Clinical Research by Community Oncologists

CA Cancer J Clin 2003;53:73-81

Volume 53 • Number 2 • March/April 2003 73

ABSTRACT Practicing and hospital-based community oncologists are increasingly

recognized as sources for clinical research activity. Although surveys have documented

patients’ and physicians’ willingness to consider participation in clinical research studies,

accrual to clinical trials by adults in cancer research studies remains embarrassingly low. This

may be due in part to a lack of knowledge about available studies by community oncologists,

a lack of time or interest, or a lack of resources to support the cost of performing clinical trials.

This article addresses these issues as an instructional module for community physicians

interested in increasing their activity in clinical trials or improving their abilities to facilitate

patient accrual to cancer research studies. (CA Cancer J Clin 2003;53:73-81.) © American

Cancer Society, 2003.

INTRODUCTION

A major mechanism to facilitate involvement of community physicians is theCooperative Group Outreach Program (CGOP), which was established in 1977.Asinitially conceived, any oncologist could accrue to Cooperative Group studies byaffiliating with a main institution of the group. This system does not require aspecific target for accruals to any particular study type (e.g., prevention, treatment,etc.), but does require a minimum number of accruals per year to remain active as agroup affiliate. Since data management for affiliates is still the primary responsibilityof the main institution, reimbursement for the cost of patient accrual and datacollection at the affiliate has been variable and often not enough to cover the costof participation in clinical trials.1,2,3,4

The National Cancer Institute (NCI) recognized the opportunity for increasedinvolvement of cancer specialists in clinical trials accrual with the initiation of theCommunity Clinical Oncology Program (CCOP) in 1983.1 In this program,community hospitals may compete for independent funding to support their clinicaltrials program through a recognized research base such as the Eastern CooperativeOncology Group (ECOG), Southwest Oncology Group (SWOG), Cancer andLeukemia Group B (CALGB), etc. This model of grant support for research bycommunity investigators has been highly successful, quelling the doubters whobelieved that research belonged only in the arena of academic institutions.1,2,3

Practicing physicians proved to be eager and capable participants in cancer clinicaltrials, providing useful data quality, appropriate adherence to eligibility criteria,effective observance of treatment protocols, and successful long-term follow-up.However, the number of physicians who could contribute to studies through

Clinical Research by CommunityOncologistsGary I. Cohen, MD

Dr. Cohen is Director, CancerCenter, Greater Baltimore MedicalCenter, Baltimore, MD, andAssistant Professor, Oncology,Sidney Kimmel ComprehensiveCancer Center, Johns Hopkins,Baltimore, MD.

This article is available online at:http://CAonline.AmCancerSoc.org

CCOPs is still limited. Participating physiciansmust be affiliated with a hospital (or group ofhospitals/clinics) that can successfully competefor a grant requiring documentation of theability to accrue substantial numbers of patientsto both treatment and prevention cancerresearch studies.1

The Clinical Trials Support Unit (CTSU) isa new program designed to broaden the base ofcommunity clinical investigators. Afterregistering online (www.ctsu.org), individualoncologists who do not have any CCOP orCGOP affiliation can participate in high-priority cooperative group studies.The CTSUmechanism also offers the option of using acentral Institutional Review Board (IRB) tofacilitate use in community hospitals. Areasonable reimbursement is provided for eachpatient accrued to help defray administrativecosts of the treating oncologist.

The CCOP and CGOP programs have beenhighly successful in promoting involvement bycommunity physicians in cancer clinical trials.Currently, contributions by CCOP and CGOPparticipants represent about two-thirds ofaccrual to Phase III cooperative group studies.1

More importantly, practicing oncologists havebecome a valued part of the research team,providing input on everything from initialstudy design to data collection, follow-upissues, consent documents, etc. Identifying the“standard of care” is essential for clinical trials,especially as it relates to coverage of treatment-related costs for patient care by third partypayers. This appreciation is the specialcontribution of practicing physicians during thedevelopment of new Phase III clinical studies.

THE CHALLENGE OF CLINICAL TRIALS FOR

COMMUNITY INVESTIGATORS

Despite the promise of enhanced accrual to clinical trials by forging a partnership among community oncologists and academic

physicians, the overall participation of adultcancer patients in research studies is stillabysmal, involving only about three percent ofnewly diagnosed patients nationally.5,6 Accrual issomewhat better at programs that have acommitment to clinical trials such as those atacademic institutions or CCOPs with one-third of eligible patients agreeing toparticipate.5,7 However, the involvement ofadults in clinical trials is still far less than the 60percent of pediatric patients who are recruitedonto studies.8 Numerous surveys have exploredthe barriers to involvement, focusing both onpatients and on the treating physicians.5,6,7,9,10,11

Patients profess the interest and desire toparticipate in trials, if only they knewbeforehand about available studies!9 Physiciansclaim that the cost of doing studies is notprimarily a limiting factor, since they recognizethe importance of clinical trials and wish tocontribute!9,12,13 So what’s the problem?

It is likely that surveys which ask simplequestions about patient and physician attitudesdo not reflect the true difficulties in matchingpatients with appropriate clinical trials.5 On asuperficial level, patients may be enthusiasticabout the altruistic concept of helping to find a“cure” for cancer. They may expect “researchstudies” to provide a treatment that is “better”than the current standard of care.14 Patients whoare evaluated at academic centers may be self-selected and more receptive to the possibility ofentering a clinical trial, but many patients atcommunity hospitals are less sophisticated anddo not expect to hear a discussion about“research” from the oncologist at their localhospital.3 Coupled with occasional “negative”media reports about the motivation ofphysicians performing clinical trials,15 patientsmay become very skeptical about participation(Table 1). However, despite some initialreluctance to agree to randomization, patientswho are properly educated and counseled maysubsequently agree to participate.16

Another subset of patients is far more

74 CA A Cancer Journal for Clinicians

Clinical Research by Community Oncologists

sophisticated, often identifying potential clinicaltrial opportunities on the Internet even beforetheir first encounter with a cancer specialist.These patients may already have formed anopinion that one particular study offers bettertreatment than another. They may bedisappointed that the choice of studies at oneinstitution is limited, and that they may not beable to simply enroll in any study that piquestheir interest. Reading lengthy consent formsmay further disillusion prospective participants,especially if the study design introducesconcepts such as randomization, placebos, etc.,which may not be fully understood after theinitial description of these procedures by theirphysician or the research assistant.17 Therefore,although patients ideally express enthusiasmabout clinical trials, their interest is oftentempered after an enlightened discussion withthe oncologist.

Physicians themselves may also have a naiveview on clinical trials.Although during surveysmany oncologists express interest inparticipation, few actually accrue patients. Therolls of potential affiliated CGOP investigatorswithin cooperative groups are large, but 80percent of patients enrolled from communityhospitals are entered by only 10 percent ofactive investigators.6 Not infrequently, a singleinstitution will have one or two effectivecontributors and several others who rarelyaccrue patients even though the resources forthose physicians (nurses, study coordinators,protocol availability, reimbursement oppor-tunities, etc.) should be equivalent. Thedifference may then reflect the comfort level orskill of the physician in imparting theimportance, value, and benefits of clinical trialparticipation to their patients.3

THE COST OF PERFORMING CLINICAL TRIALS

RESEARCH

Most oncologists deny that financial

incentives are the primary motivation in thedecision to participate in clinical trials.Nevertheless, inadequate reimbursement forcosts of trials certainly creates a barrier toparticipation, either directly or indirectly (Table 2).4,5,6,11 The availability of a dedicatedresearch nurse or (certified) research associate(CRA) is essential. Effective data managementcan not be performed by secretarial or office staffwho are not properly trained. Therefore, thecommitment to clinical trials research involvesa commitment to expand the office (hospital)payroll to facilitate the research study.The roleof the CRA may also include: completingexhaustive paperwork related to IRBrequirements;17,18 assuring that test proceduresare performed on schedule; monitoring testresults for appropriate treatment adjustments;reviewing physician notes to assure properdocumentation of responses or side effects, etc.Even when the assigned study treatment is“standard of care,” the complexity of caring fora patient “on study” may be much more timeconsuming (and therefore “costly”) for thetreating physician than caring for similarpatients not on study. The overall workefficiency of oncologists caring for patients onclinical trials may decrease if “the protocol”must be consulted each time a dose adjustmentis required or to ensure compliance withrecommended testing parameters rather than



Patients’ Concerns Regarding Clinical Trials

• Getting an “inferior” treatment.

• Excess tests.

• Uncertain/unknown side effects of “experimental” arm.

• Randomization: getting “placebo.”

• Investigator motivation: being a “guinea pig.”

• Costs not covered by insurance.

• Overwhelming information/consent form.

• Lack of flexibility in treatment schedule.

• Travel distance to a “treatment center.”

TABLE 1

simply using “good judgment” to address thoseissues.

Other hidden costs might include officeoverhead such as workspace, computer services,telephone, fax, etc., and secretarial support.Some studies might require test procedures thatcan not be billed to third party payers becausethey relate purely to a research question ratherthan being standard of care. For example, thecost of a second radiographic study performedone month after achieving remission, simply todocument stability of the response, should be

covered by the study sponsor.Claims that mightbe rejected by insurance must be anticipated inadvance and paid by a separate accountingsystem through the clinical trials budget.

It is difficult to get reliable estimates foracceptable workloads for CRAs.The Society ofClinical Research Associates (SoCRA)estimates that one CRA could effectivelymanage approximately 30 new patient accrualsper year.19 However, as a program matures, theincreased workload due to follow-up reportingrequirements on previously treated patients maysignificantly alter the equation. In addition, thenumber of new patient accruals may not alwaysaccurately reflect the work of the CRAs whomust check participant eligibility, test results,informed consent, and other items for allpotential study patients regardless of whetherthey ultimately agree to participate or not.Figure 1 shows the number of patients whowere evaluated for inclusion in clinical trials atGreater Baltimore Medical Center (GBMC)and the number of patients actually accrued,grouped in six-month intervals from 1997through 2001. There is significant variation inactivity by physicians, nurses, CRAs, andsupport staff in any time period.The fluctuationis due in part to differences in the number ofstudies available for common malignancies andphysician enthusiasm for those studies.

The physician encounter with a potentialcandidate for a clinical trial is very timeconsuming.The additional time could total fourhours.12 To practicing physicians in thecommunity, this extra time (which is nowunavailable for seeing other patients whoultimately help cover the overhead costs ofoffice expenses) represents a cost as well.Although personal remuneration for time spentmay not be a requirement by most physiciansparticipating in clinical trials, the reimbursementshould at least cover expenses (Table 3). TheNCI has estimated that the cost of performinggovernment-sponsored clinical trials averagesapproximately $3,000/patient (ranging from



Costs Associated with Clinical Trials byCommunity Physicians

• Personnel.

Nurse, Certified Research Associate (CRA).

Secretarial.

Pharmacist services.

• Office Overhead.

Workspace.

Computer access.

Phone, fax, mail, etc.

• Physician Time.

Review of study feasibility.

Institutional Review Board (IRB) involvement.

Discussions with patient.

Assuring compliance with protocol parameters.

• Meeting Time.

Loss of productivity.

Physicians, Nurses, CRA.

Travel expenses.

• Often overlooked expenses/time.

Assessing insurance issues.

Paying for non-covered protocol requirements.

IRB fees.

Audits.

Chart storage fees.

Legal advice for contracts with study sponsor.

TABLE 2

$600 to $5,000).2 While studies initiated bypharmaceutical companies usually providereimbursements that meet or exceed the cost ofperforming such trials, the more challengingand scientifically important cooperative grouptrials often do not. Oncologists are thereforeforced to choose whether to participate inclinical trials based on the amount ofreimbursement by the study sponsor, eventhough payment for study involvement may bea low priority for them overall.

At GBMC in 2001, the clinical trials budgetwas $330,000. Our mature clinical trialsprogram had 60 active studies, accrued 125patients to various studies, and had five full-time non-physician staff members. Therevenues obtained from various contracts andresearch affiliations in 2001 were $330,000.Therefore, although a financial commitmentwould be required for a new program (perhaps

for two to three years), it is likely that withgood management, clinical trials can eventuallybecome available to patients in communityhospitals with no additional expenses to thesponsoring institutions.

ONCOLOGISTS BENEFIT FROM PERFORMING

CLINICAL TRIALS

Although cancer physicians may incur costsbecause of clinical trials activity (both realexpenses and the “cost” of time spent withoutadditional remuneration), the benefits are alsoconsiderable.3,4 Oncologists performing clinicaltrials will be more aware of current treatmentoptions and available experimental therapies.Participation in national group meetings with ECOG, SWOG, CALGB, etc., repre-sents an excellent source of continuing med-



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*Six-month increments.

FIGURE 1

Greater Baltimore Medical Center (GBMC) Clinical Trials Activity, 1997 to 2001*

-ical education. Furthermore, the personalinteraction among community oncologists andexperts in the field enhances the opportunityfor subsequent consultations with world-renowned physicians via phone or e-mail in ajudicious manner. With their enhancedknowledge and “connections,” local oncologistsmay then become a resource to both patientsand other physicians as a “second opinion” inthe community. Their expertise may berecognized regionally and could justify a part-time faculty appointment at an academiccenter, which may further enhance theircredentials. More importantly, participation inclinical trials provides specialists with the self-satisfaction that they are contributing to a bodyof knowledge that every oncologist needs tocontinue providing patients with the bestpossible care. Expressed in that way, oncologistsshould feel a moral obligation to donate some of

their time to clinical trials.The main beneficiaries are our patients. At

GBMC,we offered paclitaxel to our ovarian andbreast cancer patients two years before it wasapproved by the Food and Drug Administration(FDA). Dozens of other therapies have beenavailable to our patients subsequently, includingmonoclonal antibodies, radiopharmaceuticals,growth factors, pegylated compounds, biologicresponse modifiers, Phase I agents, targeted small molecules, novel antiemetics, antisensecompounds, hormonal agents, prevention stra-tegies, cancer vaccines and angiogenesisinhibitors. These new therapies providedtreatment interventions for patients who hadlittle hope with their advanced or aggressivemalignancies. As these agents gain FDAapproval, the physicians who have used them in clinical trials become a resource to areaoncologists.

Another useful benefit of physician involve-ment in clinical trials is the carryover to nursingservices. Our nurses share the desire forexcellence, and have participated in nursingclinical trials directed at patient support,symptom control, quality of life, etc., resulting inregional and national recognition for our nursesand enhanced care for our cancer patients.

TALKING POINTS FOR PATIENTS

Physicians must budget additional time forpatients who may be candidates for clinicaltrials. The discussion should begin with aconceptual framework about “Here’s where weare today,” for treating the malignancy inquestion. This discussion involves a historicalapproach to “Here’s what has changed in ourtreatment over the past 10 to 20 years.” Theinference is that we have improved thetreatment (survival?) over that time periodbecause of the lessons learned from previousclinical trials. Now, “Here’s where we need togo,” is a natural evolution of the process of



Institutional Compensation for Clinical TrialsActivity

Per Patient*

Cooperative Groups

ECOG, RTOG, NSABP, GOG $1,000 - $2,400

Pharmaceutical Studies

Post marketing $500 - $2,000

Phase III $2,500 - $8,000

Phase I/II $6,000 - >$20,000

Other

Nursing studies none/grants

Quality of life none

Tissue bank/genetics none/variable

Compassionate use none

Investigator initiated none/grants

TABLE 3

*Values based on Greater Baltimore Medical Center(GBMC) experience.ECOG = Eastern Cooperative Oncology Group.RTOG = Radiation Therapy Oncology Group.NSABP = National Surgical Adjuvant Breast and Bowel Project.GOG = Gynecologic Oncology Group.

scientific discovery, which will lead us to evenbetter results.We need the participation of ourpatients to realize the promise of improvedtreatments for cancer. Some will participatebecause of the unselfish desire to be helpful,some out of fear that friends or relatives may getthe same disease and can benefit fromknowledge gained in the future. Some patientswill refuse for their own stated or privatereasons (Table 1). Such barriers to patientparticipation have been well describedelsewhere and will not be further reviewedhere. However, it is clear that while somepatients will have a failure of trust, which limitstheir desire to participate,15 others who eagerlyseek involvement in clinical trials will bedeemed ineligible because of rigid study entrycriteria.3,5,6

Many physicians feel insecure aboutrecommending studies that involve ran-domization or placebos.3,5,6,11,12 Although theymight have had similar discussions with patientsduring their fellowships at academicinstitutions, those patients may have been self-selected and more receptive to participation insuch studies. In choosing to participate in aclinical trial, the oncologist must first be certainthat he/she believes in the integrity of thescience, the feasibility of the treatmentprogram, and the benefit for patients. Areasonable “test” is for the investigator to askhim or herself whether he/she would bepersonally willing to participate in the study ifthe tables were reversed and he/she was thepatient? The answer to that question must be“yes.” When the patient finally asks, “Whatwould you do if you were me?” the physicianmust be honestly able to answer, “I would beenrolling myself into this study!” If that is notan honest answer, patients will likely identifyhesitation in the physician’s reply, and the trustbetween physician and patient could beunalterably affected.

ECOG 1594 is a good example of a PhaseIII randomized clinical trial involving four

seemingly disparate treatment regimens.20 Thiswell known study compared four differenttreatments for lung cancer: paclitaxel/cisplatin,gemcitabine/cisplatin, docetaxel/cisplatin, andpaclitaxel/carboplatin. In order to participate inthis clinical trial, the investigator must earnestlybelieve that each of the four study regimenstruly has potential effectiveness and acceptabletoxicity. One treatment arm uses paclitaxelgiven over 24 hours, although this schedule wasno longer “standard” by the mid-1990s and wasoccasionally rejected by insurance companies.Was the 75 mg dose of docetaxel too low forlung cancer treatment? Was 225 mg ofpaclitaxel too much? Was three weekly doses of1,000 mg of gemcitabine too myelotoxic? Whatwas the comfort level with either 75 or 100 mgof cisplatin in various arms? Finally, thetreatment cycle could be every three weeks orevery four, depending on the arm assigned, andmight involve treatment three weeks out offour, one week out of three, or hospitalizationfor 24 hours.



Discussion Points for Patients: EasternCooperative Oncology Group (ECOG) 1594

(Four different chemotherapy doublets for advancedlung cancer)

• Each of these therapies is currently used at somecenters; no placebo or “experimental” therapy.

• Each treatment has known activity in lung cancer.

• Historical response rates are approximately equal forall four regimens.

• There may only be differences in toxicity, but eventhis is important information for oncologists.

• Patients in clinical trials get more supervision (better care?).

• Advanced lung cancer is a major health problem;advancing our knowledge is essential.

• Information here may someday help others (family?)who may similarly suffer in the future.

TABLE 4

A full discussion about this protocol couldquickly swamp the patient with confusion. Ifthe investigator truly believes in the potentialequivalency of these treatment arms, thediscussion should focus instead on the sim-ilarities (Table 4). All of these regimens haveproven effectiveness in lung cancer. If there isno response, we can still consider second linetherapy.

After the discussion, which should onlybroadly review the various experimentaltreatment arms, the patient should be given theconsent form, introduced personally to aresearch nurse or CRA, asked to take theconsent form home to read, and asked tocommunicate any further questions with thenurse or physician.The CRA can then reviewthe chart for eligibility and recommend anyfurther tests required before starting the study.

A second example is NSABP B-33 forwomen who have completed five years ofadjuvant tamoxifen for breast cancer, and

involves randomization to two years ofexemestane or placebo. Although the use of“placebo”might disturb some patients, this is animportant study, and the placebo-based conceptis essential for scientific integrity.Talking pointsare outlined in Table 5.

GETTING STARTED

A mature clinical trials program can offernumerous opportunities for patients andphysicians, including interesting newcompounds prior to FDA approval. However,such community programs have a high level of complexity coupled with organizationalcomponents that rival that of the CCOPs thatare funded separately by federal grants.Although achievable, large programs shoulddevelop gradually. Here are some guidelines for starting a clinical trials program:

• Begin with no more than four or fivePhase III studies that are directed at commonmalignancies, and which are endorsed byseveral associated physicians. The effort shouldbe led by one highly committed physician.Theendorsement of respected local surgeons iscritical.10,13

• Choose studies that have clinical/scientificimportance and which will accrue well.

• Employ a dedicated oncology nurse orCRA on a full or part-time basis, but do notdivide his or her duties among other officeactivities.

• Consider participating in a pharmaceutical“Phase IV study” (post-marketing) or Qualityof Life/Supportive Care study to get started.These studies are useful to prime the staff forpatient eligibility questions, data collection,IRB issues, etc.

• Check out the following Web sites forstart-up help: www.clinicaltrials.gov, www.trialcheck.org and www.ctsu.org.21

• Have fun!



Discussion Points for Patients: National SurgicalAdjuvant Breast and Bowel Project (NSABP) B-33

(Exemestane versus placebo after five years adju-vant tamoxifen)

• There is no role for continuing tamoxifen beyond five years.

• The standard of care is “observation” alone.

• There is still some risk of relapse, even after five years.

• In the event of relapse, therapy would likely involveanother hormone, such as an aromatase inhibitor.

• Exemestane has little or no toxicity; some patientsnote arthralgias.

• Osteoporosis may actually be improved by exemes-tane, but this is not yet certain; osteoporosis can bemonitored and treated with medication if needed.

• The medications are provided free; no additionaltests or visits beyond the customary follow-ups.

TABLE 5

FINAL THOUGHTS

The number of new drugs available forcancer patients will continue to escalatethrough the next decade. Defining the propercombinations and sequences of therapeuticswill require careful, well-designed, largerandomized studies. The pharmaceuticalindustry now increasingly partners withcommunity investigators in an effort tocomplete studies quickly and get the data

necessary for FDA approval. However, evenafter approval, we often do not yet understandthe best way to use many of these drugs.Testingvarious combinations is important, but willnever be the primary focus of scientificinvestigations for our colleagues at academicinstitutions. Greater involvement in clinicaltrials by community physicians is an essentialelement of progress in our battle against cancer.We can win this war. CA



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Clinical Research by Community Oncologists