Planning and implementing clinical trials

Planning

and Implementing

Clinical

Trials

Teresa J. Melink and Margaret Y. Whitacre

HE PRIMARY GOAL of clinical cancer research is to identify treatments that ultimately translate into improved quality of life and survival. Prospective clinical trials provide the foundation for identifying new treatments.The impetus for thesestudies is varied, but eachshould be driven by a hypothesis considered worthy of evaluation.’ These can range from clinical-laboratory correlations to complex comparisons of multimodality therapies. Due to a greater appreciation for the need of orderly drug development, a better understanding of cancer heterogeneity, the vital role of biostatistics, and the increased skills of multidisciplinary research teams, cancer trials are being designed and conducted with an ever increasing level of sophistication. Careful planning and organization are essential in the design and conduct of a clinical trial. Thorough and proper testing of the treatment will provide confidence in the results and the role of the therapy, or lack there of, in future trials. This discussion will focus on developing clinical protocols for cancer research, protecting research participants, assuring quality data in cancer trials, and identifying the elements of nursing participation in the clinical trial process.

T

THE CLINICAL PROTOCOL

In planning and developing the clinical trial, a formal document known as a protocol is written to clearly describe the proposed experiment. Such a document provides a rationale for the study and gives clear and concise directions for those involved, directly or indirectly, in its conduct. Each protocol consists of several common components (Table 1). In a well-designed clinical trial, eachof these components is integrated to assure the successful conduct of the study. The study objectives, rationale, and patient selection criteria describe the purpose of the study, why the question posed is worth asking, and in whom it will be asked. The study design provides the framework for achieving these goals. The following will summarize some of the essential features of a protocol. Comprehensiveguidelines for the preparation of protocols have been published elsewhere.’ Seminars

in Oncology

Nursing,

Vol

7.

No

4 (November),

1991:

pp 243-251

Study Objectives

The study objectives are the specific questions or hypothesesthat should be answeredupon completion of the trial. The other components of the protocol should be written to assurethat these answersare obtainable. These goals should be stated in clear, concise terms. There is usually a primary objective which is the fundamental reasonfor conducting the trial.3 Frequently, one or more complementary objectives may also be answerable with the study design used. A common pitfall in writing protocols is the inclusion of secondaryobjectives which cannot, in fact, be achievedbecause of the design of the study, the samplesize, or some other factor. Study Rationale or Background Information

Sufficient background information should be provided so that the rationale for the study is clear. This section describesprevious work which led the investigators to develop the hypotheses to be tested. This may be a brief description of the treatment experiencefor a particular tumor type and of the new treatmentto be administered. On the other hand, it may involve a complex description of novel therapies such as interactions among cytotoxics and biological responsemodifiers. This section should also include the rationale for the secondary and tertiary study objectives. If the hypothesis is based on unpublished work, the investigator should be particularly careful to provide the data leading up to the proposed study. Study Population

The eligibility criteria defines which patients will participate in the study and who will be exFrom the University of Maryland Cancer Center, Baltimore, MD. Teresa J. Melink, RN, C, MSN, ANP: Assistant Professor of Medicine, University of Maryland Cancer Center: Margaret Y Whitacre, RN, OCN: Oncology Research Nurse Manager, Universiry of Maryland Cancer Center. Address reprint requests to Teresa J. Melink, RN, C, MSN, ANP, Assistant Professor of Medicine, University of Maryland Cancer Center, 22 S Greene St, Baltimore, MD 21201. Copyright 0 1991 by W.B. Saunders Company 0749-2081/9110704-0003$5.OOlO

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Table 1. Essential

Components

of a Protocol

Objectives of the study Scientific background and study rationale Patient selection criteria Pharmaceutical information Study design Treatment plan Toxicity evaluation criteria Dose adjustment plan Required study parameters for patient monitoring Response evaluation criteria Statistical considerations Criteria for study termination Special companion studies Data submission requirements and forms References Consent form

eluded. Standard items of inclusion are pathologically confirmed diagnosis, type and amount of prior therapy allowed or required, age and performance status restrictions, and baseline bone marrow, renal, and liver function requirements. Most studies, except phaseI protocols, require a specific tumor type and stage and the presenceof measurable disease. Reasons for exclusion may be the presenceof a prior or concurrent malignancy. In addition, patients may be excluded for other conditions that increase the likelihood that the treatment will result in excessivetoxicity or which will make it difficult to differentiate treatment toxicity from other causesof organ dysfunction.394 The eligibility criteria should not be so restrictive that an insufficient number of patients will qualify for the study. Neither should these criteria be so narrowly defined that the results are not broadly applicable to the patient population in which the diseasecommonly occurs. However, the patient population should be reasonably homogeneous so that patients have a similar stage of diseaseand prognosis. Inherent in the study population, although not always stated, is the requirement that patients be willing and able to comply with protocol requirements involving treatmentand post therapy followup. Additionally, patients must understandthe investigational nature of the proposedtreatment, the potential risks and benefits, and be able to give written consent to participate.5 Study Design

The study design considers the stated goals of the trial and the methodology for achieving these goals. Other important considerations include se-

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letting a patient population, assuring an adequate samplesize, and minimizing the effect of bias due to variable patient factors. In addition, treatment regimens, follow-up schedules,and monitoring requirementsshould not be so difficult or demanding that they result in poor patient compliance, protocol violations, and missing data.6 A schematicdiagram should be used in more complicated trial designs to illustrate the patient’s course of treatment while on protocol.3 The heterogeneity of cancer and the need for orderly developmentof new treatmentsis reflected by the various study designsthat are implemented. In a phaseI trial, the primary goal is to determine the maximally tolerated dose(MTD) of a new drug or drug combination with a given schedule. It also defines the quantitative and qualitative toxicities of the compound for future trials. The design of a phase I trial involves selecting a starting dose as determinedfrom preclinical toxicology, or in some cases,early clinical trials. This is followed by sequential dose escalations in groups of three or more patients until the MTD is achieved. At or near the MTD, six or more patients are evaluated at each dose level to better support and define the MTD and recommendeddose for phase II trials.7 PhaseII studies are performed in a specific tumor type to obtain an approximation of the antitumor effect of a treatment or combination of treatments. Other endpoints of this phase may include the assessmentof drug schedule dependency and the evaluation of cumulative and delayed toxicity. PhaseII trial designstypically use a fixed dose and schedule that may or may not incorporate other treatment modalities such as surgery and/or radiotherapy. Based on the observed treatment-related side effects, instructions for dose adjustmentsare important for the conduct and evaluation of the trial. PhaseIII trials are randomized studies in which the efficacy and toxicity of two or more treatments will be compared. These trials are generally more complex in their design. They may compare the results of efficacy trials with a new drug to standard treatment, or may involve integrating treatment regimens with other modalities such as surgery, radiotherapy, or biological responsemodifiers. The use of randomized trials is considered an effective method of achieving scientifically valid improvements in the treatment of cancer.’ In ran-

PLANNING AND IMPLEMENTING CLINICAL TRIALS

domized studies, neither the investigator nor the patient know which treatment the patient will be allocated to before registration on the study. In double-blind randomized trials, neither the patient nor the physician know which treatmentthe patient receives until after the patient stops therapy. The purpose of randomization is to remove potential biases in allocating patients to each treatment so that similar numbers of “like” patients receive each treatment. Blinded studies are particularly useful in situations where investigators are likely to expect different toxicities or effectiveness.439 Unbiased comparability in treatment arms dependson several factors. Criteria for patient selection should be the samein all arms of the protocol. Randomization should take place as close as possible to the time at which treatments diverge. In many studies this is at the initiation of therapy. In others, however, all patients receive the sameinitial treatment with differences occurring later in the study. The benefit of delaying randomization is that, in general, fewer patients will go off study after randomization, thus removing the potential bias caused by “drop-ins” and “drop-outs.“” Regardlessof the timing of randomization, toxicity assessment, patient management, and removal from the study should be treated similarly. Most important, criteria to determine the treatment effectiveness must be comparable in all aims.334311 Randomization alone cannot assurebalance between treatment groups.3x1’It is important to prospectively identify prognostic factors so that patients with different characteristics are allocated equally between treatment groups. These stratification factors may include patient characteristics such as diseasestage, age, performancestatus, and percentageof weight loss. For example, if an adjuvant therapy study is conductedin which patients with node-negative and node-positive breast cancer are eligible, the protocol should stratify for nodal status. If stratification were not done, one treatment group might have an excessive number of patients with node-negative disease. As this group has a better prognosis, differences in treatment outcome may be a result of this imbalance in prognostic groups, greater efficacy of one of the treatments, or both. As the sample size increases, stratification factors become less important becausethe likelihood of having clinically meaningful imbalances between treatment groups decreases.9

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Study Endpoints

The primary goal in cancerclinical researchis to develop new therapeutic strategies that will improve the care of patients with cancer. Endpoints in determining the efficacy of new treatmentshave traditionally included survival, disease-free survival, response rate, duration of response, and treatmenttoxicity. Regardlessof the endpoint to be measuredor evaluated,protocols must include precisely statedcriteria that are evaluatedin a systematic fashion to avoid bias. The type of study being conductedusually dictates the intended endpoints. PhaseI trials by definition are dose-finding studies that use toxicity as a major endpoint. Although focus is on toxicological information, phaseI trials are conducted with therapeutic intent. Evaluation of response in these initial trials is a secondary goal. In phaseII and III efficacy trials, the endpoints may vary according to the specific disease and whether or not other effective treatmentsare available. For example, a phase II trial in malignant melanomawould have very different expectations and endpointsthan a trial in patients with germ cell tumors. Becausethere is little effective treatment for metastatic melanoma, the sole endpoints may be identifying the responserate and toxicity of a new therapy. On the contrary, germ cell tumors are known to be chemosensitiveand therefore such a trial would focus on a more narrowed definition of responsewith the critical endpoint being the induction of complete remission. Additionally, duration of response,survival, and degree of toxicity may receive major attention.l2 In phase III trials, improvement upon existing treatments is primary. Stricter endpoints such as improved rates of complete responseand prolonging the disease-freeand overall survival are important. The clinical research history of MOPP (nitrogen mustard, oncovin, prednisone, and procarbazine) in the treatment of Hodgkin’s disease provides an example of how phase III trials may change the primary focus of their endpoints.i3 In the first generation randomized studies of MOPP, completeremission was a critical endpoint but disease-freesurvival, overall survival, and acute toxicity also became important. By the time of the second and third generation trials, the major endpoint was survival and assessmentof long-term toxicity.

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Quality of life hasrecently becomean additional valuable endpoint in measuring the outcome of cancer treatment.14-17Over the past decade, the effect of treatment on one’s well being has gained increasing importance in patient management. Quality of life is multidimensional and difficult to define and assessdue to individual perceptions, attitudes, and judgements. Efforts are now under way to develop evaluation standardsthat will facilitate the inclusion of quality-of-life measures and endpoints in future clinical trials. 16-19The National Cancer Institute supports these efforts and has included improvement of quality of life as a high priority endpoint in cancer trials. 18,*’ PROTECTION OF RESEARCH PARTICIPANTS

The protection of patients participating in clinical trials is paramount to its conduct. Since the early 1960s Institutional Review Boards (IRB) have served the public as patient advocatesat institutions where researchinvolving human subjects is performed.21The composition and activities of thesecommitteesare guided by federal regulations and include physicians, nurses, clergy, scientists, lawyers, and lay people who are not affiliated with the proposed research project. This committee is designed to ethically review a proposed study for scientific validity and most importantly for the risk/benefit concernsof the participants. Approval by the IRB is required before a clinical protocol can be activated and then is annually reviewed until study completion. Investigators are required by law to obtain informed consentof all participants before entry into a clinical trial.4 Informed consentis obtained when verbal and written explanation of the content of the study is assimilated and understood. The patient must also be given the opportunity to consider, without coercion or persuasion, his or her willingness to participate. The specific elements of informed consent mandated by federal regulation** are outlined in Table 2. These required guidelines offer protection of patients’ rights by providing them with important details regarding their participation. It is fundamentally necessarythat the consentform be written in languagethat is understandable to the patient. It should be emphasizedthat patients may terminate participation in the study at any time without jeopardizing their continued care. Conversely, the investigator may also terminate a

Table 2. Elements

Required

for Informed

AND WHITACRE

Consent

Statement regarding: Investigational nature of the study l Study purpose l Description of drugs, treatments, or techniques that are experimental l Duration of participation l Description of procedures to monitor the patient Description of potential risks and benefits Disclosure of treatment alternatives to participation Statement of confidentiality Explanation of compensation and emergency treatment Names and numbers of persons to contact for further information regarding the study (both for patient rights and research-related questions) Statement of voluntary participation: care will not be compromised for refusal or discontinuation of participation l

patient’s continuation in a study in the event of disease progression or life-threatening toxicity .23,24 The diagnosis of cancer with few treatment alternatives or failure of several prior treatmentscan make the patients particularly vulnerable research subjects.25’26 They may feel that participation in a researcheffort is necessaryas they cannot wait for the outcomeof the investigation. A number of cancer patients, while motivated to participate in clinical trials by hope of their own response,also genuinely express their willingness to participate in order to contribute to scientific information that may help other cancer patients.24In all cases,the study investigator must consider the risk/benefit ratio for each individual participant. QUALITY CONTROL

Quality control is as important to the conduct of clinical trials as is good planning. Clinical trial activities are monitored for quality data to assure valid results. Built-in measuresfor assessingquality should consist of a well-established, ongoing processthat begins with development of the protoco1.27Before activation, protocols are subjected to multiple levels of approval for scientific validity, feasibility, and the protection of human rights. When the approval processis complete, emphasis is then placed on monitoring the data during the conduct of the study. It is important that eachmonitoring systembe prospective so that corrective action can be taken. Such a “check” is designed to assesscompletenessand accuracy of the informa-

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tion acquired. Whether the study is conductedas a single institution or as part of a multicenter cooperative group, this responsibility lies first with the protocol-coordinating team within eachinstitution, followed by the study sponsors or group-wide quality control committee. It must be assuredthat each patient entered has met the study eligibility requirements and has signed a consent form. All data relevant to the patients’ treatment and followup care are recorded on standard study report forms or flow sheets.These data are forwarded at designatedintervals to a central data office. At the data office, all information undergoesan impartial review for accuracy, consistency, and completeness. If discrepancies are found, the involved investigator and/or institution is notified and corrections, clarifications, or additional information are requested.The overall patient data and summaries are checked by the principal investigator or study chairpersonwho continually evaluatesthe progress of the study. Reports summarizing the quality of the data are compiled and include degree and frequency of deviations in the protocol. It is important that each institution provides adequate support within its own system to allow prompt reporting of data and to facilitate accurate and timely evaluations.* Delayed reporting can seriously effect the study analysis and often give misleading results, such as advantageof one treatment over another.27Of utmost importance is the prompt reporting of adversedrug reactions. Once a serious toxicity is reported, this information is immediately communicated to all investigators conducting a similar trial with the samecompound or regimen in order to alert them of the potential toxicity and hopefully avoid similar occurrences. A critical link in quality control includes a site visit to participating centers. These are conducted by the sponsoring firm or cooperative group auditing committees. During these visits, the data which were submitted to the central data office are verified by review of the original medical records, drug accountability records, radiotherapy records, radiographic documents, and any other associated details. Cooperative groups sometimes require central review for confirming pathological diagnosis and review of radiotherapy port films.* The importance of quality control measurescannot be overemphasized.Efforts to maintain quality control in clinical trials is vital to assuring the validity of the conclusions.27

NURSING PARTICIPATION AND RESPONSIBILITIES

The successof a clinical trial is dependenton the efforts of a multidisciplinary team. Although many responsibilities are shared among the research team members, it is the unique expertise of the individual professionsworking collaboratively that constitutesits overall success.’Nurses are integral members of the clinical research team whether their focus is primary patient care or the conduct of clinical trials. Nurseswho deliver primary care to patients participating in researchtrials play an important role. Although their specific patient care responsibilities vary, they provide individualized care on an ongoing basis over multiple hospital admissions and Maintaining continuity of outpatient visits. 25*28,29 care significantly contributes to the physical and emotional well-being of patients treated on protocols and the successof the investigation. Nurse practitioners offer a relatively new and unique dimension to the research team. These nurses, trained in physical diagnosis, treatment, and medical management,representan effective means of maintaining both quality researchand patient care while maximizing use of limited resources. For purposesof this article, we will focus predominantly on the role of the oncology research nurse whose specialty pertains to clinical trials. Basic to this role is a detailed understandingof the principles of oncology combined with an overall appreciation and knowledge of the purpose and design of phase I, II, and III trials. Oncology research nurses can contribute to all aspectsof the clinical trial process3o from design and conduct through analysis, scientific presentation, and publication (Fig 1). Development of the Clinical Protocol and Consent Form

Once the details concerning the plan of investigation are outlined or written in protocol format, nurses in a variety of settings participate in the planning and/or review of protocols before activation.5231Cooperativegroups such as the Southwest Oncology Group (SWOG), Eastern Cooperative Group (ECOG), and Cancer and Leukemia Group B (CALGB) recognize the value of nursing participation at this level. Within these groups, nurses

PROTOCOL DEVELOPMENT AND CONSENT FORM a Review for feasibility 8 nursing responsibilities 0

Participate/write

consent form

1

IRB APPROVAL AND PROTOCOL ACTIVATION Prepare & submit for approval Process amendments

l l

CONDUCT OF THE CLINICAL TRIAL Patient & Staff Education 0

Provide general information

l

Coordinate

regarding

8 provide continuity

the specific

protocol/treatment

of care

Screeninq for Protocol Eliclibility 0 Assess patients for study entry according

to eligibility

criteria

informed Consent l

Ensure patients comprehend aspects of the trial

0

Assist patients in their decision

the investigational to participate

nature of treatment

by acting as patient advocate

Administration of Treatment and Companion Studies 6 Register patient for study entry 8 randomization (ii appropriate) l

Assess patient prior to initiation of therapy supportrve care

0

Administer

l

Observe,

0

Obtain pharmacokinetic indicated

treatment

at specified

& determine

dose and schedule

quality of life evaluations,

Follow-UP Evaluations 0 Schedule required studies l

Maintain follow up and monitor protocol

l

Evaluate delayed/cummulative

adherance

toxicities

Data Collection & Anal& 0

Assure ongoing

l

Complete

l

Participate in overall study review: toxicity, response, assessment of evaluable/inevaluable patients

l

Correspondence with IRB 8 Drug Sponsor Assist with audits

0

needs for

record and report all acute toxicities sampling,

data collection

& submit data forms; review quality of data

STUDY TERMINATION l

Participate

l

Prepare for publication

/ present study results

Fig 1. Nursing

responsibilities

& all

in clinical

trials.

etc., if

PLANNING

AND IMPLEMENTING

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TRIALS

actively participate in disease-orientedcommittees and review all protocols developedfor clarity, feasibility, and nursing responsibilities. Such a review permits the study to be performed uniformly by all involved participants. In reviewing protocols for feasibility, nursesexamine whether the proposed treatment plan/ scheduleand study requirements including special or companion studies are attainable with respectto time, space, manpower, and patient resources.As a patient advocate, the nurse considers issuespertaining to risk/benefit and quality-of-life of patients during study participation. Attention must also be directed at whether protocol adherenceand patient compliance is possible with respect to the overall study design. At completion, the protocol should be a self-contained document that the nurse and other study investigators use with a clear understanding of its contents and achievable endpoints. The oncology research nurse may assumeprimary responsibility in writing the consent form or participate as a reviewer to ensurethat appropriate, understandable, and meaningful information is outlined for the patient.5*23M25 After the protocol and consent are approved by the sponsoring organization (National Cancer Institute or pharmaceutical company), the nurse may be responsible for submitting the document for approval to the institutional IRB and/or other required hospital review committees. Implementation and Conduct of the Clinical Trial With activation of the protocol, the oncology research nurse acts as consultant to other health professionals caring for patients on research protocols. Information regarding the rationale for conducting the study and specific protocol requirements is disseminated to all involved participants to insure continuity and quality of patient care throughout the treatment. As coordinator for the study, the researchnurse assumes an active role in determining whether patients are eligible for entry on the clinical trial.5,23-25732333 Specific eligibility requirements including organ function, performance status, and the patient’s general medical and mental statusare reviewed to be certain that the patient’s prior or concurrent conditions will not be adversely effected by receiving the proposed treatment. Physicians and nursestogether must assumeresponsibility for obtaining an informed consent.5’34

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They must be certain that patients comprehendthe investigational nature of the proposed treatment, the potential risks and benefits, as well as any treatment alternatives. The specifics of the treatment including route of administration, duration of therapy, and frequency of treatmentsmust be discussed in a manner that is understandableto the patient. Special study requirementsie, blood sampling, bone marrow procedures,and incorporation of other treatment modalities such as surgery or radiotherapy, must also be outlined in detail. If the study involves randomization, the physician and nurse needto explain the randomization processin simple terms similar to that of a “flip of a coin.” All treatment arms must be outlined as it often is unknown which treatment the patient will be assigned to at the time informed consentis obtained. Patients must also understand the importance of regular follow-up evaluations to assessboth toxic and favorable effects of treatment. Chemotherapy administration and management of treatment-relatedtoxicities is an area in which nurses have gained unprecedentedexpertise.23V35-37 In preparation for treatment administration, pretreatmentstudies and the patient’s clinical status are again reviewed to assessongoing eligibility and evaluated for any newly developed contraindications for therapy. Before treatment administration, the researchnurse should confirm the correct drug dose(s) and insure that the plan for administration is in accordancewith that outlined in the protocol. If indicated, supportive measures such as antiemetics or antipyretics must also be considered. Proper and safe drug delivery cannot be overemphasized. One of the objectives of clinical researchtrials is to collect information regarding acute, cumulative, and delayed toxicities of cancer therapy. Whether the treatment involves a new investigational agent with uncertain toxicities or a standardtherapy, the potential effects in a given patient cannot always be predicted. A major responsibility of the research nurse is to identify and document drugrelated toxicities and evaluatethem with respectto severity and reversibility. Patients are carefully monitored during and following drug administration for both expectedand previously unidentified side effects. The assessmentof toxicity is continued throughout the treatment course to evaluate both delayed and cumulative effects. Communication and accuraterecording of this information is essential. With this information the researchnurse

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then collaborates and informs those involved in the research project and primary care of the patient including the study investigator, sponsors, and care providers. All life-threatening reactions and fatal eventsmust be reported within 24 hours to the study sponsor.This in turn is disseminatedto other investigators studying the sametreatment in order to alert and caution them of potentially harmful effects that may require treatment modifications or put the trial on hold.38 Regardlessof the study design, an important aspect of any trial is the identification of antitumor effect. Research nurses, together with the study investigator and/or primary care provider, evaluate responseto treatment using specific responsecriteria outlined in the protocol. Other responsibilities of researchnursesinvolve measuresdesigned to assurequality data and conduct of the trial. As co-investigators, the physician and nurse review and discuss the data on an ongoing basis to insure patient safety and evaluate the progress of the study.5 Additionally, research nurses are involved in site visits or audits conducted by the study sponsor to verify treatment administration, reported toxicity, and response

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data. In this role, nursesshareresponsibilities with physicians for correspondencewith IRBs and drug sponsors, particularly with respect to reporting toxicities, requesting protocol amendments, and providing interim and final study reports. Finally, research nurses participate in the analysis of the study results and assist in the preparation of data for presentationat scientific meetings and publication. CONCLUSIONS

Advances in cancer treatment are achieved through the conduct of carefully planned and wellorganized clinical trials. The protocol provides a framework that clearly describesthe proposed experiment and outlines the meansfor achieving specific endpoints. Important issues in planning and implementing cancer trials include protecting research participants and assuring quality control. Oncology researchnursesplay an important role as members of the multidisciplinary research team. Their involvement in the design and conduct of trials has had a favorable impact on the quality of researchconductedand quality of patient care provided .

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