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The Oncologist News Bulletin
Cost To Oncologist For Enrolling A Patient On Trial About $2,000, ASCO Survey FindsA series of surveys by the American Society of Clinical Oncology (ASCO) and an NCI-sponsored study at the Mayo Clinic have finally brought to the table a key ingredient severely lacking in discussions about the participation of oncologists in clinical trials and the costs of enrolling patients on trials:
Data
Among the findings of the three ASCO surveys, presented at the society's annual meeting in Atlanta last May:
- The average cost to oncologists of enrolling a patient on a government or industry trial is $2,000 per patient, with a range of $581 to $5,028 for government trials and $569 to $6,567 for industry trials.
- NCI-sponsored clinical trials reimburse on average only a quarter of the actual costs to oncologists of participation. Current NCI reimbursement is $750 per patient; average industry reimbursement is $2,500 per patient.
- Despite higher reimbursement from industry, oncologists said they prefer to work on NCI-sponsored trials, because the trials are considered well-designed, important, and intellectually challenging.
- The single greatest barrier identified by oncologists to enrolling patients was strict eligibility criteria. Other barriers included administrative burden and inadequate data management staff.
- A majority of oncologists—85 percent—view clinical trials as the essential means of discovering new therapies to improve patient care, and 80 percent report having participated in clinical research within the last three years.
"The encouraging news is that most oncologists view clinical research as fundamental to their jobs, despite significant disincentives to participate," said Allen Lichter, dean of the University of Michigan Medical School and past president of ASCO. "The bad news is that a lack of trained personnel, inadequate funding, increased pressure to do reimbursable work, and a lack of dedicated research time serve as powerful deterrents to conducting such research."
Joseph Bailes, who took office as ASCO's president for 1999-2000, said the society is planning to examine patterns of care over the next year.
The Mayo Clinic study published in the May 19 issue of the Journal of the National Cancer Institute found that the costs for care provided as part of clinical trials are slightly higher than costs for standard treatment. However, based on the study's findings, the authors recommend third-party payment for patients' treatment in NCI-approved clinical trials.
Preliminary results of two other NCI-supported cost studies were presented to the National Cancer Advisory Board in June. 
Cost-Counters Cut Back Participation
The ASCO Public Issues Committee, chaired by Lowell Schnipper of Beth Israel Hospital, Boston, undertook three surveys:
- Oncologists' perceptions and participation in clinical trials, conducted by the Center for Survey Research at the University of Massachusetts. The survey had 3,550 respondents of 8,000 ASCO members surveyed.
- Pharmaceutical industry participation in cancer trials, conducted by Barnett International. Of the 116 companies surveyed, 32 responded; data from 19 were evaluable.
- Costs associated with clinical cancer research, conducted by the Lewin Group. There were 17 respondents to this in-depth survey of oncologists' office practices.
Oncologists who had calculated the costs of participating in clinical research were more likely to have decreased their participation over the past year, said Ezekiel Emanuel, chief of the Department of Clinical Bioethics at the NIH Clinical Center, who presented the results of the oncologists' perception survey at the ASCO Presidential Symposium on May 16.
Half of the respondents said their participation in industry-sponsored trials had increased in the past three years, while 31 percent said their participation in NCI-supported clinical trials cooperative groups had increased.
Oncologists estimated that 20 percent of their patients were eligible for participation in trials, and said they approached 10 percent about participation, but only 5 percent of their patients actually enrolled.
In contrast, pediatric oncologists said 70 percent of their patients were eligible for trials and 68 percent of them enrolled.
Oncologists who enroll fewer patients on trials are those who have no protected research time and who have pressure to generate revenue, the survey found. Reasons given for not enrolling include strict eligibility criteria and lack of informed consent.
Only 20 percent of those who responded said they had protected time for research, and those were more likely to work in academic settings. Protected time consisted of about one day a week.
"The younger you are, the more likely you are to have protected time," Emanuel said. "If you have protected time, you are 73 percent more likely to enroll more than 5 percent of your patients on trials."
Oncologists who reported more reimbursement from managed care firms were more likely to participate than those who reported less managed care reimbursement.
The survey found that 75 percent of oncologists report not having been a principal investigator or co-principal investigator on a trial during a fellowship. This indicates a major lack of training in clinical research, Emanuel said. "This is an extremely sad statement on our training programs," he said. "We expect this to be gleaned by osmosis."
Enrolling patients on trials was not felt to lead to career advancement, oncologists said.
Reimbursement for patient care costs in trials not involving bone marrow transplantation (BMT) did not seem to be a problem for these oncologists. Oncologists reported submitting claims for reimbursement more than 95 percent of the time, and getting reimbursed in more than 95 percent of the cases. However, for BMT studies, oncologists reported submitting claims in 95 percent of the cases, but getting reimbursed less than 20 percent of the time.
More than half the respondents said cooperative groups run the most effective trials, while 25 percent said industry trials were most effective. Three-fourths of the respondents said they would participate in cooperative group trials if given $1,500 per patient.
The pharmaceutical industry survey found that 9 percent of industry clinical trials are devoted to new anti-cancer agents, compared to 25 percent on cardiology and 17 percent in neurologic diseases, Schnipper said.
The survey found that the top five cancers being investigated in industry trials are: prostate, colon, melanoma and lung. An estimated 13,000 patients are enrolled in industry sponsored trials.
It is estimated that 116 companies are conducting clinical research in cancer, and that 267 anticancer compounds are being tested in 647 different trials, Schnipper said.
The study of costs associated with clinical research selected 25 sites of varying sizes. Seventeen of the sites completed the survey, including seven academic centers, three HMOs, and 12 group practices.
The study proposed a mock phase III trial and assumed each site would enroll 20 patients for a 13-week treatment period with 12 months of follow-up. Oncologists said they must conduct 15 separate activities to participate in the trial and enroll a patient. The most time-consuming actions include recruiting patients, seeing patients, and completing forms.
Overall, 200 hours of work are required to see one patient through the clinical trial process, or 4,000 hours for the 20 patients. Nurses and data managers spend about 1,800 hours and 1,500 hours per trial, respectively, the study found.
The direct labor minus the patient care costs came out to about $2,000 per patient, Schnipper said. "These estimates are conservative," he said. "If anything, time was underestimated."
"If trials were adequately funded and supported, we could shorten the time it takes to complete patient accrual, and thus the time it takes to complete research," Lichter said. "This would allow us to undertake more trials and learn the results faster. This is critical because in oncology the majority of what we know to be effective has come to us through the clinical trial process."
Costs Of Care In Trials Slightly Higher
NCI has sponsored three studies on patient care costs in clinical trials. The Mayo Clinic study, the first of these to be published, was conducted as a matched-case comparison of the incremental medical costs for participation in cancer treatment trials from the date of trial entry until either death or 60 months following entry into the trial.
Case subjects were residents of Olmsted County, MN, who entered phase II or III cancer treatment trials at Mayo Clinic from 1988 through 1994. Control subjects were patients who did not enter clinical trials, but who were eligible based on their tumor types and other information provided in their medical records. Each case was followed with its corresponding control case for up to five years following the date of clinical trial entry for case subjects or from an equivalent date for control subjects. Hospital, physician and ancillary service costs were estimated from a population-based cost database developed at Mayo Clinic.
The study found that the costs of treating patients in clinical trials were less than 10 percent higher than for treating patients who were eligible for the trials but opted for standard treatment, according to the study. The average total five-year cost in 1995 inflation-adjusted dollars among trial enrollees was $46,424, compared with $44,133 for those who did not enter clinical trials.
"The widely held view by third-party payers is that clinical trials are much more expensive than standard treatment," said Steve Alberts, Mayo Clinic oncologist and the study's principal investigator. "We now know that costs are not budget breaking. We hope this will encourage reimbursement by third-party payers, which will translate into better access to clinical trials for patients. This access in turn should lead to improved survival and quality of life for patients, and faster advancements in the search for new treatments for all cancers."
Mayo Health Plan, a health maintenance organization affiliated with Mayo Foundation, announced an agreement in 1997 with several national cancer cooperative groups to cover patient care costs of treatment provided as part of NCI-approved trials. This was the first agreement of its kind between the oncology community and private payers and health plans doing business on a region-wide basis.
Based in part on early information from the Mayo Clinic study, UnitedHealthcare, the national health benefits subsidiary of UnitedHealth Group with 7.9 million members, made a similar agreement with the Coalition of National Cancer Cooperative Groups Inc., that became effective last October.
Results of this study also are being considered by a committee at the Institute of Medicine of the National Academy of Sciences that is considering potential Health Care Financing Administration policy changes with respect to Medicare coverage of clinical trial costs. Medicare does not pay for routine patient care delivered in a clinical trial unless that care would be necessary without the trial.
Sen. Connie Mack (R-FL) has introduced a bill, the Medicare Cancer Clinical Trials Act of 1999, that would cover routine patient costs for Medicare patients taking part in approved cancer clinical trials.
Preliminary Results Of Two Studies
The preliminary results of the two other NCI-supported studies of patient care costs on trials were presented June 8 to the National Cancer Advisory Board's Clinical Trials Subcommittee. Martin Brown, chief of the Health Services and Economics Section in the NCI Division of Cancer Control and Population Sciences, said the data had been reported to NCI last July, and cautioned that there may be revisions in these results when they appear in final publication. Both studies have been submitted for publication.
In a study at the Group Health Cooperative of Puget Sound, cost data were obtained for patients who participated in five different breast cancer trials conducted by the Southwest Oncology Group (SWOG) and five different SWOG colorectal cancer trials from 1990-1996. There were 49 cases of breast cancer and 20 cases of colorectal cancer.
After two years, the routine care cost for breast cancer patients enrolled on trials was $23,494, compared to $18,596 for matched controls not enrolled on trials, a difference of $4,898. For the colorectal cancer trials, the difference was $1,498.
In a study at Kaiser Permanente of Northern California, cost data were obtained for patients on trials by SWOG or the National Surgical Adjuvant Breast and Bowel Project. After one year, the cost of routine patient care for those enrolled on trials was $17,003, compared to $15,515 for patients not enrolled on trials, a difference of $1,487.
Brown said much of the differential on the Kaiser study was attributable to patients enrolled on bone marrow transplant trials.
The three studies had small sample sizes, and the trials, patients, and practice settings may not be representative of the population, Brown said. Also, he said, the technique of matched pair analysis may introduce selection bias and weaken the generalizability of the results.
Gore Proposes New War On Cancer, Double Research Funding Over 5 Years
Presidential candidate Al Gore distinguished himself from other candidates and the Administration he serves as vice president by proposing a new war on cancer he would launch if elected.
"No one can promise a cure for cancer; no one can promise what has escaped decades of our best science and our hardest efforts," Gore said in a speech at Thomas Jefferson University June 28. "But we can do better. We must set a national goal: to work tirelessly toward a vision of a 21st Century America that is free of cancer as the killer it is today."
The most notable aspect of the program advanced by Gore is that it addresses cancer specifically. Other initiatives, proposed by Congress and the Administration in recent years, address biomedical research in general.
"I believe we should double federal cancer research over five years—which will double our current progress in preventing cancer and saving lives," Gore said in his speech.
The speech comes at the time when President Clinton is advancing a plan to spend the federal surplus to upgrade Medicare and to introduce a prescription drug benefit. The administration plan does not address cancer research specifically.
Several observers said that, regardless of the outcome of the election, Gore's campaign promises, if matched or surpassed by other candidates, could make cancer research a major issue in the year 2000 presidential race.
In addition to doubling funding for cancer research over five years, Gore called for:
- Enhancing diagnostic technology through programs that include the NCI Cancer Genome Anatomy Project and the NIH Human Genome Project.
- Assuring patient access to cancer clinical trials by passing legislation to assure Medicare reimbursement for clinical trials and to require health plans to reimburse patient care costs incurred in clinical trials. "We cannot cure cancer if only two percent of America's cancer patients are enrolled in cutting-edge clinical trials," Gore said. "I want to swing open the doors to the latest cancer clinical trials for Americans of all ages, who don't have the luxury of time. I call for funding to ensure a fivefold increase in the number of cancer patients able to join in clinical trials through our National Cancer Institute."
- Strengthening cancer prevention and early detection by expanding access to proven cancer screening tests, launching a national informational campaign on screening and early detection, and eliminating Medicare deductibles for mammography and colorectal and prostate cancer screening. The initiative also calls for launching a $200 million campaign to prevent children from smoking, penalizing tobacco companies that market to children, and passing legislation that would reaffirm FDA authority to curb tobacco advertising aimed at minors. "It is time to match big tobacco's big advertising campaigns with a national, counter-advertising campaign about the dangers of smoking and the risks of cancer," Gore said.
- Assuring patient access to specialists, protecting privacy of medical information, preventing discrimination against those found to be genetically susceptible to cancer. "We need a law that says to every doctor and health plan in America: Medical records must be kept private, or you will be punished with the full force of our laws," Gore said.
Gore's proposals appear to be consistent with the message of The March: Coming Together To Conquer Cancer, an event last September (reprinted in The Oncologist 1998;3:135-142). His initiatives on cancer research appear to restate several key recommendations contained in The March Research Task Force Report, a document that is currently being used as something of a manifesto by professional societies and several members of Congress (reprinted in The Oncologist 1999;4:145-183).
"We are pleased that the Vice President's proposal emphasizes the application of recent findings from molecular genetics and molecular biology to significantly improve the early detection, treatment and prevention of cancer," said Anna Barker, co-chair of The March Research Task Force and a member of the board of directors of the American Association for Cancer Research (AACR).
The Gore initiative was applauded by AACR, the American Society of Clinical Oncology, the National Coalition for Cancer Survivorship, and the National Prostate Cancer Coalition.
Campaign promises notwithstanding, the appropriations picture on Capitol Hill remains uncertain. The House and Senate appropriations subcommittees are yet to act on spending bills that fund NIH as subcommittee leadership is seeking to increase the subcommittees' allocations.
Dave Kohn, a spokesman for Rep. John Porter (R-IL), chairman of the House Labor, HHS and Education Appropriations Subcommittee, said the allocation for the subcommittee is so low that drafting a bill would be a pointless exercise.
"The allocation would require a cut of about $11 billion below current level spending, from about $89 billion to about $78 billion," Kohn said. "This level of reduction is so draconian that if he were to write a bill, that bill would not pass the full House, or even the committee."
Both Porter and his Senate counterpart, Arlen Specter (R-PA) have asked the Republican leadership to increase the allocation.
The budgetary caps that have frustrated the appropriations process were put in place in the 1997 Balanced Budget Act. "When that bill was enacted, there was a great deal of concern about the economy," said Kohn. "In the ensuing two years our economy has continued to perform magnificently, and there is, in effect, a pretty good situation."
NCI Begins Phase III Trial In Colorectal Cancer
The U.S. National Cancer Institute is launching a large research study that will test two of the most promising new drugs for metastatic colorectal cancer. The study will be conducted in hundreds of medical centers throughout the U.S. and Canada.
Now beginning to enroll about 1,700 patients, the Cooperative Colorectal Cancer Combination Chemotherapy Clinical (6C) Trial will evaluate the new drugs CPT-11 and oxaliplatin as the initial therapy for advanced colorectal cancer.
The drugs will be tested in combination with each other and with other drugs and these combinations will be compared with the current standard treatment for colorectal cancer.
Oxaliplatin and CPT-11 have each shown promise in earlier, separate studies. Used in combination with the drugs 5-fluorouracil (5-FU) and leucovorin, which are known to be effective in colorectal cancer, the combinations have shown higher response rates than 5-FU and leucovorin alone. The results are still too early to draw definitive conclusions about improved survival, NCI said in a statement. Some studies have suggested that combinations of these drugs may be synergistic, boosting each other's effectiveness.
The 6C Trial will attempt to sort out which combinations and which methods of giving the drugs may result in better survival rates and the longest times to tumor progression, compared to the standard treatment. It will also yield important information about the side effects of the various combinations and about quality of life of patients on the different regimens.
"These are the first new drugs we have had to treat colorectal cancer in many years," said Barbara Conley, of NCI's Cancer Therapy Evaluation Program. "This will be the first large, randomized North American study to evaluate both of these new agents. The results may move the treatment of colorectal cancer a significant step forward."
The trial will enroll patients with advanced (metastatic or recurrent) colorectal cancer. The patients will be divided randomly into six groups.
One group will receive 5-FU and leucovorin, which are now widely considered the standard treatment in the U.S.
Two groups will receive this standard therapy plus CPT-11, and two other groups will receive the standard therapy plus oxaliplatin.
The sixth group will receive oxaliplatin and CPT-11. In the groups receiving the same drugs, investigators will compare different methods and schedules for administering them.
The 6C Trial will take place in virtually every part of the U.S. and in Canada, and will involve many of NCI's Clinical Trials Cooperative Groups.
"With this many institutions able to take part, we hope to complete enrollment in three years or less," said Michael O'Connell, chairman of the North Central Cancer Treatment Group, which is leading the study.
"This will enable us to answer key questions about these new treatments quickly, giving patients and their physicians much more information than they have now about the benefits and risks of the different regimens."
O'Connell said the trial would also give researchers leads on how to design future trials to improve treatment further.
If needed, a second part of the trial has been planned to evaluate the most effective regimens against each other.
NCI expects enrollment to take about three years. Up to a 12-month follow-up period is planned. Results could be available in five years or less.
For further information, call NCI's Cancer Information Service at 800-4-CANCER or go to NCI's Internet web site for clinical trials, http://cancertrials.nci.nih.gov.
6C Trial Randomization
Administration of all drugs is intravenous.
Arm 1 (standard therapy): 5-FU plus leucovorin on days 1-5, every 4-5 weeks.
Arm 2: CPT-11 and 5-FU plus leucovorin once a week for 4 weeks, with 2 weeks rest.
Arm 3: CPT-11 on day 1 and 5-FU plus leucovorin on days 2-5, every 3 weeks.
Arm 4: Oxaliplatin on day 1 and 5-FU plus leucovorin on days 1-5, every 3 weeks.
Arm 5: Oxaliplatin on day 1 and 5-FU with leucovorin given for 48 hours, every 2 weeks.
Arm 6: Oxaliplatin and CPT-11 on day 1, every 3 weeks.
CPT-11
CPT-11, also known as Camptosar, belongs to a class of anti-cancer drugs that keep cells from multiplying by blocking an enzyme called topoisomerase I.
CPT-11 is approved in the U.S. and most other countries for the second-line therapy of metastatic colorectal cancer after failure of first-line 5-FU and leucovorin.
Studies have shown that it shrinks tumors and may prolong survival when used alone and with other drugs.
CPT-11's primary side effects include diarrhea and low white blood cell counts, as well as hair loss and weakness in some patients.
There have also been infrequent reports of breathing difficulties in patients receiving CPT-11.
CPT-11 is made by Pharmacia & Upjohn of Bridgewater, NJ, which is supplying the drug for this trial without charge.
Oxaliplatin
Oxaliplatin is a platinum compound that binds to certain components of actively dividing cells, such as cancer cells, and kills them.
In early trials, the drug has shrunk tumors in some patients with advanced colorectal cancer, both when used alone and in combination with other drugs.
Oxaliplatin is approved for treating advanced colorectal cancer in France (where it is called Eloxatine) and 14 other countries, where it is marketed by Sanofi-Synthelabo, of Paris.
The drug is considered an investigational drug in the U.S.
Oxaliplatin's side effects are like those of many chemotherapy agents; it causes some nausea and vomiting and diarrhea, and it can lower the number of white blood cells and platelets in a patient's blood.
In a small percent of patients, the drug can also interfere with muscular coordination and may cause numbness in fingers and toes; these side effects disappear or subside in most patients after treatment is stopped.
Oxaliplatin is under development by Sanofi-Synthelabo.
A joint venture with Eli Lilly and Co. for the further development and marketing of oxaliplatin in the U.S. was recently announced.
Sanofi-Synthelabo is supplying the oxaliplatin for the 6C Trial without charge.
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