The Conduct of a Cooperative Clinical Trial (Recent Results in Cancer Research)

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The first workshop, Improving the Quality of Cancer Clinical Trials, held on October 4 and 5, , focused on the science underpinning clinical trials; collaborations among Cooperative Groups, industry, and academia; and the regulatory issues affecting clinical trial development, especially the early stages of development.

The second workshop, Multi-Center Phase III Clinical Trials and NCI Cooperative Groups, held on July 1 and 2, , explored the organization and operations of the Cooperative Group Program, patient and physician involvement in Cooperative Group research, and data collection requirements, as well as clinical trial cost and reimbursement issues. Throughout the workshops, speakers conveyed the importance of Cooperative Group clinical trials in setting the standard of care for cancer treatment, prevention, and detection. However, speakers voiced a number of concerns over the current system, prompting the workshop chair, John Mendelsohn, to note that there was general agreement among workshop participants that the Cooperative Group Program is approaching a state of crisis IOM, Other presenters discussed ways in which innovative trial designs, therapeutic combinations, drug-diagnostic codevelopment, molecular imaging, and correlative science have the potential to significantly improve cancer care if the barriers are appropriately addressed.

The NCI asked the IOM to examine a broad a number of topics relevant to cancer clinical trials and the organization and operation of the Cooperative Group Program and to make recommendations that could improve the quality of cancer clinical trials conducted through the program Box To address the charge, the IOM appointed a member committee whose members had a broad range of expertise and experience.

Among these individuals were experts in biomedical research, clinical investigation in academia and community practice, statistics, radiology, research and development in the biotechnology and pharmaceutical industries, management research, systems engineering, the health insurance industry, and patient advocacy. Attention will be focused on how to improve, modernize, and streamline the process, with special consideration given to the recent emphasis on targeted therapies due to an improved understanding of the biology of cancer.

Given the limits on funding for cancer clinical trials, there is a particular need to improve efficiency and make efficient use of time, effort, and resources. Specifically, the committee will recommend ways to. The committee recognized that the numerous reviews of the Cooperative Group Program have not resulted in transformative programmatic change.

Many aspects of the clinical trials infrastructure have not changed dramatically since the s, whereas biomedical discoveries and technology development have been advancing rapidly in recent years. The collective environment in which clinical trials are conducted influences the pace of clinical advances.

The committee then described the needs of an ideal cancer clinical trials system of the near future, circa see Box The committee envisions a dynamic system that could efficiently respond to emerging scientific knowledge, involve the broad cooperation of stakeholders, and leverage evolving technologies that could provide high-quality, practice-changing research. Clinical trial participation would be the preferred option for patients and physicians because it would provide access to innovative therapies that reflect patient preferences and that are appropriately reimbursed.

This list of ideal characteristics laid the groundwork for the committee deliberations to develop goals and specific recommendations to achieve them.


  • Starlight Lagoon.
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  • Collaboration Between Cooperative Groups and Industry: Journal of Oncology Practice: Vol 4, No 3.
  • Maid for Me?
  • Clinical Research Practices.
  • Clinical Research.
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The committee concluded that the academic, governmental, and commercial sectors must join with the public to develop a 21st-century clinical trials system to more effectively leverage scientific advancements and translate them into public health benefits by improving the science, technology, efficiency, and timely completion of the very best cancer clinical trials. The committee reviewed the available published literature and obtained input from experts in the field, interested individuals, and institutions to formulate its recommendations. Collaboration among stakeholders, with effective and timely communication, in developing the most promising treatments.

Streamlined procedures for rapid planning, approval, and launch of clinical trials, with accountability for meeting timelines and rewards for productivity. Efficient incorporation of new technologies and scientific questions, such as the identification and application of biomarkers and molecular imaging, into clinical trials. A strong publicly supported clinical trials system in the United States that complements commercial trials to develop drugs and devices. A highly efficient and flexible system for innovative, rigorously prioritized clinical trials.

Addresses questions and collects data that are relevant and meaningful to the diverse U. Publicly accessible tissue repositories with high-quality, fully annotated, and inventoried samples collected and stored in a standardized fashion. Chapter 2 provides an overview of the science underpinning the development of cancer therapies and the challenges that must be overcome to achieve the goals of personalized medicine for cancer. Chapter 3 provides an overview of the structure, organization, and funding of cancer clinical trials and the Cooperative Group Program. It also delineates the inefficiencies in the current system and discusses the collaborative nature of cancer clinical trials.

A consistent and dynamic process for rapidly setting national standards and unified procedures for new technologies such as diagnostics, with reproducibility and effective incorporation into clinical trials. Harmonized and synchronized rules and guidelines across federal regulatory agencies. Guidance grounded in an understanding of contemporary science as new paradigms develop for therapeutic approaches as well as for clinical trials methodology. Training and retention of professionals to efficiently and swiftly carry out important clinical research.

Recognition and appropriate rewards for collaborative clinical research in academic advancement and community practice careers. Adequate reimbursement of costs for actively participating institutions and physicians. Third-party payor coverage of nonexperimental costs of patient care to ensure that patients do not forgo participation in trials because of financial hardship. Participation in the design, implementation, and conduct of trials, and in the communication and dissemination of clinical trial results.

Chapter 4 examines the incentives and disincentives for participation in cancer clinical trials, for both patients and clinicians. Appendix A reviews the recommendations from past evaluations of the Cooperative Group Program and ongoing changes in response to those recommendations. Clinical trials trickling away. Drug Discovery and Development Quarter 3 7 , http: Coalition of Cancer Cooperative Groups. Patient advocates and cooperative groups. Seminars in Oncology 35 5: The Southwest Oncology Group: Progress in cancer research.

Globalization of the Radiation Therapy Oncology Group: Implementation of a model for service expansion and public health improvement. Journal of Clinical Oncology 26 7: Clinical Trials Cooperative Groups: The role of cancer Cooperative Groups within the spectrum of cancer care. Cancer Control 11 1: Improved survival in stage III non-small-cell lung cancer: Journal of the National Cancer Institute 88 Invisible barriers to clinical trials: The impact of structural, infrastructural, and procedural barriers to opening oncology clinical trials.

Journal of Clinical Oncology 24 Processes to activate Phase III clinical trials in a cooperative oncology group: The case of Cancer and Leukemia Group B. Development of clinical trials in a cooperative group setting: The Eastern Cooperative Oncology Group. Clinical Cancer Research Steps and time to process clinical trials at the Cancer Therapy Evaluation Program. Journal of Clinical Oncology 27 Publishing cancer clinical trial results: A scientific and ethical imperative.

The Oncologist 13 9: Communities as Partners in Cancer Clinical Trials: Changing Research, Practice, and Policy. Comparison of radical mastectomy with alternative treatments for primary breast cancer. A first report of results from a prospective randomized clinical trial.

Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. New England Journal of Medicine Tamoxifen for prevention of breast cancer: Journal of the National Cancer Institute 90 Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. Twenty-five year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation.

Global clinical trials activity in the details.

Applied Clinical Trials September 1, Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin FOLFOX4 for previously treated metastatic colorectal cancer: Journal of Clinical Oncology 25 The role of the Eastern Cooperative Oncology Group in establishing standards of cancer care: Over 50 years of progress through clinical research. Ethical and scientific implications of the globalization of clinical research. New England Journal of Medicine 8: The first 50 years of the Cancer and Leukemia Group B.

Final report of Intergroup Journal of Clinical Oncology 23 Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. Journal of Clinical Oncology 21 6: Impact of the Cooperative Groups , edited by B. IOM Institute of Medicine. Improving the Quality of Cancer Clinical Trials: The National Academies Press.

From screening to clinical research: The cure of leukemia and the early development of the Cooperative Oncology Groups, — Bulletin of the History of Medicine 76 2: Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. A pooled analysis of Eastern Cooperative Oncology Group and intergroup trials of adjuvant high-dose interferon for melanoma.

Clinical Cancer Research 10 5: Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach gastroesophageal junction.


  • Rear View Mirror The Contemporary Romance.
  • Ice Age.
  • Acknowledgment.
  • INTRODUCTION.

Journal of Clinical Oncology 17 5: Barriers to clinical trials. Knowledge and attitudes of health care providers. The role of cooperative groups in cancer clinical trials. Cancer Treatment and Research Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma.

Role of Clinical Trial Participation in Cancer Research: Barriers, Evidence, and Strategies

New England Journal of Medicine 6: Journal of Clinical Oncology 13 Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. Decades of Progress to Community Clinical Oncology Program. The promise and pitfalls of clinical trials overseas. Progress in childhood cancer: Progress in gynecologic cancer research: The Gynecologic Oncology Group experience.

Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. Journal of Clinical Oncology 18 8: Medicines in Development for Cancer Pharmaceutical Research and Manufacturers of America. Diagnostic performance of digital vs. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: A clinical trial coordinated by the Eastern Cooperative Oncology Group.

Journal of Clinical Oncology 24 3: Practicing on the tip of an information iceberg? Evidence of underpublication of registered clinical trials in oncology. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. Radiation Therapy Oncology Group. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer.

Prospective randomized trial of low- versus high-dose radiation therapy in adults with supratentorial low-grade glioma: Journal of Clinical Oncology 20 9: Organizational barriers to physician participation in cancer clinical trials. The American Journal of Managed Care 11 7: The ordinary miracle of cancer clinical trials. Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in stage 1B non-small cell lung cancer NSCLC: Journal of Clinical Oncology 22 14 Suppl.

The influence of finasteride on the development of prostate cancer. New England Journal of Medicine 3: Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: Journal of the American Medical Association Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: Vinorelbine plus cisplatin vs.

Origins and development of chemotherapy research at the National Cancer Institute. Cancer Treatment Reports 68 1: However, the program is falling short of its potential, and the IOM recommends changes that aim to transform the Cooperative Group Program into a dynamic system that efficiently responds to emerging scientific knowledge; involves broad cooperation of stakeholders; and leverages evolving technologies to provide high-quality, practice-changing research.

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Looking for other ways to read this? Page 42 Share Cite. Page 43 Share Cite. Page 44 Share Cite. Page 45 Share Cite. Page 46 Share Cite. Page 47 Share Cite. Breast cancer Landmark trials supporting the use of more conservative, less disfiguring treatment of breast cancer, altering the standard of care toward breast-conserving therapy. Page 48 Share Cite. Page 49 Share Cite. Genitourinary cancer Demonstration that finasteride can significantly alter the risk of prostate cancer in men over 55 years of age SWOG.

Page 50 Share Cite. Brain cancer Demonstration that lower-dose radiation therapy is as effective as and less toxic than higher-dose radiation therapy for patients with low-grade glioma NCCTG. Gynecologic cancer Determination of the standards for multiagent chemotherapy for all gynecologic sites. Page 51 Share Cite. Identification of the limited value of reassessment laparotomy GOG. Head and neck cancer Definition of the role of taxanes in the treatment of head and neck cancers ECOG.

Skin cancer Establishment of the role of high-dose interferon alpha-2b as the first FDA-approved adjuvant therapy for high-risk malignant melanoma ECOG. Adult Solid Tumors and Hematologic Malignancies. Page 52 Share Cite. Page 53 Share Cite. Adjuvant Therapy for Solid Tumors. Page 54 Share Cite. Cancer Prevention and Detection. Page 55 Share Cite. Page 56 Share Cite.

Some current examples of Cooperative Group trials that probably would not have been conducted by industry alone include: Page 57 Share Cite. Page 58 Share Cite. Page 59 Share Cite. Phase III Study of 2 doses of temozolomide conventional dose vs. Phase III Neoadjuvant hormonal study in breast cancer. Phase III Neoadjuvant study in breast cancer. Phase III Study includes 3 arms in order to test a duration question relative to bevacizumab-based therapy.

Phase III Evaluates the potential benefit of chemotherapy in a patient population selected by a diagnostic test. Phase III Evaluates an agent ibandronate that is off-patent but may have important benefits for the selected patient population. Phase III Involves a direct head-to-head comparison of 2 types of monoclonal antibody-based therapy combined with chemotherapy with overall survival as the primary endpoint.

Phase III Study in a very rare subset of a rare disease, in a clinical setting using a specific therapeutic approach trimodality therapy. Phase III Evaluates an agent in combination with radiation therapy in a rare disease and for a very select therapeutic approach in a specific patient population nonoperative therapy. Page 60 Share Cite. Page 61 Share Cite. Phase III Adjuvant study comparing 2 drugs from different companies to observation. Phase III Included 3 arms in order to test a duration question relative to bevacizumab-based therapy. Phase III A relatively rare clinical scenario in which chemotherapy is being tested with standard agents.

Phase III A study in a very rare tumor type—leiomyosarcoma of the uterus. Phase III A study in a relatively rare clinical scenario evaluating standard agents. Phase III A study in a rare tumor type evaluating standard agents. Phase III Evaluating chemoradiation with or without adjuvant chemotherapy in women with high-risk early-stage cervical cancer after hysterectomy with involving standard agents. Phase III A study of radiation therapy vs. Phase II A study of temsirolimus with or without hormonal therapy in women with recurrent endometrial cancer in a very rare clinical scenario.

Page 62 Share Cite. Page 63 Share Cite. A rare disease subset that required significant collaboration. Phase III Evaluation of standard agents that involves molecular profiling. Phase III Evaluating whether favorable outcomes can be achieved in a very rare disease with more limited therapy with approved agents. Phase III Evaluating competing therapies involving agents from 2 different companies.

Phase III A study in small cell lung cancer with 2 new investigational agent-based therapies from different companies. Phase II Evaluating both induction and maintenance therapy in patients who are less than 10 years of age. Phase III Evaluating the benefit of augmented intensity consolidation as a therapeutic approach. Page 64 Share Cite. Page 65 Share Cite.

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Inefficient Group Processes and Burdensome Oversight. Page 66 Share Cite. Movement of Industry Trials Overseas. Page 67 Share Cite. Page 68 Share Cite. Page 69 Share Cite. Page 70 Share Cite. Page 71 Share Cite. Page 72 Share Cite. Page 73 Share Cite. Page 74 Share Cite. Page 75 Share Cite. Page 76 Share Cite. Page 41 Share Cite. Login or Register to save! Hematologic malignancies Development of the framework for the current therapy of patients with AML.

Brain and Central Nervous System Cancers. Gastrointestinal and Neuroendocrine Cancers. Brief Rationale for Selection. Neoadjuvant hormonal study in breast cancer. Neoadjuvant study in breast cancer. Adjuvant study comparing 2 drugs from different companies to observation. A study in a very rare tumor type—leiomyosarcoma of the uterus. Study of intravenous IV vs. For example, the Common Rule allows patients to provide consent for future research to be performed with the biosamples collected from the patient in a clinical trial, whereas the Privacy Rule does not.

The Common Rule is the term used by 18 federal agencies that have adopted the same regulation governing the protection of human subjects of research Subpart A of 45 Code of Federal Regulations [C. Two HHS regulations 14 require researchers supported by HHS funding to obtain and document informed consent from patients participating in their clinical trials.

In addition, researchers who want to use and report on protected health information may have to obtain HIPAA authorization from research subjects. One study showed that even IRBs failed to meet their own standards for readability Paasche-Orlow et al. Several studies confirm that research subjects often do not understand fundamental concepts required for their participation in clinical trials Coletti et al.

One study assessed the readability of HIPAA authorization forms from the academic medical centers that receive the most funding from NIH and found that the median reading level for the authorization templates was the 13th grade i. The authors concluded that many research participants cannot understand the forms that they are required to sign. Not only are HIPAA authorization forms and ICFs written at a higher level of reading than most of the public has attained, but they also are often too lengthy, which is a burden for both the research subjects who need to read and understand them and the physicians who need to spend.

Studies show that the length of informed-consent documents has increased over time LoVerde et al. At a recent IOM workshop, one clinical researcher noted that because of the increasing complexity of cancer clinical trials, his average ICF is between 30 and 35 pages long, which is too long for patients to digest without medical staff devoting a considerable amount of time to verbally summarize them IOM, c. The extra time required to do this, he pointed out, can deter physicians from engaging in clinical research.

This can hamper efforts to adequately protect research subjects, as studies involving greater risk tend to have longer and more complex ICFs Dresden and Levitt, Several researchers have tried to address the shortcomings of ICFs by creating simpler or shorter forms that are easier to read.

Most of those studies have found that these simpler forms foster a better comprehension by the potential research participants Campbell et al. Those subjects who received the shorter, less detailed form scored the highest on comprehension. Several organizations have tried to remedy the ICF comprehension problem by creating guidelines and templates that call for ICFs to be more concise and written in simpler language. In addition, participants at a recent IOM workshop suggested providing a short form that can be layered on top of a long, complicated consent form IOM, c.

The short form would state in a few words what is going to happen to the patient and then provide links to the rest of the document for those who want more detail. AAMC is trying to develop such a short-form approach to consent forms. Current regulations and guidance HHS, , however, do not allow the use of a shortened summary document to obtain informed consent. Has an ongoing project to promote universal use of short and simple informed-consent documents. Has an ongoing panel that will make recommendation on how to improve the informed-consent form and process.

Cooperative Group Phase III trial concepts that are specifically identified as supporting a licensing indication are forwarded to FDA at the concept stage, and some efforts have been made to integrate and coordinate special protocol assessments with the CTEP review processes. However, other concepts for Phase.

III trials with INDs or commercial agents are also forwarded to FDA for informational purposes, even if the study has not been specifically identified as supporting a potential licensing indication. The committee recommends that NCI do more to coordinate reviews and oversight with FDA in trials involving an IND or investigational device exemption to eliminate iterative review steps.

FDA is a complex agency comprising five product centers and many offices. Because more than one center may have jurisdiction over an oncology product, there may be conflicting regulatory expectations. In addition, no single FDA center or office offers the full range of specialized oncologic expertise needed to review all types of cancer therapeutics and diagnostics, including biologics such as monoclonal antibody-based products , standard chemotherapies, genetic tests and other in vitro diagnostics, or imaging modalities. The Office of Combination Products is charged with facilitating reviews that involve more than one center.

However, that office is not oncology specific, and more than coordinated review is needed. A coordinated cancer program at FDA would bring together relevant areas of science and regulation to both advise sponsors and enable the efficient review of applications that involve either combinations of agents some of which might not have independent activity, as described in Chapter 2 or drugs that are developed together with diagnostic devices to facilitate their use.

Such a program could provide more consistency and expertise in the review of oncology products Epstein, A major challenge of putting all responsibility for all aspects of the regulation of cancer products in one place within FDA is that the many types of expertise needed, which currently reside in differ-.

For example, cancer vaccines are reviewed in the Office of Vaccine Research and Review, whereas cellular and gene therapy products are reviewed in the Office of Cellular and Gene Therapies.

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Both of these offices are part of the Center for Biologics Evaluation and Research. Nonetheless, the committee recommends that FDA establish a coordinated Cancer Pro gram across its centers that regulate oncology products to improve both efficiency of and consistency of regulatory standards for review of oncol ogy products. To gain FDA approval, FDA requires data that indicate the effectiveness of the tested product for a specific indication, as well as data on adverse effects.

The types and amounts of data required, however, are not specified in detail in FDA guidance because expectations may vary according to what is already known about a drug and how different a proposed new use of the drug is. A guidance document developed in noted that fewer data may be necessary if extensive safety data on a drug already exist because it has been on the market for another indication, if a drug has been tested in other trials with similar patient populations, or if the proposed new use of the drug is similar to that of already approved uses of the drug FDA, The lack of a standard required data set leads to inconsistency in the data collected for cancer trials that can affect the quality of the study and limit cross-study comparisons Curt, ; Epstein, ; McClellan and Benner, For example, studies on the collection of data on adverse events AEs find that the rates of reported AEs depend on how information is gathered.

Other factors that may affect the reporting of adverse events include the frequency of follow-up visits Ioannidis et al. The validity of progression-free survival as an indicator of treatment effectiveness can also vary according to the frequency of assessment and can be further confounded by the variability of tumor measurements, as noted in Chapter 2 , particularly in unblinded trials Amit et al.

The use of blinded independent central review BICR of imaging to assess tumor progression in randomized clinical trials has been advocated to control the bias that might result from errors in progression assessments. A review of the literature for studies of breast, colorectal, lung, and renal cell cancer using retrospective BICR found high rates of discrepancy between the local and the central reviews, but these differences did not lead to different conclusions about treatment efficacy.

The authors concluded that although BICR reduces some potential biases, it does not remove all biases from evaluations of treatment effectiveness. Furthermore, they found that BICRs,. Although investigators intuitively wish to collect as much data as possible, there is a risk that the magnitude of data collection may compromise the overall quality of the data by creating an enormous burden on investigators and clinical study sites Schilsky et al. The collection of excess data increases the cost and duration of clinical trials, and the administrative burden not only for data collection but also for ensuring the quality control procedures for all these data contributes to the reluctance of investigators to participate in trials and enroll patients.

The extensive collection of unused data can be detrimental to the overall quality of the data and the subsequent data analysis Abrams et al. For example, all data collected must be quality controlled and edited, if necessary, so the collection of nonessential data is a drain on limited resources. In a poll of several Cooperative Group and industry trial sites, more than 85 percent noted that data optimization would moderately or significantly impact the resources of the trial site, allowing the collection of higher-quality, targeted data and greater participation in clinical trials Abrams et al.

The committee recommends that FDA update its regulatory guidelines for the minimum data required to establish the safety and efficacy of experimental therapies including combinations of products. Standards for data collection that differ according to whether the clinical trial is for a primary or a secondary indication could reduce the collection of excess data and improve the quality of the data collected, studies suggest. A retrospective review of the data sets from completed Phase III cancer trials, many of which were used for FDA supplemental approvals, found that gathering toxicity data for a subsample of the participants in a trial for a drug for which a substantial toxicity profile already exists led to the same conclusions that were reached in the original study that gathered this information for all patients enrolled Abrams et al.

A similar retrospective analysis of the Avastin Non-Small Cell Lung Cancer Trial found that if toxicity data on Grade 1 and 2 AEs were collected from a subset of patients per arm rather than from all trial participants, there would have been a time savings of 2, hours and no. Standard analyses assume that the progression course of censored individuals is the same as that for patients remaining under observation; if not, censoring is informative and will bias the results.

The collection of Grade 3 and 4 AE data from a subset of such patients found that those AEs that occurred at least 5 percent more frequently in the study drug arm were almost always seen in the smaller subset, whereas those AEs that occurred at an increased frequency of 2 percent were missed about half the time Schilsky et al. Whether such subset analyses will be adequate depends on what is already known about the safety of the drug and is likely to be sufficient for many clinical trials undertaken for supplemental indications. That panel suggested that a core set of data elements be identified, along with how those data elements need to be modified for certain situations.

Ideally, such standards would be recognized by regulatory agencies worldwide. Increased investment in regulatory science studies that assess how best to craft regulations on the basis of the scientific evidence, as recently advocated by the FDA commissioner, might aid with the determination of such data standards Christel, ; Grant, The complexity of the collaborative process and multi-institutional oversight of Cooperative Groups has fostered inefficiencies and long start-up times for clinical trials, with many investigators raising concerns about burdensome bureaucratic procedures that create undue delays NCI, a.

To provide insight into the organizational challenges in the development of clinical trials, several studies have been undertaken to document all the steps and time required to launch Cooperative Group clinical trials opened by the Cancer and Leukemia Group B CALGB Dilts et al. Many of the steps in the startup process are redundant and do not improve the value of the study, according to these analyses Dilts et al.

The problem is not how much time each step takes but. These repetitive steps result in an inefficient system that could be made more efficient by getting all parties e. Furthermore, minor changes often do not significantly improve the clinical trial yet trigger another lengthy series of reviews. Contributing to the inordinate amount of time required to develop a clinical trial is the fact that many of the steps are conducted serially rather than in parallel. Although synchronicity is an issue for any clinical trial, it is exacerbated in Cooperative Group trials because of the need to deal with multiple external agencies Dilts et al.

Because of these scientific developments, the protocol may no longer be relevant when the trial is launched. New scientific findings might also require additional changes to the protocol be made, and these changes, in turn, require additional reviews. The length of the development process for a clinical trial also appears to affect the accrual success of the trial. The longer that trials take to be developed, the less likely it is that they will meet their minimum accrual goals Cheng et al.

The ultimate inefficiency is a clinical trial that is never completed because of insufficient patient accrual, and this happens far too often. A total of 8, patients 17 percent of the accruals accrued to those studies that were unable to achieve the projected minimum accrual goal Cheng et al.

Among the Phase III trials, It should also be noted, however, that some trials close early because of unanticipated side effects or because the results from another trial unexpectedly make it no longer ethical to continue the trial. Another study, a survey of study chairs and lead statisticians for phase III trials by five national cooperative groups. The analysis considered all trials that began and closed between and As a result, trials that had begun during that time but were still ongoing were excluded.

In addition, some trials were closed for a planned interim analysis for positive or negative results. A more detailed analysis over a longer period is ongoing personal communication, Jeffrey Abrams, National Cancer Institute, September 22, The graph shows the relative odds that a clinical trial with the indicated development time will meet its accrual goals.

The dotted line indicates the median development time. Triangles above the dotted line indicate greater success in meeting accrual goals; triangles below the line indicate less success. Trials with a development time of 9 to 12 months were significantly more likely to achieve their accrual goals, whereas those whose development times exceeded 27 months were significantly less likely to achieve their accrual goals. A sense of urgency: Evaluating the link between clinical trial development time and the accrual performance of CTEP-sponsored studies. Journal of Clinical Oncology 27 18s: The findings in these studies are congruent with to those of Ramsey and Scoggins , who reported that 59 percent of the clinical trials performed by NCI-supported clinical trials networks had been published during a similar time period.

A computer model that was developed on the basis of those analyses found that if individual Cooperative Groups or CTEP singly tried to improve its processes, each would cut only a few days off the trial development timeline, but if they worked together to improve the entire process, the timeline could be substantially shortened.

For example, a process map. That Group established specific, measurable goals that the IOM committee endorses. Those recommendations include staffing changes, more coordinated, parallel reviews, and improved project management and protocol tracking see also Appendix A for more details. The recommendations also include time-date goals that specify, for example, that a clinical trial must open and accrue patients within 18 calendar months for Phase II trials or 2 years for Phase III trials or it will be closed although some exceptions may be necessary, for example, in the case of rare diseases.

The timeline excludes IRB review, as well as contracting and drug supply activities. Protocols would be terminated if not activated within 2 years. Reports indicate that the review of operational data on the development of clinical trials can reveal steps that are redundant and do not add value to the resulting protocol, and could thus be eliminated Kurzrock et al. For example, when the Mayo Clinic reviewed the steps and time taken from receipt of a new trial protocol through submission to an approving authority such as NCI or the IRB, it discovered numerous redundant review steps, as well as delays caused by waiting for e-mail responses.

It then eliminated steps that added no value and provided deadlines for responding to e-mails. A review of 64 protocols submitted since the implementation of this streamlining process revealed that the mean turnaround time for both internally and externally authored protocols dropped by about 60 percent McJoynt et al. In one recent Phase I trial at the center, the study was activated and the first patient enrolled 46 days after completion of the final study protocol and about 48 hours after final FDA approval of the IND, reducing the overall timeline by about 3 months Kurzrock et al.

Real-time electronic tracking of the steps in trial protocol development, with the same protocol tracking number for each review step, would help with these evaluations and enable problems to be detected more quickly as trial development proceeds Steensma, The creation of standard operational metrics and best practices for the clinical trial development process for use across institutions could further facilitate improvements in the process.

The operational processes used to conduct clinical trials are idiosyncratic to individual institutions or Cooperative Groups, with little sharing of best practices or lessons learned. Although Good Clinical Practice guidelines ICH, provide an international ethical and scientific quality standard for designing, conducting, recording, and reporting on the results of clinical trials that involve the participation of human subjects, there is currently no mechanism for the systematic identification of best management and administrative practices that can be used as benchmarks by a clinical trials office in a Cancer Center or a Cooperative Group, nor can such best practices be used to aid up-and-coming Cancer Centers.

Furthermore, there are few standard processes or metrics of what constitutes operational quality in the development or management of clinical trials. Organizations need to know how they are performing, independently over time and in comparison with their peer institutions. Thus, the operational performance metrics used to evaluate Cancer Centers and Cooperative Groups need to be enhanced and redefined to include metrics for the measurement of quality, outcomes, and timing.

The committee recommends that NCI work with governmental and non governmental agencies with relevant expertise to facilitate the identifica tion of best practices in the management of clinical research logistics and develop, publish, and use performance, process, and timing standards and metrics to assess the efficiency and operational quality of a clinical trial.

There is also a need to make interagency processes more efficient. For example, simplifying and harmonizing regulatory methods such as reporting of AEs , to the extent possible within the constraints of the responsibilities of the different agencies involved, could be beneficial. Inefficiencies could also be improved by standardizing the information technology infrastructure as well as data elements, collection, and reporting, as noted above in the section on trial oversight.

Some steps are already being taken to streamline reviews. However, there is a need for bolder changes. For example, some consolidation of the Cooperative Groups and of common activities could increase operational efficiencies and conserve resources, ease the workloads of the Cooperative Groups, and offer more consistency to providers enrolling patients in trials launched by different Cooperative Groups. Back-office operations, such as information technology support and payroll systems, primarily occur outside the view of customers and do not differentiate the product or the service provided to the customer, so they have been the focus of consolidation in many industries and other organizations, including banking, nonprofit organizations, and governmental agencies Dare and Reeler, ; Davis, ; Grosser, ; Kraus and Marjanovic, ; Lacity et al.

In clinical trials, back-office operations include activities such as data collection and management, data queries and reviews to ensure that the data collected are complete and accurate, patient registration, audit functions, processing of case report forms, training of clinical research associates, image storage and retrieval, drug distribution, and credentialing of. Although the ways in which the Cooperative Groups accomplish these functions vary, there is little technical rationale for why they must be unique to the scientific focus of each Group.

The consolidation of offices and personnel to conduct these information-based activities across all the Cooperative Groups should help to streamline the operations, reduce redundancy, lead to greater consistency, and conserve resources. The com mittee recommends that NCI require and facilitate the consolidation of these back-office administration and data management operations of the Cooperative Groups.

It will be essential, however, to maintain high-service-quality work and a high level of responsiveness to the principal investigators and Cooperative Groups. The committee thus recommends that NCI facilitate some consolidation of the Cooperative Group front office operations to conserve resources while still maintaining rigorous competition for trial ideas. One possible way to reorganize the Group front offices would be by disease type. For example, there could be four multidisciplinary Groups dedicated to adult cancers, with the task of performing trials for different diseases and with true cooperation occurring among all the Groups.

Each Group could perhaps have four disease-specific committees to ensure broad coverage and some overlap for each disease. In other words, two Groups would undertake trials for lung cancer, two for colon cancer, two for breast cancer, two for head and neck cancer, two for hematology, and so on.

One way to achieve consolidation would be to alter the peer-review process for the Cooperative Groups to focus on the accomplishments of disease committees. The committee recommends that the Cooperative Groups be reviewed and ranked using defined metrics on a similar timetable and that funding be linked to the review scores.

Committees that do well in review should be funded, and committees with low scores should be eliminated. Committees should be organized with a multidisciplinary focus on disease sites, and Group leaders should consolidate disease site committees from different Groups to strengthen their productivity and review scores. This approach would ensure that only the most innovative and successful disease site committees would thrive and expand their membership.

The logical extension of the proposed consolidations will be a reduction in the number. For example, Groups focused on a single disease site or modality would likely need to merge with multidisciplinary Groups under this system. It will, however, be important to preserve a sense of community among the investigators focused on a particular disease. The goal of that merger was to consolidate talent and resources to minimize duplication, make better use of dwindling funds, and increase the efficiencies of conducting clinical trials Benowitz, ; Murphy, Although concerns were raised about creating a scientific monopoly that would stifle innovation and deter involvement by young investigators who would have fewer opportunities for leadership and recognition Benowitz, , according to current Group leadership, there is still competition at the international level Reaman, In addition, the total accruals have increased and the national childhood cancer mortality rate continues to fall.

To nurture young investigators, COG has developed a formal mentoring program, and each study must have an early career investigator as the chair, with a more seasoned investigator being the cochair or vice chair. Furthermore, the CTSU does not address the issue of redundancy in the activities supported by the front offices of the Cooperative Groups.

Several organizations may serve as models for the efficient conduct of clinical trials. One is the Multiple Myeloma Research Consortium MMRC , which integrates the research efforts of 15 member institutions and whose mission is to accelerate the development of novel and combination treat-. The Southwest Cancer Chemotherapy Study Group, the forerunner of the Southwest Oncology Group SWOG , was originally organized as a pediatric oncology group in and only later expanded to include evaluation of adult malignancies.

POG grew to be virtually equal in size to CCG in terms of institutional members and patient accruals. By the late s, the four pediatric Groups had a long history and tradition of both friendly competition and close collaboration. In , the leadership of all four of the pediatric Groups, including the chair, vice chair, statisticians, and Cooperative Group administrators, gathered to discuss ways to improve the efficiencies of the intergroup process. There had been long-standing frustration with the cumbersome intergroup process, and a number of ongoing changes led to the decision to eliminate the intergroup mechanism entirely and merge into one Group.

First, because of the significant success with the treatment of all forms of childhood cancer, survival rates had successively improved, such that larger and larger numbers of patients were needed to enroll in randomized clinical trials to achieve reasonable study objectives of demonstrating significant improvements in overall results within a reasonable time frame. Given the relative rarity of pediatric cancers in general and the increasing sophistication of the stratification of trials into smaller and smaller risk-adapted subgroups, it had become necessary to increase collaboration to accrue sufficient numbers of patients.

Second, at that time, NCI was requiring all of the cancer Cooperative Groups to make extensive changes to their informatics infrastructures, to adopt common toxicity codes and data dictionaries, to streamline and harmonize data reporting, and to migrate from the use of paper forms to electronic forms. This work was both onerous and expensive, and the Group leaders thought that it would be better to work together to accomplish all the upgrades to the informatics systems. Third, the Groups hoped that providing a single source for pediatric clinical trials, a single point of service, and the promise of increased accruals and more rapid completion of Phase I and II trials would improve interactions.

This process of working with industry was inherently challenging because the pharmaceutical industry had relatively little interest in developing and licensing drugs for childhood cancers due to the small market. Fourth, the Group leaders believed that by working together, they could articulate a stronger case to the public for pediatric cancer clinical trials. Parents, the public, and philanthropic foundations and individuals were often confused about why there were multiple Groups and what the differences were.

The merger took 3 years and proved to be very challenging, with perhaps the biggest challenge being the merging of the very different cultures of the Groups. The merger was labor-intensive, entailing the development of a memorandum of understanding, the creation of an interim governing council, the creation of a new constitution, the development of transitional committees for every disease and discipline, a new membership committee to review the performance and qualifications of each institutional member, new rosters, greatly increased communications, and many additional interim meetings.

NCI provided some additional funding to cover some of the additional travel costs associated with interim meetings, but no extra staff was hired, and it was difficult to retain valued staff who were concerned that their jobs would be eliminated by the merger many ultimately were. Reaching consensus on Group data management and statistics was a major challenge. The transition team sought external assessment and guidance, and the result was a distributed network of statistical offices and staff. Another major challenge was the merging of disease-specific committees, which had historically been competitive, often on the basis of competing scientific strategies developed over the course of serial studies.

Of necessity, compromises were reached and some stakeholders were not satisfied with the outcome. A great deal of work was also involved with revising the budgeting for the Group U10 grants during the transition, but an additional challenge entailed merging the foundations that CCG and POG had established for private funding, which had very different structures for their c3 corporations.

COG now has more than 5, individual members. MMRC has also implemented metrics and reward systems into its clinical research endeavors to improve its processes. For example, a scorecard tracks the time required to open and accrue clinical trials. It also tracks the level of engagement of the principal investigators, which is determined by monitoring their participation in monthly calls and face-to-face meetings and how often they bring new ideas to the consortium.

Those centers performing in the top one-third receive funding to cover the full salary of a clinical research coordinator, who provides dedicated oversight of all MMRC clinical trials percent full-time equivalent [FTE]. After the release of the first scorecard results at the end of , percent of the principal investigators participated in the monthly call for the first time. The speed and efficiency of its clinical trials are also priorities, with MMRC setting aggressive goals in this regard: Other informative examples include the Center for International Blood and Marrow Transplant Research mentioned in the previous section and the HIV Prevention Trials Network, 22 a worldwide collaborative clinical trials network that develops and tests the safety and efficacy of primarily nonvaccine interventions designed to prevent the transmission of HIV.

Several initiatives and centers are dedicated to studying and improving the efficiencies of clinical trials Box It has been difficult to accurately document the costs of all the various components and procedures of clinical trials. These costs vary significantly, depending on the nature of the trial. Additionally, there is a great deal of unfunded volunteerism in developing and conducting trials, particularly by investigators who are deeply committed to the assessment of cancer therapies.

The investigators are not fully compensated for this time and effort. Several groups have attempted to discern the various steps involved in the successful conduct of a clinical trial and the costs linked to carrying out those steps. Clinical trials can be broken down into seven basic functional steps C-Change and Coalition of Cancer Cooperative Groups, To support the improved operation of clinical trials and expand patient enrollment, the Association of American Cancer Institutes AACI has launched a communications forum for administrative leaders and managers of cancer center clinical research facilities across the AACI network.

The forum, called the Clinical Research Working Group, will examine the systems and procedures that clinical trials offices use to perform management and oversight functions and compare the office metrics used for clinical trials: The forum aims to promote efficient use of resources and personnel. The AACI CRI will examine and share best practices that promote the efficient operation of cancer center clinical research facilities and will leverage the ability of the AACI cancer center network to advocate for improvement in the national clinical trials enterprise http: The recently created FDA Clinical Trials Transformation Initiative CTTI brings together all interested stakeholders to identify practices that, through their broad adoption, will increase the quality and efficiency of clinical trials.

CTTI is currently assessing ways to improve the system of reporting and interpreting serious adverse events. CTSA institutions work together as a national consortium with the goal of improving human health by transforming the research and training environment to enhance the efficiency and quality of clinical and translational research across the country.

IPPCR: Clinical Trial Registration and Results Reporting

This consortium includes 46 medical research institutions located throughout the nation. When fully implemented by , about 60 institutions will be linked together to strengthen the discipline of clinical and translational science. To set a national research agenda, the CTSA consortium established five overarching strategic goals that will guide consortium-wide activities: The Tufts Center for the Study of Drug Development Tufts CSDD has a mission to develop strategic information to help drug developers, regulators, and policy makers improve the quality and efficiency of pharmaceutical development, review, and utilization.

An independent, academic, nonprofit research group affiliated with Tufts University, Tufts CSDD provides independent analyses on the nature and pace of new drug development. This center has conducted studies on drug development operational processes, including a benchmark analysis of activities related to the initiation of clinical research studies.

The Center for Management Research in Healthcare was designed with the focus of providing advances in management disciplines for health care-related applications by integrating theory founded on academic principles and industry best practices. The goals include the transfer of management knowledge to health care settings and the dissemination of findings that arise between the intersection of health care and management. The organizers concluded that solutions to many of the problems would require a coordinated response from academic trialist groups, regulatory agencies, pharmaceutical companies, and health care providers worldwide.

A follow-up meeting of the Sensible Guidelines group took place in Oxford on September 5—6, The principal aims were to 1 update the review of the main barriers preventing efficient trials; 2 share the experiences of those who are attempting to deal with these barriers; and 3 agree to possible solutions to the main difficulties and encourage their promotion through international collaboration. Study and site feasibility assessment, including scientific review and evaluations of budgets and timelines. Of these seven steps, four are related to federal regulations: An average of 35 percent of clinical research costs is spent on compliance with such regulations C-Change, About half of the time spent on a clinical trial is devoted to study startup endeavors IOM, c.

Startup costs for clinical trials include staff training, IRB approval, time for reviews, and staff time for startup visits and the completion of forms C-Change and Coalition of Cancer Cooperative Groups, For Cooperative Group trials, some startup costs may be somewhat lower because of the existing infrastructure and operating procedures, but many unique aspects of each clinical trial also contribute to these costs.

Many of the startup steps can involve several iterations, because changes made in response to one review body trigger re-reviews by other bodies. Contracts among multiple parties can require many layers of review that may take months to complete, and the financial review of a study may be done separately from a contract review C-Change and Coalition of Cancer Cooperative Groups, Numerous steps are also involved in the initial execution of clinical trials, including on-site training of personnel, the establishment of billing and budget procedures, and the screening and recruitment of patients C-Change and Coalition of Cancer Cooperative Groups, These fixed startup costs are independent of the number of subjects enrolled in a clinical trial and are more economically efficient when large numbers of patients are enrolled in the trial.

Only about half of open government-sponsored trials, however, have subjects enrolled, one study found C-Change, , and an NCI study of four NCI-funded Comprehensive Cancer Centers found that many trials accrue few or even no patients. As noted earlier in this chapter, a review of these four Cancer Centers along with two large Cooperative Groups and CTEP revealed that the amount of time it takes to start up a study is nearly 3 years Dilts and Sandler, ; Dilts et al. The substantial startup costs of trials with low rates of accrual often. Once a clinical trial is under way, in addition to administering the experimental treatment to patients, much time is spent on patient follow-up.

This follow-up is much more involved for clinical studies than it would be for standard patient care, as detailed case report forms, as well as forms that report adverse events must be filled out C-Change and Coalition of Cancer Cooperative Groups, In addition, new requirements from OHRP specify that if a substantial new toxicity becomes apparent during a clinical trial, the trial must again be reviewed by the IRB at the local institution, and the written consent form must then be modified accordingly Abrams and Mooney, ; Goldberg, Even billing is more complex for patients in clinical trials, with Medicare requiring the costs for routine care of the patients to be listed separately from the research costs on the bills submitted to Medicare IOM, c.

The data centers also have many tasks, such as quality control efforts editing data, sending out queries, updating the database , creating and circulating reports on the progress of the study to investigators and funders, and preparing reports to data and safety monitoring boards. Many of the costs of clinical trials are overlooked or understated Waldinger, , such as the costs of specimen collection, processing, and shipping, especially if the processing of the specimens is time sensitive and the specimens must be shipped individually, as well as the costs of standard imaging and pathology evaluations.

These are increasingly important economic issues, as Cooperative Group studies are doing more genetic and other analyses of tumor or blood samples in the movement toward personalized medicine, which depends on the collection and analysis of such samples. This focus on personalized medicine increases the complexity and cost of clinical trials, as there is a greater need for the documentation of patient characteristics, imaging, and biomarker tests see also Chapter 2.

In addition, for trials that Cooperative Groups undertake with industry support, there can be lengthy negotiations over the ownership and use of the biological specimens collected during the trial because they might be useful for future studies IOM, c. The use of such biospecimens can also require additional time to craft more complex ICFs and explain them to patients.

Furthermore, current NCI policies require that research studies that propose to use specimens collected from intergroup protocols undergo scientific review by a scientific steering committee before specimens are made available. However, this review is not linked to funding, and thus, investigators must often seek funding by other mechanisms.

The increasing number of global clinical trials adds more complexity and costly bureaucratic burdens as researchers try to comply with the wider range of regulations that vary from country to country C-Change and Coalition of Cancer Cooperative Groups, Even variations in local regulations can add to the complexity and can be burdensome in multicenter trials, especially because many participating sites contribute 10 patients or less, yet they must still undergo cumbersome regulatory reviews. One study estimated that 30 to 40 percent of all funding for cancer clinical trials is used to cover the costs of local regulatory compliance C-Change and Coalition of Cancer Cooperative Groups, For example, an investigator who participates in just one clinical trial over 7 years may be required to have between 35 and 50 interactions with the IRB, each of which requires about hours of staff preparation time C-Change and Coalition of Cancer Cooperative Groups, In addition, the workload associated with audits, data queries, and blinded central reviews has been increasing see also the previous section on oversight of clinical trials.

Further insight into the costs involved in conducting Cooperative Group trials in particular is expected in , when NCI will publish its analysis of the costs of Cooperative Group clinical trials. The analysis is expected to identify areas of inadequate funding, as well as to identify best practices and opportunities for enhanced efficiency.

Preliminary results indicate that most groups spend about 50 percent of their budgets on infrastructure and about 50 percent on accruing and managing patients. Most allocate the largest portion of their infrastructure to statistics and data management, but there is large variability in the percentage allocated to various other infrastructure components and subcomponents, such as administration costs.

Some of this variation may be due to the way in which expenses are described in the grant applications. The analysis also found that the amounts of funds awarded were always less than the amounts requested and that no group spent the funds that it was awarded at exactly. Research and patient care costs must be met if the trial is to be efficiently and effectively completed. As one participant at an IOM workshop noted, it may be unethical to attempt to do a clinical trial when those who are running it are not getting paid enough to do it well IOM, c. However, despite the long history of accomplishments of the NCI Cooperative Group Program as described in Chapter 1 , the program has been chronically underfunded because of limitations in NCI funding and the increasing complexity and costs of clinical trials.

The lack of sufficient funds for the program was noted with concern more than 10 years ago, in the Armitage report NCI, , but the funding situation for the program has not substantially improved since that report recommended increased funding. This figure reflects a 20 percent decline in funding since when the effects of inflation are considered.

In real dollars, the current funding level is less than it was in This situation is increasingly unsustainable. The committee recommends that NCI allocate a larger portion of its research portfolio to the Clinical Trial Cooperative Group Program to ensure that the Program has sufficient resources to achieve its unique mission. Congress determines the total funding allotment for NCI each year, but the NCI director is responsible for proposing a budget and for allocating the available funds among the various programs and funding mechanisms within NCI.

Allocation of NCI funds among the competing needs of its various programs is a major challenge for the NCI director, who must take many factors into consideration. Decisions must be made about how much funding to devote to basic, laboratory research versus clinically oriented research across several major categories that include cancer causation, prevention, and control; cancer biology; detection, diagnosis, and treatment; and resource development reviewed by IOM, Furthermore, the clinical trials program supported by NCI is multifaceted, with the Cooperative Group Program being just one of several clinical research endeavors that NCI supports Figure The actual obligations of NCI funds by mechanism are shown, in millions of dollars.

R01, R03, R21, R37, and P01 grant-supported trials in treatment, control, and prevention. Cancer Center support grant: The Board of Scientific Advisors BSA could also influence allocations within the NCI budget, as one of its charges is to advise the NCI director on the policy, progress, and future directions of the extramural scientific research program within each division.

This includes evaluations of awarded grants, cooperative agreements, and contracts and examination of extramural programs and their infrastructures to evaluate whether changes are necessary to ensure that NCI is positioned to effectively guide and administer the needs of science research in the foreseeable future reviewed by IOM, The committee recommends that these external advisory boards have a greater role in advising NCI on how it allocates its funds to support a national clinical trials program.

This would help to ensure the most rational distribution of funds, in light of such factors as scientific opportunity and clinical need. In —, the mechanism of support for the Cooperative Group Program was converted from a grant to a cooperative agreement U10 award. This was a major change for the program because the cooperative agreement funding mechanism is intended to be a cross between a grant and a contract and thus allowed NCI to have a much more active role in the conduct, management, and oversight of research than grants typically require.

Investigators funded through other grant mechanisms the bulk of NCI extramural funding based on peer review are not subjected to such oversight. There is considerable variability across the NIH with regard to the balance between oversight and support of trials by the sponsoring institution, and unlike many other NIH clinical trials arrangements, funding for the Cooperative Groups is not linked to specific clinical trials but, rather, to the infrastructure that supports the trials.

In fiscal year , the program supported 47 community oncology sites and 12 research bases, as well as 14 minority-based CCOP sites. The Cooperative Groups are evaluated at a maximum of 6-year intervals on the basis of various performance criteria. The criteria include the numbers of publications and accruals, the scientific merit and innovation of their trial proposals and whether they meet national priorities, timeliness of study completion, leadership, and whether there is a strong commitment to active, meaningful participation in NCI Phase III treatment trials NCI, However, the Cooperative Groups have different timelines for review and so are not compared directly with each other in the evaluation process.

In addition, the amount of funding received is not directly linked to the review score, and because of NCI funding limitations, the Cooperative Groups usually receive 30 to 50 percent less than the total grant money requested on their applications and approved by peer review. CCOP grantees get funds for research costs in advance and earn credits against this funding by enrolling patients into trials NCI, b. CCOP grants also undergo a peer-review process, largely on the basis of accruals and data quality, different from the review process for the Cooperative.

Groups that they have joined NCI, CCOP funding also covers only about two-thirds of the actual costs of conducting clinical trials in community settings IOM, c. Such insufficient funding has become unsustainable as trials have become more complex. As noted in Chapter 2 , such activities are increasingly part of Cooperative Group clinical trials to assess patient subgroups for whom therapy is especially effective or especially toxic.

However, that funding may be insufficient for these efforts, as tests may cost thousands of dollars per patient. Another major factor contributing to the underfunding of Cooperative Groups is inadequate reimbursement of per patient costs. This short-fall was recognized in the U. House of Representatives appropriations report for fiscal year , 24 albeit only in regard to gynecologic oncology trials. A recent survey of Cooperative Group sites found that of the respondents 32 percent who were planning to limit their Cooperative Group participation, three-quarters cited inadequate per case reimbursement for the decline in their level of participation Blayney, Some cancer centers have also.

See House Report H. The committee recommends that NCI increase the per case reimbursement and adequately fund highly ranked trials to cover the costs of the trial, includ ing the costs for biomedical imaging and other biomarker tests that are integral to the trial design. In addition, the new focus on targeted and combination therapies tends to make the process for obtaining informed consent more difficult and to increase the structural complexity of trials, as well as the complexity of data collection and analysis, all of which increase the costs and personnel time devoted to a trial NCI, e.