A Time-Trend Economic Analysis of Cancer Drug Trials.

BACKGROUND: Scientific advances have led to the discovery of novel treatments with high prices. The cost to publicly fund high-cost drugs may threaten the sustainability of drug budgets in different health care systems. In oncology, there are concerns that health-benefit gains are diminishing over time and that the economic evidence to support funding decisions is too limited. METHODS: To assess the additional costs and benefits gained from oncology drugs over time, we used treatment protocols and efficacy results from U.S. Food and Drug Administration records to calculate cost-effectiveness ratios for drugs approved to treat first- and second-line metastatic or advanced breast, colorectal, and non-small cell lung cancer during the years 1994-2013. We assessed reimbursement recommendations reached by health technology assessment agencies in the U.K., Australia, and Canada. RESULTS: Cost-effectiveness ratios were calculated for 50 drugs approved by the U.S. regulator. The more recent approvals were often based on surrogate efficacy outcomes and had extremely high costs, often triple the costs of drugs approved in previous years. Over time, the effectiveness gains have increased for some cancer indications; however, for other indications (non-small cell lung and second-line colorectal cancer), the magnitude of gains in effectiveness decreased. Reimbursement recommendations for drugs with the highest cost-effectiveness ratios were the most inconsistent. CONCLUSION: Evaluation of the clinical benefits that oncology drugs offer as a function of their cost has become highly complex, and for some clinical indications, health benefits are diminishing over time. There is an urgent need for better economic evidence from oncology drug trials and systematic processes to inform funding decisions. IMPLICATIONS FOR PRACTICE: High-cost oncology drugs may threaten the ability of health care systems to provide access to promising new drugs for patients. In order to make better drug-funding decisions and enable equitable access to breakthrough treatments, discussions in the oncology community should include economic evidence. This study summarizes the extra benefits and costs of newly approved drugs from pivotal trials during the postgenomic era of drug discovery. The reader will gain an appreciation of the need for economic evidence to make better drug-reimbursement decisions and the dynamics at play in today's oncology drug market.

Development of the AGREE II, part 2: assessment of validity of items and tools to support application.

BACKGROUND: We established a program of research to improve the development, reporting and evaluation of practice guidelines. We assessed the construct validity of the items and user's manual in the beta version of the AGREE II. METHODS: We designed guideline excerpts reflecting high-and low-quality guideline content for 21 of the 23 items in the tool. We designed two study packages so that one low-quality and one high-quality version of each item were randomly assigned to each package. We randomly assigned 30 participants to one of the two packages. Participants reviewed and rated the guideline content according to the instructions of the user's manual and completed a survey assessing the manual. RESULTS: In all cases, content designed to be of high quality was rated higher than low-quality content; in 18 of 21 cases, the differences were significant (p < 0.05). The manual was rated by participants as appropriate, easy to use, and helpful in differentiating guidelines of varying quality, with all scores above the mid-point of the seven-point scale. Considerable feedback was offered on how the items and manual of the beta-AGREE II could be improved. INTERPRETATION: The validity of the items was established and the user's manual was rated as highly useful by users. We used these results and those of our study presented in part 1 to modify the items and user's manual. We recommend AGREE II (available at www.agreetrust.org) as the revised standard for guideline development, reporting and evaluation.

Development of the AGREE II, part 1: performance, usefulness and areas for improvement.

BACKGROUND: We undertook research to improve the AGREE instrument, a tool used to evaluate guidelines. We tested a new seven-point scale, evaluated the usefulness of the original items in the instrument, investigated evidence to support shorter, tailored versions of the tool, and identified areas for improvement. METHOD: We report on one component of a larger study that used a mixed design with four factors (user type, clinical topic, guideline and condition). For the analysis reported in this article, we asked participants to read a guideline and use the AGREE items to evaluate it based on a seven-point scale, to complete three outcome measures related to adoption of the guideline, and to provide feedback on the instrument's usefulness and how to improve it. RESULTS: Guideline developers gave lower-quality ratings than did clinicians or policy-makers. Five of six domains were significant predictors of participants' outcome measures (p < 0.05). All domains and items were rated as useful by stakeholders (mean scores > 4.0) with no significant differences by user type (p > 0.05). Internal consistency ranged between 0.64 and 0.89. Inter-rater reliability was satisfactory. We received feedback on how to improve the instrument. INTERPRETATION: Quality ratings of the AGREE domains were significant predictors of outcome measures associated with guideline adoption: guideline endorsements, overall intentions to use guidelines, and overall quality of guidelines. All AGREE items were assessed as useful in determining whether a participant would use a guideline. No clusters of items were found more useful by some users than others. The measurement properties of the seven-point scale were promising. These data contributed to the refinements and release of the AGREE II.

Conceptual and practical challenges for implementing the communities of practice model on a national scale--a Canadian cancer control initiative.

BACKGROUND: Cancer program delivery, like the rest of health care in Canada, faces two ongoing challenges: to coordinate a pan-Canadian approach across complex provincial jurisdictions, and to facilitate the rapid translation of knowledge into clinical practice. Communities of practice, or CoPs, which have been described by Etienne Wenger as a collaborative learning platform, represent a promising solution to these challenges because they rely on bottom-up rather than top-down social structures for integrating knowledge and practice across regions and agencies. The communities of practice model has been realized in the corporate (e.g., Royal Dutch Shell, Xerox, IBM, etc) and development (e.g., World Bank) sectors, but its application to health care is relatively new. The Canadian Partnership Against Cancer (CPAC) is exploring the potential of Wenger's concept in the Canadian health care context. This paper provides an in-depth analysis of Wenger's concept with a focus on its applicability to the health care sector. DISCUSSION: Empirical studies and social science theory are used to examine the utility of Wenger's concept. Its value lies in emphasizing learning from peers and through practice in settings where innovation is valued. Yet the communities of practice concept lacks conceptual clarity because Wenger defines it so broadly and sidelines issues of decision making within CoPs. We consider the implications of his broad definition to establishing an informed nomenclature around this specific type of collaborative group. The CoP Project under CPAC and communities of practice in Canadian health care are discussed. SUMMARY: The use of communities of practice in Canadian health care has been shown in some instances to facilitate quality improvements, encourage buy in among participants, and generate high levels of satisfaction with clinical leadership and knowledge translation among participating physicians. Despite these individual success stories, more information is required on how group decisions are made and applied to the practice world in order to leverage the potential of Wenger's concept more fully, and advance the science of knowledge translation within an accountability framework.

The role of guidelines in quality improvement for cancer surgery.

In February 2008, Cancer Surgery Alberta hosted a conference on surgical outcomes and quality. The objective here is to review the interactions between quality/outcomes and guidelines, highlighting surgeons' roles. Potential interactions between quality measurement and guidelines are discussed. We analyzed data from practitioner surveys about guidelines to determine surgeons' participation compared with other specialists. The response rate of surgeons in both community-based and academic practices to guideline development surveys was equivalent to other cancer disciplines.

Accounting for reasonableness: Exploring the personal internal framework affecting decisions about cancer drug funding.

OBJECTIVES: Drug decision-makers are involved in developing and implementing policy, procedure and processes to support health resource allocation regarding drug treatment formularies. A variety of approaches to decision-making, including formal decision-making frameworks, have been developed to support transparent and fair priority setting. Recently, a decision tool, 'The 6-STEPPPs Tool', was developed to assist in making decisions about new cancer drugs within the public health care system. METHODS: We conducted a qualitative study, utilizing focus groups and participant observation, in order to investigate the internal frameworks that supported and challenged individual participants as they applied this decision tool within a multi-stakeholder decision process. RESULTS: We discovered that health care resource allocation engaged not only the minds of decision-makers but profoundly called on the often conflicting values of the heart. CONCLUSIONS: Objective decision-making frameworks for new drug therapies need to consider the subjective internal frameworks of decision-makers that affect decisions. Understanding the very human, internal turmoil experienced by individuals involved in health care resource allocation, sheds additional insight into how to account for reasonableness and how to better support difficult decisions through transparent, values-based resource allocation policy, procedures and processes.

Practitioners as experts: the influence of practicing oncologists "in-the-field" on evidence-based guideline development.

PURPOSE: Panels of experts are used to develop clinical practice guidelines (CPGs) intended to be used by practitioners "in-the-field." Therefore, oncologists' participation in CPG development is an important strategy to promote CPG adoption. The purpose of this study was to evaluate the contributions of oncologists in-the-field to evidence-based CPG development using data from Ontario's cancer system. METHODS: CPG development in Ontario includes surveys of oncologists' opinions, using a structured questionnaire, about draft recommendations that were developed from rigorous systematic reviews of evidence prepared by expert panels. Two research assistants reviewed background documents to trace the changes in CPG recommendations from draft to final stage to determine the contribution of oncologists' input to final recommendations. Changes to recommendations were categorized as either substantive (content or tone) or minor (ideas clarification or edits). RESULTS: From 2000 to 2003, 43 CPGs were developed. There were 87 changes to draft recommendations for 31 CPGs, of which 40 changes to 19 CPGs could be attributed to survey input from practicing oncologists. Of the 40 changes, 28 (70%) were judged to be substantive. CONCLUSION: Despite a rigorous evidence-based process for CPG development, practicing oncologists contribute substantially to the final recommendations approved by the expert panel. It is hypothesized that the responsiveness of expert panels to input from oncologists in-the-field will facilitate adoption of CPGs.

American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004.

PURPOSE: To update the 2003 American Society of Clinical Oncology technology assessment on adjuvant use of aromatase inhibitors. RECOMMENDATIONS: Based on results from multiple large randomized trials, adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer should include an aromatase inhibitor in order to lower the risk of tumor recurrence. Neither the optimal timing nor duration of aromatase inhibitor therapy is established. Aromatase inhibitors are appropriate as initial treatment for women with contraindications to tamoxifen. For all other postmenopausal women, treatment options include 5 years of aromatase inhibitors treatment or sequential therapy consisting of tamoxifen (for either 2 to 3 years or 5 years) followed by aromatase inhibitors for 2 to 3, or 5 years. Patients intolerant of aromatase inhibitors should receive tamoxifen. There are no data on the use of tamoxifen after an aromatase inhibitor in the adjuvant setting. Women with hormone receptor-negative tumors should not receive adjuvant endocrine therapy. The role of other biomarkers such as progesterone receptor and HER2 status in selecting optimal endocrine therapy remains controversial. Aromatase inhibitors are contraindicated in premenopausal women; there are limited data concerning their role in women with treatment-related amenorrhea. The side effect profiles of tamoxifen and aromatase inhibitors differ. The late consequences of aromatase inhibitor therapy, including osteoporosis, are not well characterized. CONCLUSION: The Panel believes that optimal adjuvant hormonal therapy for a postmenopausal woman with receptor-positive breast cancer includes an aromatase inhibitor as initial therapy or after treatment with tamoxifen. Women with breast cancer and their physicians must weigh the risks and benefits of all therapeutic options.

Platinum-based concurrent chemoradiotherapy for tumors of the head and neck and the esophagus.

The addition of concurrent chemotherapy (CT) to standard radiotherapy (RT) for locoregional treatment has been established to improve overall survival in a variety of solid tumors. Among the many CT regimens evaluated in combination with RT in randomized controlled clinical trials and summarized in meta-analyses, platinum-containing regimens have consistently shown a survival benefit across tumor types. Cisplatin and carboplatin have been studied both as single agents and in combination with other cytotoxic drugs, concurrently with RT, but the optimal platinum-based regimen to be combined with RT continues to be explored with further investigation. In this article, the role of platinum-based CT as part of concurrent CT/RT will be discussed using 2 tumor sites in the aerodigestive tract as a paradigm: squamous-cell carcinomas of the head and neck and esophageal carcinomas. For each tumor type, we will review the state of the evidence and comment on the current state of practice and on future directions for clinical research in combined modality CT/RT.

Innovations in American Society of Clinical Oncology Practice Guideline Development.

Since the beginning of its guidelines program in 1993, ASCO has continually sought ways to produce a greater number of guidelines while maintaining its commitment to using the rigorous development methods that minimize the biases that threaten the validity of practice recommendations. ASCO is implementing a range of guideline development and implementation innovations. In this article, we describe innovations that are designed to (1) integrate consideration of multiple chronic conditions into practice guidelines; (2) keep more of its guidelines current by applying evolving signals or (more) rapid, for-cause updating approaches; (3) increase the number of high-quality guidelines available to its membership through endorsement and adaptation of other groups' products; (4) improve coverage of its members' guideline needs through a new topic nomination process; and (5) enhance dissemination and promote implementation of ASCO guidelines in the oncology practice community through a network of volunteer ambassadors. We close with a summary of ASCO's plans to facilitate the integration of data from its rapid learning system, CancerLinQ, into ASCO guidelines and to develop tactics through which guideline recommendations can be embedded in clinicians' workflow in digital form. We highlight the challenges inherent in reconciling the need to provide clinicians with more interactive, point-of-care guidance with ASCO's abiding commitment to methodologic rigor in guideline development.

Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology.

Anemia resulting from cancer, or its treatment, is an important clinical problem increasingly treated with the recombinant hematopoietic growth factor erythropoietin. To address uncertainties regarding indications and efficacy, the American Society of Clinical Oncology and the American Society of Hematology developed an evidence-based clinical practice guideline for the use of epoetin in patients with cancer. The guideline panel found good evidence to recommend use of epoetin as a treatment option for patients with chemotherapy-associated anemia with a hemoglobin level less than 10 g/dL. Use of epoetin for patients with less severe anemia (hemoglobin < 12 g/dL but never below 10 g/dL) should be determined by clinical circumstances. Good evidence from clinical trials supports the use of subcutaneous epoetin thrice weekly (150 U/kg tiw) for a minimum of 4 weeks. Less strong evidence supports an alternative weekly (40,000 U/wk) dosing regimen, based on common clinical practice. With either administration schedule, dose escalation should be considered for those not responding to the initial dose. In the absence of response, continuing epoetin beyond 6 to 8 weeks does not appear to be beneficial. Epoetin should be titrated once the hemoglobin concentration reaches 12 g/dL. Evidence from one randomized controlled trial supports use of epoetin for patients with anemia associated with low-risk myelodysplasia not receiving chemotherapy; however, there are no published high-quality studies to support its use for anemia in other hematologic malignancies in the absence of chemotherapy. Therefore, for anemic patients with hematologic malignancies, it is recommended that physicians initiate conventional therapy and observe hematologic response before considering use of epoetin.

American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for women with hormone receptor-positive breast cancer: status report 2002.

OBJECTIVE: To conduct an evidence-based technology assessment to determine whether the routine use of anastrozole or any of the aromatase inhibitors in the adjuvant breast cancer setting is appropriate for broad-based conventional use in clinical practice. POTENTIAL INTERVENTIONS: Anastrozole, letrozole, and exemestane. OUTCOMES: Outcomes of interest include breast cancer incidence, breast cancer-specific survival, overall survival, and net health benefit. EVIDENCE: A comprehensive, formal literature review was conducted for relevant topics and is detailed in the text. Testimony was collected from invited experts and interested parties. The American Society of Clinical Oncology (ASCO)-prescribed technology assessment procedure was followed. BENEFITS/HARMS: The ASCO panel recognizes that a woman and her physician's decision regarding adjuvant hormonal therapy is complex and will depend on the importance and weight attributed to information regarding both cancer and non-cancer-related risks and benefits. CONCLUSION: The panel was influenced by the compelling, extensive, and long-term data available on tamoxifen. Overall, the panel considers the results of the Arimidex (anastrozole) or Tamoxifen Alone or in Combination (ATAC) trial and the extensive supporting data to be very promising but insufficient to change the standard practice at this time (May 2002). A 5-year course of adjuvant tamoxifen remains the standard therapy for women with hormone receptor-positive breast cancer. The panel recommends that physicians discuss the available information with patients, and, in making a decision, acknowledge that treatment approaches can change over time. Individual health care providers and their patients will need to come to their own conclusions, with careful consideration of all of the available data. (Specific questions addressed by the panel are summarized in Appendix 3.) VALIDATION: The conclusions of the panel were endorsed by the ASCO Health Services Research Committee and the ASCO Board of Directors.

Evaluating the role of quality assessment of primary studies in systematic reviews of cancer practice guidelines.

BACKGROUND: The purpose of this study was to evaluate the role of study quality assessment of primary studies in cancer practice guidelines. METHODS: Reliable and valid study quality assessment scales were sought and applied to published reports of trials included in systematic reviews of cancer guidelines. Sensitivity analyses were performed to evaluate the relationship between quality scores and pooled odds ratios (OR) for mortality and need for blood transfusion. RESULTS: Results found that that whether trials were classified as high or low quality depended on the scale used to assess them. Although the results of the sensitivity analyses found some variation in the ORs observed, the confidence intervals (CIs) of the pooled effects from each of the analyses of high quality trials overlapped with the CI of the pooled odds of all trials. Quality score was not predictive of pooled ORs studied here. CONCLUSIONS: Had sensitivity analyses based on study quality been conducted prospectively, it is highly unlikely that different conclusions would have been found or that different clinical recommendations would have emerged in the guidelines.

Chemotherapy for older patients with newly diagnosed, advanced-stage, aggressive-histology non-Hodgkin lymphoma: a systematic review.

PURPOSE: To conduct a systematic review assessing chemotherapeutic regimens in patients at least 60 years of age with previously untreated, advanced-stage, aggressive-histology non-Hodgkin lymphoma. DATA SOURCES: Computerized databases were searched for reports from 1966 to April 2000. Relevant journals, textbooks, and reference lists of published articles were hand searched. Abstract reports were not considered. STUDY SELECTION: Randomized trials comparing different chemotherapy regimens were selected. Two independent assessors, who were blinded to authors, institution, and results of the report, reviewed the retrieved citations. DATA EXTRACTION: One author abstracted data on patient characteristics, study quality score, survival, disease response and control, toxicity, and quality of life; pooling was not done because of study heterogeneity. DATA SYNTHESIS: 12 randomized trials that compared chemotherapeutic regimens were reviewed. Progression-free and overall survival were improved when anthracycline-containing regimens, such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CTVP (cyclophosphamide, pirarubicin, vincristine, and prednisone), were compared with other regimens. CONCLUSIONS: For treatment of older patients with advanced-stage, aggressive-histology lymphoma who do not have significant comorbid illnesses, an anthracycline-containing regimen, such as CHOP, given in standard doses and schedule, provides for superior outcomes compared with other regimens.

When is good, good enough? Methodological pragmatism for sustainable guideline development.

BACKGROUND: Continuous escalation in methodological and procedural rigor for evidence-based processes in guideline development is associated with increasing costs and production delays that threaten sustainability. While health research methodologists are appropriately responsible for promoting increasing rigor in guideline development, guideline sponsors are responsible for funding such processes. DISCUSSION: This paper acknowledges that other stakeholders in addition to methodologists should be more involved in negotiating trade-offs between methodological procedures and efficiency in guideline production to produce guidelines that are 'good enough' to be trustworthy and affordable under specific circumstances. The argument for reasonable methodological compromise to meet practical circumstances is consistent with current implicit methodological practice. This paper proposes a conceptual tool as a framework to be used by different stakeholders in negotiating, and explicitly reporting, reasonable compromises for trustworthy as well as cost-worthy guidelines. The framework helps fill a transparency gap in how methodological choices in guideline development are made. The principle, 'when good is good enough' can serve as a basis for this approach. The conceptual tool 'Efficiency-Validity Methodological Continuum' acknowledges trade-offs between validity and efficiency in evidence-based guideline development and allows for negotiation, guided by methodologists, of reasonable methodological compromises among stakeholders. Collaboration among guideline stakeholders in the development process is necessary if evidence-based guideline development is to be sustainable.

Improving the quality of 'personalized medicine' research and practice: through an ethical lens.

The evolving vision for personalized medicine (PM) implies a systems approach to the re-organization of healthcare and how we define the boundary between care and research. Calls for scaling PM up to a systems level requires a broad definition of quality not restricted to how the different elements of the system perform (e.g., laboratory quality control, biomarker prediction, biobanking, information systems, data sharing and security, and clinical outcomes) but how these elements work together to optimize population relevant quality indicators - effectiveness, affordability, system sustainability, public confidence and accessibility. Examples of PM-associated information technologies and innovative clinical evaluation methods with a focus on cancer medicine are provided to demonstrate how quality and ethics are inextricably linked to a PM systems approach. While current, traditional ethical standards sometimes challenge the PM approach, PM is challenging us to review ethical standards and improve ethical frameworks to meet new and future realities.