport System – The Pediatric Brain Tumor Consortium Phase I Experience

Abstract

The Pediatric Brain Tumor Consortium (PBTC) is a multidisciplinary cooperative research organization devoted to the study of correlative tumor biology and new therapies for primary CNS tumors of childhood. The PBTC was created in 1999 to conduct early phase studies in a rapid fashion in order to provide sound scientific foundation for the Children’s Oncology Group to conduct definitive trials. The Operations and Biostatistics Center (OBC) of the PBTC is responsible for centrally administering study design and trial development, study conduct and monitoring, data collection and management as well as various regulatory and compliance processes. The Phase I designs utilized for the consortium trials have accommodated challenges unique to pediatric trials such as BSA-based dosing in the absence of pediatric formulations of oral agents. Further during the past decade, the OBC has developed and implemented a state-of-the-art secure and efficient internet-based paperless distributed data management system. Additional web-based systems are also in place for tracking and distributing correlative study data as well as neuro-imaging files. These systems enable effective communications among the members of the consortium and facilitate the conduct and timely reporting of multi-institutional early phase clinical trials.

Introduction

The Pediatric Brain Tumor Consortium (PBTC) (www.pbtc.org) was initially funded by the NCI in 1999 as a multidisciplinary cooperative research organization devoted to the study of correlative tumor biology and new therapies for primary CNS tumors of childhood. The PBTC’s mission is to contribute rapidly and effectively to the understanding and cure of these tumors through the conduct of multi-center, multidisciplinary, innovative studies with designs and analyses based on uniformly high quality statistical science. While the primary mission of the PBTC is to identify through laboratory and clinical science superior treatment strategies for children with brain cancers, the PBTC investigators also recognize their profound responsibility to meet the special needs of the children and families as they face this enormous challenge. PBTC member institutions include most of the larger pediatric neuro-oncology centers, translational biology laboratories in pediatric CNS neoplasia, pediatric pharmacology programs including NCI’s Pediatric Preclinical Testing Program, pediatric neurosurgical and radiation therapy centers and pediatric neuroimaging programs. The member academic centers and children’s hospitals diagnose and treat approximately 30% of children with primary brain tumors in the United States.

As indicated above, PBTC’s main objective is to develop and carry out novel phase I, phase II and pilot trials of new cytotoxic and molecularly targeted therapies (MTAs or cell signaling agents), novel treatment delivery technologies and radiation treatment strategies in children aged up to 21 years with primary central nervous system (CNS) tumors. As part of this objective the consortium has invested substantial effort in identifying and studying direct or surrogate markers of brain tumors’ responses to new therapies as well as conducting laboratory research on brain tumor specimens to further understand the biology of pediatric brain tumors. Another focus has been to develop and coordinate innovative neuro-imaging techniques. The PBTC’s Neuro-Imaging Center (NIC), co-housed at the PBTC’s Operations and Biostatistics Center (OBC) in Memphis, TN and at Children’s Hospital Boston, MA, was established in May 2000. To date the NIC has largely concentrated on research activities evaluating new treatment response criteria and understanding regional brain effects including the study of significant neuro-toxicity in developing children’s central nervous system.

Figure 1 provides a schematic of the PBTC organizational chart. A key component of the PBTC is its OBC. The OBC centrally administers many of the operational processes of the PBTC including data collection from participating institutions and laboratories using a secure electronic data transfer system. The OBC, under the direction of the Executive Director and with oversight by The PBTC Chair and Steering Committee, is responsible for coordinating concept review and scoring, protocol development, protocol amendments/status changes, study conduct, study monitoring, data management, quality control/assurance, regulatory compliance, on-site audits, PBTC semi-annual meetings, performance monitoring, managing the fiscal affairs of the PBTC and statistical design and analysis of trials and studies.

Figure 1
PBTC Organizational Chart

The following sections discuss in more detail the electronic communications and data sharing infrastructure, operational procedures for patient registration and data acquisition during Phase I trials as well as statistical designs and analyses employed. The paper concludes with a brief discussion.

Electronic Communications and Data Acquisition Infrastructure

The OBC is responsible for establishing electronic communication with Member Institutions to facilitate protocol development and study monitoring; as well as aiding in the activities of protocol, scientific and administrative committees. The OBC infrastructure supports communication among the PBTC member institutions, PBTC-NIC, Quality Assurance Review Center (QARC), PBTC laboratories and central reviewers. Relevant communication methods include web site postings, e-mail (containing no patient specific data), teleconferences, and video conferences. Secure Virtual Private Network (VPN) communications are used for data transfers between member institutions and the OBC; neuroimaging file transfers between member institutions and the OBC and between the OBC and the NIC component at Children’s Hospital Boston; data transfers between the OBC and PBTC correlative laboratories; and data reporting, data sign-offs and patient evaluation between the OBC, protocol study chairs and monitoring committees.

The Consortium employs a paperless distributed data management infrastructure, which is illustrated in Figure 2. The site laptops are equipped with the CISCO Virtual Private Network (VPN) software client to connect securely to the OBC. The OBC has two multi-processor based high-end servers for the various patient databases, correlative laboratory database, image analysis database, other auxiliary databases, and for archiving neuroimaging data, which is illustrated in Figure 3. The database servers run Microsoft SQL Server and Microsoft Office suite for database needs and eFilm software for the neuro-imaging DICOM data transfers. The OBC also provides File Transfer Protocol (FTP) service to the member institutions to facilitate database transfers and web services to access web-based forms for sites to submit requests and data to the OBC as well as to provide real-time data reports to PBTC investigators. We believe it is no longer necessary or desirable to rely on paper-based systems for data collection, data monitoring, reviewing and for storing regulatory documents and informed consent forms. The driving principle of our evolving electronic infrastructure is to implement data driven human activity. Hence we strive to develop comprehensive computer systems to monitor and process accumulating data and to notify appropriate individuals when processing by a human is required.

Patient Registration/Reservation, Data Entry and Data Uploads to the OBC

Site CRAs use their local area network to connect to the Internet and initiate a secure VPN connection to the OBC via the VPN client on their PBTC window-based laptops. They then use Internet Explorer to connect to the Online Patient Registration system to register a patient, to reserve a slot or to be placed in the standby queue for a given PBTC protocol. If a slot is available and the site knows that a patient is eligible, then the patient may be registered. If eligibility remains to be confirmed then the slot can be reserved and the site has 7 days to register the patient. Standby queues are maintained for all clinical trials when there are no available slots. At the time slots become available standbys are automatically elevated to reservation status based on their position in the queue. After registering a patient, the database program is initiated to retrieve the patient registration information into their replica database. This process of system-based complete patient registration – wherein the Patient IDs are directly entered by the OBC server into the site’s replica database – ensures total data integrity and an error-free system. Sites fax consent forms and other regulatory paperwork to the OBC using the FAX server. Via Microsoft Exchange mail-integration, the faxed documents are distributed within the OBC by email to the appropriate protocol coordinator (PC) and are also archived as net-based documents, which are used as hyperlinks in the Consortium databases for easy, electronic access by OBC staff.

Sites are required to upload the data file to the OBC at least once a week to ensure data backup and are encouraged to upload data as it is entered. Uploaded database replicas are synchronized several times a day to generate the PBTC centralized hub database that provides data on a real-time basis for the various web-based data reports. The hub database is also loaded into the SQL server backend database in the OBC to enable the PCs to monitor changes made to the data in essentially real-time.

When the PBTC started in 1999, not all member sites had fully functional, high-speed internet as well as wireless networking capability. Hence, we opted to set up the main clinical database, PedBraTum in Microsoft Access, providing for site-specific databases to be complete as described above. During the second grant period which resumed in 2004, the PBTC Computing staff developed both the ProtoLab system that captures all the correlative data including pharmacokinetics, pharmacodynamics and neuropathology data from the various correlative laboratories and the Image Analysis database that captures imaging parameters from the NIC at Children’s Hospital Boston and unlike PedBraTum, these are web-based, secure, remote data entry (RDE) systems. Today, all eight PBTC sites have high-speed Internet as well as wireless networking capability. During the next 5-years, PedBraTum will also become a web-based system with secure, remote data-entry capability.

Procedures for Data Transmittal, Editing and Quality Control/Verification

There are required procedures and assurances for assessing patient eligibility, evaluability for dose-finding as well as toxicity outcome in phase 1 trials that need to be followed within pre-specified timelines. When a patient is registered or the dose-finding period has been completed, the site CRA has two working days to complete and upload the required data to the OBC. Note that site CRAs are expected to upload these accumulating data weekly during treatment courses and the OBC PCs review these accumulating data daily for completeness which leads to regular data queries that are generated as necessary to the site CRA. Only investigators and CRAs at a given PBTC site have authority to change data submitted for patients treated at their site. The site CRA and responsible OBC PC have eight additional working days to ensure that the data are complete, consistent and ready for investigator review. At the end of this step, the data are “locked” and cannot be changed without a formal request to initiate OBC “unlocking” procedures. The locked data are then provided to the patient’s attending physician (AP) with the OBC PC’s assessment of whether the patient is eligible for the study or evaluable for the dose-finding objective. The AP must electronically sign that the data are complete and accurate as well as signify whether they agree with the OBC PC’s assessment. The data are then provided to the PSC who is required to review and confirm that the data are accurately interpreted per protocol by electronic “sign-off” resulting in the final evaluation status. Both the AP and the PSC may send queries back to the OBC PC requesting clarification or additional information in order to be able to “sign-off.” The same procedures are used for AP and protocol study chair (PSC) reviews and “sign-offs” of all protocol data as patients complete each course of therapy. The prospective data review and signoff not only provides quality control of our data in terms of verification by the AP and interpretation by the PSC but also allows us to promptly identify and correct inaccurate and missing information and ensure timely publication of protocol findings. Furthermore our main clinical database maintains a complete auditing trail of all modifications of submitted data. The close interaction of site CRA, OBC protocol coordinator, AP, and PSC provides quality control of our data in terms of verification by the AP and interpretation by the PSC. The on-site audits which are conducted at least once every two years also provide an alternative means for data verification and completeness.

Assigning Drug Dose Levels During Phase I trials

Following the PSC affirming evaluability of a patient that had completed the dose-finding period of a phase I trial and signing-off on the assessment of whether the patient experienced a DLT as defined by the protocol, an automatic e-mail is generated to notify the statistical team so that a recommendation regarding the next step in the trial can be communicated to the PSC. The decisions include dose escalation or de-escalation for the next cohort of patients or declaring the MTD as estimated or expanding the cohort at the current dose. If the design is traditional, then the review and recommendation is simpler but nevertheless requires review by at least two statisticians before a recommendation is made to the PSC. If the trial uses the Continual Reassessment Method (CRM)1,2 for dose finding, then at least two independent calculations of the CRM estimated MTD are required by the team of statisticians who review the data and the associated model estimates. Following a consensus the designated study statistician forwards the recommendation to the PSC for approval.

There are currently 3 PhD and 3 MS level statisticians who are part of the OBC staff, though none are assigned full time to the OBC. All six statisticians have access to the dose finding data for all PBTC Phase I trials which can be accessed on trial-specific password protected, internal web-pages, called the DLT monitoring pages. These pages are populated automatically once the relevant data are entered in the databases and are signed-off by the PSC. The DLT monitoring pages not only provide easy and secure access to the data but they also contain all the relevant information needed for dose escalation/de-escalation decisions for all patients who have been enrolled on the trial e.g. eligibility and evaluability status, assigned and BSA adjusted actual dose, DLT outcome etc. Hence it is rare that the statistical review of assigning a dose to the next cohort of patients is not completed within a few hours of the triggering e-mail and never longer than a day.

Phase 1 Clinical Trials: Designs and Analyses

For PBTC dose-finding clinical trials, the maximum tolerated dose (MTD) of a therapeutic regimen is typically selected from a pre-specified set of dosages. The approach employed to estimate the MTD is one of two types of designs: (1) a modified version of the CRM or (2) the traditional dose-escalation, also known as the 3+3 empirical design. The CRM is the preferred approach for many of the PBTC trials because of its favorable operating characteristics2 and because of its ability to incorporate specific problems encountered in the MTD estimation such as lack of a pediatric formulation, missed DLTs, and dosing errors. We use the traditional design mostly for lead-in assessments of one or two dosages that do not require estimating an MTD or when other constraints require it.

Table I lists the seventeen Phase I trials that have been conducted to date by the PBTC. Most of these trials are complete and have been published while others are currently active. Stratification was employed in 7 of the 17 (41.18%) phase I trials and in 12 studies (70.58%) CRM was the dose finding algorithm.

Table I
Overview of PBTC Phase I Clinical Trials

A significant proportion of the Phase 1 agents/regiments tested within the PBTC have been oral and many do not have a pediatric formulation (e.g., PBTC-003, PBTC-020, & PBTC-023). Since oral agents are typically dosed in children based on body surface area (BSA), lack of a pediatric formulation may result in large discrepancies between the closest deliverable dose and the targeted dose to which patients are assigned. For PBTC-0069 for example, Figure 4 shows the relationship between the assigned dosages (horizontal lines) versus the actual deliverable dosages as a function of BSA (hatched lines). The overlapping hatched lines (also marked by the arcs on the figure) highlight areas of concern. For example, patients assigned to either 150mg/m2 or 200mg/m2 with BSAs between 0.50m2 and 0.62m2 receive exactly the same dosage; thus, if one must “dose-reduce” due to toxicity observed at 200mg/m2 then patients assigned to 150mg/m2 with BSAs between 0.50m2 and 0.62m2 would receive the same too-toxic dose. Furthermore two patients assigned to 200mg/m2, one with a BSA of 0.62m2 receives 238mg/m2 and another with a BSA of 0.87m2 receives 172mg/m2 – a 38% difference at the same dose level. Clearly such cases raise safety concerns in the context of Phase I trials. Thus, if the pediatric formulation limitations make it impossible to safely deliver the lower dose of the agent to patients in the target population, this would be taken into account. In the PBTC we have managed such safety concerns by restricting further accrual to patients with larger BSAs at the affected dose levels.

Figure 4
Variations from Target Doses: BSA Adjusted Actual Daily Dose(mg/m2) vs. Body Surface Area(m2) for PBTC-006 (Phase I Trial of STI571 in Children with Newly Diagnosed Brainstem Gliomas)

If in fact one of the affected dose levels is declared as the dose to be carried forward to a Phase II study, it is of course possible that limiting accrual to patients with larger BSAs during the Phase I trial may result in restrictions on eligibility for the Phase II trial. This may encourage investigators to consider alternative dosing strategies for smaller patients such as dosing by weight during the phase I trial. Alternatively and perhaps more desirably, such potential restrictions have provided an added impetus for the company to make a pediatric formulation for the study in some cases. The issue for subsequent phase II trials is again one of assigned versus deliverable dosages. We have not yet designed a follow up phase II trial when these restrictions were noted in the phase I investigation, but expect that it is only a matter of time. In the PBTC we would design the phase II trial by imposing the same restrictions based on BSA as were adapted in the phase I trial. The recommendation to apply these restrictions for subsequent phase II trials would be included in the published manuscript describing our phase I experience. It is also possible that a pediatric formulation would have become available by the time a phase II trial is initiated; thus, eliminating the necessity for subsequent constraints. While studying dose-toxicity relationships, the above-described variations from the targeted dose may significantly impact the MTD estimate. In phase I studies with no pediatric formulation, the traditional design is thus questionable as the method assumes the delivered doses are identical to the targeted doses which clearly is not the case. As Figure 4 also indicates the discrepancies between the assigned and the actual dose are most notable for smaller patients, typically with BSAs less than 1m2, which represents approximately 45% of the PBTC patient population.

Though rarely reported in the literature, dosing errors or missed DLTs do occur during the conduct of Phase I trials and the PBTC being no exception. In the former case, rather than discarding the data from a miss-dosed patient, the CRM can incorporate the DLT outcome from such a case at the actual delivered dosage. Similarly in cases where missed DLTs are identified retrospectively, a re-estimate of the MTD is needed. Such events may create difficulty in reinterpreting results for the 3+3 designs. For example, if the retrospective DLT is identified at a dose level that already had 6 patients and 1 DLT but the dose level above it was studied and found to be safe, it is not clear what the interpretation of the new DLT should be with respect to the MTD. Such a situation is not a problem for the CRM as the MTD is estimated using all data from all dose levels and thus the model would simply be re-run to estimate the MTD with the revised toxicity assessment. A third scenario where this property of the CRM has proven to be very useful was encountered in the context of a currently-ongoing PBTC phase 1 trial, where late toxicities prompted the DSMB to recommend extending the dose-finding period from 4- to 6-weeks. This change led to 2 new DLTs being incorporated into the CRM model and were used in determining the starting dose of the amended trial.

Correlative Study Objectives

It should be noted that a fundamental difference with respect to correlative studies between pediatric and adult phase I trials is that participation in such studies is voluntary in the former. This option emanated from a 2002 workshop sponsored by the National Cancer Institute Cancer Therapy Evaluation Program that was comprised of cancer patient advocates, pediatric and medical oncologists, bioethicists and institutional review board members3. Since requiring participation in PK or correlative biology could be considered coercive (unless the results of these studies directly impact the treatment of the patient or the analysis of a primary study objective), the PBTC has followed a policy similar to that of other pediatric cooperative groups and advocated that participation in correlative studies should be optional. Despite the limitations of voluntary participation, the PBTC has routinely had adequate subject participation to meet secondary correlative study aims, which typically address PK, PD, biology and imaging questions. This success has been substantially aided by protocol and correlative study-specific shipping accounts set up by the OBC that offer real time tracking information and has been facilitated by the web-based correlative databases such as ProtoLab, which allow the labs to enter and retrieve data in a convenient fashion.

As Table 1 clearly indicates, various correlative study questions are routinely integrated into the PBTC Phase I trials. Not surprisingly all of our Phase I trials involved a PK objective, 4/17 (23.5%) incorporated PG/PD endpoints, 14/17 (87.5%) and 11/17 (64.7%) integrated biology and neuro-imaging objectives, respectively. Though we have demonstrated the feasibility of collecting adequate correlative data/specimens/images to address these secondary objectives, we have also encountered various challenges. Naturally small sample sizes are expected from studies that rely on voluntary components of a pediatric phase I trial but it is also the case that some sites have more strict regulations regarding research procedures such as PET scans, frequency and amount of blood draws, further decreasing the sample size available for correlative studies. In addition our experience indicates that approximately 70% of patients who participate in our Phase I trials are off treatment within the first 2 courses. Hence objectives that involve collection of data beyond course 2 are often infeasible. Further since pre-treatment specimens are often needed in order to properly analyze and interpret the post-treatment measures in such small sample settings, unless pre-treatment specimens/images are obtained from a patient, collecting post-treatment correlative information is discouraged.

Despite the fact that each Phase I trial provides a relatively small number of patients from whom correlative data is available, the PBTC is well positioned to run cross-protocol analyses since the consortium has studied agents with similar mechanisms of action (e.g. anti-angiogenic agents) in the same patient population almost simultaneously or in close succession. Such cross-protocol analyses, which are currently in progress, would have more power and may provide additional information to help formulate hypotheses that can be prospectively tested in future trials.

Discussion/Conclusions

The PBTC represents a closely coordinated clinical research trials group focused on multidisciplinary investigations in the challenging area of pediatric brain tumors. During the past decade, through scientists based in member institutions, contacts with the NCI and pharmaceutical companies and interactions with the predecessor consortia of the new Adult Brain Tumor Consortium (ABTC), the PBTC has aimed to identify and translate innovative therapies from the laboratory to early phase clinical testing. As indicated above, one of our major foci has been on the molecularly targeted agents. These PBTC trials have often served as the initial phase I experience of these agents in children. The Phase I designs utilized for the consortium trials have accommodated challenges unique to pediatric trials such as BSA-based dosing in the absence of pediatric formulations of oral agents and as well as optional participation in correlative studies. In disease categories where outcome has lagged behind other types of childhood cancer (i.e., brainstem gliomas, malignant gliomas, infant embryonal tumors, refractory medulloblastomas and ependymomas), we have introduced molecularly targeted studies with novel trial designs to (1) assess the presence of the target in patient-specific tissue (where possible), (2) test the ability of the agent to down-regulate the signaling target, and (3) correlate findings with response to the molecular antagonist. The Consortium has systematically studied the pharmacokinetics of new agents in childhood brain tumors, selectively analyzing pharmacodynamics and pharmacogenomics. With its unique resources and collective expertise, the PBTC is well positioned to generate valuable knowledge via translational science that can be carried forward to more definitive trials.

As outlined in the previous sections, the consortium has also developed various operational procedures as well as a data acquisition/storage and communication infrastructure that may serve as a model for other consortia. The OBC has designed, developed, implemented and maintains a state-of-the-art secure internet-based paperless distributed data management system that is efficient and has effectively supported every PBTC protocol developed to date. Additional web-based systems are also in place for collecting, anonymizing, storing and distributing neuro-imaging files as well as for tracking specimen, tissue and slide collection, submission and processing. These systems facilitate effective communications among the members of the consortium. The OBC has also demonstrated that fully-electronic and secure, distributed data management and neuro-imaging transport systems are not only technically feasible but as implemented, will facilitate the conduct and timely reporting of multi-institutional early phase clinical trials.

Acknowledgments

This work was supported in part by NIH grant U01 CA81457 for the Pediatric Brain Tumor Consortium (PBTC) and American Lebanese Syrian Associated Charities. The authors acknowledge helpful discussions with the staff of the Operations and Biostatistics Center for the Pediatric Brain Tumor Consortium as well as the support of the PBTC investigators and in particular, Dr. Larry Kun, Chair of the PBTC.

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