Two years ago, NCI officials made a promise to increase the budget of the cooperative groups program by $25.6 million.
The boost, which was approved by the NCI Board of Scientific Advisors, was part of an effort to revamp the groups inspired by a report from the Institute of Medicine.
On March 1, as the cooperative group program officially becomes the NCI National Clinical Trials Network, new money will not be a part of the transformation.
Leaders of the network groups say they haven’t been told what their budgets will be for the rest of the year. However, they have been told that total enrollment in the four adult groups will drop to about 17,500—of whom 14,000 will be adults. In recent years, enrollment has been between 20,000 and 23,000 (The Cancer Letter, Feb. 21).
“We don’t have a budget, as of today,” Robert Comis, co-chair of ECOG-ACRIN Cancer Research Group, said to The Cancer Letter in an interview Feb. 26. “The old grant is over as of March 1. We were told that we would receive some notification before March 1 as to what our level of funding might be, but we haven’t received it yet. We are continuing to do our work, for now.”
Walter Curran, co-chair of NRG Oncology, said his group hasn’t received a notice of award either.
“When a group like NRG is making decisions on how to prioritize our trials, it’s very difficult to do this without knowing the scope of our budget,” Curran said in an interview Feb. 25. “One of the frustrating things—and it’s not the fault of CTEP [the NCI Cancer Therapy Evaluation Program]—is that due to delays in the federal budgeting process, we are literally four days from starting this network, and none of us know our budgets.
“This system begins this Saturday, and we only have a general idea on what funding will run this operation. And these are all new awards to reorganized entities. While we are going to be able to use some carryover funds from our legacy groups, it’s a very difficult process to be going through without knowing what kind of support we have.”
Charles Blanke, chair of SWOG, said he is assuming that the budget, when there is one, will be flat, which would amount to a bit more than $150 million for the entire program. “But we are all a little bit scared, and we would like to know,” Blanke said to The Cancer Letter.
Jeff Abrams, director for clinical research of the NCI Division of Cancer Treatment and Diagnosis, said NCI is in no position to award the money to the network groups.
“Unfortunately, NIH/NCI has not yet received the actual monetary funds, so we are not able to make group awards yet,” Abrams said to The Cancer Letter. “We hope to do it soon, but it may take till the end of March or even longer.”
Promised $25.6 Million
Two years ago, NCI had solid rationale for promising the $25.6 million boost to the groups.
The new funds were intended to help double the per-case payments to high-performing clinical sites for putting patients on studies. This is needed, because institutions have been complaining that per-case payments have been so low that they lose money when they put patients on cooperative group trials.
With the money failing to materialize, the only thing NCI can do is drop accrual targets for fiscal 2014.
“I think Dr. Varmus was committed to that, and that was the budget that was approved by the BSA,” said Comis, who is also the president and chairman of the Coalition of Cancer Cooperative Groups and professor of medicine at Drexel University. “The additional $25 million was going to primarily cover increased capitation for high-performing sites, raising the level of funding from $2,000 to $4,000.
“With a flat budget, that $25 million is going to come out of the existing dollars, which is a huge cut, compounded by the fact that we were all—NIH, NCI and us—working on about a negative 20 percent buying power to start with. It’s a big hit. We all worked in good faith with the NCI to establish the NCTN, but it has come to pass at a time that couldn’t be worse with regard to availability of dollars.”
NCI’s Abrams said there is a chance that funds may be reprogrammed to NCTN.
“It is true that we were approved to have an increase of $25 million when we presented the RFA,” Abrams said to The Cancer Letter. “However, due to sequester and an overall flat budget, NCI is not able to provide this $25 million at this time. Later in this fiscal year, if we have additional funds after existing commitments are paid, we may be able to increase the NCTN line but this is uncertain at present.”
Group leaders cooperated in NCI-mandated consolidation of cooperative groups to create NCTN, and most describe the new structure as promising.
“The NCTN represents a dramatic change from the former cooperative groups,” said Monica Bertagnolli, chair of the Alliance for Clinical Trials in Oncology.
“On the positive side, there is an unprecedented level of collaboration and advances in study design in the activation of exciting new trials for patients with molecularly-defined tumors. On the negative side, budgetary constraints are severely limiting the scope of research, and many important questions will go unanswered.
“We already know that far fewer patients have the opportunity to participate in publicly-funded trials, and we are also concerned that lack of opportunity for scientific progress will reduce the number of U.S. researchers committed to clinical trials.”
Bertagnolli is also chief of the Division of Surgical Oncology at Brigham and Women’s Hospital and a professor of surgery at Harvard Medical School.
Curran sees promise in integrating cancer centers and cooperative groups.
“A lot of positive things can come out of this reorganization,” said Curran, executive director of Winship Cancer Institute of Emory University. “I believe that the decision to give many cancer centers Lead Academic Participating Site (LAPS) U10 awards is actually an excellent way to align the cancer centers with the network groups. I think it incentivized the centers to be active across all four of the new adult network groups.
“It’s incentivized some centers to be more conscious of enrolling their patients on these trials and to look at how their leaders can provide scientific leadership to the groups. As GOG, RTOG and NSABP came together, this integration has enabled us to learn from one another and bring many scientific efforts together .We believe this should translate into higher quality clinical trials for our members and patients.
“All the groups underwent peer review. They were all favorably reviewed, and all have important as well as complementary visions of what we can do. We of course need sufficient resources to execute this.”
Additional Scrutiny for Large Trials
To stay within budgetary targets, NCI will scrutinize trials that enroll 1,000 or more patients, officials said. Though these trials will be subjected to a secondary level of review, it’s unclear what this additional scrutiny will entail.
“The rationale is simply that we are paying higher reimbursement per case—$4,000/case compared to $2,000/case—for about 50 percent of the patients we enroll overall,” Abrams said to The Cancer Letter. “To do this, we have to live more strictly within our budget and thus not overshoot our total enrollment, estimated at about 17,000 interventional patient and 2,500 screened patients. To ensure that we don’t overshoot as we transition into this new system, NCI is holding up approval of large, costly trials as we are uncertain whether our budget will permit us to support all of them. If only some can be supported, we will have a second level review to compare these trials across diseases and make prioritization decisions.
“The process for this second level review is currently under discussion.”
Comis described the overall accrual target as “meager.”
“The primary emphasis at the NCI is now on phase II trials, as opposed to large phase III trials, which reflects current thinking relative to the new age of targeted treatments, but there is no question in my mind that large, definitive studies sponsored by the public side of the system are still required to work out, for instance, the PD-1 and immune checkpoint inhibitors.” Comis said. “I think we should still be in that game, and it is not clear to me how this will play out given the financial realities.”
Limits on enrollment will be particularly constricting to adjuvant trials, group leaders say.
SWOG, for example, is unable to go forward with an adjuvant trial in melanoma.
“There is a lot of discussion among all the groups in terms of what publicly funded research should look like,” Blanke said. “We are moving toward targeted therapy, where we expect the bang per drug to be much higher in a smaller population. That said, a drug like imatinib has happened four times in the history of oncology. I think we’ve made huge gains incrementally through these large trials. In colon cancer, the median survival used to be six months. Now it’s well over two years, and it was not achieved with any single drug being a blockbuster. It was three-month gains, and a lot of it was through benefit in the adjuvant setting.”
The industry is unlikely to ask many of the questions cooperative groups can address.
For example, industry would be unwilling to conduct a trial aimed to show that a smaller dose or shorter duration of treatment can produce equivalent results. Blanke said that one of the most interesting trials now conducted in colorectal cancer is a non-inferiority study comparing three months of FOLFOX with six months of the regimen.
“I would argue that if that’s a positive trial and if the people who get FOLFOX don’t get neuropathy, that will be the biggest gain in colon cancer ever, bigger than any single drug is going to achieve in terms of patient benefit,” Blanke said. “You can imagine that the company that makes the drug isn’t going to be particularly interested in selling three months less of the drug. There is no other mechanism for doing that kind of trial but the cooperative groups.”
Over 10,000 patients to show non-inferiority, and roughly 2,500 are being accrued in the U.S. trial.
“It’s going on now, but it wouldn’t have a chance if it were proposed today,” Blanke said. “If this trial were proposed today, even if it were approved, the activation would be suspended. Whether or not there is an appetite to do this type of trial is questionable.”
Adjuvant trials aren’t getting started, group chairs say. “While there are currently active breast cancer adjuvant trials, to the best of our knowledge, no new breast adjuvant concept has been approved in the last six months,” Blanke said.
Comis said NCI’s new-generation trials of targeted agents are focused on small populations.
“If you look at the targeted agents, you see that, aside from Herceptin, very few of them have been shown to cure people or have a huge impact in the adjuvant setting.” Comis said. “A few upcoming trials will be more directed, like ALCHEMIST, where we are going to assess lung cancer patients with regional disease for enrollment onto one of two adjuvant trials based on specific mutations, but there are tens of thousands of other lung cancer patients who are still being treated with therapies from the 1980’s and 1990’s. Who will perform the large trials necessary to define new treatments for these patients?”
Altogether, 30 academic centers were chosen to receive increased per-patient reimbursement. According to critics, this will have a negative impact on many important academic groups that are not well supported.
“It’s unfortunate that funds did not permit to fund more than 30,” Abrams said. “For sites that don’t have Lead Academic Participating Sites awards, they will have their participation funded via subcontract by the NCTN Operations Centers. They will be funded at the $2,000 per case rate instead of the higher $4,000 rate that the LAPS will get. If more funds become available, we would be able to have another round of competition and potentially increase the number of LAPS awards.”
Changes Affect Reference Labs
NCI is also changing the way tissue banks are funded. Reference labs will no longer be supported through funds received for group operations.
“This is a major concern for the groups because our reference laboratories generate the science that forms the basis for our trial designs. For example, our characterization of leukemic cells led us to generate the innovative study designs that you see in our current leukemia trials, so the NCI decision really doesn’t make a lot of sense to me.” Comis said. “In addition, the NCI seems determined to control the use of our resources at exactly the wrong time. The biorepositories are our lifeblood, in the sense that we have the best annotated tissue banks in the country, if not the world. At a time when budgets are tight at the NCI, both philanthropy and industry are interested in working with us on innovative research efforts that require the scientific resources produced by our labs. With NCI dollars becoming less and less a component of our overall portfolio, we ought to be free to use our laboratory resources directly with industry and foundations and not have them controlled by a system that has made the decision not to support them financially.”
Abrams said that in the past, NCI funded banks partially out of a U24 infrastructure mechanism and partially out of some funds that were given to the Operations Centers of the Groups.
“Going forward, the banks will be supported entirely out of the U24 mechanism,” Abrams said. “I guess this has led to some unhappiness among some group members as some may miss the funds they received to support banking via the Group Ops. However, the overall funding for banks is not going down—it will just be given via the U24. What is changing is ‘reference labs.’
“Support for standing reference labs will no longer be possible in the group operations awards as we need all the funds to support the actual trials. If biomarkers or other lab tests are needed to conduct a trial, the groups will have to seek support for this on a trial-by-trial basis.
“Possible sources of such support are an NCI mechanism called BISQFP which sets aside about $10 million per year for this purpose. Groups also seek industry and philanthropic support for this sort of thing to supplement the NCI funds.”
Another unknown is the role the new NCI Community Oncology Research Program will play in the new clinical trials infrastructure. NCORP is created through a merger of the Clinical Cancer Oncology Program, which was run through the Division of Cancer Prevention and the Community Cancer Centers Program, which was administered as a subcontract with what was then called SAIC-Frederick Inc., now called Leidos-Frederick Inc.
Historically, CCOPs contributed substantially to accrual to group trials. Though the funding level for the new NCORP isn’t publically known, it’s expected that it will be lower than the sum of the two programs. Also, NCORP has another major mandate: to engage in health services research.
“In the recent RFA for the NCORP Research Base that we just responded to in January, there wasn’t much money allotted for cancer care delivery research, yet the application criteria required us to put a lot of effort into this area of research.” Comis said. “We are going to have to wait and see how it all plays out.”
All of this is frustrating, group chairs say.
“The cooperative groups still continue to conduct transformational research,” Curran said. “Our budgets have been, in actual dollars, stable for a dozen years, even during the periods when the overall NIH and the NCI budgets have gone up. Despite the fact that we have had no real increases in our funding, we’ve continued to execute remarkable work.
“It’s tough to go initiate a new system with such budgetary uncertainty.”
Lower Support Leads to Lower Output
Recently, Bertagnolli examined the effect of funding cuts on Cancer and Leukemia Group B, one of the groups that merged to form Alliance, which she chairs.
“Even before the funding cuts brought on by sequestration, funding deficits have significantly limited our ability to conduct potentially transformative clinical research,” Bertagnolli said in a talk at the 2013 ASCO annual meeting. The talk is summarized on the ASCO website.
The groups’ NCI funding fell by 12 percent from 2003 to 2011. Adjusted for inflation, the decrease resulted in a 29 percent loss of purchasing power. Over that same period, the group’s rate of new clinical trials fell. “The shape of the curve precisely matches what we’ve had in terms of dollar fluctuation,” Bertagnolli said.
The number of patients enrolled in trials dropped also. “The current 33 percent reduction in patients treated on NCTN trials is one tangible example of the loss in research productivity experienced due to lack of research funding over the past four years,” Bertagnolli said.
The number of scientific publications of research results has fallen as well.
“Publications always lag in timing, because it takes a while to begin the study, get the patients on, and then analyze the data, but you see a three-year lag in these curves tracking exactly the same,” Bertagnolli said.
“So in every measure of our productivity, the number of studies we can get going, the number of patients we can study, and the numbers of publications and results—all of these important variables are directly and dramatically affected by the 29 percent reduction in our public support. These reductions also lead to fewer numbers of qualified researchers to conduct trials, as young people entering the field are discouraged from pursuing a career without opportunities to advance their ideas.
“As a result, the effects of budget cuts can persist for many years.”
