ABSTRACT

Publicly sponsored trials, conducted primarily by cooperativegroups sponsored by the National Cancer Institute, and com-mercially sponsored trials are necessary to create newknowl-edge, improve thecareofoncologypatients, anddevelopnewdrugs and devices. Commercial sponsors launch clinical trialsthat will result in drug approval, label extension, expansion ofmarket share, and an increase in shareholder value. Con-versely, publicly sponsored trials seek to optimize therapy foraparticulardisease, createnewknowledge,and improvepub-lic health; these trials can also result in label extension of adrugandeven in initialdrugapproval.Publiclysponsoredtrialsmay combine and/or compare drugs developed by differentcommercial sponsors, develop multimodality therapies (e.g.,the combination of chemotherapy and radiation), or developnovel treatment schedules or routes of drug administration(e.g., intraperitoneal chemotherapy). Publicly sponsored tri-als are more likely to focus on therapies for rare diseases and

to study survivorship and quality of life; these areas may notbe a priority for commercial entities. Screening and preven-tion strategies havebeendevelopedalmost exclusively by thepublic sector given the large sample size and long follow-upperiodneeded to complete the trial and, therefore, the lackofshort-termcommercial gain. Finally, giventhepublicnatureofthe funding, clinical investigatorsareexpectedtopublish theirresults even if theoutcomesareunfavorable for the investiga-tional therapy. With the ongoing reorganization of the coop-erative groups to form a national clinical trials network,opportunities exist to create a robust platform for biomarkerdiscovery and validation through the expanded collection ofwell-annotated biospecimens obtained from clinical trial par-ticipants. Thus, publicly funded trials are vital to developingand refiningnewcancer treatments anddisseminating resultsto themedical community and the general public. TheOncolo-gist2013;18:000–000

INTRODUCTION

Thereare twomainsponsorsofcancer therapeutic trials in theU.S.: (a) publicly sponsored trials, conducted primarily by thecooperative groups sponsored by the National Cancer Insti-tute (NCI), soon tobeknownas theNationalClinical TrialsNet-work (NCTN) and (b) commercially sponsored trials. Bothtypes of trials are necessary to create new knowledge, ad-vance the care of oncology patients, and develop new drugsand devices. Despite these similarities and a commonmissionto improve outcomes for patients with cancer, the goals ofpublic and commercial sponsors ultimately diverge (Table 1).Commercial sponsors launch clinical trials that will result indrug approval, label extension, expansion of market share,andan increase in shareholder value. Publicly sponsored trialsseek to optimize therapy for a particular disease, create newknowledge,and improvepublichealth; these trials canalso re-sult in label extension of a drug and even in initial drug ap-proval. Because publicly sponsored trials often dependon theavailability of commercialized drugs and technologies, thesestudies may be performed in collaboration and with supportof a commercial sponsor. A report issued by the Institute ofMedicine on comparative effectiveness research noted that“publicly funded clinical trials play a vital role by addressingquestions that are important to patients but are less likely to

be toppriorities of industry” [1]. In general, commercial spon-sors have little interest in studying the optimal dosing of com-mercially available or generic agents, the integration ofcombined modality therapies into treatment paradigms, orcomparing the effectiveness of established therapies. Studiesof radiation and surgical therapies also often lack commercialsponsors.

Publicly sponsored trials often seek to directly comparethe effectiveness of various treatment options. They maycombine and/or compare drugs developed by different com-mercial sponsors, develop multimodality therapies (e.g., thecombination of chemotherapy and radiation), or developnovel treatment schedules or routes of drug administration(e.g., intraperitoneal chemotherapy for ovarian cancer). Pub-licly sponsored trials are more likely to focus on therapies forrare diseases and to study survivorship and quality of life;these areas may not be a priority for commercial entities. Bycollecting and banking biospecimens, these trialsmay be ableto identify patient and tumor subsets that are most likely tobenefit from the intervention being studied or experience se-vere toxicities or poor outcomes. Given the public nature ofthe funding, clinical investigatorsareexpectedtopublish theirresults even if the outcome is unfavorable for the investiga-

Correspondence: Richard L. Schilsky, M.D., American Society of Clinical Oncology, 2318Mill Road, Suite 800, Alexandria, VA 22314, USA. Tele-phone: 571-483-1315; Fax: 571-366-9551; e-mail: richard.schilsky@asco.org Received October 31, 2012; accepted for publication January 7,2013; first published online in The Oncologist Express on January 30, 2013. ©AlphaMed Press 1083-7159/2013/$20.00/0 http://dx.doi.org/10.1634/theoncologist.2012-0423

Publicly FundedClinical Trials and theFutureofCancerCare

RICHARD L. SCHILSKYSection of Hematology-Oncology, The University of Chicago, Chicago, Illinois, USADisclosures of potential conflicts of interestmay be found at the end of this article.

TheOncologist®

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tional therapy. Finally, screening and prevention strategieshave been developed almost exclusively by the public sectorgiven the large sample size and long follow-up period neededto complete the trial and, therefore, the lack of short-termcommercial gain (Table 2).

IMPACT OF THE COOPERATIVE GROUPSThe publicly funded cooperative group program was estab-lished in1955with thegoalsof conductingclinical trialsofnewcancer treatments, studyingcancerpreventionanddetection,andassessingqualityof lifeduringandaftercancer treatment.At the time of their formation, virtually all cancer drug devel-opment was supported by the NCI because the pharmaceuti-cal industryhadnotyetassembledthenecessary researchanddevelopment infrastructure to develop anticancer drugs.From their inception, the cooperative groups have had an es-tablished infrastructure with administrative and data man-agement centers that are organized to develop and conducttrials, as well as quality assurance programs to ensure proto-col adherence and accurate data. With the inclusion of theCommunity Clinical Oncology Program, many trials are con-ducted in settings that are similar to those in which the inter-vention will be employed in practice [2]. The cooperativegroup program includes more than 14,000 oncology profes-sionals working atmore than 3,100 unique sites, enrolling pa-tients thatarerepresentativeof theU.S.populationasawhole[1]. With its biorepositories, image archives, and referencelaboratories, the cooperative group program is able to collecthigh-qualitybiospecimensand images for researchthatwill al-low investigators to furtherdeveloppersonalizedcancer care.Publicly funded clinical trial groups also operate internation-ally, such as the National Cancer Institute of Canada (NCIC)Clinical Trials Group, and the European Organization for Re-search and Treatment of Cancer, these groups are funded byphilanthropyaswell as government; and through foundationssuchastheMultipleMyelomaResearchFoundationandStandUp to Cancer.

Publicly fundedclinical trials arewell suited tocompareef-fective and promising regimens with each other as well as tothe standard of care. Studies that directly compare prevailingtreatment regimens or agents that are recently introduced bydifferent sponsors for the same indication are unlikely to beperformed by commercial firms but generate informationthat is of high interest to patients and physicians. An early ex-ample comes from the treatment of non-Hodgkin lymphoma(NHL). Cyclophosphamide, vincristine, doxorubicin, andpred-nisone (CHOP) was the first combination chemotherapy regi-men for NHLwith proven efficacy in a cooperative group trial.In the decade following its introduction, alternative regimenswith six or eight different drugs were developed by academicinstitutions that reported higher response rates and seem-

ingly improved survival. The Southwest Oncology Grouplaunched a phase III study in 1986 comparing CHOP to (a)methotrexate, bleomycin, doxorubicin, cyclophosphamide,vincristine, and dexamethasone; (b) cyclophosphamide,doxorubicin, etoposide cytarabine, bleomycin, vincristine,methotrexate, and prednisone; and (c) methotrexate withleucovorin rescue, doxorubicin, cyclophosphamide, vincris-tine, prednisone, and bleomycin in patients with advancedstagediffuse largeB-cell lymphoma.Despitepromising single-institutionexperiencewitheachof these regimens, CHOPwasdetermined tobe the superior treatment as it had a similar re-sponse rate and overall survival compared to the other regi-mens andwas notably less toxic [3].

In 1996, the Eastern Cooperative Oncology Group (ECOG)reported results of a phase III trial comparing four differentplatinum-based doublet chemotherapy regimens that hadbeendevelopedfor treatmentofadvancednon-small cell lungcancer (NSCLC). The ECOG study randomized over 1,200 pa-tients to receive cisplatin/paclitaxel, cisplatin/gemcitabine,cisplatin/docetaxel, and carboplatin/paclitaxel, with a pri-mary endpoint of overall survival [4]. It is important to notethat three of the drugs (paclitaxel, docetaxel, and gemcit-abine)were being developed by three different pharmaceuti-cal companies for use in NSCLC as part of a platinum doublet,yet there was little data comparing the effectiveness of theseregimenstoeachother.TheECOGstudyestablishedthatnoneof the four regimens offered a significant advantage over theothers in termsof response rate or survival but differed signif-icantly in toxicity profile. Although this study did not lead to aclearadvance in treatmentofNSCLC, it provided important in-formation to help physicians and patientsmake informed de-cisionsabout theoptimal treatment regimenbasedonpatientpreferences, comorbidities, and tolerances.

More recently, the Cancer and LeukemiaGroupB (CALGB)completed study 40502, a randomized trial of weekly pacli-taxel compared toweekly nanoparticle albumin-bound (nab)-paclitaxel or ixabepilonewithorwithoutbevacizumabas first-line therapy for locally recurrent or metastatic breast cancer.The study sought to understand which of three anti-microtu-bule agents approved by the U.S. Food and Drug Administra-tion improved progression-free survival in combination withbevacizumab for the first-line treatment of metastatic breastcancer. CALGB 40502 compared the standard of care, weekly

Table 1. Goals of therapeutic clinical trials

Commercial sponsor Public sponsor

Register drug Optimize treatment

Label extension Label extension

Expandmarket share Create new knowledge

Create shareholder value Improve public health

Table 2. Role of publicly funded trials

Compare the effectiveness of various treatment options

Combine/compare drugs developed by different sponsors

Develop therapies for rare diseases

Address optimal dosing

Testmultimodality therapies, such as radiation therapy incombinationwith drugs

Identify patient and tumor subsetsmost likely to benefit frominterventions

Study screening and prevention strategies

Focus on survivorship and quality of life

Publish negative results

Assess cost and cost-effectiveness

Provide “gold standard” databases for registry studies

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generic paclitaxel, with two novel branded agents, albumin-bound nab-paclitaxel and ixabepilone, that are marketed bydifferent pharmaceutical companies and are considerablymoreexpensive thangenericpaclitaxel. Twopreplannedanal-yses of the primary endpoint (progression-free survival) bythe CALGB Data and SafetyMonitoring Board in June and No-vember 2011 determined that neither experimental armwaslikely to be superior to generic paclitaxel [5]. Importantly, thebiospecimens collected as part of this trialmay enable studiesthat provide insights into which group of patients are mostlikely tobenefit fromeachtreatmentarmbasedonexpressionof a number of putative predictive biomarkers.

Publicly funded clinical trials are also an important mech-anism to develop novel therapies for rare diseases with smallcommercial markets and to optimize the dosing and schedul-ing of commercially available agents. 5-Azacitidine, the firstFDA-approved treatment for myelodysplastic syndrome, wasdeveloped entirely through a series of publicly funded trialsconductedby investigators at theMount SinaiMedical Centerin New York City with the pivotal phase III trial performed bythe CALGB. The study showed clear clinical benefit for 5-aza-citidine comparedwithbest supportive care inevent-free sur-vival, time to progression to acute myeloid leukemia (AML)and patient quality of life [6]. Cooperative group studies alsodemonstrated the superiority of intraperitoneal chemother-apyover intravenous treatment for stage III ovarian cancer [7]as well as the favorable impact of “dose-dense” chemother-apy as adjuvant treatment for stage II breast cancer [8]. Thesestudies changed the standard of care simply by optimizing thedelivery of available drugs. Nowhere has this been more evi-dent than in treatment of pediatric acute lymphoblasticleukemia, forwhich a series ofwell-designedandefficientlyconducted publicly funded clinical trials improved the curerate of children with this disease from less than 10% tomore than 80% over four decades of clinical investigation[9].

Studies of combined modality therapy, such as chemo-therapy plus radiation, are generally of little interest to com-mercial companies and thus have been primarily pursuedthrough the public sector. Many of these studies have beenpractice changing andhave improvedpatient survival or qual-ity of life, such as the use of chemoradiation following surgerywhich established a new standard of care for patients withearly-stage gastric cancer [10], and the addition of cisplatinchemotherapy to radiation to enable organ preservation inpatients with laryngeal cancer [11].

Just as importantly, cooperativegroupstudieshave some-timesmoved the field away frommore aggressive therapy bydemonstrating similar outcomes and less toxicity for simplertreatment approaches. For example, in an era when thou-sands of women with breast cancer were seeking high-dosechemotherapy and stem cell transplantation based on the re-sults of single-institution, nonrandomized trials, the CALGBand other cooperative groups completed prospective ran-domized clinical trials that proved that such toxic and expen-sive therapy was not superior to more standardchemotherapy approaches [12], essentially putting an end tothe use of high-dose chemotherapy for treatment of breastcancer.

Cancer prevention studies have primarily been sponsoredby the public sector because commercial sponsors are gener-ally not interested in such studies that typically require a largesample size and a long time to reach the primary endpoint of

cancer prevention. TheNational Surgical Adjuvant Breast andBowel Project P2 study compared tamoxifen with raloxifenefor the prevention of invasive breast cancer (Study of Tamox-ifen and Raloxifene [STAR] trial) in a population ofwomen de-termined to be at high risk for invasive breast cancer [13]. Atthe time the study was conducted, tamoxifen had been ap-proved for the reduction of breast cancer risk (as well as thetreatment of breast cancer); raloxifene, a second-generationselective estrogen receptor modulator, had been developedas a drug to treat osteoporosis. In 2006, the study investiga-torspublished results showing that raloxifenewasaseffectiveas tamoxifen in reducing the risk of invasive breast cancer buthada lower riskof thromboemboliceventsandcataracts,witha median follow-up time of 47 months. The results of thisstudy lead to FDA approval of raloxifene for the prevention ofbreast cancer in postmenopausal women. The STAR trial wasupdated in 2010 after amedian of 81months follow-up time.Interestingly, the updated results indicated that althoughraloxifene still haddecreased toxicity in comparison to tamox-ifen, it no longer appeared as effective in preventing invasivebreast cancer [14]. The updated results revealed that al-though raloxifene had a decreased incidence of uterine can-cer, the rate of invasive breast cancerswas 24%higher than inpatients treated with tamoxifen. Both drugs can be consid-ered goodpreventive choices forwomenat high risk of breastcancer depending on a woman’s individual cancer risk, bonehealth, and gynecologic history. This type of trial likely couldhave been performed only in the cooperative group setting;although it resulted in a label extension for raloxifene, the du-ration of the study and large sample size (nearly 20,000 ran-domized patients) limited the interest of commercial entitiesin conducting such a trial.

In recent years, the rapidly rising costs of health care havefocused the attention of patients, physicians, and payers onimproving health outcomes, enhancing value in health careand improving health care delivery to individual patients. Asthe second leading cause of death in adults in the U.S., canceris a disease that affects many Americans and their families.The delivery of cancer care requires multiple medical special-ists, complexmedical systems, and toxic drugs; therefore, the

Studies of combined modality therapy, such as che-motherapyplus radiation, are generally of little inter-est to commercial companies and thus have beenprimarily pursued through the public sector.Many ofthese studies have been practice changing and haveimprovedpatient survivalorqualityof life, suchas theuse of chemoradiation following surgery which es-tablishedanewstandardofcare forpatientswithear-ly-stage gastric cancer, and the addition of cisplatinchemotherapy to radiation toenableorganpreserva-tion in patients with laryngeal cancer.

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cost of cancer care is increasingmore quickly than health carecosts in general. By conducting economic analyses alongsideclinical trials, publicly funded studies have been able to shedlight on the costs of cancer care in a way that commerciallysponsored studies are often unable or reluctant to do. For ex-ample, a cost-effectiveness analysis of Krasmutation testingtoguideadministrationofcetuximabwasperformedbasedondata from NCIC study CO.17. The analysis revealed a cost-ef-fectiveness ratio of $199,742 per life year gainedwhen cetux-imab is administered to all patients with advanced colorectalcancer, which could be reduced to $120,061 per life yeargained if the drug is administered only to patients with Kraswild-type tumors [15].

COMPARATIVE EFFECTIVENESS RESEARCHIn2009, the InstituteofMedicine (IOM)publisheda reportde-lineating the goals and promise of comparative effectivenessresearch (CER). Their report defined CER as the “generationand synthesis of evidence that compares the benefits andharms of alternativemethods to prevent, diagnose, treat andmonitora clinical condition,or to improve thedeliveryof care.The purpose of CER is to assist consumers, clinicians, purchas-ers, and policy makers to make informed decisions that willimprovehealth care at both the individual andpopulation lev-els” [16]. Table 3 outlines the goals and methods of CER de-scribed by the IOM.

Oncology has a rich history of improving clinical outcomesand advancing research through randomized controlled trials(RCTs). As described above, RCTs for oncology indicationshave led to thedevelopmentofnewdrugs that canpotentiallycure or improve survival of patients with cancer, refined themethods of delivery and scheduling of oncology drugs, identi-fied subpopulations of patients that aremost likely to benefit(or be harmed) from a specific therapy, and established theutilityofcombiningdifferent treatmentmodalities totreatpa-tients.Manyof these studies, often conductedby thenationalcooperative group program, fulfill the goals of CER as de-scribedbythe IOM.Thesetrialsalsoprovide investigatorswitha platform to prospectively study patient-reported outcomesand quality of life, aswell as to collect economic data for cost-effectiveness analyses and economic modeling. Thus, RCTscan be considered not only the criterion standard of efficacyresearch but the cornerstone of CER.

Comparative effectiveness research primarily seeks toevaluate the applicability and/or superiority of a particulartherapy among the existing options in real-world settings. Forexample, in recent years, minimally invasive surgical tech-niques such as robotic and laparoscopic procedures havebeen developed and replaced more invasive, open proce-dures. As new surgical innovations generally do not requireregulatory approval, newer techniques are often adopted inclinical practice without comparative research or RCTs. Forsurgical oncology, it is important to determine that the surgi-cal innovation not only decreases surgical morbidity but alsoproduces at least equivalent cancer-related outcomes. Lapa-roscopic colectomy was initially introduced for resection ofcolon cancer in the early 1990s. Subsequently, a randomizednoninferiority trial comparing laparoscopic colectomy toopen colectomywas conducted with 872 patients enrolled at48 institutions by the Clinical Outcomes of Surgical Therapy

(COST) StudyGroup [17]. After amedian follow-up timeof 4.4years, rates of tumor recurrence (the primary endpoint) andoverall survival in the twoarmswere found tobesimilarwithahazardratioof0.86 (95%confidence interval:0.63–1.17),withthe laparoscopic patients experiencing a 16% rate of recur-renceandoverall survival rateof86%.Thepatients in the lapa-roscopic group also had a faster perioperative recovery andshorter hospitalization.

The success of laparoscopic colectomy was also demon-strated in the U.K. Medical Research Council’s CLASSIC (Con-ventional Versus Laparascopic-Assisted Surgery in ColorectalCancer) trial, a randomized trial comparing laparoscopic ver-sus open colectomy [18]. These two RCTs, both performed inselected institutionswith experienced surgeons, provide con-clusive evidence that laparoscopic surgery is an efficacioustreatment for colon cancer. The translation of laparoscopiccolectomy to thegeneral populationwas recently analyzedbyBillmoria et al. [19], who examined the National Cancer Data-base to determine the outcomes of laparoscopic versus opencolectomy. The analysis demonstrated that laparoscopic co-lectomy is an effective option; among some groups of pa-tients, itwas associatedwith improved survival in comparisontoopencolectomy.However, the3-and5-year ratesofoverallsurvival in theanalysis (74.9%and64%, respectively)werenotas good as those obtained in the COST trial (86% and 76.4%overall survival rates at 3 and 5 years, respectively). This dis-crepancy in survival outcomes illustrates the difference be-tweenefficacy andeffectiveness thatmayoccurwhenanovelsurgical technique is applied in clinical practice.

Of course, not all advances supportedby clinical trial ev-idence lead to changes in clinical practice. Uptake of intra-peritoneal chemotherapy for treatment of advancedovarian cancer has been constrained by the technical diffi-

Table 3. Goals andmethods of comparative effectiveness

research

Goals

Directly inform a specific clinical decision from a patientperspective or a health policy decision from the populationperspective

Compare the intervention under study to the best/mostcommonly used alternatives in practice or development (notnecessarily placebo)

Describe results at the population and subgroup levels

Measure outcomes (both benefits and harms) that areimportant to patients

Employmethods and data sources appropriate for thedecision of interest

Be conducted in settings that are similar to those inwhich theinterventionwill be used in practice

Methods

Pragmatic clinical trials

Prospective observational studies

Prospective or retrospective registries

Meta-analyses

Literature review

Technology assessments

Adapted from [16].

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culty of the approach. Also, acceptance of tamoxifen forprevention of breast cancer among high-risk women hasbeen far less than predicted because of concerns about tox-icity in otherwise healthy women. It is also often difficult topull back from established interventions, such as postoper-ative breast irradiation following lumpectomy for olderwomen with breast cancer. In 2004, the CALGB publishedresults of a prospective, randomized controlled trial ofpostoperative breast radiation in women 70 years andolder who received tamoxifen for early stage, estrogen re-ceptor-positive breast cancer [20]. The data revealed noimpact on overall survival for use of breast radiation; in-deed, most of the deaths in this patient population werefrom causes unrelated to breast cancer. The data were up-dated in 2010 and confirmed the initial findings. Yet, a re-cent Surveillance, Epidemiology and End Results–Medicareanalysis of radiation use in older womenwith breast cancerrevealed no change in radiation use after publication of theclinical trial results [21].

LOOKING FORWARDInmore recent years, the pharmaceutical industry has largelyreplacedthepublicly fundedclinical trials infrastructureas theprimary mechanism for development of new anticanceragents. Nevertheless, cooperative groups, Specialized Pro-gramsofResearchExcellence, andotherNCI- and foundation-funded research programs retain an important place indeveloping new treatments and improving the quality of can-cer care. Through the collection of high-quality, clinically an-notated biospecimens from patients enrolled in prospectiveclinical trials, the cooperative groups are well positioned toidentify and validate prognostic and predictive biomarkers

that are necessary for the implementation of precisionmedi-cine. The CALGB, for example, has routinely collected leuke-mia specimens from patients with AML enrolled in CALGBprotocols for more than 20 years. These specimens have en-abled identification of many molecular subtypes of AML withvarying prognosis and have facilitated development of tar-geted therapies in some disease subtypes. A 2001 report byCALGB identified internal tandemduplicationof theFLT3geneas an adverse prognostic factor and FLT3 as a potential targetfor treatment [22].Thisobservation ledtothedesignofCALGB10603, a prospective randomized controlled trial of adding aFLT3 inhibitor tostandardchemotherapy inpatientswithAMLharboring the FLT3 internal tandem duplication or mutation.The study, developed collaboratively with a pharmaceuticalcompany sponsor, was conducted at sites in North and SouthAmerica and Europe, using standardized and harmonized lab-oratoryassays forFLT3mutations, toquicklyscreenandenrollthe required number of patients with this rare subtype ofAML.

The collection of tumor blocks from patients with coloncancer enrolled in CALGBadjuvant studies for stage II and IIIdisease allowed the group to assess the prognostic impor-tance of Kras [23] and Braf [24] mutation and to provide anindependent validation data set for the Onctoype Dx colonassay that was developed by a commercial firm [25]. Simi-larly, the collection of tumor blocks from patients with ad-vanced NSCLC enrolled in a randomized phase II study ofchemotherapy with celecoxib led to the hypothesis thathigh COX-2-expressingNSCLC has an adverse prognosis andthat celecoxib might be beneficial when added to chemo-therapy in patientswith COX-2 overexpressing tumors [26].

Figure 1. Reconfiguration of the adult cooperative groups. The Cancer and LeukemiaGroupB, North Central Cancer TreatmentGroup,and the American College of Surgeons Oncology Group have merged to form the Alliance for Clinical Trials in Oncology. The NationalSurgical Adjuvant Breast and Bowel Project, the Radiation Therapy Oncology Group, and the Gynecologic Oncology Group have joinedforces to formN-R-G. TheAmericanCollegeofRadiology ImagingNetwork (ACRIN)and theEasternCooperativeOncologyGroup (ECOG)havemerged to formACRIN-ECOG. SWOG (formerly the Southwest Oncology Group) has remained independent.

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These hypotheses are now being studied prospectively in arandomized clinical trial, CALGB 30801 [27]. These andother studies demonstrate the ability of the cooperativegroups to collect high-quality biospecimens from patientsenrolled in clinical trials as well as to conduct clinical trialsof targeted therapies in biomarker-selected populations.Indeed, the future of publicly funded clinical trials will likelydepend on the ability of the system to adapt its infrastruc-ture and procedures to achieve these goals of precisionmedicine. Going forward, the Alliance for Clinical Trials inOncology has developed a pilot protocol to perform pro-spective molecular profiling on tumors from patients withcertain advanced cancers with the goal of then matchingthose patients to prospective studies of targeted agents.

Despite its robust infrastructure and past achievements,the national cooperative group program has been criticizedfor its operational inefficiencies and slowness to adapt to newscientific opportunities. In 2009, the IOM issued a report thatlauded the accomplishments of the NCI Cooperative GroupProgrambut alsodelineated importantdeficiencies in the sys-tem [1]. The report noted system inefficiencies, such as pro-longedstartuptimesfor trialsandonlya50%rateofsuccessfultrial accrual. It was noted that the program has been ham-

pered by a 20% reduction in funding over the past decade anda cumbersome oversight infrastructure that reduces effi-ciency. The IOM report called for strengthening the publiclyfundedcancer clinical trials in theU.S., aswell as formodifyingthe system so that it is scientifically nimble, efficient in triallaunch and completion, and accessible to all members of theU.S. population.

These recommendations have prompted a reorganiza-tion of the cooperative group program, including themerger of several cooperative groups (Fig. 1). In addition,the NCI established an operational efficiency workinggroup with a goal of reducing study activation time by 50%by placing strict timelines on the clinical trial developmentprocess [28]. The cooperative group program is nowunder-going radical change as groups merge and re-organize toform theNCTN (Fig. 2). The goals of theNCTN are to providean essential national infrastructure for publicly funded tri-als in cancer prevention, screening, diagnosis, and treat-ment; to provide a unified national platform fortranslational research; and to efficiently answer importantclinical questions that are not well supported in a commer-cial environment. There are risks to replacing the coopera-tive group program, but there will be many rewards to

Figure 2. Schematic representation of the National Clinical Trials Network.Abbreviations: CCOPS, Community Clinical Oncology Programs; COG, Children’s OncologyGroup; DEA, Division of Extramural Activ-

ities; IRB, institutional review board; MB-CCOPs, Minority-based Community Clinical Oncology Programs; Mgt, management; NCI, Na-tional Cancer Institute; Ops, operations; Stats, statistics.

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patients if the publicly funded cancer research enterprisecan be transformed from a conventional clinical trials pro-gram into an engine for precision medicine and personal-

ized cancer care.

DISCLOSURESRichardL. Schilsky:FoundationMedicine (C/A,H,OI).(C/A)Consulting/advisory relationship; (RF)Research funding; (E) Employment; (H)Honoraria

received; (OI)Ownership interests; (IP) Intellectual property rights/inventor/patentholder; (SAB)

Scientific advisoryboard

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