Clinical Trials: Impact Evaluation Implementation Considerations
and
Constance Engelking
HE CLINICAL TRIALS mechanism has served as the pathway for scientifically defining effective anticancer therapies since 1955 when the Cancer Chemotherapy National Service Center (CCNSC) was established at the NCI.’ Clinical trials can involve new drugs, biologicals, radiation, or surgical approachesas well as evaluations of patient care devices and quality-of-life issues. A traditional focus of cancer clinical trials has been on building an armamentarium of antineoplasticagentsthat would be effective in treating a wide range of malignant diseases.The conduct of clinical trials since the mid 1950s has resulted in more than 35 conventional antineoplastic agents and numerous standard therapeutic regimens providing effective treatment options for many cancers.2 Although the discovery of new agentsremains a focal point, the goal of clinical researchin oncology has expandedbeyond the testing of new agents alone. Today, ongoing cancer clinical trials can be described in essentially two categories: (1) those designedto enhancetumor responsivenessand (2) those that seek to identify new methods of minimizing the toxicities associated with anticancer therapy. In both categories,a variety of therapeutic interventions are being evaluated as shown in Table 1. Clinical researchis a major thrust in the field of oncology. The National Cancer Institute is currently sponsoringnineteen “high priority” clinical trials designed to increase accrual and survival rates. According to a recent report, accrual rates for cooperative group clinical trials have improved considerably.3 These augment the many cooperative groups and institutionally sponsored cancer clinical trials acrossthe country. The high volume of clinical research in cancer care has madeit typical for oncology nursesto care
T
From the Westchester County Medical Center, Valhalla, NY. Constance Engelking, MS, RN: Oncology Clinical Nurse Specialist. Address reprint requests to Constance Engelking, MS, RN, 98 Armonk Rd, Mt. Kisco, NY 10549. Copyright 0 1992 by W.B. Saunders Company 0749-2081/92/0802-OQO9$5.00/0
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for individuals who have some affiliation with investigational therapies. Patients may be actively involved in a clinical trial; they may have been accrued to a study in the past; or they may be considering investigational treatment options for the future. Therefore, it is essential for nurses involved in cancer care to develop and keep current their researchknowledge base. Being knowledgeable about clinical trials preparesthe nurse to respondto patient/family and consumerquestions, to dispel misperceptionsthat create anxiety, fear and distress, to appropriately structure the content of patient education, and to select suitable print materials that will reinforce information delivered verbally to the patient. Beyond direct caregiving, nurses are becoming increasingly involved in projecting patient acuity associatedwith clinical trials in order to accurately forecast staffing needsand resulting budgetary requirements.4In addition, nurses are entering into partnershipswith hospital administrators and physician investigators to proactively plan study implementation strategies designed to increase efficiency and decrease patient risk for avoidable injury.5 Nurses are also implementing companion studiesthat dovetail with cooperative group protocols.6 This article briefly reviews key conceptsregarding clinical trials and discussesissuesthat need to be resolved before the initiation of clinical research. A model to guide impact projections and decision-making relevant to nursing involvement in clinical researchwill also be proposed. CLINICAL TRIALS DEFINED
Clinical trials evaluate the safety and effectivenessof new therapies in humans. Designed in accordance with the principles of scientific experimentation, clinical trials build a sound database relevant to the treatment of various illnesses and provide the only reliable basis for clinician recommendationsfor medical treatment.’ A detailed protocol standardizesthe approach to patient accrual and care as well as the methods by which tumor responsivenesswill be measured and data anaSeminars in Oncology Nursing, Vol 8, No 2 (May), 1992: pp 148-155
CLINICAL
TRIALS
149
Table 1. Examples
of Cancer Clinical
Trials According
to Research
Goal and Therapeutic
Strategies GOAL: 1. Evaluate
Strategy
Examples Enhance
tumor
responsiveness;
new agents
eliminate tumor resistance Taxol, Navelbine, Amonafide, Trimetrexate
Curacemide,
2. Evaluate conventional agents in varying dosages, combinations, schedules, routes of administration
High v low doses (e.g., cytarabine) Continuous infusion v intermittant dosing fluorouracil) Parenteral v oral routes Circadian-based scheduling (e.g., FUDR) Alternating non-cross-resistant drugs
3. Evaluate
treatment
Chemotherapy
1. Evaluate
new agents
2. Evaluate
new formulations
modality
combinations GOAL:
3. Evaluate supportive treatment
Minimize
of conventional
therapies
as adjuncts
toxicities
+ radiation
Didemnin
B,
(e.g., 5-
and/or biologicals
associated with anticancer therapy DDTC for cisplatinum-induced nephrotoxicity ADR-529 for anthracycline-induced cardiotoxicity
agents to aggressive
lyzed, thus avoiding bias and minimizing the risk of generating faulty data.879 Clinical testing of therapeutic strategiesis a progressive and systematic process that can take 10 years or longer to complete in the United States. After demonstrationof antitumor activity in human tumor cell lines and animal models, clinical trials involving human subjects are performed in progressivephases,each with its own goals and metbods (Table 2). In addition to goals and methods, characteristics that distinguish one phase of testing from another include the type of patients who are eligible, the number of subjectsthat need to be accrued to obtain statistically significant results, and the amount Table 2. A Descriotion
Liposomal
doxorubicin
Dose intensive chemotherapy regimens + bone marrow, peripheral stem cell and/or growth factor support
of data available about the agents being studied (i.e., in phase I trials very little is known about toxicities and efficacy in humans;by phaseIII trials a considerable data base has been generated about the agent). The literature is replete with detailed descriptions of the phasesof clinical trials. Informed consent, a federally mandatedand legally binding requirementof all clinical research,lo is also well described in the literature. Briefly stated, all patients entering a clinical trial must be provided with a detailed explanation of the proposedtreatment plan, its potential risks and benefits, and other treatmentoptions (including no therapy). These must be described to the patient in language that is understandableand noncoercive. of Clinical
Trials
Phase
GO&
Obiectivas
I
Initial testing in humans following animal studies. Organized as escalating dose trials in which subjects are entered into a series of progressively higher dosage levels until lifethreatening, irreversible, or fatal toxicity is experienced.
Identify dose-limiting toxicities. Establish maximally tolerated dose; optimal dosage range. Describe pharmacology of agent (e.g., metabolism, distribution, excretion).
Testing in selected tumor types ranging from highly chemosensitive to chemoresistant.
Determine activity and therapeutic range of tumor types. Validate toxicity and dosage data.
Randomized trial comparing new therapy with existing therapies in terms of duration and quality of survival. Trial may have multiple study arms and involve sample stratification.
Determine value of new therapy in relation to existing therapies. Generate and publish recommendations for the medical community.
efficacy
in a
150
CONSTANCE
A written consentdetailing theseand other consent requirements must be signed by the patient to indicate that consent has been granted before initiating investigational therapy.’ l-l3 Informed consent is obtained when verbal and written explanation of the content of the study is assimilated and understoodby the patient.l4 Not satisfying this mandateis a transgressionof patients’rights andplacesinvolved health care providers in legal jeopardy. ISSUES ASSOCIATED WITH CLINICAL TRIALS IMPLEMENTATION
Conducting clinical trials is, at best, a difficult task, especially in settings not specifically geared to research (e.g., physician’s office and clinics). Rather than the idiosyncrasiesof the trial itself, the difficulties encounteredrelate primarily to implementation issues. What is the impact to available resourcesand to the existing organizational structure of the setting in which the trial will take place? Who will provide funding to support the trial? How will patient safety be ensured while participating in the trial? How will study integrity be maintained and by whom? The successof a clinical study relies heavily not merely on speculating about theseissuesbut by having actually answered these questions before initiating the trial. Nurses can be instrumental in providing the data necessary and recommending workable strategiesfor resolving the issues. Ideally, theseresolutions should be built into the researchproposal or can be included in a responseto the proposal. Determining ResourceImpact In any institution or agency, there are a finite number of resources-nurses and other patient caregivers, hospital beds or clinic space, equipment and supplies, and ultimately, the funds to pay for their use. Whenever a new treatmentstrategyis introduced, there can be a drain on some or all of those resources.Currently, the potential impact of introducing investigational therapies has been heightenedby what Antman et all5 describe as the collapse of the coalition among the federal govemment, universities, the pharmaceutical industry, and third party payers which has for years supported the researcheffort. In the past, each group routinely assumedfiscal responsibility for specific aspectsof research.However, today the burden of exorbitant health care costs has altered that partnership. Government funding is becoming less
ENGELKING
available; insurance companies are drawing the line on reimbursement for experimental therapies and many are not providing reimbursementfor offlabel drug usage (i.e., used in dosages and for indications unapproved by the FDA)16; and institutions must often cover the patient care costs of unfunded research. Consequently, institutions and agencies are increasingly reluctant to make commitments to research unless they can be assured that the expenditure of funds and other resources needed to support the study will not exceed the potential benefits of institutional involvement. Although the direction this trend will take remains unclear, systematically projecting the impact research will have on the resources of the facility is becoming a common requirement for study approval. Some institutions have convened special committees charged with the task of resourceimpact evaluation.5 Developing impact projections involves the consideration of a variety of interrelated factors. Factors in four categories are discussedbelow. Specific questions to be considTable 3. Questions to Consider When Evaluating Rasourcs Impact of Proposed Clinical Trials
the
Casemix
What patient types will be attracted? Does this group have special needs? How will this group fit with the remaining casemix?
Location
Inpatient or outpatient? Concentrated or scattered beds? Can available beds or clinic space accommodate study requirements? How will emergencies be handled? Will transfers be necessary in the event of life-threatening occurrences?
Staffing
What level and how many FTEs are required to accommodate the study? At what cost? Is it feasible to restructure existing staffing patterns to manage sudden rises in patient acuity? How can that be accomplished?
Operations
To whom will various aspects of the study be delegated? Staff, research nurse, physician’s assistant, physician? By what mechanism will information about research protocols be disseminated to involved team members or community caregivers? How will patients be accrued? Randomized; identified once “on study”? What method will be used to distinguish between similar trials? How will unique features of an agent or treatment approach be handled?
CLINICAL
TRIALS
ered in each of these four categoriesappearin Table 3. Casemix. The availability of investigational therapies for the treatment of specific cancerswill generally attract patients of certain profiles to the sponsoring institution in larger than normal numbers. This is especially true when the particular treatment is not offered at other sites within the immediate geographic area. Special patient subpopulations can create significant demands for care. For example, patients with leukemia and high-grade lymphomas create a large demand for blood component support and antimicrobial therapy and often require lengthy hospital stays. Research studies involving the elderly in outpatient settings may createspecial needsfor transportation or in-home support during treatment. Nursing care must anticipate and respond to such special needs within the context of the remaining patient mix served in that setting. Location. The site in which a clinical trial will be conducted involves several considerations. If it is the inpatient setting, bed availability and length of stay become issues, especially with the limitations of prospective payment and the restrictions often imposed by third party payers. Another issue is whether patients will be concentratedin one area of the hospital or integrated with other patient populations and scatteredthroughout the facility. This is important because it may alter staffing needs significantly enough to necessitatea changein the established staffing pattern. When study patients are located on one nursing unit, familiarizing staff with the researchprotocol and establishing accountability and lines of communication can be accomplished with relative ease. However, if patients are integrated throughout the facility, it is more difficult and less efficient to prepare the staff to care for study patients and may insteadwarrant a team of nurse clinicians, researchnurses, or clinical nurse specialiststo deliver study-related care.i7,i8 In the outpatient facility, the proximity to acute care services and the ability to transfer a patient in the event of life-threatening or otherwise serious reactions needs to be explored. Clinic space may also be an issue. For example, if the investigational regimen includes 2 hours of prehydration and a 4- to 6-hour drug infusion(s) with timed blood sampling for pharrnacokinetics, that patient space may not be available for another patient
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for an entire day. Weighing that fact against the daily caseloadwill help to determinethe feasibility of performing the trial in that setting. Srufing. The method by which nursing services are provided to support clinical researchvaries with the complexity and volume of research, available funding or other resources, and organizational structure of the institution or agency. The expectation may be that a research nurse and/or other study personnel (e.g., data manager)will be provided by the investigator. In some institutions, where there is a high volume of funded clinical research, one or more full-time nursing lines are dedicatedto the care of patients accruedto clinical trials. Regardless of the availability of research nurses, all or part of the care required by patients receiving investigational therapies is still provided by the general nursing staff on a designatedinpatient unit or in an outpatient setting. When clinical trials are proposed,it is important to determine what interventions will be required, the specific responsibilities expectedof the nursing staff (e.g., administration of drugs, blood sampling, and frequency of vital signs monitoring), the projected duration of the trial and the number of patients to be accrued.Thesedata are all necessary to accurately project staffing requirements (i.e., the number and level of nursing staff). Time and motion studies can also be conducted to cost out actual nursing involvement in the triali Another important variable to be considered in impact evaluations is patient acuity. Lifethreatening reactions to investigational agents (e.g., anaphylaxis, respiratory distresssyndromes, and severe hypotensive episodes) can suddenly create the need for 1:1 nursing care, altering an established 1:4 or 15 nurse/patient ratio drarnatitally. The ability to spontaneouslyrestructure the staffing pattern to accommodate for sudden changesin patient acuity must be preplanned. This is particularly important with phase I and early phaseII trials becausethe incidence of unpredictable toxicities is higher and data regarding agentassociatedtoxicities are limited. Although ideal, placing patients in a critical care area where 1:1 or 1:2 nurse/patient ratios is the norm is not always possible or cost-effective. Somecentershave dealt with this issueby creating separatelystaffed concentratedcare or critical care areason the nursing unit responsible for clinical trials. In other facilities, “on call” nursing staff
152
are available or the provision of 1:1 nursing support on demand has been negotiated with the investigator. Operational issues. The operation of a nursing unit or clinic is likely to be affected in some way when a clinical trial is superimposedon existing functions. Roles and responsibilities of staff may changeto accommodatethe trial. Often the change is an addition of new responsibilities or an increase in the frequency of routinely performed care. These addedresponsibilities can be stressful if the staff is unprepared. Bringing an outside caregiver (e.g., researchnurse) to deliver study-specific care does not always reduce the staff’s investment of time. The individual may arrive at a time that conflicts with other schedulednursing care or may be unfamiliar with procedures, equipment, and supplies necessitating orientation assistance from staff. Clearly defining who is responsible for coordinating study-related care with other routine care and making sure that external caregivers are integrated can help to reduce confusion that may arise. Another operational issue relates to disseminating information about the trial. Providing information about the research protocol to hospital team membersand community caregivers and educating staff about the details of a clinical trial are essential to ensure compliance with study requirements (e.g., treatment schedules, follow-up lab and diagnostics). In addition to in-service education, placing a protocol summary or fact sheetthat designates the patient to be “on study” describesthe regimen, monitoring parameters,interventions for adversereactions,andcontactpeopleon the patient’s medical record and is an ideal strategyfor disseminating this information to key camgivers(Fig 1). Wheele?’ refers to this type of reference sheet as a “protocol abridgement,” pointing out that these can also serve as a vehicle for alerting caregivers to protocol amendments. Crawford et al*l cite an advantageof fact sheetsover in-service education as the “on site” availability of information for those who did not have the opportunity to attend a class. In addition, the summary sheet can follow-up the patient to outpatient and community settings and thus, reduce the risk of errors especially if there are similar trials ongoing in the same facility or if there are special considerations such as drug incompatibilities. Drug preparation can interfere with or compli-
CONSTANCE
ENGELKING
Protocol Title/#: Provide full title and/or protocol number and clinical trial phase. Treatment Schema: Describe treatment regimen including drugs, dosage/m*, route of administration, and treatment days. When there is more than one treatment arm, summarize each using letters or numbers to differentiate among them. Administration Conslderatlons: Note unique points regarding drug administration such as stability factors (e.g., short stability following admixture requires immediate drug administration), incompatibilities (e.g., amsacrine incompatible with chloride-containing solutions), contraindications (e.g., not to be administered in conjunction with steroids, nonsteroidal antiinflammatory drugs, or narcotics), special preparative regimens (e.g., antiemetic regimen, hydration, electrolyte supplementation). Monitoring Parameters: Outline required evaluations including vital sign frequencies, specific physical assessments, pharmacokinetics. Pretreatment: Durlng Treatment: Post Treatment: Adverse Reaction Management: Outline clinical manifestations indicative of adverse reactions and plan for management. Include criteria for discontinuing drug administration and specific interventions (e.g., antidotes, parenteral fluids, positioning, etc.) Principal Investigator: Name and contact number Nursing Contact Person: Name and contact number Fig 1.
Sample
protocol
summary
sheet.
cate unit operations as well. Investigational agents sometimesrequire specialpreparation or a regimen may have a unique schedulethat is not compatible with unit or clinic function. For example, if a drug with stability of only 4 hours is to be administered as a 24-hour infusion, it will require around-theclock admixture every 3.5 hours. If pharmacy services are unavailable on a 24-hour basis, another plan for drug preparationmust be developedbefore study implementation. Documentation can also impact unit or clinic function. Becausegathering data is a main objective of all clinical research,documentationrequirements with patients on clinical trials is increased especially for phase I and II trials. Data sheets
CLINICAL
TRIALS
153
containing all parameters to be monitored and guidelines as to documentationfrequenciesaccompany a protocol. Determining whether those data sheetswill becomea permanentpart of the medical record is essential. If they are considered worksheets only, then routine data (e.g., vital signs, intake and output, and patient responses)must be transcribed onto the appropriate standard documents (e.g., flow sheets, graphic sheets, and narrative nurses notes) which are ordinarily included in the medical record. This processcan be laborintensive and should consequently be planned for at the outset. A SYSTEMATIC
DECISION-MAKING
APPROACH
Investigator expectations for nursing involvement in clinical trials may be incompatible with existing nursing resourcesand/or the organization of nursing services. This discrepancy can lead to conflicts that undermine nurse-physician relationships and, ultimately, the integrity of the trial. Establishing a processfor proactively evaluating the impact of proposed clinical researchand defining parametersfor the participation of nursing service createsan avenuefor primary nursing involvement in the planning of clinical trials. Preplanning to match protocol requirements with available resources(i.e., manpower, space, and time) and to resolve identified deficits and problems before activating a study encouragesnegotiation and helps to avoid conflicts that arise from incompatible expectations. Developing the processentails several discrete steps. Establish a Structure for Protocol ReviewlApproval as an Adjunct to Human Subjects Review
In addition to human subjects review (i.e., Institutional Review Board [IRB]), which is confined to risk versusbenefit and study design issues, identify an independentgroup to be responsiblefor internal protocol review that addressesresource utilization. This can be accomplished either by convening a separatecommittee or by adding this resource impact review responsibility to an existing committee. The group should be authoritybased (e.g., designated committee of the medical board of a hospital or reporting to the Chief Executive Officer of an agency) and multidisciplinary,
involving key individuals responsible for facility operations as well as direct patient care. The size of the committeeis entirely dependenton the character of the institution or agency. For example, in a small outpatient setting, two or three key individuals may be sufficient representation;however, in an acute tertiary care setting, an existing cancer committeecould either serve in this capacity or act as a resourceto the group convenedspecifically for this purpose. It may be helpful to have at least one member of the IRB serve on the resource review committee in a liaison capacity. Design a Standardized Method for Protocol Evaluation
Becauseof federally mandatedcontent requirements,22researchprotocols can be unwieldy to review. Without cues or guidelines, information important to impact evaluations can be easily overlooked. A nonstandardized protocol format contributes to the complexity of the review process. Timing can also be an issue, particularly if multiple studies are proposedsimultaneously. Developing a research protocol submission mechanism that dovetails with application for human subjectsreview and establishesa clear pathway for review and approval can streamline the process. The mechanismshould include (1) a standardized protocol format with summary sheet (which could later be placed on the patient’s medical record as a quick reference for involved caregivers as previously described), (2) designationof a central office or individual to whom submissionsare made, (3) a schedule of submission and review dates, (4) resource impact checklist to guide the reviewer(s), and (5) a method for communicating review results (e.g., standardapproval letter). Nursing service supplies the major resource neededto conduct clinical research.Yet, determining the extent of nursing involvement in research that is feasible and that will not place patients or staff in an unsafe situation remains a difficult task. Besides the use of patient classification and cost data,” specific methodologiesand parametersfor protocol evaluation by nursing have not been described in the oncology literature. Considering the existing staffing shortage, cost containment, and liability trends, it is imperative that nursing develop approachesto conducting research impact evaluations. Table 4 suggestspossible criteria that might be used for this purpose. By using these
154 Table 4. Criteria
for Determining Nursing Clinicel Research
involvement
in
Availability of data regarding the incidence of adverse effects and resulting patient acuity Complexity of care Preparative regimens, sequencing of strategies Actual agent administration; coordination of pharmacokinetic studies Monitoring parameters-type/intensity/frequency Regimen for managing patient reactions Required educational preparation of nursing staff Complexity of protocol/specific agents/monitoring Performance of new or expanded skills (special or unique procedures; use of new equipment or devices) Availability of teaching resource materials v need to develop Special documentation requirements Projected expenditure of nursing time in patient care hours Availability of and access to needed resources or ancillary support services Anticipated effect on unit or clinic operations Compatibility with existing institutional organization, philosophy, policy/procedure, and standards of care
criteria, nursing administration can basedecisions regarding nursing involvement in proposedclinical researchon data compiled from systematicreview of a proposal rather than making arbitrary determinations. Adopt a Contingency-Based Protocol Approval Approach
There may be times when nurse reviewers recognize the merit of a particular study and conclude that nursing support for the conduct of the trial could be provided under certain circumstances. But without a mechanism for assuring that those conditions would or could be met, there is reluctance to commit nursing resourcesto the clinical trial. Establishing a contingency-basedmechanism in which approvals are dependenton ensuring that specific conditions are in place is a workable solution to that problem. Such a mechanism can stimulate negotiation and compromise among and between nursing, medicine, and hospital administration. For example, across-the-boardimplementation of researchmay require that certain supporting documents (e.g., standing orders reflective of protocol detail, nursing assessmentguidelines, and protocol summary sheets) are made available on the patient’s medical record at the time of admission or study accrual. When the potential for serious adversereactions is high or the investigational
regimen is complex and labor-intensive, placing a cap on the total number of patients that can be serviced simultaneously or requiring that patient admissions be staggeredby a certain number of days may help to more evenly distribute projected patient acuity and workload. Or perhaps, shared involvement in which the investigator is expected to supply nursing support to offset the workload and more evenly distribute personnel costs could make nursing service participation more feasible. In the case of phase I trials, making accurate acuity projections is particularly difficult since information about adverse effects is generally limited. In this situation, the trial could be initiated with the understandingthat patient acuity would be tracked using acuity dataretrieved from the patient classification system for a designated number of patients. At the completion of data collection; the ability of nursing to continue to service the trial would be reevaluated. However, a back-up plan should be in place at the outset so as not to interrupt the trial should institutional nursing service be unable to continue the commitment of resourcesat the samelevel. Develop a Mechanism for Communicating Approvals and Contingencies
Once an evaluation has been conducted and the trial is approved for implementation as is or with conditions, that information needs to be communicated to the investigator and staff who will be involved. Verbal communication should always be followed with written approval that details expectations or contingencies upon which approval was based.This is particularly important when multiple studies are approved simultaneously. Keeping a protocol approval manual or notebook that includes copies of the approval letters sentto the investigator can be a quick referencefor staff who will be involved in the care of patients enteredon the trial. For example, if a contingency statesthat the oncology researchnurse will administer investigational agent and the nursing staff is responsible for administering additional conventional agents, responsibility is clearly spelled out. Establish a Monitoring System
Outlining conditions or contingencies necessary for study implementation implies that sometype of monitoring system be in place to follow up on
155
CLINICAL TRIALS
compliance. Generally, the nurse in charge of the unit or clinic in which the trial will be conducted can use the protocol approval manual to be certain that conditions have been met and to review assignment of responsibility, numbersof patients being treated, and any other guidelines that have been set. Staff is also a part of the monitoring system if policy and procedure are organized to include review of contingencies before caring for the patient since most will have beenestablishedto ensure patient safety. When contingencies are not met, direct communication with the investigator can usually resolve the issues. CONCLUSION
The ability to conduct clinical trials is essential to the development of therapeutic strategiesfor individuals with cancer. During the past 40 years,
clinical trials have resulted in a wide range of effective anticancertherapies. However, clinical researchcan impose a significant impact on the resources of sponsoring institutions or agencies, especially in today’s environment of cost containment. Consequently, institutions are becoming increasingly involved in systematicresource impact evaluations to determine the commitment they are willing and able to make to cancer clinical trials. Becauseit is the primary health care resource affected by clinical research, nursing has both a mandateand a unique opportunity to engagein or, perhaps, to spearheadin their own facilities a systematic research evaluation process. Taking this opportunity will provide an organized approachto determining the extent of nursing involvement in clinical trials that is feasible and will also createan avenueto enhancing the visibility of nursing contributions in the clinical researcharena.
REFERENCES 1. Burke MB, Wilkes GM, Berg D, Bean CK, Ingwerson K (eds): Cancer Chemotherapy: A Nursing Process Approach. Boston, MA: Jones and Bartlett, Inc. 1991 2. Tenenbaum L: Chemotherapeutic agents used in treatment of cancer, in Tenenbaum L (ed): Cancer Chemotherapy: A Reference Guide. Philadelphia, PA: Saunders, 1989, pp 42-98 3. National Cancer Institute: Update. Bethesda, MD, NCI, October, 1991 4. Garre PP, Barr JT: Increasing severity of illness among patients undergoing phase 1 trials: Implications for nursing resources. Cancer Nurs 12: 107-l 11, 1989 5. Engelking C: Facilitating clinical trials: The expanding role of the nurse. Cancer 67:1793-1797, 1991 (Suppl) 6. McEvoy MD: The professional role for nurses in clinical trials. Semin Oncol Nurs 7:268-274, 1991 7. Weinstein SM: Use of investigational drugs. NITA 5:336347, 1987 8. Gross J: Clinical research in cancer chemotherapy. Oncol Nurs Forum 13:59-65, 1986 9. Cassidy J, Macfarlane DK: The role of the nurse in clinical cancer research. Cancer Nurs 14:124-131, 1991 10. 45 CFR $46. Public Welfare Final Regulations Amending Basic HHS Policy for Protection of Research Subjects. Federal Regulations. 4:8366-8392, 1981 11. Bujorian GA: Clinical trials: Patient issues in the decision-making process. Oncol Nurs Forum 15:779-783, 1988 12. Chamorro T, Appelbaum J: Informed consent: Nursing issues and ethical dilemmas. Oncol Nurs Forum 15:803-808, 1988
13. Schoene-Seifert B, Childress J: How much should the cancer patient know and decide? CA 36:85-94, 1986 14. Melink TJ, Whitacre MY: Planning and implementing clinical trials. Semin Oncol Nurs 7:243-251, 1991 15. Antman KH, Aledort LM, Yarbro J, et al: Costeffectiveness and reimbursement in patient care. Semin Hemato1 26:32-45, 1989 (suppl 3) 16. Muscat0 J: Reimbursement problems in the unlabeled use of FDA-approved drugs. Biotherapy and Cancer. Tri Clinica Communications, New York, NY, 2:1,6, 1989 17. Hubbard SM: Cancer treatment research: The role of nurses in clinical trials of cancer therapy. Nurs Clin North Am 17:763-783, 1982 18. White-Hershey D, Nevidjon B: Fundamentals for oncology nurse/data managers: Preparing for a new role. Oncol Nurs Forum 17:371-377, 1990 19. Engelking C, Sullivan P: Costing out nursing involvement in hospital-based clinical trials. Proc Oncol Nurs Sot 13:88, 1986 (abstr 133A) 20. Wheeler V: Preparing nurses for clinical trials: The cancer center approach. Semin Oncol Nurs 7:275-279, 1991 21. Crawford S, Beardsley RS, Lamy PP, et al: Comparing fact sheets and lectures to provide investigational drug information. J Nurs Staff Dev 6:35-39, 1990 22. National Cancer Institute: Investigator’s Handbook. Cancer Therapy Evaluation Program, Division of Cancer Treatment, Bethesda, MD: 1986
and
Constance Engelking
HE CLINICAL TRIALS mechanism has served as the pathway for scientifically defining effective anticancer therapies since 1955 when the Cancer Chemotherapy National Service Center (CCNSC) was established at the NCI.’ Clinical trials can involve new drugs, biologicals, radiation, or surgical approachesas well as evaluations of patient care devices and quality-of-life issues. A traditional focus of cancer clinical trials has been on building an armamentarium of antineoplasticagentsthat would be effective in treating a wide range of malignant diseases.The conduct of clinical trials since the mid 1950s has resulted in more than 35 conventional antineoplastic agents and numerous standard therapeutic regimens providing effective treatment options for many cancers.2 Although the discovery of new agentsremains a focal point, the goal of clinical researchin oncology has expandedbeyond the testing of new agents alone. Today, ongoing cancer clinical trials can be described in essentially two categories: (1) those designedto enhancetumor responsivenessand (2) those that seek to identify new methods of minimizing the toxicities associated with anticancer therapy. In both categories,a variety of therapeutic interventions are being evaluated as shown in Table 1. Clinical researchis a major thrust in the field of oncology. The National Cancer Institute is currently sponsoringnineteen “high priority” clinical trials designed to increase accrual and survival rates. According to a recent report, accrual rates for cooperative group clinical trials have improved considerably.3 These augment the many cooperative groups and institutionally sponsored cancer clinical trials acrossthe country. The high volume of clinical research in cancer care has madeit typical for oncology nursesto care
T
From the Westchester County Medical Center, Valhalla, NY. Constance Engelking, MS, RN: Oncology Clinical Nurse Specialist. Address reprint requests to Constance Engelking, MS, RN, 98 Armonk Rd, Mt. Kisco, NY 10549. Copyright 0 1992 by W.B. Saunders Company 0749-2081/92/0802-OQO9$5.00/0
148
for individuals who have some affiliation with investigational therapies. Patients may be actively involved in a clinical trial; they may have been accrued to a study in the past; or they may be considering investigational treatment options for the future. Therefore, it is essential for nurses involved in cancer care to develop and keep current their researchknowledge base. Being knowledgeable about clinical trials preparesthe nurse to respondto patient/family and consumerquestions, to dispel misperceptionsthat create anxiety, fear and distress, to appropriately structure the content of patient education, and to select suitable print materials that will reinforce information delivered verbally to the patient. Beyond direct caregiving, nurses are becoming increasingly involved in projecting patient acuity associatedwith clinical trials in order to accurately forecast staffing needsand resulting budgetary requirements.4In addition, nurses are entering into partnershipswith hospital administrators and physician investigators to proactively plan study implementation strategies designed to increase efficiency and decrease patient risk for avoidable injury.5 Nurses are also implementing companion studiesthat dovetail with cooperative group protocols.6 This article briefly reviews key conceptsregarding clinical trials and discussesissuesthat need to be resolved before the initiation of clinical research. A model to guide impact projections and decision-making relevant to nursing involvement in clinical researchwill also be proposed. CLINICAL TRIALS DEFINED
Clinical trials evaluate the safety and effectivenessof new therapies in humans. Designed in accordance with the principles of scientific experimentation, clinical trials build a sound database relevant to the treatment of various illnesses and provide the only reliable basis for clinician recommendationsfor medical treatment.’ A detailed protocol standardizesthe approach to patient accrual and care as well as the methods by which tumor responsivenesswill be measured and data anaSeminars in Oncology Nursing, Vol 8, No 2 (May), 1992: pp 148-155
CLINICAL
TRIALS
149
Table 1. Examples
of Cancer Clinical
Trials According
to Research
Goal and Therapeutic
Strategies GOAL: 1. Evaluate
Strategy
Examples Enhance
tumor
responsiveness;
new agents
eliminate tumor resistance Taxol, Navelbine, Amonafide, Trimetrexate
Curacemide,
2. Evaluate conventional agents in varying dosages, combinations, schedules, routes of administration
High v low doses (e.g., cytarabine) Continuous infusion v intermittant dosing fluorouracil) Parenteral v oral routes Circadian-based scheduling (e.g., FUDR) Alternating non-cross-resistant drugs
3. Evaluate
treatment
Chemotherapy
1. Evaluate
new agents
2. Evaluate
new formulations
modality
combinations GOAL:
3. Evaluate supportive treatment
Minimize
of conventional
therapies
as adjuncts
toxicities
+ radiation
Didemnin
B,
(e.g., 5-
and/or biologicals
associated with anticancer therapy DDTC for cisplatinum-induced nephrotoxicity ADR-529 for anthracycline-induced cardiotoxicity
agents to aggressive
lyzed, thus avoiding bias and minimizing the risk of generating faulty data.879 Clinical testing of therapeutic strategiesis a progressive and systematic process that can take 10 years or longer to complete in the United States. After demonstrationof antitumor activity in human tumor cell lines and animal models, clinical trials involving human subjects are performed in progressivephases,each with its own goals and metbods (Table 2). In addition to goals and methods, characteristics that distinguish one phase of testing from another include the type of patients who are eligible, the number of subjectsthat need to be accrued to obtain statistically significant results, and the amount Table 2. A Descriotion
Liposomal
doxorubicin
Dose intensive chemotherapy regimens + bone marrow, peripheral stem cell and/or growth factor support
of data available about the agents being studied (i.e., in phase I trials very little is known about toxicities and efficacy in humans;by phaseIII trials a considerable data base has been generated about the agent). The literature is replete with detailed descriptions of the phasesof clinical trials. Informed consent, a federally mandatedand legally binding requirementof all clinical research,lo is also well described in the literature. Briefly stated, all patients entering a clinical trial must be provided with a detailed explanation of the proposedtreatment plan, its potential risks and benefits, and other treatmentoptions (including no therapy). These must be described to the patient in language that is understandableand noncoercive. of Clinical
Trials
Phase
GO&
Obiectivas
I
Initial testing in humans following animal studies. Organized as escalating dose trials in which subjects are entered into a series of progressively higher dosage levels until lifethreatening, irreversible, or fatal toxicity is experienced.
Identify dose-limiting toxicities. Establish maximally tolerated dose; optimal dosage range. Describe pharmacology of agent (e.g., metabolism, distribution, excretion).
Testing in selected tumor types ranging from highly chemosensitive to chemoresistant.
Determine activity and therapeutic range of tumor types. Validate toxicity and dosage data.
Randomized trial comparing new therapy with existing therapies in terms of duration and quality of survival. Trial may have multiple study arms and involve sample stratification.
Determine value of new therapy in relation to existing therapies. Generate and publish recommendations for the medical community.
efficacy
in a
150
CONSTANCE
A written consentdetailing theseand other consent requirements must be signed by the patient to indicate that consent has been granted before initiating investigational therapy.’ l-l3 Informed consent is obtained when verbal and written explanation of the content of the study is assimilated and understoodby the patient.l4 Not satisfying this mandateis a transgressionof patients’rights andplacesinvolved health care providers in legal jeopardy. ISSUES ASSOCIATED WITH CLINICAL TRIALS IMPLEMENTATION
Conducting clinical trials is, at best, a difficult task, especially in settings not specifically geared to research (e.g., physician’s office and clinics). Rather than the idiosyncrasiesof the trial itself, the difficulties encounteredrelate primarily to implementation issues. What is the impact to available resourcesand to the existing organizational structure of the setting in which the trial will take place? Who will provide funding to support the trial? How will patient safety be ensured while participating in the trial? How will study integrity be maintained and by whom? The successof a clinical study relies heavily not merely on speculating about theseissuesbut by having actually answered these questions before initiating the trial. Nurses can be instrumental in providing the data necessary and recommending workable strategiesfor resolving the issues. Ideally, theseresolutions should be built into the researchproposal or can be included in a responseto the proposal. Determining ResourceImpact In any institution or agency, there are a finite number of resources-nurses and other patient caregivers, hospital beds or clinic space, equipment and supplies, and ultimately, the funds to pay for their use. Whenever a new treatmentstrategyis introduced, there can be a drain on some or all of those resources.Currently, the potential impact of introducing investigational therapies has been heightenedby what Antman et all5 describe as the collapse of the coalition among the federal govemment, universities, the pharmaceutical industry, and third party payers which has for years supported the researcheffort. In the past, each group routinely assumedfiscal responsibility for specific aspectsof research.However, today the burden of exorbitant health care costs has altered that partnership. Government funding is becoming less
ENGELKING
available; insurance companies are drawing the line on reimbursement for experimental therapies and many are not providing reimbursementfor offlabel drug usage (i.e., used in dosages and for indications unapproved by the FDA)16; and institutions must often cover the patient care costs of unfunded research. Consequently, institutions and agencies are increasingly reluctant to make commitments to research unless they can be assured that the expenditure of funds and other resources needed to support the study will not exceed the potential benefits of institutional involvement. Although the direction this trend will take remains unclear, systematically projecting the impact research will have on the resources of the facility is becoming a common requirement for study approval. Some institutions have convened special committees charged with the task of resourceimpact evaluation.5 Developing impact projections involves the consideration of a variety of interrelated factors. Factors in four categories are discussedbelow. Specific questions to be considTable 3. Questions to Consider When Evaluating Rasourcs Impact of Proposed Clinical Trials
the
Casemix
What patient types will be attracted? Does this group have special needs? How will this group fit with the remaining casemix?
Location
Inpatient or outpatient? Concentrated or scattered beds? Can available beds or clinic space accommodate study requirements? How will emergencies be handled? Will transfers be necessary in the event of life-threatening occurrences?
Staffing
What level and how many FTEs are required to accommodate the study? At what cost? Is it feasible to restructure existing staffing patterns to manage sudden rises in patient acuity? How can that be accomplished?
Operations
To whom will various aspects of the study be delegated? Staff, research nurse, physician’s assistant, physician? By what mechanism will information about research protocols be disseminated to involved team members or community caregivers? How will patients be accrued? Randomized; identified once “on study”? What method will be used to distinguish between similar trials? How will unique features of an agent or treatment approach be handled?
CLINICAL
TRIALS
ered in each of these four categoriesappearin Table 3. Casemix. The availability of investigational therapies for the treatment of specific cancerswill generally attract patients of certain profiles to the sponsoring institution in larger than normal numbers. This is especially true when the particular treatment is not offered at other sites within the immediate geographic area. Special patient subpopulations can create significant demands for care. For example, patients with leukemia and high-grade lymphomas create a large demand for blood component support and antimicrobial therapy and often require lengthy hospital stays. Research studies involving the elderly in outpatient settings may createspecial needsfor transportation or in-home support during treatment. Nursing care must anticipate and respond to such special needs within the context of the remaining patient mix served in that setting. Location. The site in which a clinical trial will be conducted involves several considerations. If it is the inpatient setting, bed availability and length of stay become issues, especially with the limitations of prospective payment and the restrictions often imposed by third party payers. Another issue is whether patients will be concentratedin one area of the hospital or integrated with other patient populations and scatteredthroughout the facility. This is important because it may alter staffing needs significantly enough to necessitatea changein the established staffing pattern. When study patients are located on one nursing unit, familiarizing staff with the researchprotocol and establishing accountability and lines of communication can be accomplished with relative ease. However, if patients are integrated throughout the facility, it is more difficult and less efficient to prepare the staff to care for study patients and may insteadwarrant a team of nurse clinicians, researchnurses, or clinical nurse specialiststo deliver study-related care.i7,i8 In the outpatient facility, the proximity to acute care services and the ability to transfer a patient in the event of life-threatening or otherwise serious reactions needs to be explored. Clinic space may also be an issue. For example, if the investigational regimen includes 2 hours of prehydration and a 4- to 6-hour drug infusion(s) with timed blood sampling for pharrnacokinetics, that patient space may not be available for another patient
151
for an entire day. Weighing that fact against the daily caseloadwill help to determinethe feasibility of performing the trial in that setting. Srufing. The method by which nursing services are provided to support clinical researchvaries with the complexity and volume of research, available funding or other resources, and organizational structure of the institution or agency. The expectation may be that a research nurse and/or other study personnel (e.g., data manager)will be provided by the investigator. In some institutions, where there is a high volume of funded clinical research, one or more full-time nursing lines are dedicatedto the care of patients accruedto clinical trials. Regardless of the availability of research nurses, all or part of the care required by patients receiving investigational therapies is still provided by the general nursing staff on a designatedinpatient unit or in an outpatient setting. When clinical trials are proposed,it is important to determine what interventions will be required, the specific responsibilities expectedof the nursing staff (e.g., administration of drugs, blood sampling, and frequency of vital signs monitoring), the projected duration of the trial and the number of patients to be accrued.Thesedata are all necessary to accurately project staffing requirements (i.e., the number and level of nursing staff). Time and motion studies can also be conducted to cost out actual nursing involvement in the triali Another important variable to be considered in impact evaluations is patient acuity. Lifethreatening reactions to investigational agents (e.g., anaphylaxis, respiratory distresssyndromes, and severe hypotensive episodes) can suddenly create the need for 1:1 nursing care, altering an established 1:4 or 15 nurse/patient ratio drarnatitally. The ability to spontaneouslyrestructure the staffing pattern to accommodate for sudden changesin patient acuity must be preplanned. This is particularly important with phase I and early phaseII trials becausethe incidence of unpredictable toxicities is higher and data regarding agentassociatedtoxicities are limited. Although ideal, placing patients in a critical care area where 1:1 or 1:2 nurse/patient ratios is the norm is not always possible or cost-effective. Somecentershave dealt with this issueby creating separatelystaffed concentratedcare or critical care areason the nursing unit responsible for clinical trials. In other facilities, “on call” nursing staff
152
are available or the provision of 1:1 nursing support on demand has been negotiated with the investigator. Operational issues. The operation of a nursing unit or clinic is likely to be affected in some way when a clinical trial is superimposedon existing functions. Roles and responsibilities of staff may changeto accommodatethe trial. Often the change is an addition of new responsibilities or an increase in the frequency of routinely performed care. These addedresponsibilities can be stressful if the staff is unprepared. Bringing an outside caregiver (e.g., researchnurse) to deliver study-specific care does not always reduce the staff’s investment of time. The individual may arrive at a time that conflicts with other schedulednursing care or may be unfamiliar with procedures, equipment, and supplies necessitating orientation assistance from staff. Clearly defining who is responsible for coordinating study-related care with other routine care and making sure that external caregivers are integrated can help to reduce confusion that may arise. Another operational issue relates to disseminating information about the trial. Providing information about the research protocol to hospital team membersand community caregivers and educating staff about the details of a clinical trial are essential to ensure compliance with study requirements (e.g., treatment schedules, follow-up lab and diagnostics). In addition to in-service education, placing a protocol summary or fact sheetthat designates the patient to be “on study” describesthe regimen, monitoring parameters,interventions for adversereactions,andcontactpeopleon the patient’s medical record and is an ideal strategyfor disseminating this information to key camgivers(Fig 1). Wheele?’ refers to this type of reference sheet as a “protocol abridgement,” pointing out that these can also serve as a vehicle for alerting caregivers to protocol amendments. Crawford et al*l cite an advantageof fact sheetsover in-service education as the “on site” availability of information for those who did not have the opportunity to attend a class. In addition, the summary sheet can follow-up the patient to outpatient and community settings and thus, reduce the risk of errors especially if there are similar trials ongoing in the same facility or if there are special considerations such as drug incompatibilities. Drug preparation can interfere with or compli-
CONSTANCE
ENGELKING
Protocol Title/#: Provide full title and/or protocol number and clinical trial phase. Treatment Schema: Describe treatment regimen including drugs, dosage/m*, route of administration, and treatment days. When there is more than one treatment arm, summarize each using letters or numbers to differentiate among them. Administration Conslderatlons: Note unique points regarding drug administration such as stability factors (e.g., short stability following admixture requires immediate drug administration), incompatibilities (e.g., amsacrine incompatible with chloride-containing solutions), contraindications (e.g., not to be administered in conjunction with steroids, nonsteroidal antiinflammatory drugs, or narcotics), special preparative regimens (e.g., antiemetic regimen, hydration, electrolyte supplementation). Monitoring Parameters: Outline required evaluations including vital sign frequencies, specific physical assessments, pharmacokinetics. Pretreatment: Durlng Treatment: Post Treatment: Adverse Reaction Management: Outline clinical manifestations indicative of adverse reactions and plan for management. Include criteria for discontinuing drug administration and specific interventions (e.g., antidotes, parenteral fluids, positioning, etc.) Principal Investigator: Name and contact number Nursing Contact Person: Name and contact number Fig 1.
Sample
protocol
summary
sheet.
cate unit operations as well. Investigational agents sometimesrequire specialpreparation or a regimen may have a unique schedulethat is not compatible with unit or clinic function. For example, if a drug with stability of only 4 hours is to be administered as a 24-hour infusion, it will require around-theclock admixture every 3.5 hours. If pharmacy services are unavailable on a 24-hour basis, another plan for drug preparationmust be developedbefore study implementation. Documentation can also impact unit or clinic function. Becausegathering data is a main objective of all clinical research,documentationrequirements with patients on clinical trials is increased especially for phase I and II trials. Data sheets
CLINICAL
TRIALS
153
containing all parameters to be monitored and guidelines as to documentationfrequenciesaccompany a protocol. Determining whether those data sheetswill becomea permanentpart of the medical record is essential. If they are considered worksheets only, then routine data (e.g., vital signs, intake and output, and patient responses)must be transcribed onto the appropriate standard documents (e.g., flow sheets, graphic sheets, and narrative nurses notes) which are ordinarily included in the medical record. This processcan be laborintensive and should consequently be planned for at the outset. A SYSTEMATIC
DECISION-MAKING
APPROACH
Investigator expectations for nursing involvement in clinical trials may be incompatible with existing nursing resourcesand/or the organization of nursing services. This discrepancy can lead to conflicts that undermine nurse-physician relationships and, ultimately, the integrity of the trial. Establishing a processfor proactively evaluating the impact of proposed clinical researchand defining parametersfor the participation of nursing service createsan avenuefor primary nursing involvement in the planning of clinical trials. Preplanning to match protocol requirements with available resources(i.e., manpower, space, and time) and to resolve identified deficits and problems before activating a study encouragesnegotiation and helps to avoid conflicts that arise from incompatible expectations. Developing the processentails several discrete steps. Establish a Structure for Protocol ReviewlApproval as an Adjunct to Human Subjects Review
In addition to human subjects review (i.e., Institutional Review Board [IRB]), which is confined to risk versusbenefit and study design issues, identify an independentgroup to be responsiblefor internal protocol review that addressesresource utilization. This can be accomplished either by convening a separatecommittee or by adding this resource impact review responsibility to an existing committee. The group should be authoritybased (e.g., designated committee of the medical board of a hospital or reporting to the Chief Executive Officer of an agency) and multidisciplinary,
involving key individuals responsible for facility operations as well as direct patient care. The size of the committeeis entirely dependenton the character of the institution or agency. For example, in a small outpatient setting, two or three key individuals may be sufficient representation;however, in an acute tertiary care setting, an existing cancer committeecould either serve in this capacity or act as a resourceto the group convenedspecifically for this purpose. It may be helpful to have at least one member of the IRB serve on the resource review committee in a liaison capacity. Design a Standardized Method for Protocol Evaluation
Becauseof federally mandatedcontent requirements,22researchprotocols can be unwieldy to review. Without cues or guidelines, information important to impact evaluations can be easily overlooked. A nonstandardized protocol format contributes to the complexity of the review process. Timing can also be an issue, particularly if multiple studies are proposedsimultaneously. Developing a research protocol submission mechanism that dovetails with application for human subjectsreview and establishesa clear pathway for review and approval can streamline the process. The mechanismshould include (1) a standardized protocol format with summary sheet (which could later be placed on the patient’s medical record as a quick reference for involved caregivers as previously described), (2) designationof a central office or individual to whom submissionsare made, (3) a schedule of submission and review dates, (4) resource impact checklist to guide the reviewer(s), and (5) a method for communicating review results (e.g., standardapproval letter). Nursing service supplies the major resource neededto conduct clinical research.Yet, determining the extent of nursing involvement in research that is feasible and that will not place patients or staff in an unsafe situation remains a difficult task. Besides the use of patient classification and cost data,” specific methodologiesand parametersfor protocol evaluation by nursing have not been described in the oncology literature. Considering the existing staffing shortage, cost containment, and liability trends, it is imperative that nursing develop approachesto conducting research impact evaluations. Table 4 suggestspossible criteria that might be used for this purpose. By using these
154 Table 4. Criteria
for Determining Nursing Clinicel Research
involvement
in
Availability of data regarding the incidence of adverse effects and resulting patient acuity Complexity of care Preparative regimens, sequencing of strategies Actual agent administration; coordination of pharmacokinetic studies Monitoring parameters-type/intensity/frequency Regimen for managing patient reactions Required educational preparation of nursing staff Complexity of protocol/specific agents/monitoring Performance of new or expanded skills (special or unique procedures; use of new equipment or devices) Availability of teaching resource materials v need to develop Special documentation requirements Projected expenditure of nursing time in patient care hours Availability of and access to needed resources or ancillary support services Anticipated effect on unit or clinic operations Compatibility with existing institutional organization, philosophy, policy/procedure, and standards of care
criteria, nursing administration can basedecisions regarding nursing involvement in proposedclinical researchon data compiled from systematicreview of a proposal rather than making arbitrary determinations. Adopt a Contingency-Based Protocol Approval Approach
There may be times when nurse reviewers recognize the merit of a particular study and conclude that nursing support for the conduct of the trial could be provided under certain circumstances. But without a mechanism for assuring that those conditions would or could be met, there is reluctance to commit nursing resourcesto the clinical trial. Establishing a contingency-basedmechanism in which approvals are dependenton ensuring that specific conditions are in place is a workable solution to that problem. Such a mechanism can stimulate negotiation and compromise among and between nursing, medicine, and hospital administration. For example, across-the-boardimplementation of researchmay require that certain supporting documents (e.g., standing orders reflective of protocol detail, nursing assessmentguidelines, and protocol summary sheets) are made available on the patient’s medical record at the time of admission or study accrual. When the potential for serious adversereactions is high or the investigational
regimen is complex and labor-intensive, placing a cap on the total number of patients that can be serviced simultaneously or requiring that patient admissions be staggeredby a certain number of days may help to more evenly distribute projected patient acuity and workload. Or perhaps, shared involvement in which the investigator is expected to supply nursing support to offset the workload and more evenly distribute personnel costs could make nursing service participation more feasible. In the case of phase I trials, making accurate acuity projections is particularly difficult since information about adverse effects is generally limited. In this situation, the trial could be initiated with the understandingthat patient acuity would be tracked using acuity dataretrieved from the patient classification system for a designated number of patients. At the completion of data collection; the ability of nursing to continue to service the trial would be reevaluated. However, a back-up plan should be in place at the outset so as not to interrupt the trial should institutional nursing service be unable to continue the commitment of resourcesat the samelevel. Develop a Mechanism for Communicating Approvals and Contingencies
Once an evaluation has been conducted and the trial is approved for implementation as is or with conditions, that information needs to be communicated to the investigator and staff who will be involved. Verbal communication should always be followed with written approval that details expectations or contingencies upon which approval was based.This is particularly important when multiple studies are approved simultaneously. Keeping a protocol approval manual or notebook that includes copies of the approval letters sentto the investigator can be a quick referencefor staff who will be involved in the care of patients enteredon the trial. For example, if a contingency statesthat the oncology researchnurse will administer investigational agent and the nursing staff is responsible for administering additional conventional agents, responsibility is clearly spelled out. Establish a Monitoring System
Outlining conditions or contingencies necessary for study implementation implies that sometype of monitoring system be in place to follow up on
155
CLINICAL TRIALS
compliance. Generally, the nurse in charge of the unit or clinic in which the trial will be conducted can use the protocol approval manual to be certain that conditions have been met and to review assignment of responsibility, numbersof patients being treated, and any other guidelines that have been set. Staff is also a part of the monitoring system if policy and procedure are organized to include review of contingencies before caring for the patient since most will have beenestablishedto ensure patient safety. When contingencies are not met, direct communication with the investigator can usually resolve the issues. CONCLUSION
The ability to conduct clinical trials is essential to the development of therapeutic strategiesfor individuals with cancer. During the past 40 years,
clinical trials have resulted in a wide range of effective anticancertherapies. However, clinical researchcan impose a significant impact on the resources of sponsoring institutions or agencies, especially in today’s environment of cost containment. Consequently, institutions are becoming increasingly involved in systematicresource impact evaluations to determine the commitment they are willing and able to make to cancer clinical trials. Becauseit is the primary health care resource affected by clinical research, nursing has both a mandateand a unique opportunity to engagein or, perhaps, to spearheadin their own facilities a systematic research evaluation process. Taking this opportunity will provide an organized approachto determining the extent of nursing involvement in clinical trials that is feasible and will also createan avenueto enhancing the visibility of nursing contributions in the clinical researcharena.
REFERENCES 1. Burke MB, Wilkes GM, Berg D, Bean CK, Ingwerson K (eds): Cancer Chemotherapy: A Nursing Process Approach. Boston, MA: Jones and Bartlett, Inc. 1991 2. Tenenbaum L: Chemotherapeutic agents used in treatment of cancer, in Tenenbaum L (ed): Cancer Chemotherapy: A Reference Guide. Philadelphia, PA: Saunders, 1989, pp 42-98 3. National Cancer Institute: Update. Bethesda, MD, NCI, October, 1991 4. Garre PP, Barr JT: Increasing severity of illness among patients undergoing phase 1 trials: Implications for nursing resources. Cancer Nurs 12: 107-l 11, 1989 5. Engelking C: Facilitating clinical trials: The expanding role of the nurse. Cancer 67:1793-1797, 1991 (Suppl) 6. McEvoy MD: The professional role for nurses in clinical trials. Semin Oncol Nurs 7:268-274, 1991 7. Weinstein SM: Use of investigational drugs. NITA 5:336347, 1987 8. Gross J: Clinical research in cancer chemotherapy. Oncol Nurs Forum 13:59-65, 1986 9. Cassidy J, Macfarlane DK: The role of the nurse in clinical cancer research. Cancer Nurs 14:124-131, 1991 10. 45 CFR $46. Public Welfare Final Regulations Amending Basic HHS Policy for Protection of Research Subjects. Federal Regulations. 4:8366-8392, 1981 11. Bujorian GA: Clinical trials: Patient issues in the decision-making process. Oncol Nurs Forum 15:779-783, 1988 12. Chamorro T, Appelbaum J: Informed consent: Nursing issues and ethical dilemmas. Oncol Nurs Forum 15:803-808, 1988
13. Schoene-Seifert B, Childress J: How much should the cancer patient know and decide? CA 36:85-94, 1986 14. Melink TJ, Whitacre MY: Planning and implementing clinical trials. Semin Oncol Nurs 7:243-251, 1991 15. Antman KH, Aledort LM, Yarbro J, et al: Costeffectiveness and reimbursement in patient care. Semin Hemato1 26:32-45, 1989 (suppl 3) 16. Muscat0 J: Reimbursement problems in the unlabeled use of FDA-approved drugs. Biotherapy and Cancer. Tri Clinica Communications, New York, NY, 2:1,6, 1989 17. Hubbard SM: Cancer treatment research: The role of nurses in clinical trials of cancer therapy. Nurs Clin North Am 17:763-783, 1982 18. White-Hershey D, Nevidjon B: Fundamentals for oncology nurse/data managers: Preparing for a new role. Oncol Nurs Forum 17:371-377, 1990 19. Engelking C, Sullivan P: Costing out nursing involvement in hospital-based clinical trials. Proc Oncol Nurs Sot 13:88, 1986 (abstr 133A) 20. Wheeler V: Preparing nurses for clinical trials: The cancer center approach. Semin Oncol Nurs 7:275-279, 1991 21. Crawford S, Beardsley RS, Lamy PP, et al: Comparing fact sheets and lectures to provide investigational drug information. J Nurs Staff Dev 6:35-39, 1990 22. National Cancer Institute: Investigator’s Handbook. Cancer Therapy Evaluation Program, Division of Cancer Treatment, Bethesda, MD: 1986
