Imaging research efforts place focus on clinical effectiveness

The early months of 2008 were unsettling for physicians with an interest in cardiac CT. In a sense, the year began for these radiologists and cardiologists with the Jan. 12 deadline to comment on Medicare's controversial proposal to establish a national coverage determination for cardiac CT. The plan would wipe out 50 state-level coverage determinations, acquired in record time in 2006, that enable providers to bill Medicare for these procedures.

More galling for CCT supporters, the national coverage determination proposed a "Coverage with Evidence Development" (CED) requirement for coronary CT angiography performed on patients with stable or unstable angina and an intermediate risk of coronary artery syndrome. The CED would limit payment to only those facilities that engage in a Medicare-approved clinical trial addressing questions about the procedure's clinical efficacy.

If adopted, the CED requirement would bar most of the providers operating roughly 2000 multislice CT scanners capable of coronary CTA in the U.S. from billing Medicare for cardiac procedures until results from the specified clinical trial are published. Such a study could take up to 10 years and cost up to $20 million, and negative trial results could lead to a permanent payment ban.

The Centers for Medicare and Medicaid Services was scheduled to publish the final rule for cardiac CT on March 13. But even before that crucial announcement, the American College of Radiology and other institutions moved ahead with plans to improve their ability to assess coronary CTA and other emerging imaging technologies. The possibility of a clinical registry instead of a trial has also been discussed. The American College of Radiology Imaging Network is expanding to perform clinical trials and develop registries outside of its traditional focus on oncology. The number of clinical registries managed by the ACR National Radiology Data Registry has been doubled. ACRIN and NRDR plan to bid for the Medicare coronary CTA trial or a possible registry research project proposed as an alternative to the trial, if CMS moves ahead with the CED requirement.

Groups outside of radiology, including the Center for Medical Technology Policy (CMTP), a San Francisco-based think tank organized by former CMS chief medical officer Dr. Sean Tunis, are also expected to bid for the project.

APPROPRIATE APPLICATIONS

Tunis and other CMS officials developed the CED concept at a time when Medicare was spending tens of millions of dollars on bone marrow transplant surgeries for advanced cancer patients. Justification for payment was based on little more than public sympathy and the unsubstantiated opinions of a few influential oncologists. CED was intended to occupy middle ground between denying coverage for promising technologies that lacked scientific verification and writing a blank Medicare check that might lead to their unjustified proliferation, Tunis said in an interview.

Lung volume reduction surgery, a popular and expensive treatment for lung cancer patients in the mid-1990s, served as the first test for the CED principle. A 1200-patient trial that took at least five years established that the procedure was of limited value to some patients and fatal to others, Tunis said. The protocol virtually disappeared from practice because of the trial, despite approved Medicare coverage for a few patients who could benefit from it.

The type of outcomes study that changed clinical attitudes about lung reduction surgery is generally considered appropriate for evaluating therapies, but advocates of coronary CTA argue that it is poorly suited for diagnostic procedures. Medical imaging diagnosis is performed early in the sometimes long sequence of events that leads to the ultimate endpoint of a disease. The numerous variables that influence outcomes make it impossible to measure the effect of a specific imaging procedure. Because outcomes studies themselves are lengthy affairs, critics note that the specific imaging platforms examined by outcomes research is often outmoded by the time results are reported.

Outcomes research addresses clinical management questions, not the diagnostic accuracy of the specific test, according to Dr. Lawrence M. Boxt, director of cardiac MRI and CT at North Shore University Hospital on Long Island.

Knowledge that a person has a serum glucose rate of 250 tells the physician that the patient has diabetes, but it doesn't reveal anything about the outcome of the disease. To make that determination, more must be known about patient management and compliance, he said.

"The application of outcomes re search cardiac CTA sounds good, but it may not be the appropriate test for the issues that are raised," Boxt said.

Outcomes studies are difficult to design, time-consuming, and expensive, but they are called for in some situations, according to former ACRIN chief Dr. Bruce Hillman. ACRIN has done outcomes studies in the past and is in the midst of doing a very large study for CT screening for lung cancer.

Barbara McNeil, Ph.D., chair of the healthcare policy department at Harvard Medical School, is skeptical about the necessity of outcomes studies for diagnostic tests in most instances. But as the incoming chair of CMS's Medical Evidence Development and Coverage Advisory Committee, she agrees with CMS about the appropriateness of an outcomes trial for coronary CTA.

"There is a very tight link between CTA and the technique it would replace-coronary angiography-and their effect on subsequent management decisions, such as stents, angioplasty, or bypass procedures," she said.

Though CMS issued assurances that CEDs would apply to only a few of the 18 to 24 national coverage determinations issued annually, two of its six active CEDs apply to medical imaging. One led to formation of the National Oncology PET Registry (NOPR), which tracks the effect of FDG-PET imaging of brain, cervical, ovarian, pancreatic, small cell lung, and testicular cancer on clinical management. The other was applied to FDG-PET for patients with mild cognitive impairment and early dementia. Reimbursement is limited to trials at the University of California, Los Angeles Medical Center, UCLA-Santa Monica Medical Center, and University of Buffalo.

PROACTIVE TRIALS

Because more CEDs will probably be aimed at promising imaging technologies, radiologists would be wise to conduct trials proactively, McNeil said. She criticized cardiologists for focusing on securing local coverage determinations for cardiac CT when they could have first organized a definitive trial to investigate its efficacy.

"The technology has been around since 2005 or 2006. If all the data had come in during the intervening years, there would have been no reason for this (CED) decision memo," she said.

CMS is less likely to require a CED when the clinical efficacy of an emerging technology has already been demonstrated in a statistically valid randomized clinical trial, according to McNeil. She cited ACRIN's Digital Mammography Imaging Screening Trial (DMIST) as an example.

McNeil applauded ACRIN for branching out from its traditional focus on oncology."That is what is needed," she said. "The concept of having a central organization that has the capability of collecting data in rigorous head-to-head comparisons-if that is the appropriate metric-is what we want."

The ACR has adopted a three-pronged strategy to expand its research capabilities. NRDR employs 40 planners and analysts hired since its inception in 2006. The division supplies data warehousing services to the NOPR and manages a small registry tracking the performance of carotid artery stenting procedures. A new registry is being prepared for CT colonography. A pilot program involving five facilities will be established in May, according to Laura Coombs, director of data registries.

NEW ROLE FOR HILLMAN

After overseeing the NOPR for all of its nine-year history, Hillman stepped down in December 2007 to serve as chief scientific officer of the ACR Imaging Metrix, a new for-profit research group. With freedom to address all modalities and disease states, the ACR Imaging Metrix is contracted by pharmaceutical, biotech, and device companies to manage clinical trials and registries. Hillman also sees a role for his group as a coordinating mechanism for a possible cardiac CT trial or registry.

"This is a two-specialty technology," he said. "Our options will depend on what organized cardiology and radiology do and finding a way for the two groups to collaborate on a clinical trial or registry for CED purposes."

If that approach does not work, Hillman believes radiologists should perform the research themselves.

Funded mainly by the National Cancer Institute, ACRIN has raised the level of scientific sophistication in radiology since 1999 through its work on more that 20 multicenter clinical trials. It has sponsored major studies concerning digital mammography, breast MRI, CT and MR for cervical cancer, MR spectroscopy for prostate cancer, and the use of FDG-PET as an early marker of therapeutic response for gastrointestinal stromal tumors. It also manages the NOPR.

ACRIN runs on a $7 million annual budget. Its big trials, such as the DMIST, have cost up to $20 million and taken up to five years to complete.

ACRIN's research infrastructure is its biggest attribute. It supports experts in statistical study design, protocol development and documentation, data management, validation, analysis, and auditing, as well as web-based instruments for data collection, tabulation, and dissemination. Its image laboratory collects diagnostic images via web tools from collaborating research sites, then stores, analyzes, and distributes them to outside parties for secondary evaluation.

It collaborates with Brown University for study design, statistical clinical outcomes, and economic analysis. Its numerous scientific committees identify research opportunities and advise ACRIN management about study design and execution.

ACRIN'S BROADER REACH

Executive director Dr. Mitchell Schnall has expanded ACRIN's reach beyond NCI-funded cancer-related projects. He capitalized on ACRIN's location of its scientific headquarters in Pennsylvania, for example, to secure grants from the state's lung cancer settlement fund for musculoskeletal and brain studies.

"We have positioned ACRIN-PA to look at very early stage technology with a first push into multicenter studies. It can look across multiple technologies even outside of cancer because it is not bound by NCI funding," he said.

ACRIN-PA is evaluating biomarkers that measure cartilage integrity and the severity of osteoarthritis, for example. The protocol may eventually serve as a surrogate measure of response for new chondroprotective therapies.

The ACRIN Fund for Imaging Innovation offers ACRIN another way to fund research, Schnall said. About $7 million has been pledged, mainly from the imaging device industry. The ACR contributed about half of the $4 million in the fund's bank account.

A grant from the fund supports the use of the DMIST images to evaluate computer-assisted diagnosis during digital screening mammography. Dr. Etta Pisano, who was principal investigator of the original DMIST trial, also leads this study.

The fund supports ACRIN's new cardiovascular advisory committee as well. Chaired by Dr. Pamela Woodard, an assistant professor of radiology at Washington University in St. Louis, the committee is directed to set cardiovascular research priorities for the network. It was formed in November 2007.

Radiologists and cardiologists have been invited to serve on the committee. Members include Dr. Mike Lauer, director of the division of prevention and population sciences at the National Heart, Lung and Blood Institute; Dr. Pamela Douglas, past president of the American College of Cardiology; Dr. David Bluemke, clinical director of MRI at Johns Hopkins University Medical Center; and Dr. Arthur Stillman, past president of the North American Society for Cardiovascular Imaging.

CMS's final decision on the CCT national coverage determination and CED requirement was considered at the committee's first meeting in March. The ACR made its position clear in February, that it would want ACRIN to lead the management of a coronary CTA trial, should one be mandated.

"If CMS comes back and says that we have to absolutely do clinical trials, we will make darn sure ACRIN will be one of the players," said Maureen Spillman-Dennis, the ACR's senior director of economics and health policy.

But Schnall stressed in an interview that ACRIN's interest in a possible trial or registry associated with the CMS rule depended on avoiding political entanglements. "We are going to draw a hard line there," he said. "We will certainly be interested in doing the science and providing the evidence, but it is not our role to engage in policy decisions and policy fights."

PROPOSED TRIAL DESIGN

Tunis's CMTP also figures prominently in the competition for a possible registry or trial. He formed the nonprofit association in 2006, a year after leaving CMS, as a sort of clean, well-lighted place to formulate public health policy.

"The whole point of CMTP is that there ought to be a place where we can have an intelligent conversation about how to deal with challenges associated with evaluations in a thoughtful way, instead of fighting about whether Medicare should or should not pay for CT angiography," he said.

CMTP identified coronary CTA as a potential pilot project for CED-style clinical trial design soon after the association's inception. Participants in the formative planning process included Dr. Molly Coyle, a former Aetna board member and founder of HealthTech, a nonprofit health policy think tank supported by healthcare providers and Dr. Wayne Aubry, former chief medical officer of Blue Shield of California.

The Blue Shield Foundation allegedly supplied funds to help start up CMTP. About half ofthe organization's staff and key advisors are former health insurance industry executives.

CMTP's insurance industry ties set Tunis up for intensive, sometimes vicious, criticism in early 2008. Anonymous attacks accused him of using his influence to try to convince CMS to attach a CED requirement to the national coverage requirement for coronary CTA to block Medicare reimbursement and help private insurers justify refusing coverage.

In an interview, Tunis said the association received no more than token financial support from health insurers and therefore had no reason to "kowtow" to them. He admitted, however, that some aspects of CMTP could raise suspicion.

"To the extent that the mission of CMTP is to facilitate higher quality studies for emerging technologies, it would look like we would be in favor of the insurance industry. I can see why people would assume that is the case," he said.

CMTP's alleged ties to health insurance interests do not trouble Hillman, who participated in its working group to discuss its proposed coronary CTA clinical trial."It would actually be very positive if the insurance industry would become involved by funding and contributing to the intellectual input of clinical trials," he said. "In the past, the insurance industry just said it was not their job."

Regardless of CMTP's allegiances, its early decision to focus on coronary CTA gave it a head start in a registry and clinical trial.

A proposed registry designed by CMTP's partners with the Population Health Research Institute at McMaster University in Hamilton, ON, would follow patients for one to two years, Tunis said. Its primary endpoints would be acute myocardial infarction and cardiac death. Secondary endpoints for patients receiving coronary CTA include cardiac catheterization, revascularization, hospitalization, and overall resource utilization.

As with the NOPR, the project could potentially involve all facilities that perform coronary CTA on Medicare beneficiaries and would not restrict reimbursement. Results could be reported as early as two years after implementation, and the research could be performed for less than $5 million, Tunis said.

CMTP's clinical trial protocol calls for a multicenter outcomes study that would compare initial diagnosis with CTA, SPECT stress-rest myocardial perfusion studies, and stress echocardiography. Up to 20,000 patients from several hundred facilities would be randomly assigned to one of the three tests. The trial would employ the same primary and secondary endpoints as the proposed registry, Tunis said. Medicare would probably not pay nonparticipating sites for coronary CTA procedures while the trial is under way.

Such formal outcomes studies typically produce usable results in five to seven years, with the first-year experience reportable after about three years. The typical cost for such a study is about $15 million, Tunis said.

Though CMTP and its partners designed the registry and trials, the association does not plan to become the clinical research organization that would perform the research, Tunis said.

"We would partner with organizations that have that capacity, including ACRIN and HMO Research Network (an NCI-funded research consortium involving 15 HMOs)," Tunis said. "Our focus is on facilitating the collaborative design."

Other research organizations considered qualified to bid on the trial include Quintiles Transnational in Durham, NC, and the Duke University Advanced Medical Technology Association.

Regardless of the direction that CMS ultimately takes on coronary CTA, its CED policy is forcing changes in professional attitudes. It is clear that the ACR is becoming more involved in clinical trials and registries. New organizations such as CMTP are also springing up to address the rising demand.

They will be needed to assess other promising medical imaging technologies seeking clinical acceptance and financial reimbursement, said Dr. Stanley Baum, professor emeritus of radiology at the University of Pennsylvania.

"Tomorrow they will begin talking about all the exciting things that are happening with neuroscience, such as with Alzheimer's disease," he said in an interview. "There are applications in development to image early-onset Parkinson's disease and very interesting work on hyperpolarized xenon for pulmonary disease and the intestinal camera. They may all be subject to CED examination."

James Brice is senior editor of Diagnostic Imaging.

Dr. Bruce Hillman, chief scientific officer, ACR Imaging Metrix. (Provided by ACR)

Dr. Mitchell Schnall has expanded the clinical scope of ACRIN to cardiovascular imaging and other applications outside of oncology. (Provided by ACRIN)