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Charting a better roadmap for clinical research protocols

Clinical Trials

The preeminent goal of the Dana-Farber/Harvard Cancer Center is to rapidly translate important discoveries to improved patient care. Yet the road from new research findings to innovative cancer treatments winds through the intricate terrain of protocol review and approval. An initiative now under way seeks to remap this terrain and cut through the underbrush of redundancy and delay that has often frustrated investigators and encumbered the clinical trials process.

“One of our highest priorities is to make significant advances in the clinical trials process at DF/HCC,” says Director Edward J. Benz Jr., MD. “We have been working very hard to address complex issues that are critically important to our success. I have asked an oversight group, consisting of Drs. Bruce Chabner, Jeff Clark, Lowell Schnipper, and Phil Kantoff, to work with our new associate director for administration, Beverly Ginsburg, to find and implement solutions and coordinate clinical trials processes.”

The group is resolute in finding solutions. “We’re looking globally as well as at every nut and bolt of this process that may affect the time to activation, staff burden, or overall quality and cost of conducting a clinical trial,” says Ginsburg. The team is already fast at work, making inroads that will become visible in the coming weeks and months. “Unfortunately, although the process is frustrating, it is also complicated and multifactorial,” Ginsburg explains. “That said, we have already taken a number of steps to reduce the time from submission to activation and to eliminate redundant processes. Most importantly, perhaps, we have organized a small group that is responsible for tackling problems and implementing solutions as quickly as possible.”

The imperative of program review

Scientific review and prioritization of protocols begin at the institutional level as well as in individual DF/HCC disease-based programs. “It is extremely important that trials be reviewed for scientific merit and administrative completeness at the program level -- before the protocol is ever submitted to the institutional committees,” says Ginsburg, who also serves as senior vice president for research at DFCI. Consistent with NCI guidelines, program leadership is in the best position to determine whether a new protocol answers an important scientific question, can accrue a targeted number of patients, and does not overlap with already approved trials. “We want our investigators, program leaders, and programs to be proactive and highly engaged in the review of clinical trials,” says Ginsburg. “The higher the quality of the science and the better shape a protocol is in before it is submitted to the Scientific Review Committee and Institutional Review Board, the fewer modifications and delays it will encounter, and the faster it will move through the process,” adds Phil Kantoff, MD, chief clinical research officer (DFCI).

The concept of an “endorsement letter” by research programs, which was recently initiated, is consistent with this philosophy. Signed by program leadership, the letter must accompany each new protocol and specify its priority and scientific value in relation to the program’s existing trials; it must also affirm the ability to accrue appropriately and demonstrate the availability of adequate resources. In addition, a team biostatistician must confirm that the trial is well designed. “Innovative approaches like the endorsement letter will help ensure that we maintain the quality and safety of our trials while minimizing unnecessary delays,” says Bruce Chabner, MD, associate director of Clinical Science at DF/HCC, who championed this concept. “As a result, the protocol will make its way through the review process promptly, while benefiting from the scientific scrutiny we all expect.”

“The fewer issues that we have to address when reviewing a protocol, the better,” adds Jeffrey Clark, MD, director of the Protocol Review and Monitoring System at DF/HCC and medical director of clinical trials at the MGH Cancer Center. “The exchanges between reviewers and the investigator regarding modifications or questions about protocol design or feasibility can take an enormous amount of time.” To expedite a protocol through the review process, Clark recommends that investigators and research programs seek the advice of research nursing and pharmacy as early as possible to be sure the trial can be done safely, and also to confirm the study sites in advance of submission to avoid delays in activation.

While the group is making improvements that will affect all trials, Chabner, as chair of the SRC, has set up a “fast-track” system, whereby the SRC routinely reserves slots on its agenda for high-priority protocols. Each quarter, research programs can earmark one protocol for fast-track review. When the SRC receives a designated high-priority protocol, the committee can slip it into the reserved time slot.

Simplifying and streamlining the process

A major step in streamlining the process is DF/HCC’s recent approval to purchase InfoED, an electronic protocol management system. “InfoED will enable us to track protocols much more efficiently,” says Clark, “and will make all reviews and signoffs far easier, simpler, and faster.” Scheduled for installation over the coming months, InfoED will allow investigators to submit documents electronically and to view the status of their protocols under review. Chabner hopes that InfoED will also provide the data needed to create a “report card,” rating each disease program using such metrics as the number of protocols activated and the rates of accrual. In the meantime, DF/HCC has developed a system of tracking protocols from initial submission to activation. “We know where every protocol is, when we send it to pharmacy, when we send it to the SRC, and when the investigator responds to an issue raised by the SRC,” says Michele Russell-Einhorn, director of the Office for the Protection of Research Subjects. The office has also recently launched FileShare, so that SRC and IRB members can access protocols online, thus decreasing costs and time to review.

Another measure to accelerate the process is the addition of a second review committee, or SRC2, to deal exclusively with cooperative-group and industry-sponsored multi-center trials, initiated outside of DF/HCC. “These trials cannot be modified in the same way that DF/HCC investigator-initiated trials can as a result of SRC review,” explains Lowell Schnipper, MD, who, with Clark, will serve as co-chair of SRC2. This second committee will provide more time each month for scientific reviews overall and help quicken the review of externally developed trials through a single committee, notes Clark. At the same time, it will allow SRC1 to focus greater attention on investigator-initiated trials, a priority of DF/HCC.

Calling all investigators

The need for a second review committee underscores the need for more faculty to participate in the scientific and ethical review processes, says Chabner. “The success of the system depends on having enough highly qualified investigators and staff engaged in sharing the responsibility,” he explains. “In return for the benefit of participating in the DF/HCC clinical trials, all investigators must become involved by serving on the SRC and IRB.” At the same time, service on a review committee offers its own reward, adds Clark. “Learning how to design and conduct the best possible clinical trials is an invaluable part of the education process for all DF/HCC investigators.”