Nearly 3 years after tasking themselves with overhauling the nation’s publicly funded cancer clinical trials system, which had been criticized as sluggish and unwieldy, researchers working for and with the National Cancer Institute are reporting a number of important successes.

The time between concept and activation of phase II trials sponsored by NCI has shrunk by more than a third, the researchers revealed at a 2-day workshop held this month in Washington. Time to activation for phase III trials has been halved since the overhaul process began.

Dr. James H. Doroshow of the NCI’s Division of Cancer Treatment and Diagnosis in Bethesda, Md., said that trial opening times would continue to shrink, with an ideal lag of between 6 and 7 months for early phase trials, compared to more than 2 years in the past.

But Dr. Doroshow and other presenters also acknowledged that the overhaul is a work in progress, with serious challenges remaining. Prominent among these, said workshop chair Monica Bertagnolli of the Dana-Farber Cancer Institute in Boston, is "maintaining the integration of the community centers into the research network" as NCI’s scientific emphasis shifts quickly from large phase III trials to smaller, biomarker-driven phase II trials. The trials cannot succeed without broad participation in cutting-edge trials at the community level.

The workshop was sponsored by the American Society for Clinical Oncology and presented by the Institute of Medicine, which had commissioned a 2010 report demanding critical changes to the NCI’s clinical trials cooperative group program. The report described the program as "approaching a state of crisis," and recommended that it streamline its bureaucracy, speed activation and improve completion rates of its trials, emphasize innovative biomarker-driven science, and increase reimbursement per patient for trial participation.

The program has since undergone a restructuring to reduce its 10 cooperative groups to 5, including 1 pediatric group. It has created common enrollment and data management systems to be used by all 3,100 affiliated community and research institutions. It standardized its agreements for industry collaborations, launched a review process for grading the quality of its trials, and is in the process of creating integrated biospecimen banks, among other accomplishments reported by NCI’s Dr. Doroshow.

The conviction that innovative, molecular phase II studies were the key to a more responsive and effective trials system was shared widely at the conference. "We need to rethink clinical trials, not just fund 7,000 patients in toothpaste A vs. toothpaste B," commented Dr. George Sledge of Stanford (Calif.) University. Presenters discussed a number of novel phase II trial designs, including "basket trials," or series of simultaneous single-arm trials matching biomarkers to target agents.

In a presentation on designing cutting-edge trials using genomic profiling for eligibility, Dr. Levi Garraway pointed to both the extraordinary possibilities and challenges of the new, nimble trial ideal.

"This is the first time that we can say for the major cancer signaling pathways, there are multiple drugs targeting multiple alterations in those pathways," said Dr. Garraway, a researcher at Dana Farber Cancer Institute in Boston, noting that in 40%-60% of tumors, there is a genetically-determined actionable target for which there is either an approved agent, an experimental agent, or an agent to avoid. Yet while genomics-driven "precision medicine," is exciting, it is"very hard, daunting even to the most advanced cancer centers," Dr. Garraway said.

Encouraging broad participation in these cutting-edge trials at the community level may prove a daunting task, however.

"The No. 1 job is to get these trials done and, without the community programs, they’re not going to get done fast enough," Dr. Steven Grubbs of Christiana Care Health System's Helen F. Graham Cancer Center in Newark, Del., told the conference. Nonacademic community oncology sites, both hospitals and private practices, are responsible for accruing between half and two-thirds of the patients currently taking part in the network’s trials, Dr. Grubbs pointed out, with most cancer patients receiving their first diagnosis outside a research center.

Dr. Robert Comis of Drexel University, Philadelphia, the cooperative groups’ chairman, commented that while the novel phase II trials "are essential to drive the process forward," many community sites hesitate to participate because these trials tend to be small, end quickly, and can be more complicated than are large phase IIIs.

As other participants noted throughout the conference, cancer trials increasingly require tissue submissions to enroll, a financial and logistical burden that falls on hospital pathology departments. Molecular research also means exponentially more data points and requires close collaboration with genetics labs – all at a time in which many of the NCI’s community-based research affiliates are plagued with tightening budgets and looming cuts.

Meanwhile, a broad new NCI initiative to consolidate the institute’s community research programs into one, whose agenda also includes parallel nonclinical research on cancer care delivery, had several of the workshop participants concerned about the potential for added financial and logistical strain on community affiliates.

"We don’t want to stress private practices," said Dr. Robin Zon of the Northern Indiana Cancer Research Consortium and Memorial Hospital in South Bend, Ind., of NCI’s added research focus on care delivery. "There has to be a streamlining, otherwise they will opt out."

Dr. Zon also cautioned that researchers on the community level face the "real issue of payers not covering clinical trial participation," at least until January 2014, when federal law will require that insurers not deny patients participation in clinical trials or limit coverage of routine patient costs stemming from a trial. "Let’s try to lobby to make sure that this becomes imperative," Dr. Zon said.

The trials network’s total funding for fiscal year 2014 was $152 million, Dr. Comis said, adding that he was hoping to increase that to $178 million. One of the stated goals of the overhaul was to increase reimbursement per patient enrolled from $2,000 to $6,000, but increases have not yet been universally adopted. The 2010 IOM report also recommended other incentives to increase accrual, such as reimbursing physicians for offering patients the option of enrolling in a trial, even if the patient ultimately chooses not to. This recommendation has not yet been adopted.

The United Kingdom’s experience overhauling its own trials network offered valuable perspective on what was happening in the United States, despite major structural differences between the countries’ health care systems. In 2001, the U.K.’s cancer trials network was reorganized out of a similar "sense of crisis and national purpose," said presenter Dr. Richard Kaplan of University College London Hospital and the U.K. National Cancer Research Network. Prior to 2001, Dr. Kaplan told the conference, research was not considered part of the National Health Service’s cancer care agenda. Now, it is understood that NHS exists partly to do clinical research, "a view that has become ever more firmly embedded in constitution of NHS."

Some of the key changes that allowed the NHS to manage clinical trials included the hiring of dedicated research staff, particularly research nurses, who cannot perform nonresearch-related duties within the hospitals. The NHS also covers costs for all patients enrolled in a trial. Currently, Dr. Kaplan said, 23% of cancer patients in the United Kingdom are enrolled in trials, and 7.5% in randomized trials. All in all 19,000 patients are currently taking part in trials, making the U.K. network comparable in size to the U.S. network, despite a vastly smaller national population. It is also comparable in terms of annual budget, Dr. Kaplan said, with the NCI trials network, with funding coming from government, charity, and industry sources.

One important difference between the United States and the United Kingdom is that novel agents are available only within license in the U.K., providing a powerful motive to both patients and providers to enroll. "The clinical oncology community within the NHS – there’s very little private oncology – were frustrated with the fact that they had limited ability to provide new agents or move forward and so, when it was given to them, they embraced it," Dr. Kaplan said.

Clinicians in the NHS system get an annual review, Dr. Kaplan said, "and nowadays they get asked how much they are participating in clinical trials. They lose face if they haven’t – people pay attention to the fact that if you’re an oncologist and don’t participate, it doesn’t look good."

Still, the U.K. trials system is not leading the way in phase II or biomarker-driven trials at the community level, Dr. Kaplan acknowledged. It has thus far emphasized phase III trials, though 4 years ago, it began to prioritize phase IIs, which have increased as a share of trials underway. Dr. Kaplan said many local NHS networks have tended to "avoid more complex studies, favoring easier studies."

Dr. Bertagnolli said in an interview following the conference that she was confident that cutting-edge science could be conducted well beyond the bounds of dedicated cancer centers in the United States.

"We need to make it possible for these types of studies to be done in our community oncology sites. I don’t think we can effectively accomplish even those goals in this era where we’re looking at smaller and smaller patient populations without engaging the community oncology sites."

Fortunately, Dr. Bertagnolli said, "we have a very experienced community oncology network in the United States, and I have no doubt whatsoever that they are capable, if properly resourced, of doing any of these studies."

TOR@elsevier.com

NCI trials overhaul eyes community-based biomarker studies