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Clinical trials and research in the community
Clinical Trials and Research in the Community Jane Murray Fall-Oickson
HE COMMUNITY has become a scientific laboratory for testing clinical hypotheses through clinical trial methodology. The community is a dynamic environment for the conduct of clinical research. There are numerous opportunities for participation in clinical research trials and the benefits for patients and their community health care providers are great.
T
HISTORY OF CLINICAL TRIALS
One of the most important patient care advances during the last 50 years was the introduction of the prospectively randomized clinical trial to clinical medicine. 1 Clinical trials, as defined by Jenkins and Curt2 are " . . . carefully controlled experiments aimed at utilizing the smallest number of subjects to determine with statistical confidence the effectiveness of treatments and at the same time maintain patient safety." The clinical trial has been instrumental in increasing our knowledge of the natural history of cancer and the therapeutic tactics needed to increase disease-free survival and survival. The clinical trial process may be used to study not only applications of new biological or pharmacological research discoveries but also advances in nursing, sociology, psychology, psychiatry, bioethics, or cancer detection and prevention. Informed consent and randomization provide an ethical and scientific basis for the clinical trial process. As Simon3 states, "Randomization ensures that the totality of unknown and controlled sources of variability will have a known symmetric distribution between the treatment groups." From The Cancer Institute and General Surgery~Shock TraumalPerioperative Clinical Nursing Division, Washington Hospital Center, Washington, DC. Jane Murray Fall-Dickson, RN, MSN, OCN: Clinical Nurse Specialist, The Cancer Institute and General Surgery/Shock Trauma/Perioperative Clinical Nursing Division, Washington Hospital Center. Address reprint requests to Jane Murray Fall-Dickson, RN, MSN, OCN, Clinical Nurse Specialist, The Cancer Institute and General Surgery/Shock TraumalPerioperative Clinical Nursing Division, Washington Hospital Center, 1t0 Irving St NW, Washington, DC 20010. Copyright 9 1993 by W.B. Saunders Company 0749-2081/93/0901-000755.00/0
38
The use of controlled clinical trials was unknown in clinical medicine until after World War II. The 1946 British Medical Research Council trial evaluating the use of streptomycin in the treatment of tuberculosis is acknowledged to be the first controlled clinical trial because the scientific method was used to show the worth of a new agent.1 Currently, the development of a new treatment strategy using chemotherapy occurs through preclinical and phase I-IlI clinical studies. The preclinical phase occurs in the laboratory and determines whether a drug should be evaluated in humans. The phase I study tests new agents for the first time in humans and establishes pharmacokinetics and the maximum tolerated dose of the agent. These studies are carefully controlled by the drug sponsor and are currently performed at individual cancer centers and recently via the clinical cooperative oncology groups at a restricted number of institutions with demonstrated expertise in phase I trials. 4 Phase II studies focus on determining the effectiveness of the drug against a given tumor. Phase Ill studies compare the effectiveness of an experimental drug or treatment with the current standard treatment. Phase III studies require large numbers of patients and are commonly conducted in the community setting. CLINICAL TRIALS IN THE COMMUNITY
All major phase I, II, and HI cancer clinical trials are sponsored by the National Cancer Institute (NCI), and the Cancer Therapy Evaluation Program (CTEP) is the main coordinator for most extramural trials. These extramural trials are conducted by the NCI through comprehensive cancer centers, by clinical cooperative ontology groups, or through Community Clinical Oncology Programs (CCOP). Traditionally, clinical trials were conducted only in large cancer treatment centers. Before 1970 most of the progress in clinical cancer research and the therapeutic approaches derived from this research were orchestrated by these centers. The 1960s and 1970s brought a shift in medical oncologists' practice location as an increasing number of medical oncologists left academic institutions to pursue community practice. 5 This shift created a Seminars in Oncology Nursing, Vol 9, No 1 (February), 1993: pp 38-43
39
CLINICAL TRIALS AND RESEARCH
cadre of medical oncglogists who enjoyed autonomous private practice and were capable of performing rigorous clinical research in the community setting. The National Surgical Adjuvant Breast and Bowel Project (NSABP), with NCI support, began a collaboration between university and community physicians. 6 The NSABP, founded in 1958, originally limited membership to university-based physicians because, as Fisher states, " . . . it was believed that they alone possessed the capabilities necessary to carry out clinical trials."7 These perceptions were found to be incorrect, and community physicians were invited to join the NSABP in the early 1970s. This successful collaboration became the model for the Cooperative Group Outreach Program (CGOP) sponsored by the NCI Division of Cancer Control. The CGOP supported the participation of all interested community physicians in clinical trials by affiliating with cooperative groups. In 1983, the NCI initiated the CCOP to provide support for physicians to enter community patients into clinical research protocols. 8 The first 3 years of this program provided funding for 62 community programs in 34 states with approximately 14,000 patients entered into NCI-approved treatment clinical trials. 8 The data from these CCOP participants met or exceeded the quality control standards set by the cooperative groups. 8 The second CCOP request for applications, issued in 1986, expanded the focus to include cancer prevention and control research. In 1991 there were 52 programs in 27 states involving more than 300 hospitals and more than 2,600 physicians treating approximately 5,000 patients per year in treatment trials and 4,000 participants per year in cancer prevention and control trials. The latest request for applications for the CCOP was issued May 25, 1992. The NCI also sponsors a minority-based CCOP (MBCCOP) that is appropriate for domestic institutions with more than 50% of new cancer patients from minority populations. The MBCCOP was created in response to the fact that in general there is limited participation in clinical trials research by Afro-American, Hispanic, Asian-American, Native American, and other minority cancer patients. There are currently 12 MBCCOPs. Specific information regarding the CCOP and MBCCOP application process may be obtained from the Office of the Chief, Community Oncology and Rehabilita-
tion Branch (CORB), Division of Cancer Prevention and Control (DCPC), NCI, Executive Plaza North, Rm 300-D, Bethesda, MD 20892, (301) 496-8541.s There are currently 12 clinical cooperative oncology groups in the United States that test multimodal regimens. Some groups limit their studies to a single oncological disease or specialty area (Appendix). 9 The Lung Cancer Study Group, originally a clinical cooperative oncology group, is now coordinated under the auspices of the Southwestern Oncology Group. Each of the cooperative clinical trials groups maintains its own data bank and has biostatistical analysis capability. The coordinators of each group are available to assist all community health care facility staff who are new to the concept of the randomized clinical trial and need to acquire new knowledge concerning protocol design, patient eligibility criteria, investigational drug procurement, randomization process, data management, and patient follow-up. Many of the groups offer data management training, often at their annual or semiannual business meetings. ACCRUAL TO CLINICAL TRIALS
The percentage of patients who take part in clinical research trials is low nationally. For example, only 3% to 4% of the more than 150,000 newly diagnosed breast cancer patients and less than 2% of the 160,000 patients with colorectal cancer participated in clinical trials during 1991.7 Even with the intense commitment of the NCI to encourage community physicians to use clinical trials as a treatment option, many of these physicians do not offer these treatment options to their patients. Wittes and Friedman 1~identified the following obstacles to clinical trial use: time requirements of obtaining informed consent and detailed patient explanations concerning study design; data management; randomizing process; potential extra cost to participating patients and philosophical aversion to the clinical trials process. Taylor et all1 evaluated the reasons physicians chose not to enter patients in a large, multicenter trial sponsored by a cooperative group. They discovered similar obstacles. In addition, Taylor et aln reported that 73% of the physicians were concerned that the clinical trial would affect the doctor/patient relationship. Johansen et a112 categorized and identified the ob-
40
stacles to clinical trial implementation as patientrelated, physician-related, and nurse-related. The problem of low patient accrual to clinical trials is complex and requires complex solutions. One such potential solution was the 1988 creation of the high-priority clinical trial process created by the staff of CTEP, the cooperative group chairpersons, and the Board of Scientific Counselors of the Division of Cancer Treatment. This process created the high-priority designation that is given to diseases that are common or exploitable or to trials that ask important questions, and it requires that the protocol should have a reasonable likelihood of leading to improvement in survival when compared with standard therapy, lo Educational efforts by the NCI have also been targeted, such as the encouragement of physicians to use the Physician Data Query (PDQ), an informational source that lists available clinical trials. 13 Numerous educational materials regarding clinical research trials are available from the NCI, including a patient teaching booklet, What are Clinical Trials All About? A Booklet for Patients with Cancer (NCI, 1989); and video tapes, Patient to Patient: Cancer Clinical Trials and You; and Physician to Physician: Perspectives on Clinical Trials (NCI and the American College of Surgeons Commission on Cancer). The materials may be ordered by calling 1-800-4-CANCER. Cassileth et a114 assessed the attitudes toward clinical research of 104 patients with cancer, 84 cardiology patients, and 107 members of the general public. Responses differed neither by subgroup nor in relation to demographic variables and, therefore, data was reported on the total population of 295 subjects. The study showed that diverse respondents view clinical trials as important, ethical, and a means of attaining superior clinical care. The vast community effort to increase patient accrual into clinical trials is a necessary response to study results such as these. Reimbursement issues are also of concern to patients who participate in clinical trials. Studies using investigational drugs or the use of off-label drugs for research purposes seem to be more commonly denied than those that explore questions regarding the use of new surgical or radiation approaches, t5 Several groups, including the American Society of Clinical Oncology, the NCI, and the Association of Community Cancer Centers
JANE MURRAY FALL-DICKSON
(ACCC), are working diligently to assess this problem nationally and construct possible solutions. Current reimbursement assistance programs for oncologists, staff, and patients are listed each year by the ACCC in their journal, Oncology 1ssues. 16 It is also important for the oncologists, pharmaceutical industry, and insurers to work together to address these reimbursement problems and to preserve the clinical trial mechanisms that have provided us with important advances in clinical medicine, t7 Many pharmaceutical and biological companies are actively involved through investigational drug contribution to the clinical trial cooperative groups research protocols. The pharmaceutical industry works closely with cooperative groups and the NCI to support clinical trials. The clinical oncology cooperative groups and pharmaceutical companies are sensitive to the financial realities of organizing clinical programs to support the administrative process of clinical trials. Each cooperative group and pharmaceutical company has written guidelines delineating the financial reimbursement structure for protocol requirements, such as patient eligibility, pathology slides/ blocks, and radiology films. Data management is usually the most significant financial commitment. Administrative start-up funds may also be available via contract negotiations with the specific research group. The main funding source for the clinical trials program is usually through the health care facility. The clinical oncology cooperative group or pharmaceutical group reimbursement funds may be used to fund educational conferences for the researchers or other small researchassociated projects. INFRASTRUCTURE OF COMMUNITY-BASED CLINICAL TRIAL PARTICIPATION
The present competitive health care climate requires that all health care administrators with responsibility for oncology product lines evaluate carefully the appropriateness of activating a clinical trial program as a patient care option. Each community-based oncology service is a microcosm of the national clinical trials effort experiencing similar obstacles to patient accrual, reimbursement problems, and patient satisfaction. The advent of prospective reimbursement and the shift of patient
CLINICAL TRIALS AND RESEARCH
care from the hospital to the ambulatory setting have caused dramatic changes in the delivery of cancer care. 6 Both new health care trends and the community environment in which the clinical trials are to be performed must be considered before a plan of action is operationalized. The clinical trials program is created to fit the needs of the service area patient population and remain within the fiscal constraints of the health care facility. The program may be as small as one protocol coordinator who adds the clinical research responsibilities to an already existing position and uses already existing support resources or as ambitious as the creation of a clinical trials center requiring new management and staff positions and increased space requirements. A key variable in this decision is the commitment of the institution and key medical personnel to the clinical research process. The process begins with a feasibility study assessing the community environment, the cancer patient population and interest among physicians in the clinical trial process, and the role of principal investigator. This information is used to select which clinical cooperative research groups are most appropriate to explore. It is vital to have physician support before the process begins. Protocol activation and start-up paper work is laborintensive, and human resource allocation is wasted when large numbers of seldom used protocols are activated. Single institution research protocols are usually reflective of the research interests of the medical director. The key position to facilitate the clinical research trial process is the protocol coordinator. Table 1 presents the many facets of this role. The protocol coordinator role is often fulfilled by an oncology nurse with experience in protocol design and conduct or a clinically experienced onTable 1. Clinical Research Trial Coordinator Responsibilities Protocol review and consent form development IRB approval and protocol activation Conduct of clinical trial Patient and staff education Screening for protocol eligibility Informed consent Patient follow-up Data collection and analysis Liaison between multidisciplinary team members Study termination
41
cology nurse interested in a research role. The oncology nurse brings a wealth of clinical experience and judgement to this role and is both costeffective and clinical research enhancing. Position titles and job descriptions for this role vary nationally. An informal study using seven major cancer centers and one clinical cooperative oncology group showed the following titles for the protocol coordinator: oncology nurse specialist; research nurse coordinator; research nurse; director of clinical research; head of protocol branch; growth factor research nurse; director of adjuvant therapy center; director of clinical coordinating; and clinical nurse specialist. The various titles show role expectations, reflect academic background, and demonstrate institutional management needs. Clinical trial development and consent form design are necessary actions in single-institution research studies and the protocol coordinator is often called on to create a consent form that clearly presents the research study following legal and ethical guidelines. All clinical trials must be approved by the Institutional Review Board (IRB) and activated following criteria outlined by the principal investigator in single-institution protocols or the cooperative clinical trial group chairperson and administrative staff. All appropriate health care providers must be made aware of the clinical trial procedures. This group of health care providers includes, but is not limited to, the medical and nursing staff, the pharmacy staff, and the social work staff. The nursing staff who will administer the investigational drugs must be aware of specific aims, treatment design, potential treatment toxicity, and reportable side effects of each trial. Investigational drug accountability is a very necessary and time consuming process, and the pharmacy department must have a coordinator to assure that all investigational drugs are dispensed appropriately and recorded correctly using investigational drug logs. The protocol coordinator is also responsible, either alone or in a shared responsibility with nurse or nonnurse data managers, for all timely data collection and reporting. Each cooperative clinical oncology group has specific data requirements and strict adherence to these requirements is necessary to assure that meaningful data is generated concerning therapeutic efficacy. Networking with satellite physician offices is often necessary to obtain
42
JANE MURRAY FALL-E)ICKSON
patient data, and the role of liaison between the clinical trial cooperative group hospital or cancer center base and private physician's office is vital to the research process. The Cancer Institute of the Washington Hospital Center, Washington, DC, has implemented an additional patient screening role for the protocol research nurse. This nurse screens all research protocol site-specific pathology reports to identify a cadre of potentially eligible protocol patients. A chart review is completed for all appropriate patients and a written letter or telephone contact is made with the private attending physician, who is informed of the protocol availability for an eligible patient. This process has proven effective and efficient in screening for all research eligible patients. Oncology nurses serving as clinical research coordinators in the community have great opportunities to improve clinical collaboration between oncologists and nurses. The contributions of nursing to clinical research is shown by the fact that many clinical cooperative groups have extended membership to nurses and financially support the development of the research nurse role, nurseinitiated research, and collaboration in medical research, t 8 CONCLUSION
The community health care setting provides necessary and fertile ground for the organization and implementation of oncology clinical trials. The vital national linkages with cooperative clinical research groups are operational, and appropriate models for community-based clinical trials operational infrastructures are available in the literature. The nurse and physician, principal investigator or co-investigator, are synergistic in this research process to provide oncology patients state-of-theart treatment in their own communities. The goal of the NCI to assure clinical trial access to all oncology patients is achieved through the availability of the latest cancer treatments to oncology patients regardless of geographic setting. The psychosocial ramifications for the patients receiving treatment while within easy access of their psychosocial support systems may be a variable that will influence patients to enter clinical trials and maintain accessibility for follow-up evaluations. The crisis often inherent in the diagnosis of cancer may
be attenuated by the knowledge that state-of-theart care is possible within a health care system familiar to the patient and significant others. Present opportunities for the oncology nurse involved in community-based clinical research are numerous and include the following: coordination of clinical research studies; mentoring oncology nurses interested in the research process; creation of protocol companion studies that may generate new knowledge vital to patient care; co-investigator status with the principal investigator; creation of patient educational materials specific to the geographic area, and refinement of clinical research skills. The oncology nurse involved in clinical research in the community is able to make a significant contribution to the health care climate both locally and nationally. APPENDIX National Cancer Institute Clinical Oncology Cooperative Groups: Brain Tumor Cooperative Group (BTCG) Barrow Neurological Institute St. Joseph Hospital & Medical Center 350 W Thomas Rd Phoenix, AZ 85013 Cancer and Leukemia Group B (CALGB) CALGB Headquarters 444 Mount Support Rd, Suite 2 Lebanon, NH 03766 (603) 646-5505 Children's Cancer Study Group (CCSG) 440 E Huntington Dr Suite 300 Arcadia, CA 91066-6012
(818) 447-0064 Eastern Cooperative Oncology Group (ECOG) ECOG Operations Office AMC Cancer Research Center 1600 Pierce Street Denver, CO 80214 (303) 239-3070 Gynecologic Oncology Group (GOG) GOG Headquarters 1234 Market St, 19th Floor Philadelphia, PA 19107 (215) 854-0770 Intergroup Rhabdomyosarcoma Study Department of Pediatrics Virginia Commonwealth University Medical College of Virginia, MCV Box 646 Richmond, VA 23298 (804) 786-9602
CLINICAL TRIALS AND RESEARCH
43
National Surgical Adjuvant Breast & Bowel Project (NSABP) University of Pittsburgh 914 Scalfe Hall, 3550 Terrace St Pittsburgh, PA 15261 (412) 648-9720 National Wilms' Tumor Study Group Roswell Park Cancer Institute Pediatric Division 666 Elm St Buffalo, NY 14263 (716) 845-2334
Pediatric Oncology Group (POG) Del Coronado Suite 2A 4949 W Pine Blvd St. Louis, MO 63108 (314) 367-3446 Radiation Therapy Oncology Group (RTOG) RTOG Headquarters American College of Radiology 1101 Market St, 14th Floor Philadelphia, PA 19107 (215) 574-3205
North Central Cancer Treatment Group (NCCTG) Mayo Clinic, Room 75-Damon 200 First St, SW Rochester, MN 55905 (507) 284-4642
Southwest Oncology Group (SWOG) 14980 Omicron Dr San Antonio, TX 78245-3218 (210) 677-8808 REFERENCES
1. Fisher B: The importance of clinical trials. News from the Commission on Cancer. Am Coil Surg 2:204, 1991 2. Jenkins J, Curt G: Implementation of clinical trials, in Baird SB, McCorkle R, Grant M (eds): Cancer Nursing: A Comprehensive Textbook. Philadelphia, PA, Sannders, 1991, pp 355-369 3. Simon R: Randomized clinical trials and research strategy. Cancer Treat Rep 66:83-87, 1982 4. Cbeson BD: Clinical trials programs. Semin Oncol Nurs 7:235-242, 1991 5. Fleming ID: Clinical trials for cancer patients: The community practicing physicians perspective. Cancer 65:23382390, 1990 6. Yates JW, Lyons C: The organization of cancer service settings, in Baird SB, McCorkle R, Grant M (eds): Cancer Nursing: A Comprehensive Textbook. Philadelphia, PA, Saunders, 1991, pp 993-999 7. Fisher B: On clinical trial participation. J Clin Oncol 9: 1927-1930, 1991 8. National Cancer Institute: Request for Applications for Cooperative Agreements: Community Clinical Oncology Program (RFA Number CA-92-15), 1-31, May 25, 1992 9. Frank-Stromborg M, Savela B: Yellow pages for the cancer nurse in Groenwald SL, Frogge MH, Goodman M, Yarbro CH (eds): Cancer Nursing Principles and Practice. Boston, MA, Jones and Bartlett, 1990, pp 1281-1308
10. Wittes RE, Friedman MA: Accrual to clinical trials. J Natl Cancer Inst 80:884-885, 1988 11. Taylor KM, Margolese RG, Soskolne CL: Physicians' reasons for not entering eligible patients in a randomized clinical trial of surgery for breast cancer. N Engl 1 Med 310:13631368, 1984 12. Jobansen MA, Mayer DK, Hoover HC: Obstacles to implernenting cancer clinical trials. Semin Oncol Nurs 7:260267, 1991 13. Benson AB, Pregler JP, Bean JA, et al: Oncologists' reluctance to accrue patients onto clinical trials: An Illinois Cancer Center study. J Clin Oncol 9:2067-2075, 1991 14. Cassileth BR, Lusk El, Miller DS, et al: Attitudes toward clinical trials among patients and the public. J Am Med Assoc 248:968-970, 1982 15. Henney JE, Greene T, Aronson N, et al: Reimbursement concerns. Cancer 65:2409-2410, 1990 16. Oncology Issues: Reimbursement assistance for oncologists, staff and patients. Oncol Issues 6:20-22, 1991 17. Purvis JD: Cancer clinical trials: A case for collaboration. Cancer 65:2391-2393, 1990 18. Hubbard SM: Cancer treatment research: The role of the nurse in clinical trials of cancer therapy. Nuts Clin North Am 17:763-783, 1982
HE COMMUNITY has become a scientific laboratory for testing clinical hypotheses through clinical trial methodology. The community is a dynamic environment for the conduct of clinical research. There are numerous opportunities for participation in clinical research trials and the benefits for patients and their community health care providers are great.
T
HISTORY OF CLINICAL TRIALS
One of the most important patient care advances during the last 50 years was the introduction of the prospectively randomized clinical trial to clinical medicine. 1 Clinical trials, as defined by Jenkins and Curt2 are " . . . carefully controlled experiments aimed at utilizing the smallest number of subjects to determine with statistical confidence the effectiveness of treatments and at the same time maintain patient safety." The clinical trial has been instrumental in increasing our knowledge of the natural history of cancer and the therapeutic tactics needed to increase disease-free survival and survival. The clinical trial process may be used to study not only applications of new biological or pharmacological research discoveries but also advances in nursing, sociology, psychology, psychiatry, bioethics, or cancer detection and prevention. Informed consent and randomization provide an ethical and scientific basis for the clinical trial process. As Simon3 states, "Randomization ensures that the totality of unknown and controlled sources of variability will have a known symmetric distribution between the treatment groups." From The Cancer Institute and General Surgery~Shock TraumalPerioperative Clinical Nursing Division, Washington Hospital Center, Washington, DC. Jane Murray Fall-Dickson, RN, MSN, OCN: Clinical Nurse Specialist, The Cancer Institute and General Surgery/Shock Trauma/Perioperative Clinical Nursing Division, Washington Hospital Center. Address reprint requests to Jane Murray Fall-Dickson, RN, MSN, OCN, Clinical Nurse Specialist, The Cancer Institute and General Surgery/Shock TraumalPerioperative Clinical Nursing Division, Washington Hospital Center, 1t0 Irving St NW, Washington, DC 20010. Copyright 9 1993 by W.B. Saunders Company 0749-2081/93/0901-000755.00/0
38
The use of controlled clinical trials was unknown in clinical medicine until after World War II. The 1946 British Medical Research Council trial evaluating the use of streptomycin in the treatment of tuberculosis is acknowledged to be the first controlled clinical trial because the scientific method was used to show the worth of a new agent.1 Currently, the development of a new treatment strategy using chemotherapy occurs through preclinical and phase I-IlI clinical studies. The preclinical phase occurs in the laboratory and determines whether a drug should be evaluated in humans. The phase I study tests new agents for the first time in humans and establishes pharmacokinetics and the maximum tolerated dose of the agent. These studies are carefully controlled by the drug sponsor and are currently performed at individual cancer centers and recently via the clinical cooperative oncology groups at a restricted number of institutions with demonstrated expertise in phase I trials. 4 Phase II studies focus on determining the effectiveness of the drug against a given tumor. Phase Ill studies compare the effectiveness of an experimental drug or treatment with the current standard treatment. Phase III studies require large numbers of patients and are commonly conducted in the community setting. CLINICAL TRIALS IN THE COMMUNITY
All major phase I, II, and HI cancer clinical trials are sponsored by the National Cancer Institute (NCI), and the Cancer Therapy Evaluation Program (CTEP) is the main coordinator for most extramural trials. These extramural trials are conducted by the NCI through comprehensive cancer centers, by clinical cooperative ontology groups, or through Community Clinical Oncology Programs (CCOP). Traditionally, clinical trials were conducted only in large cancer treatment centers. Before 1970 most of the progress in clinical cancer research and the therapeutic approaches derived from this research were orchestrated by these centers. The 1960s and 1970s brought a shift in medical oncologists' practice location as an increasing number of medical oncologists left academic institutions to pursue community practice. 5 This shift created a Seminars in Oncology Nursing, Vol 9, No 1 (February), 1993: pp 38-43
39
CLINICAL TRIALS AND RESEARCH
cadre of medical oncglogists who enjoyed autonomous private practice and were capable of performing rigorous clinical research in the community setting. The National Surgical Adjuvant Breast and Bowel Project (NSABP), with NCI support, began a collaboration between university and community physicians. 6 The NSABP, founded in 1958, originally limited membership to university-based physicians because, as Fisher states, " . . . it was believed that they alone possessed the capabilities necessary to carry out clinical trials."7 These perceptions were found to be incorrect, and community physicians were invited to join the NSABP in the early 1970s. This successful collaboration became the model for the Cooperative Group Outreach Program (CGOP) sponsored by the NCI Division of Cancer Control. The CGOP supported the participation of all interested community physicians in clinical trials by affiliating with cooperative groups. In 1983, the NCI initiated the CCOP to provide support for physicians to enter community patients into clinical research protocols. 8 The first 3 years of this program provided funding for 62 community programs in 34 states with approximately 14,000 patients entered into NCI-approved treatment clinical trials. 8 The data from these CCOP participants met or exceeded the quality control standards set by the cooperative groups. 8 The second CCOP request for applications, issued in 1986, expanded the focus to include cancer prevention and control research. In 1991 there were 52 programs in 27 states involving more than 300 hospitals and more than 2,600 physicians treating approximately 5,000 patients per year in treatment trials and 4,000 participants per year in cancer prevention and control trials. The latest request for applications for the CCOP was issued May 25, 1992. The NCI also sponsors a minority-based CCOP (MBCCOP) that is appropriate for domestic institutions with more than 50% of new cancer patients from minority populations. The MBCCOP was created in response to the fact that in general there is limited participation in clinical trials research by Afro-American, Hispanic, Asian-American, Native American, and other minority cancer patients. There are currently 12 MBCCOPs. Specific information regarding the CCOP and MBCCOP application process may be obtained from the Office of the Chief, Community Oncology and Rehabilita-
tion Branch (CORB), Division of Cancer Prevention and Control (DCPC), NCI, Executive Plaza North, Rm 300-D, Bethesda, MD 20892, (301) 496-8541.s There are currently 12 clinical cooperative oncology groups in the United States that test multimodal regimens. Some groups limit their studies to a single oncological disease or specialty area (Appendix). 9 The Lung Cancer Study Group, originally a clinical cooperative oncology group, is now coordinated under the auspices of the Southwestern Oncology Group. Each of the cooperative clinical trials groups maintains its own data bank and has biostatistical analysis capability. The coordinators of each group are available to assist all community health care facility staff who are new to the concept of the randomized clinical trial and need to acquire new knowledge concerning protocol design, patient eligibility criteria, investigational drug procurement, randomization process, data management, and patient follow-up. Many of the groups offer data management training, often at their annual or semiannual business meetings. ACCRUAL TO CLINICAL TRIALS
The percentage of patients who take part in clinical research trials is low nationally. For example, only 3% to 4% of the more than 150,000 newly diagnosed breast cancer patients and less than 2% of the 160,000 patients with colorectal cancer participated in clinical trials during 1991.7 Even with the intense commitment of the NCI to encourage community physicians to use clinical trials as a treatment option, many of these physicians do not offer these treatment options to their patients. Wittes and Friedman 1~identified the following obstacles to clinical trial use: time requirements of obtaining informed consent and detailed patient explanations concerning study design; data management; randomizing process; potential extra cost to participating patients and philosophical aversion to the clinical trials process. Taylor et all1 evaluated the reasons physicians chose not to enter patients in a large, multicenter trial sponsored by a cooperative group. They discovered similar obstacles. In addition, Taylor et aln reported that 73% of the physicians were concerned that the clinical trial would affect the doctor/patient relationship. Johansen et a112 categorized and identified the ob-
40
stacles to clinical trial implementation as patientrelated, physician-related, and nurse-related. The problem of low patient accrual to clinical trials is complex and requires complex solutions. One such potential solution was the 1988 creation of the high-priority clinical trial process created by the staff of CTEP, the cooperative group chairpersons, and the Board of Scientific Counselors of the Division of Cancer Treatment. This process created the high-priority designation that is given to diseases that are common or exploitable or to trials that ask important questions, and it requires that the protocol should have a reasonable likelihood of leading to improvement in survival when compared with standard therapy, lo Educational efforts by the NCI have also been targeted, such as the encouragement of physicians to use the Physician Data Query (PDQ), an informational source that lists available clinical trials. 13 Numerous educational materials regarding clinical research trials are available from the NCI, including a patient teaching booklet, What are Clinical Trials All About? A Booklet for Patients with Cancer (NCI, 1989); and video tapes, Patient to Patient: Cancer Clinical Trials and You; and Physician to Physician: Perspectives on Clinical Trials (NCI and the American College of Surgeons Commission on Cancer). The materials may be ordered by calling 1-800-4-CANCER. Cassileth et a114 assessed the attitudes toward clinical research of 104 patients with cancer, 84 cardiology patients, and 107 members of the general public. Responses differed neither by subgroup nor in relation to demographic variables and, therefore, data was reported on the total population of 295 subjects. The study showed that diverse respondents view clinical trials as important, ethical, and a means of attaining superior clinical care. The vast community effort to increase patient accrual into clinical trials is a necessary response to study results such as these. Reimbursement issues are also of concern to patients who participate in clinical trials. Studies using investigational drugs or the use of off-label drugs for research purposes seem to be more commonly denied than those that explore questions regarding the use of new surgical or radiation approaches, t5 Several groups, including the American Society of Clinical Oncology, the NCI, and the Association of Community Cancer Centers
JANE MURRAY FALL-DICKSON
(ACCC), are working diligently to assess this problem nationally and construct possible solutions. Current reimbursement assistance programs for oncologists, staff, and patients are listed each year by the ACCC in their journal, Oncology 1ssues. 16 It is also important for the oncologists, pharmaceutical industry, and insurers to work together to address these reimbursement problems and to preserve the clinical trial mechanisms that have provided us with important advances in clinical medicine, t7 Many pharmaceutical and biological companies are actively involved through investigational drug contribution to the clinical trial cooperative groups research protocols. The pharmaceutical industry works closely with cooperative groups and the NCI to support clinical trials. The clinical oncology cooperative groups and pharmaceutical companies are sensitive to the financial realities of organizing clinical programs to support the administrative process of clinical trials. Each cooperative group and pharmaceutical company has written guidelines delineating the financial reimbursement structure for protocol requirements, such as patient eligibility, pathology slides/ blocks, and radiology films. Data management is usually the most significant financial commitment. Administrative start-up funds may also be available via contract negotiations with the specific research group. The main funding source for the clinical trials program is usually through the health care facility. The clinical oncology cooperative group or pharmaceutical group reimbursement funds may be used to fund educational conferences for the researchers or other small researchassociated projects. INFRASTRUCTURE OF COMMUNITY-BASED CLINICAL TRIAL PARTICIPATION
The present competitive health care climate requires that all health care administrators with responsibility for oncology product lines evaluate carefully the appropriateness of activating a clinical trial program as a patient care option. Each community-based oncology service is a microcosm of the national clinical trials effort experiencing similar obstacles to patient accrual, reimbursement problems, and patient satisfaction. The advent of prospective reimbursement and the shift of patient
CLINICAL TRIALS AND RESEARCH
care from the hospital to the ambulatory setting have caused dramatic changes in the delivery of cancer care. 6 Both new health care trends and the community environment in which the clinical trials are to be performed must be considered before a plan of action is operationalized. The clinical trials program is created to fit the needs of the service area patient population and remain within the fiscal constraints of the health care facility. The program may be as small as one protocol coordinator who adds the clinical research responsibilities to an already existing position and uses already existing support resources or as ambitious as the creation of a clinical trials center requiring new management and staff positions and increased space requirements. A key variable in this decision is the commitment of the institution and key medical personnel to the clinical research process. The process begins with a feasibility study assessing the community environment, the cancer patient population and interest among physicians in the clinical trial process, and the role of principal investigator. This information is used to select which clinical cooperative research groups are most appropriate to explore. It is vital to have physician support before the process begins. Protocol activation and start-up paper work is laborintensive, and human resource allocation is wasted when large numbers of seldom used protocols are activated. Single institution research protocols are usually reflective of the research interests of the medical director. The key position to facilitate the clinical research trial process is the protocol coordinator. Table 1 presents the many facets of this role. The protocol coordinator role is often fulfilled by an oncology nurse with experience in protocol design and conduct or a clinically experienced onTable 1. Clinical Research Trial Coordinator Responsibilities Protocol review and consent form development IRB approval and protocol activation Conduct of clinical trial Patient and staff education Screening for protocol eligibility Informed consent Patient follow-up Data collection and analysis Liaison between multidisciplinary team members Study termination
41
cology nurse interested in a research role. The oncology nurse brings a wealth of clinical experience and judgement to this role and is both costeffective and clinical research enhancing. Position titles and job descriptions for this role vary nationally. An informal study using seven major cancer centers and one clinical cooperative oncology group showed the following titles for the protocol coordinator: oncology nurse specialist; research nurse coordinator; research nurse; director of clinical research; head of protocol branch; growth factor research nurse; director of adjuvant therapy center; director of clinical coordinating; and clinical nurse specialist. The various titles show role expectations, reflect academic background, and demonstrate institutional management needs. Clinical trial development and consent form design are necessary actions in single-institution research studies and the protocol coordinator is often called on to create a consent form that clearly presents the research study following legal and ethical guidelines. All clinical trials must be approved by the Institutional Review Board (IRB) and activated following criteria outlined by the principal investigator in single-institution protocols or the cooperative clinical trial group chairperson and administrative staff. All appropriate health care providers must be made aware of the clinical trial procedures. This group of health care providers includes, but is not limited to, the medical and nursing staff, the pharmacy staff, and the social work staff. The nursing staff who will administer the investigational drugs must be aware of specific aims, treatment design, potential treatment toxicity, and reportable side effects of each trial. Investigational drug accountability is a very necessary and time consuming process, and the pharmacy department must have a coordinator to assure that all investigational drugs are dispensed appropriately and recorded correctly using investigational drug logs. The protocol coordinator is also responsible, either alone or in a shared responsibility with nurse or nonnurse data managers, for all timely data collection and reporting. Each cooperative clinical oncology group has specific data requirements and strict adherence to these requirements is necessary to assure that meaningful data is generated concerning therapeutic efficacy. Networking with satellite physician offices is often necessary to obtain
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JANE MURRAY FALL-E)ICKSON
patient data, and the role of liaison between the clinical trial cooperative group hospital or cancer center base and private physician's office is vital to the research process. The Cancer Institute of the Washington Hospital Center, Washington, DC, has implemented an additional patient screening role for the protocol research nurse. This nurse screens all research protocol site-specific pathology reports to identify a cadre of potentially eligible protocol patients. A chart review is completed for all appropriate patients and a written letter or telephone contact is made with the private attending physician, who is informed of the protocol availability for an eligible patient. This process has proven effective and efficient in screening for all research eligible patients. Oncology nurses serving as clinical research coordinators in the community have great opportunities to improve clinical collaboration between oncologists and nurses. The contributions of nursing to clinical research is shown by the fact that many clinical cooperative groups have extended membership to nurses and financially support the development of the research nurse role, nurseinitiated research, and collaboration in medical research, t 8 CONCLUSION
The community health care setting provides necessary and fertile ground for the organization and implementation of oncology clinical trials. The vital national linkages with cooperative clinical research groups are operational, and appropriate models for community-based clinical trials operational infrastructures are available in the literature. The nurse and physician, principal investigator or co-investigator, are synergistic in this research process to provide oncology patients state-of-theart treatment in their own communities. The goal of the NCI to assure clinical trial access to all oncology patients is achieved through the availability of the latest cancer treatments to oncology patients regardless of geographic setting. The psychosocial ramifications for the patients receiving treatment while within easy access of their psychosocial support systems may be a variable that will influence patients to enter clinical trials and maintain accessibility for follow-up evaluations. The crisis often inherent in the diagnosis of cancer may
be attenuated by the knowledge that state-of-theart care is possible within a health care system familiar to the patient and significant others. Present opportunities for the oncology nurse involved in community-based clinical research are numerous and include the following: coordination of clinical research studies; mentoring oncology nurses interested in the research process; creation of protocol companion studies that may generate new knowledge vital to patient care; co-investigator status with the principal investigator; creation of patient educational materials specific to the geographic area, and refinement of clinical research skills. The oncology nurse involved in clinical research in the community is able to make a significant contribution to the health care climate both locally and nationally. APPENDIX National Cancer Institute Clinical Oncology Cooperative Groups: Brain Tumor Cooperative Group (BTCG) Barrow Neurological Institute St. Joseph Hospital & Medical Center 350 W Thomas Rd Phoenix, AZ 85013 Cancer and Leukemia Group B (CALGB) CALGB Headquarters 444 Mount Support Rd, Suite 2 Lebanon, NH 03766 (603) 646-5505 Children's Cancer Study Group (CCSG) 440 E Huntington Dr Suite 300 Arcadia, CA 91066-6012
(818) 447-0064 Eastern Cooperative Oncology Group (ECOG) ECOG Operations Office AMC Cancer Research Center 1600 Pierce Street Denver, CO 80214 (303) 239-3070 Gynecologic Oncology Group (GOG) GOG Headquarters 1234 Market St, 19th Floor Philadelphia, PA 19107 (215) 854-0770 Intergroup Rhabdomyosarcoma Study Department of Pediatrics Virginia Commonwealth University Medical College of Virginia, MCV Box 646 Richmond, VA 23298 (804) 786-9602
CLINICAL TRIALS AND RESEARCH
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National Surgical Adjuvant Breast & Bowel Project (NSABP) University of Pittsburgh 914 Scalfe Hall, 3550 Terrace St Pittsburgh, PA 15261 (412) 648-9720 National Wilms' Tumor Study Group Roswell Park Cancer Institute Pediatric Division 666 Elm St Buffalo, NY 14263 (716) 845-2334
Pediatric Oncology Group (POG) Del Coronado Suite 2A 4949 W Pine Blvd St. Louis, MO 63108 (314) 367-3446 Radiation Therapy Oncology Group (RTOG) RTOG Headquarters American College of Radiology 1101 Market St, 14th Floor Philadelphia, PA 19107 (215) 574-3205
North Central Cancer Treatment Group (NCCTG) Mayo Clinic, Room 75-Damon 200 First St, SW Rochester, MN 55905 (507) 284-4642
Southwest Oncology Group (SWOG) 14980 Omicron Dr San Antonio, TX 78245-3218 (210) 677-8808 REFERENCES
1. Fisher B: The importance of clinical trials. News from the Commission on Cancer. Am Coil Surg 2:204, 1991 2. Jenkins J, Curt G: Implementation of clinical trials, in Baird SB, McCorkle R, Grant M (eds): Cancer Nursing: A Comprehensive Textbook. Philadelphia, PA, Sannders, 1991, pp 355-369 3. Simon R: Randomized clinical trials and research strategy. Cancer Treat Rep 66:83-87, 1982 4. Cbeson BD: Clinical trials programs. Semin Oncol Nurs 7:235-242, 1991 5. Fleming ID: Clinical trials for cancer patients: The community practicing physicians perspective. Cancer 65:23382390, 1990 6. Yates JW, Lyons C: The organization of cancer service settings, in Baird SB, McCorkle R, Grant M (eds): Cancer Nursing: A Comprehensive Textbook. Philadelphia, PA, Saunders, 1991, pp 993-999 7. Fisher B: On clinical trial participation. J Clin Oncol 9: 1927-1930, 1991 8. National Cancer Institute: Request for Applications for Cooperative Agreements: Community Clinical Oncology Program (RFA Number CA-92-15), 1-31, May 25, 1992 9. Frank-Stromborg M, Savela B: Yellow pages for the cancer nurse in Groenwald SL, Frogge MH, Goodman M, Yarbro CH (eds): Cancer Nursing Principles and Practice. Boston, MA, Jones and Bartlett, 1990, pp 1281-1308
10. Wittes RE, Friedman MA: Accrual to clinical trials. J Natl Cancer Inst 80:884-885, 1988 11. Taylor KM, Margolese RG, Soskolne CL: Physicians' reasons for not entering eligible patients in a randomized clinical trial of surgery for breast cancer. N Engl 1 Med 310:13631368, 1984 12. Jobansen MA, Mayer DK, Hoover HC: Obstacles to implernenting cancer clinical trials. Semin Oncol Nurs 7:260267, 1991 13. Benson AB, Pregler JP, Bean JA, et al: Oncologists' reluctance to accrue patients onto clinical trials: An Illinois Cancer Center study. J Clin Oncol 9:2067-2075, 1991 14. Cassileth BR, Lusk El, Miller DS, et al: Attitudes toward clinical trials among patients and the public. J Am Med Assoc 248:968-970, 1982 15. Henney JE, Greene T, Aronson N, et al: Reimbursement concerns. Cancer 65:2409-2410, 1990 16. Oncology Issues: Reimbursement assistance for oncologists, staff and patients. Oncol Issues 6:20-22, 1991 17. Purvis JD: Cancer clinical trials: A case for collaboration. Cancer 65:2391-2393, 1990 18. Hubbard SM: Cancer treatment research: The role of the nurse in clinical trials of cancer therapy. Nuts Clin North Am 17:763-783, 1982