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Clinical Trials in the Spotlight

Robert & Beverly Lewis Family Cancer Care Center and Wilshire Oncology Medical Group, Inc., Pomona, California, USA

Correspondence: Douglas W. Blayney, M.D., Robert & Beverly Lewis Family Cancer Care Center and Wilshire Oncology Medical Group, Inc., 1910 Royalty Drive, Pomona, California 91767, USA. Telephone: 909-865-9960; e-mail: Dblayney{at}concentric.net

	The Clinical Trial Process in the Spotlight

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Four events in May 1999 combined to remind us that clinical research is necessary, is expensive to conduct, and is cumbersome to do well:

• In a widely anticipated plenary session at the Spring meeting of the American Society of Clinical Oncology (ASCO), results of three randomized clinical trials of breast cancer therapy, in which one arm was high dose therapy with stem cell support, were presented [1]. The results were seen by many as a validation of the clinical research process and refined the role of an expensive and toxic therapy.
  
• At the same meeting, ASCO released three surveys addressing reimbursement for clinical trial activities [2]. Though limited by the methodology employed, the results suggested that clinical trials were well accepted by oncologists in their daily practice, that research-related expenses were under-compensated, and that clinical research was a voluntary activity—essentially a labor of love.
  
• The New York Times published back-to-back articles dealing with contract research organizations (CROs) and clinical trials. The series began on May 16 and was generally negative in its approach and its conclusions. As a result, the readers' confidence in their clinical researcher/physicians was undermined. Perhaps more damaging to the clinical research effort, readers could correctly confuse reimbursement for legitimate, research-related expenses with blatant fraud [3].
  
• In a publicity-generating move, a newly vigorous Office for the Protection of Research Risks of the National Institutes of Health halted clinical research activities at Duke University Medical Center.
  

	The Clinical Research Enterprise

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A legitimate part of any activity must be continual improvement of the process, the products and the outcomes. This is true of family life, of organizing and running a business, or of administering a large research organization. The process of generating a hypothesis, designing an experiment to test the hypothesis, conducting the experiment and evaluating the hypothesis in light of the observations is fundamental to science and to businesses and organizations. In treating the cancer patient, clinical research is the continual improvement process.

Furthermore, care of the cancer patient is driven by data. I know that many of my colleagues are drawn to our subspecialty for this reason. Opportunities to generate new data, to continuously improve our practices, and to help relieve the burden of human suffering motivate most of us. The clinical trial process is a fundamental part of our professional lives.

	Clinical Research has Costs

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Two components of cost exist in relation to clinical trial participation: A) the data collection and management costs and B) the incremental costs associated with patient care specified by the trial protocol, which might be over and above the cost for routine patient care

Most attention focuses on the incremental patient care costs. Many payers (including the U.S. Health Care Financing Agency, which is responsible for administering the Medicare Program) are concerned about excess patient care costs. Estimates are that clinical trial participation adds about ten percent to routine patient care costs. Three studies, all done on special population samples, in which most clinical care was provided in a geographically circumscribed area, or was provided within a closed panel of physicians, provide the best data to address the patient care cost issue:

• Olmsted County, Minnesota residents who entered phase II or phase III cancer treatment trials at the Mayo Clinic from 1988 through 1994 have been studied. Clinical trial participants were matched with patients who did not enter trials but who were similar on the basis of tumor registry matching and medical record review. Sixty-one matched pairs were followed for up to five years. Hospital, physician, and ancillary service costs were estimated from a population-based cost database developed at the Mayo Clinic. Trial enrollees incurred modestly (no more than 10%) higher costs over variousfollow-up periods. The mean cumulative five-year cost in 1995 inflation-adjusted U.S. dollars among trial enrollees was $46,424 compared with $44,133 for control patients. After one year, trial enrollee costs were $24,645 compared with $23,964 for control patients [4].
  
• In an as yet unpublished study presented to the National Cancer Advisory Board (NCAB), five breast cancer and five colorectal cancer trials conducted at the Group Health Cooperative of Puget Sound were studied. Sixty-nine cases treated between 1990 and 1996 were included. Extra costs associated with clinical trials were $4,899 for the breast cancer patients, and $1,489 for the colon cancer patients [5].
  
• In another unpublished study recently presented to the NCAB, beneficiaries who were covered by the Kaiser Permanente of Northern California health plans were analyzed. Cost data for patients treated on National Surgical Adjuvant Breast and Bowel Project breast cancer studies conducted at Kaiser clinics were obtained. Routine patient care for clinical trial enrollees was $17,003, compared to $14,515 for patients not enrolled on clinical trials [5].
  

Data collection costs, the second component of clinical trial costs, are usually underestimated and are poorly reimbursed. Estimates of data management costs of clinical trial patients are more difficult to acquire. Under ASCO's auspices, 17 research sites (seven academic centers, three HMO closed panel practices and 12 group practices) were asked to estimate costs associated with a mock phase III trial. Each site would enroll 20 patients for a 13-week treatment period with 12 months of follow-up. Preliminary results from the ASCO-funded survey found that approximately 200 hours of data management work were required to see a patient through this effort. The costs of enrolling and managing the data for one patient on a clinical trial were estimated at $2,000 [2].

Certainly, trials vary in the intensity of data management, nursing effort and physician involvement they require. I agree with Dr. Schnipper, who oversaw conduct of the study for ASCO, that 200 hours of labor for workers costing $20 per hour is an underestimate of the resources required. To take some examples, costs of the care and feeding of the Institutional Review Board is one under-appreciated cost, as the clinical scientists at Duke are no doubt discovering. The cost of data monitoring—the verification of the data entered into case report forms, which is required for pivotal phase III trials—is another cost not usually appreciated by investigators. Furthermore, retention and storage of trial-related records are also under-appreciated. These costs have a way of mounting up, and are often not initially considered by investigators when they cost out a trial, nor by sponsors when they consider reimbursement for a trial. These under-appreciated costs are reasons why clinical research is usually a labor of love.

	Clinical Research has Benefits

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Longer lived patients, improved patient care, better quality of life for those patients whom we treat, improved pain control, and more cost-effective treatments are all potential benefits of clinical research. Oncologists are fond of pointing to our success in obtaining long-term remission and probably cure of testicular cancer, childhood leukemia, lymphomas, acute promyelocytic leukemia, and some cases of early breast, colon, and lung cancer. Survivors of these tumors, who are alive today, have benefited from rudimentary in vitro observations, which were then verified through the clinical trial process.

Though they are widely viewed as negative, results of the clinical trials in advanced breast cancer therapy, which were discussed at the plenary session of the Spring ASCO meeting, also stand to benefit patients and their third party payers. It seems unlikely that women with widely metastatic breast cancer will be offered high-dose stem cell therapy, or their insurers will be asked to pay for this therapy, when it is given outside of a randomized clinical trial. This change in practice can be directly attributed to these well-conducted trials.

Clinical trials not only result in translation of laboratory findings into new therapies, they also should tune our applications of existing drugs and therapies. If nothing concentrates the mind like the prospect of a hanging, as the saying goes, few things focus the energy, attention and resources of trial sponsors more than the money on the line for developing new therapeutic agents. Industry-sponsored registration trials, aimed at bringing new drugs to market, are usually quite good at answering tightly focused questions. Once the drug is approved for sale, manufacturers have few incentives to support further clinical testing. News that a lower dose or a less frequent schedule is superior to the labeled dose and schedule, or that a combination of drugs, including some not manufactured by the sponsor, might be superior, is also hard to take, and not eagerly sought. Clinical trials that refine the use of drugs off-label (e.g., for indications other than those on a package insert) are usually poorly supported and are often difficult to conduct. Nonetheless, these kinds of trials are critical to effective patient care. Commercial support for many of these trials comes from the marketing budgets of approved compounds.

Those involved in managing the health-care of our patients should help us improve the process. Process improvement, re-engineering and total quality management are terms that have leaked from the manufacturing sector into the health care industry, including managed care organizations. Selling the clinical trial process in these terms may help convey our message. Instead of focusing on the costs involved, we should change the focus to the benefits. Patients, their loved ones, and their third party payers should be clamoring for clinical trial participation. We need to increase the demand for our product—the clinical trial.

	Fraud Does (and Has) Existed

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Fraudulent research conduct at the Southern California Research Institute was alleged in The New York Times series. There was alleged failure to uncover fraud by the involved contract research organizations, by the large pharmaceutical company sponsors, by the Federal oversight agencies, and by the researchers and their staffs [3].

• Diffusion of clinical research away from its traditional university basis presents special problems for data verification and fraud detection.
  
• Fabricated source documents are difficult to detect when the perpetrator is experienced, determined, and supported by a large cast of characters. Appropriate monitoring of the asthma studies and the arthritis studies conducted by the Southern California Research Institute was apparently done. However, source documents were allegedly altered by removing pages of the medical record which referred to the patients smoking history or to other elements which might disqualify patients from steady participation. Radiographs from other patients with arthritic knees were relabeled and submitted to the central radiologist for review in place of study participants' radiographs, or the study investigator generated reports reflecting nonexistent arthritis on study participants.
  
• Contract research organizations, which have incentives to complete trials by rapidly accruing patients and clinical investigators, can be too accommodating to the needs of investigators and ignore hints of fraudulent conduct. In the case of the Southern California Research Institute, hints pointing to potentially fraudulent conduct were widely ignored. The various CROs were intimidated into changing study monitors and other personnel when their questioning and inquiries became uncomfortable.
  

Data fabrication in the clinical trial process is not new, of course, and has occurred in carefully controlled, reputable academic settings as well as free-standing institutions [6-8]. Fabrication in so fragile an enterprise as clinical research undermines the physician-patient bond, and the foundations of evidence-based medicine.

	We Have Done A Poor Job—We Need To Do Better

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We have done a poor job of communicating the benefits of the clinical trial enterprise. Very seldom do I, or my academic colleagues, encounter patients who demand to be clinical trial participants. Payers do not demand that their beneficiaries' care improve the care process.

As oncologists, our commitment to process improvement, to examining our results, and to the clinical trial process needs to remain firm. In the care of our patients, our specialty should continue to be the model of a data-driven enterprise. Fraud, whether it occurs in clinical trials, in billing and reimbursement, or in reporting of other data is a stain on our system and on our reputation, and is intolerable.

Furthermore, we should not be ashamed to seek fair reimbursement for our efforts. Fair compensation for the direct and indirect costs of our training, education and experience, and for expenditure of the emotional energy required to care for a scared, vulnerable, and sick cancer patient is necessary and just. Non-pharmaceutical support (i.e., governmental or institutional) is vanishing. Our product—clinical research—is of demonstrable benefit to other sponsors, and we should offer it to them. Managed care organizations and integrated delivery systems stand to benefit from our research and development efforts. Our clinical trial efforts should be portrayed in terms where the benefit to the sponsors is obvious.

We must continue our advocacy efforts on our patients' behalf. Advocacy must occur in the examination room, when we approach patients about a trial, and when we advocate for their participation in a trial, so that future patients may benefit. Advocacy must occur on a regional and national level so that patients and society who stand to benefit most from clinical research are not forgotten. Advocacy on behalf of tomorrow's clinical investigators, whom we will recruit into the field and train, and who will care for us baby boomers as we age, needs to happen.

And finally, we must do a better job with the clinical trial process itself. The infrastructure required to conduct trials is mostly paper-based and is hopelessly outdated. Protocols are often complicated to follow and have limited field-testing before inauguration. Questions that are asked are often poorly conceived or based on limited preclinical data. The knowledgeable patient and family, Internet-based technologies, and the cadre of well-trained community oncologists are participants in the trial process, and their continued participation needs to be encouraged. Our nation's cancer centers should conduct well-managed, honest, and important trials, and help develop the community infrastructure for carrying them out. Cancer centers and commercial firms will need to work together to develop a sound, process-improvement-oriented infrastructure. All should be enlisted to make our trials more successful and clinically relevant.

	References

Top The Clinical Trial Process... The Clinical Research Enterprise Clinical Research has Costs Clinical Research has Benefits Fraud Does (and Has)... We Have Done A... References

 

1. American Society of Clinical Oncology (1999). Plenary Session. Virtual Meeting. http://www.asco.org
2. American Society of Clinical Oncology (1999). Presidential Symposium: Report of the Clinical Trials Subcommittee. Virtual Meeting. http://www.asco.org
3. Eichenwald K, Kolata G. Drug trials hide conflicts for doctors. The New York Times, May 16, 1999.
4. Wagner JL, Alberts SR, Sloan JA et al. Incremental costs of enrolling cancer patients in clinical trials: a population-based study [see comments]. J Natl Cancer Inst 1999;19:847-853.
5. Goldberg KL. Preliminary results of two studies. Cancer Lett 1999;25:4.
6. Engler RL, Covell JW, Friedman PJ et al. Misrepresentation and responsibility in medical research. N Engl J Med 1987;317:1383-1389.[Abstract]
7. Friedman PJ. Correcting the literature following fraudulent publication. JAMA 1990;263:1416-1419.[Abstract/Free Full Text]
8. Angell M, Kassirer JP. Setting the record straight in the breast-cancer trials. N Engl J Med 1994;330:1448-1450.[Free Full Text]

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