Going round in circles
Traditionally, clinical research was conducted as a linear process with a product moving sequentially through defined phases of development. Consequently the procedures established to conduct and manage clinical trials have developed to support this bench-to-bedside process. However, as discussed in the P.I.L.S Executive Report “Translational Research in Oncology”, clinical research, especially in the area of oncology, is no longer a sequential step-by-step process. Scientific advances especially in molecular medicine are enabling clinicians and scientists to work much more closely on implementing bi-directional or circular plans. This process change is enabling improved decision making at the pre- clinical/clinical interface through more informed lead selection and the earlier termination of high-risk projects. The clinical trial process is changing dramatically from a treatment delivery platform to a product discovery platform. The challenge now is to redesign the clinical trial infrastructure to allow for the emerging possibilities of genomics, proteomics, imaging, nanotechnology, and information technology and make better products available to patients.
Revamping the system
One individual spearheading the move towards an improved clinical trial design and management system is Dr. Andrew C. von Eschenbach, Director of the National Cancer Institute (NCI). Von Eschenbach was recently quoted as saying “I can tell you that Wal-Mart knows more about the status of a box of cereal in any one of their franchises across the entire United States than I know about the situation of prostate cancer patients and clinical trials in this country, in real time.” Thankfully von Eschenbach has plans to change the situation. In January 2004, he established the Clinical Trials Working Group (CTWG) to advise the National Cancer Advisory Board’s Clinical Investigations Subcommittee on issues concerning NCI-supported cancer clinical trials. The CTWG is a panel of 40 representatives drawn from cancer centers, clinical trials groups, community clinical oncology programs, advocacy organizations, government agencies, and the research community. Von Eschenbach charged the CTWG with the formidable task of increasing the efficiency of cancer clinical trials, decreasing redundancy and administrative burdens, and establishing improved coordinating activities to enhance the development and delivery of the best therapies to cancer patients.
Proposals for change
In June 2005, the CTWG announced their ideas to meet the challenge of conducting cancer trials in the 21st. century. The proposals recommended by the CTWG recognize that the challenge of evaluating highly specific agents will require a national clinical trials enterprise to integrate the knowledge, insights, and skills of multiple fields into a new kind of cross disciplinary, scientifically-driven, cooperative research endeavor. The group organized their proposals into five categories:
- Coordination Initiatives
- Prioritization/Scientific Quality Initiatives
- Standardization Initiatives
- Operational Efficiency Initiatives
- Enterprise-Wide Initiatives
Within each of the 5 sections, the initiatives are organized into two sub-categories, New Initiatives and Enhancement Initiatives. The New Initiatives propose fundamental and significant changes in the operation of the current NCI clinical trials system, whereas the Enhancement Initiatives propose an expansion or enhancement of an activity already underway within the Institute. The National Cancer Advisory Board (NCAB) of the NCI accepted the 22 strategic proposals to revamp the NCI's clinical trials system. The plan is expected to take five years to implement and cost upward of $113 million. When finalized it will completely change the way oncology clinical trials are managed.
Initiatives from the CTWG
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Coordination Initiatives
- Create a comprehensive database containing information on all NCI-funded clinical trials to facilitate better planning and management across clinical trial venues.
- Realign NCI and academic incentives to promote collaborative team science.
- Increase cooperation between NCI, the U.S. Food and Drug Administration (FDA), and industry to enhance the focus and efficiency of oncology drug development.
- Expand awareness of the NCI-FDA expedited approval process to speed trial initiation.
- Work with the Centers for Medicare and Medicaid Services (CMS) to identify clinical studies that address both NCI and CMS objectives, and for which CMS may be able to reimburse some routine and investigational costs.
Prioritization/Scientific Quality Initiatives
- Create an Investigational Drug Steering Committee to work with NCI to enhance the design and prioritization of early-phase drug development trials.
- Create a network of Scientific Steering Committees, which leverage current Intergroup, Cooperative Group, Specialized Programs of Research Excellence (SPORE), and Cancer Center structures, to work with NCI in the design and prioritization of phase III trials to better allocate scarce resources, improve scientific quality, and reduce duplication.
- Increase community oncologist and patient advocate involvement in clinical trial design and prioritization to improve the rate of patient accrual, and better address practical and quality of life concerns in the design of trials.
- Develop a funding and prioritization process to ensure that critical correlative science and quality of life studies can be conducted in a timely manner in association with clinical trials.
- Develop a standards-setting process for the measurement, analysis, and reporting of biomarker data in association with clinical trials to enhance data comparisons, reduce duplication, and facilitate data submission for regulatory approval.
- Investigate integration of phase II trials into the overall prioritization process to further coordinate the national clinical trials system.
Standardization Initiatives
- Create, in partnership with the extramural cancer research community, a national cancer clinical trials information technology infrastructure fully interoperable with NCI's cancer Bioinformatics Grid to improve cost effectiveness and comparability of results across trials and sites.
- In consultation with industry and FDA, develop standard case report forms incorporating common data elements to improve information sharing among cancer researchers and to optimize data requirements.
- Build a credentialing system for investigators and sites recognized by NCI and industry to allow faster trial initiation and keep the investigative community abreast of legal, safety, and regulatory changes.
- Develop commonly accepted clauses for clinical trial contracts with industry to reduce the lead-time needed to open trials.
Operational Efficiency Initiatives
- Restructure the phase III funding model to promote rapid patient accrual rates and cost-effectiveness.
- Reduce institutional barriers to timely trial initiation.
- Increase patient and public awareness and understanding of clinical trials.
- Increase minority patient access to clinical trials to improve the participation of underserved and underrepresented populations.
- Promote adoption of the NCI Central Institutional Review Board facilitated review process to reduce the time and resources needed to open trials at individual sites.
Enterprise-Wide Initiatives
- Create a Clinical Trials Oversight Subcommittee of the NCAB to advise the NCI director on conduct of clinical trials across the institute.
- Develop a coordinated NCI organizational structure to manage the entire clinical trials enterprise supported by the institute.
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Big plans for caBIG
Although implementation of all the recommended 22 initiatives will require up to five years to complete the majority are projected to be implemented by the end of the third year. This will require tremendous effort. Initial energy will be focused on making infrastructure improvements, with an emphasis on bioinformatics through the existing voluntary network that enables the sharing of cancer data and tools, known as the cancer Biomedical Informatics Grid (caBIG™,) and also the establishment of biorepositories and laboratories that can support clinical assays for biomarkers. Longer term initiatives such as trial review and prioritization procedures and possible revisions to the classic trial phases, with a focus on combination/targeted intervention studies with occur at the end of the implementation period.
Unified, integrated, and efficient
An additional effort that will dovetail with the work of the CTWG includes the launching a joint oncology task force, populated equally by members of the US Food and Drug Administration (FDA) and the NCI. The FDA and the NCI have distinctly separate missions but a common goal in the fight against cancer. The mission of the NCI is to foster discovery and development of new medical products whereas the mission of the FDA is to assure the safety, efficacy, and quality of manufacturing of new medical products prior to marketing. The joint NCI/FDA Task Force will enable the two agencies to take a more unified, integrated, and efficient approach to facilitate the development of new cancer drugs and ultimately speed their delivery to patients.
Exciting times ahead
Exciting times are ahead for all involved in the clinical trial process, especially in the challenging field of oncology. Hopefully the result of the efforts initiated by von Eschenbach will enable the advances in genomics, proteomics, imaging and nanotechnology, to be used effectively to progress beyond the current toxic treatments and allow the development of targeted therapies, based on an understanding of the genetic and cellular mechanisms underlying specific cancers. Each of us involved in the clinical trial process in any therapeutic area should see von Eschenbach’s actions as a challenge. We all need to step back and look closely at our contribution and ask ourselves, “Even though this works, how can I make it work better?”
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