Feature

NCI-sponsored clinical trials cost-effective, ‘practice influential’

James H. Doroshow, MD 
James H. Doroshow
Joseph M. Unger, PhD 
Joseph M. Unger

A study by the NCI-sponsored SWOG Cancer Research Network showed nearly half of the network’s phase 3 clinical trials influenced clinical care guidelines or new drug approvals.

These trials, funded largely by the public, yielded evidence at a modest cost compared with pharmaceutical company-funded trials, and even studies with negative findings nevertheless influenced clinical practice, according to the study.

“I think NCI-sponsored trials have been very effective in evaluating the standard of care, developing new standards of care with new therapies, or defining that new therapies are actually no better than previous therapies,” James H. Doroshow, MD, director of NCI’s division of cancer treatment and diagnosis, which oversees the National Clinical Trials Network (NCTN), told HemOnc Today. “These are valuable studies that are unlikely to have been conducted in the commercial sector.”

A 30,000-foot perspective

Lead author Joseph M. Unger, PhD, a health services researcher and biostatistician for SWOG at Fred Hutchinson Cancer Research Center, told HemOnc Today that he was inspired by the U.S. Patent and Trademark Office’s Cancer Moonshot Challenge to evaluate cancer studies from a research process perspective.

Founded in 1965 and known for decades as the Southwest Oncology Group, SWOG has amassed a huge data set that includes detailed information on over 1,400 cancer clinical trials. The group’s 60th anniversary, celebrated 3 years ago, prompted Unger and colleagues to look at this data set to quantify the impact of these trials.

“I have worked in the setting of NCI-sponsored clinical trials as a trialist and statistician, and the fact that SWOG as a group had just turned 60 made me realize that SWOG, or more broadly, the NCI-sponsored network groups, are a research process,” he said. “This research process has not been examined from a 30,000-foot perspective in terms of its value to [patients with] cancer.

Unger and colleagues reviewed data from 182 phase 3 trials conducted by SWOG or led by other NCTN groups in collaboration with SWOG between 1980 and 2017 that included 148,028 participants.

“We examined each of the trials in terms of whether they had been cited in the guidelines. That enabled us to examine the clinical impact as measured by informing guideline care,” Unger said. “We also evaluated whether trials were part of an FDA indication package label.”

Researchers found 82 (45%) of the trials to be “practice influential,” meaning they influenced National Comprehensive Cancer Network clinical guidelines (n = 70), new FDA drug approvals (n = 6) or both (n = 6).

The value of negative trials

The study also challenged conventional wisdom regarding the impact of negative trial results. The researchers found that of the 82 trials deemed practice influential, 35 (43%) had negative findings. Nearly half of these trials (n = 17) reinforced evidence supporting the current standard of care rather than the experimental treatments being evaluated.

“A lot of negative trials informed guideline care because they ended up showing what treatments should not be used,” Unger said. “That surprised us, because the focus tends to be only on positive findings.”

Unger cited a well-known example of negative trials that influenced clinical practice for the better. He said in the late 1980s and into the 1990s, a trend toward the use of autologous hematopoietic stem cell transplantation for patients with metastatic breast cancer had been gathering momentum.

“It was gaining traction in the treatment community, but it had never been well-evaluated in a randomized setting,” he said. “A series of trials was conducted, and it was found that transplant patients didn’t do any better than nontransplant patients and, in fact, patients were more likely to suffer worse morbidity and even early mortality due to the transplant itself.”

Doroshow discussed another study that “would be unlikely to be done by anyone other than the NCI.”

In that study, NCI cooperative groups participated with other cooperative groups around the world to evaluate whether three cycles chemotherapy for patients with colorectal cancer was as beneficial as six cycles.

“It turned out for a very significant proportion of patients who would, in standard of care, get six cycles of chemotherapy, three was just as good,” he said. “That’s really important if the therapy contains drugs that can produce long-lasting side effects. If you give less, the incidence of side effects is diminished.”

Cost comparison

The researchers also sought to determine the costs of the trials in the study, specifically differences in the costs of obtaining FDA approvals between publicly funded trials and trials sponsored by pharmaceutical companies, biotech firms and other private funders.

They estimated overall federal investment in the 182 trials at $1.36 billion. Based on this figure, researchers calculated average costs of $7.5 million per completed phase 3 trial, $16.6 million per “practice-influential” trial, and $123.6 million per trial supporting a new FDA drug approval.

Their assessment of 10 articles examining the average costs of industry-funded trials linked to new drug approvals generated a mean inflation-adjusted cost of $1.73 billion per single new drug approval. This estimate represented more than the entire federal investment supporting the conduct of the 182 trials Unger and colleagues examined.

The researchers acknowledged the limitations of this type of comparison, noting that pharmaceutical company trials can be more costly due in part to regulatory costs. The evaluation nevertheless emphasized the value of the NCTN program, they noted, both for taxpayers and the patients who reap its benefits.

Patients who participated in these trials also deserve recognition, according to Unger.

“Hundreds of thousands of patients and investigators have participated in these trials over the decades, and I always want to be sure to recognize them, especially the patients,” he told HemOnc Today. “For a patient, to contribute to a trial is a significant commitment and a tremendous leap of faith.” – by Jennifer Byrne

Reference:

Unger JM, et al. JAMA Netw Open. 2019;doi:10.1001/jamanetworkopen.2019.10593.

For more information:

Joseph M. Unger, PhD, can be reached at 1100 Fairview Ave., Seattle, WA 98109; email: junger@fredhutch.org.

James H. Doroshow, MD, can be reached at National Cancer Institute, Building 31, Room 3A44, Bethesda, MD 20892; email: doroshoj@mail.nih.gov.

Disclosures : Doroshow and Unger report no relevant financial disclosures. Other study authors report receiving grants from the NCI related to this research.

James H. Doroshow, MD 
James H. Doroshow
Joseph M. Unger, PhD 
Joseph M. Unger

A study by the NCI-sponsored SWOG Cancer Research Network showed nearly half of the network’s phase 3 clinical trials influenced clinical care guidelines or new drug approvals.

These trials, funded largely by the public, yielded evidence at a modest cost compared with pharmaceutical company-funded trials, and even studies with negative findings nevertheless influenced clinical practice, according to the study.

“I think NCI-sponsored trials have been very effective in evaluating the standard of care, developing new standards of care with new therapies, or defining that new therapies are actually no better than previous therapies,” James H. Doroshow, MD, director of NCI’s division of cancer treatment and diagnosis, which oversees the National Clinical Trials Network (NCTN), told HemOnc Today. “These are valuable studies that are unlikely to have been conducted in the commercial sector.”

A 30,000-foot perspective

Lead author Joseph M. Unger, PhD, a health services researcher and biostatistician for SWOG at Fred Hutchinson Cancer Research Center, told HemOnc Today that he was inspired by the U.S. Patent and Trademark Office’s Cancer Moonshot Challenge to evaluate cancer studies from a research process perspective.

Founded in 1965 and known for decades as the Southwest Oncology Group, SWOG has amassed a huge data set that includes detailed information on over 1,400 cancer clinical trials. The group’s 60th anniversary, celebrated 3 years ago, prompted Unger and colleagues to look at this data set to quantify the impact of these trials.

“I have worked in the setting of NCI-sponsored clinical trials as a trialist and statistician, and the fact that SWOG as a group had just turned 60 made me realize that SWOG, or more broadly, the NCI-sponsored network groups, are a research process,” he said. “This research process has not been examined from a 30,000-foot perspective in terms of its value to [patients with] cancer.

Unger and colleagues reviewed data from 182 phase 3 trials conducted by SWOG or led by other NCTN groups in collaboration with SWOG between 1980 and 2017 that included 148,028 participants.

“We examined each of the trials in terms of whether they had been cited in the guidelines. That enabled us to examine the clinical impact as measured by informing guideline care,” Unger said. “We also evaluated whether trials were part of an FDA indication package label.”

Researchers found 82 (45%) of the trials to be “practice influential,” meaning they influenced National Comprehensive Cancer Network clinical guidelines (n = 70), new FDA drug approvals (n = 6) or both (n = 6).

PAGE BREAK

The value of negative trials

The study also challenged conventional wisdom regarding the impact of negative trial results. The researchers found that of the 82 trials deemed practice influential, 35 (43%) had negative findings. Nearly half of these trials (n = 17) reinforced evidence supporting the current standard of care rather than the experimental treatments being evaluated.

“A lot of negative trials informed guideline care because they ended up showing what treatments should not be used,” Unger said. “That surprised us, because the focus tends to be only on positive findings.”

Unger cited a well-known example of negative trials that influenced clinical practice for the better. He said in the late 1980s and into the 1990s, a trend toward the use of autologous hematopoietic stem cell transplantation for patients with metastatic breast cancer had been gathering momentum.

“It was gaining traction in the treatment community, but it had never been well-evaluated in a randomized setting,” he said. “A series of trials was conducted, and it was found that transplant patients didn’t do any better than nontransplant patients and, in fact, patients were more likely to suffer worse morbidity and even early mortality due to the transplant itself.”

Doroshow discussed another study that “would be unlikely to be done by anyone other than the NCI.”

In that study, NCI cooperative groups participated with other cooperative groups around the world to evaluate whether three cycles chemotherapy for patients with colorectal cancer was as beneficial as six cycles.

“It turned out for a very significant proportion of patients who would, in standard of care, get six cycles of chemotherapy, three was just as good,” he said. “That’s really important if the therapy contains drugs that can produce long-lasting side effects. If you give less, the incidence of side effects is diminished.”

Cost comparison

The researchers also sought to determine the costs of the trials in the study, specifically differences in the costs of obtaining FDA approvals between publicly funded trials and trials sponsored by pharmaceutical companies, biotech firms and other private funders.

They estimated overall federal investment in the 182 trials at $1.36 billion. Based on this figure, researchers calculated average costs of $7.5 million per completed phase 3 trial, $16.6 million per “practice-influential” trial, and $123.6 million per trial supporting a new FDA drug approval.

Their assessment of 10 articles examining the average costs of industry-funded trials linked to new drug approvals generated a mean inflation-adjusted cost of $1.73 billion per single new drug approval. This estimate represented more than the entire federal investment supporting the conduct of the 182 trials Unger and colleagues examined.

PAGE BREAK

The researchers acknowledged the limitations of this type of comparison, noting that pharmaceutical company trials can be more costly due in part to regulatory costs. The evaluation nevertheless emphasized the value of the NCTN program, they noted, both for taxpayers and the patients who reap its benefits.

Patients who participated in these trials also deserve recognition, according to Unger.

“Hundreds of thousands of patients and investigators have participated in these trials over the decades, and I always want to be sure to recognize them, especially the patients,” he told HemOnc Today. “For a patient, to contribute to a trial is a significant commitment and a tremendous leap of faith.” – by Jennifer Byrne

Reference:

Unger JM, et al. JAMA Netw Open. 2019;doi:10.1001/jamanetworkopen.2019.10593.

For more information:

Joseph M. Unger, PhD, can be reached at 1100 Fairview Ave., Seattle, WA 98109; email: junger@fredhutch.org.

James H. Doroshow, MD, can be reached at National Cancer Institute, Building 31, Room 3A44, Bethesda, MD 20892; email: doroshoj@mail.nih.gov.

Disclosures : Doroshow and Unger report no relevant financial disclosures. Other study authors report receiving grants from the NCI related to this research.

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