Is the Patient's Voice Being Heard?

EvidenceMatters A PUBLICATION OF UNITED BIOSOURCE CORPORATION

Inside this Issue Cover Story: Is the Patient’s Voice Being Heard? Quantification of the Cost-of-Illness.............................. 1 Payers Respond to Clinical Trial Assessment Instruments.............. 5 Personalized Medicine in Breast Cancer............................... 6 ePRO Studies via a Standardized User Interface Template................ 7 Time and Motion Studies.............. 8 Upcoming Presentations............. 10 CRO/Pharmaceutical Collaborations............................. 11 Establishing Routine and Effective Communication with Sites.......... 12 Study Quality Metrics.................. 14 Data Mining Clinical Trial Databases.................................. 15

O C T O B E R 2 0 0 9 V O L U M E X V I S S U E 3

SCIENCE & POLICY OPINION

Decision Making about the Value of Health Care Technologies— “Is the Patient’s Voice Being Heard?” By Ingela Wiklund, PhD, Senior Research Leader and Asha Hareendran, PhD, Senior Research Scientist, Center for Health Outcomes Research

With increasing concerns about the rising health care costs around the globe, approaches to assessing the value of new technologies are continually being adapted and extended. The importance of measures reflecting patients’ assessments and concerns about their conditions and treatment have been receiving increased attention from Health Technology Assessment (HTA) bodies and regulatory agencies such as the Food and Drug Administration (FDA) and the European Medicines Agency (EMEA). These agencies, responsible for the licensing and funding of new drugs and devices, are willing to listen to the “patient’s voice” but need to be convinced that the measures used to capture the patient’s voice are indeed an accurate reflection of patient concerns. Only with a well-thought through strategy of measuring the impact of a new technology on patients, and of demonstrating the rigour of the measures used, will trial sponsors convince the relevant agencies that this evidence does indeed reflect the “patient’s voice”. continued on page 3

UBC Presents at ISPOR............... 16 PROs in Product Labeling............ 19 UBC Experts Publish on Industry Issues........................... 21

Quantification of the Cost-of-Illness: Possible Approaches

Recent Publications.................... 22

By Radoslaw (Radek) Wasiak, PhD, Research Scientist, Center for Health Economics & Science Policy

Recent Presentations.................. 25 News Briefs................................ 27 Science Policy Corner................. 31

Evaluation of the burden of illness is often a necessary step in the process of generating evidence that a new health care intervention is required. The term “burden,” simply implies the negative impact of a health condition on either an individual or society.1 The predominant approach to evaluation of burden of illness is to focus on the personal impact of a health condition—measuring direct or indirect costs of illness. The cost may be economic, social, or psychological and reflected in the associated costs of medical management, absenteeism, productivity, or other measurable aspects of one’s life.2 Four types of data are typically needed for a cost-of-illness study and are part of a broadly-defined resource use associated with a health condition: health care utilization and pharmacotherapy use; utilization of non-medical support services; health-related outcomes, either reported by the patient or including productiv-

ity measures such as lost work time or reduced productivity; and other data measuring potential impact, e.g., lost earnings potential, career opportunities, educational opportunities. Therefore, a careful evaluation of the specific data need required for the analyses, as well as the identification of sources from which these data can be obtained, are important preliminary research tasks necessary in order to properly evaluate the cost of illness. Data needs are typically determined by the nature of the health condition as well as the type of required analysis.3 Incidence-based studies, which aim to estimate lifetime costs, measure the costs of an illness from onset to conclusion for cases beginning within the period of the study, usually one year. Incidence costs include the discounted, lifetime medical, morbidity, and mortality costs for the continued on page 2

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Quantification of the Cost-of-Illness continued from front page

incident cohort. Prevalence-based studies, which estimate annual costs, measure the costs of an illness in one period, usually one year, regardless of the date of onset. Prevalencebased studies include all medical care costs and morbidity costs for a disease within the study year. However, the mortality and permanent disability costs of prevalence-based studies are calculated differently from the other costs. Finally, direct costs can be estimated using one of three approaches: the top-down approach, the bottom-up approach, or the econometric approach. Regardless of the approach, the proper assessment of the cost of illness requires resource use data that represent the true pattern of care for patients with a health condition. Several study designs can help gain such information. Interviews with key opinion leaders (KOLs) are the simplest and most straightforward way to gather this information; however, data obtained are rarely robust enough to warrant publication and, in many circumstances, not accepted by reimbursement authorities as meeting the standards of scientific evidence. Another way of obtaining data needed is to identify patients meeting specific criteria and prospectively follow them up for a specific period of time to establish the pattern of resource use. One of the main advantages of this approach is the ability to design a study in a way to collect all the necessary data elements. This type of design is often associated with lengthy timelines not only due to the prospective nature of the study, but also because of the need for ethical approval and subsequent patient recruitment. Prospective studies may also be prone to the Hawthorne Effect, the phenomena whereby patterns of care may be altered as a result of the subjects and/or care providers being aware that they are being observed. Retrospective data analyses, void of the Hawthorne Effect, offer the opportunity to take advantage of the existing data sources and, in many cases, offer a timely and cost-effective solution. Medical chart reviews allow for extraction of relevant data elements directly from charts; therefore, they allow for a high level of data customization and control of data extraction to maintain high data quality. The drawback associated with this study design is the uncertainty associated with the characteristics of the recruited sites (i.e., whether the sites represent typical treatment) and the quality of information that medical charts contain (see May 2009 issue of EvidenceMatters; Evidence Gathering In Support of Health Economics Evaluations.) Existing, patient-level data sources provide the alternative— claims or patient-record datasets provide detailed information on resource use in a pre-specified setting—either at a country, regional, or local level. Claims datasets are typically

generated for billing purposes but can be mined for resource use data, as use of health care triggers the payment and, therefore, has to be tracked to ensure appropriate reim bursement. On the other hand, patient-record datasets are typically established to track the experience of a patient and, therefore in many situations, offer greater depth of data than claims databases. Both offer real-life, quite generalizable data on large numbers of patients, which is consistently recorded across many patients, but do not allow for customization and may lack detail necessary to estimate cost of illness properly. Another, but rather rarely used source of information for cost-of-illness studies is the clinical trial. Clinical trial data frequently contain all data elements needed to establish the cost-of-illness for a given health condition, as they have been designed to evaluate an intervention in patients with that condition. However, caution should be used when using resource use information from clinical data repositories. Participants in the clinical trials are typically highly selected, thus not very representative, and trial subjects may be induced to seeking care that is not needed except by virtue of participation in a clinical trial. Furthermore, the usability of resource use data from patients in the treatment arm for the purposes of cost-of-illness study is questionable as it does not represent a standard of care. However, where clinical trial data are potentially very useful is to inform the intangible aspects of burden of illness, particularly those that require patientreported outcomes, which are more and more frequently included in clinical trials. As is the case for most health economic studies, the data needs have to then be contrasted with data availability, which calls for appropriate and early scientific input as the design of a successful cost-of-illness study may not be straightforward. The search for appropriate data sources should be informed by the theoretical and conceptual components which in many cases are disease specific. Then, potential data sources have to be evaluated in the context of the disease, both in terms of data content as well as patient numbers, to properly assess their strengths and limitations and the impact on cost-of-illness estimates. For more information, please contact [email protected].

References McGuire T, Wells KB, Bruce ML, Miranda J, Scheffler R, Durham M, Ford DE, Lewis L. NIMH Affective Disorders Workgroup. Burden of Illness. Review. Ment Health Serv Res. 2002 Dec; 4(4):179-185.

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Hodgson TA. Costs of Illness in Cost-Effectiveness Analysis. A Review of the Methodology. Pharmacoeconomics 1994 Dec; 6(6):536-552.

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Hodgson TA. The State of the Art of Cost-of-Illness Estimates. Adv Health Econ Health Serv Res. 1983; 4:129-164.

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E V I D E N C E M AT T E R S • W W W. U N I T E D B I O S O U R C E . C O M

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“Is the Patient’s Voice Being Heard?” continued from front page Health technology evaluations have clearly been influenced by emerging trends in patient involvement in making decisions about their health and care, as well as more stringent methodology required by decision-making agencies for incorporating the patient’s view of treatment benefit and value. While these impacts vary across countries, there is evidence to show that the patient’s voice is being increasingly taken into account. Traditionally, in the earlier stages of product development, strategies for generating such evidence from the patient’s view focused on the requirements of regulatory agencies and on demonstrating the appropriateness of the measures used. Considerations for generating evidence of patients’ views of benefit for health care decision-making bodies were usually considered too late in the product development cycle, and often left a gap in the evidence that would meet the requirements of HTA-type agencies. For example, the sample sizes, duration of treatment,1 and comparator data may not have been appropriate to provide clear evidence of efficacy based on patient-reported outcomes. This has implications for the development of strategies to generate evidence of patient views of treatment benefit and value in product development, to support registration of the product, as well as to ensure market access and successful commercialization. The patient’s voice, especially via advocacy groups, is increasingly being heard in the content of product registration approvals. A headline in the Wall Street Journal, February 13, 2007, read “Cancer Patients Gain Say in Drug Approvals” and reported that while a cancer drug’s effectiveness has long been measured in two important ways (whether it shrinks a tumor and whether it extends patients’ lives), both researchers and regulators are paying increasing attention to another criterion—how a patient feels while taking the medicine. In the UK, the effort of the Kidney Cancer Association contributed, in part, to the National Institute of Health and Clinical Excellence (NICE) reversal this year of an earlier decision about the availability of a drug for metastatic renal cell carcinoma on the National Health Service (NHS). The association applauded the decision as Regulatory bodies such as the FDA a “Change of Tack Shows Policy Shift and Saves Lives.2” Another example is and EMEA have started to add patientthe success of women’s health organizations in the UK using “…because you are worth it” displayed on placards at a patient demonstration for a specific reported outcomes (PROs) in their breast cancer treatment intended to influence NICE decision making a favordisease area guidance documents, able decision about that treatment on the UK NHS.

which can be interpreted as a reflection

Patients have also often formally been involved in advisory board discussions of their increasing desire to capture conducted by the FDA and NICE appraisal committees. In fact, UK NICE how patients value treatment benefits. has a Patient Involvement Unit devoted to encouraging patient participation, and patient groups, such as “citizens’ councils,” are being included in health technology coverage decisions in some other countries. Emerging trends about reforming health care in the U.S. indicate that patients would be required to take greater responsibility for their health care by actively looking for health care providers that meet their demands in terms of quality and costs.3 It is important to recognize the context of health care decision making while developing the strategies to demonstrate “value” of a product from the patient’s point of view. Regulatory bodies such as the FDA and EMEA have started to add patient-reported outcomes (PROs) in their disease area guidance documents, which can be interpreted as a reflection of their increasing desire to capture how patients value treatment benefits. In the UK, NICE evaluates products across disease areas to inform decisions about allocation of resources. It calculates a drug’s “value for money” by assessing increased life expectancy and quality of life set against the price by using the cost per Quality-Adjusted Life Year (QALY) to provide a common denominator for decision making. If a treatment is too expensive relative to the benefits, it will not be approved. In Germany, the Institute for Quality and Efficiency in Health Care’s (IQWiG) decision making focuses on efficacy, which includes improvement in health status and health-related quality of life.4 IQWiG requires the benefit of an intervention to be based on the results of studies that have investigated the effects of an intervention on patient-relevant outcomes. In France, the Transparency Commission’s definition of the clinical benefit includes the evaluation of the impact on patients’ health status for assessing “medical benefit” and “improvement in medical benefit” and for any decision making about reimbursement of pharmaceuticals. continued on page 4


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“Is the Patient’s Voice Being Heard?” continued from page 3 Methods that are currently used by HTA agencies to evaluate evidence of patient-relevant benefits have been questioned, opening the door for challenging existing methods (e.g., QALY thresholds). Concerns about these methods are leading to the development of innovative methods for generating evidence that is relevant to the context of decision making. Porter et al.3 recently suggested that as part of the reforms in the U.S. health care system, a value-based system, incorporating “what is value for patients” should replace the current system which is driven and sustained by health insurance companies. The authors suggest that, health plans should be required to measure and report their subscribers’ health outcomes starting with a select group of medical conditions to ensure that the health care delivery system provides value for patients. On a similar note, WellPoint’s chief pharmacy officer has suggested that WellPoint “expects manufacturers to present the case for their product in quality of life terms” when he discussed the 2008 formulary submission guidelines. Manufacturers should consider patient-reported outcomes and quality of life as the default outcome measures in cost-effectiveness claims.”5 In the UK, when NICE’s decisions on some cancers, Alzheimer’s disease, rheumatoid arthritis, and macular degeneration products were severely criticized by the media after NICE severely restricted or ruled out their usage on the basis of costs despite proven efficacy, the decisions were defended on the basis that NICE’s objective was to ensure a fair and unbiased appraisal reflecting a broad perspective. The recent Kennedy6 report about appraising the value of innovation for NICE recommended that NICE appraisals should continue to be based on the incremental cost-effectiveness ratio (ICER)/QALY, but suggests that explicit consideration could be made of “relevant benefits.” However, while the report recognized the need for better understanding of health-related benefits to be taken into account, it cautions that the presence of such benefits should not result in an increase in the current thresholds being used. These developments could make room for incorporation of innovative methods of quantifying risk and benefit. In summary, the evidence required to be generated to support the value of a product is changing. The current way of developing drugs in the private sector is unsustainable; regulations around the health care product development process have become ever more complex; and HTAs arguably happen too late in the drug development process.7 There is need for more rapid discrimination between potential new therapies at earlier stages of drug development. The Kennedy report also appears to recommend an early discussion of claims about ”benefits” to be considered for appraisals.6 In fact NICE has implemented a process whereby pharmaceutical companies can have early discussions to help plan the type of evidence that needs to be generated to support product development. It is important that when decisions about patient-relevant benefits to support label claims are made at early stages of product development, the longer-term value of these data for HTA is also taken into account. This is not only to support registration but also to ensure successful commercialization, including differentiation and market access, including reimbursement. The way different stakeholders determine the “value” of new products should be kept in mind while developing strategies to measure outcomes reflecting benefit to patients. For more information, please contact [email protected] or [email protected].

References 1

McCoy NL. Estrogen Levels in Relation to Self-Reported Symptoms and Sexuality in Perimenopausal Women. (Summary). In: Flint M, Kronenberg F, Utian W, eds. Multi-Disciplinary Perspectives in Menopause. Vol 292. NY: Ann NY AcadSci; 1990:450-452.

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Kidney Cancer Association Applauds UK Drug Approval. 2009 Feb. 5. Press Release, Kidney Cancer Association Web site. http://www.z2systems.com/np/clients/kca/news.jsp?news=432. Accessed August 27, 2009.

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Porter ME. A Strategy for Health Care Reform—Toward a Value-Based System. N Engl J Med 2009 Jul 9; 361(2):109-112.

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General Methods. 2008 May, Ver. 3. Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG).Web site. http://www.iqwig.de/download/IQWiG_General_methods_V-3-0.pdf

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WellPoint Seeks More Quality of Life, Cost Data in Formulary Submissions. The Pink Sheet, October 28, 2008.

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Kennedy I. Appraising the Value of Innovation and Other Benefits: a Short Study for NICE. 2009 July. National Institute for Health and Clinical Excellence (NHS) Web site. http://www.nice.org.uk/aboutnice/howwework/researchanddevelopment/ KennedyStudyOfValuingInnovation.jsp?domedia=1&mid=98F4713F-19B9-E0B5-D491C3341152D0C1

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Cooksey D. A Review of UK Health Research Funding. 2006 Dec. HM Treasury Web site. http://www.hm-treasury.gov.uk/ d/pbr06_cooksey_final_report_636.pdf


Payers Respond to Clinical Trial Assessment Instruments By Dan Fantore, MHSA, Senior Research Manager; Carol Ware, CPC, Senior Research Manager; Beth Hahn, PhD, Managing Director, Center for Pricing & Reimbursement

Manufacturers understand that third-party payer reimbursement is vital to the uptake and market success of drugs and biologicals. UBC maintains that reimbursement is so vital, that efforts to secure optimal reimbursement should parallel the drug development process from proof-of-concept through launch. This article explores, as a case study, a project where UBC convened a Payer Advisory Board to engage payers in the clinical trial development process; specifically, in the review and evaluation of patient assessment instruments and how the data from the clinical trials— beyond safety and efficacy—would inform the coverage and reimbursement decision making process. Background Manufacturers develop clinical trials incorporating requirements of the Food and Drug Administration (FDA), but may be surprised to find after approval that payers, whether private, Medicare, or Medicaid, are reluctant to cover those FDAapproved drugs because of decisions made about clinical trials design. After FDA approval, some manufacturers learn that payers will unexpectedly impose high patient copayments or coinsurance, step therapy or prior authorization requirements, or even not cover the newly approved therapy, resulting in a negative impact on uptake of the product. As part of their research on drugs for coverage and reimbursement decisions, payers may review the approval data supporting the product’s safety and efficacy. They may ask questions such as: hy study a drug for a chronic condition for only W eight weeks? hy compare with placebo when there are five theraW peutic alternatives already approved in that area? hy use patient-reported outcomes instead of W physician assessments? Payers say, “If you only had talked to us about your clinical trials, we could have told you what is important.” To anticipate and perhaps obviate some of these questions from payers, one manufacturer sought payer input early in the development process, focusing on the assessment instruments to be used during clinical trials. Case Study: Payer Advisory Board In June 2009, UBC convened an Advisory Board of eight payer decision makers. Due to the therapeutic area, which was predominately paid for by Medicaid and private payers, the Advisory Board consisted of state Medicaid

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programs (retired participants) and private payer pharmacy and medical directors (active participants). The objectives of the Advisory Board were to: rovide payers with an understanding of the burden P of the disease for which drug(s) are being developed; est the reaction and responses of the payers to the T assessment instruments used in trials; and etermine where payers saw opportunities to provide D value in the assessment of the disease, beyond traditional safety and efficacy measures. To establish the baseline for the one-day meeting with the payers, the client and invited speakers gave presentations to describe the clinician’s view of treatment of the disease, the clinical development process for drugs in the disease area, and a thorough explanation of the assessment instruments to be used in trials in the disease area. The presentations and facilitated discussions amongst the payers provided valuable insight into payers’: Perceptions of the disease state; ecognition of the unmet needs in the treatment R arena; ppreciation of the “behind the scenes” process of A clinical trial and assessment instrument development; and orecasts for coverage and payment based on the F days’ learning. The Payer Advisory Board accomplished the client’s objectives for the meeting in terms of learning how payers approach coverage and reimbursement decision making, and what aspects of clinical trials are important to them. Payers are not experts in the regulatory approval process, with one Advisory Board participant conceding, “The fact that the FDA has established a grading scale that [the drug] has to pass, that information is important. But what that scale is becomes less important.” Nonetheless, the broader objective was achieved, that of gaining feedback from payers that would allow the manufacturer to proceed in the regulatory development process while also being mindful of and addressing the needs and requirements of third-party payers. Conclusion It is increasingly important to consider the perspective of the payer early in the drug development process as many manufacturers are finding that gaining approval from the FDA is different than gaining favorable coverage from payers. For understanding how payers will respond to their products and the data from their clinical trials, a Payer Advisory Board is a valid method to gather data and insight. For more information, please contact [email protected], [email protected], or [email protected].


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Oncology Update—Personalized Medicine in Breast Cancer By Kevin B. Knopf, MD, MPH, Senior Scientist, Center for Health Economics & Science Policy, and Oncologist, Pacific Hematology Oncology Associates

Personalized medicine is the latest buzzword within the health care environment, and specifically in the area of cancer, with much optimism about the future of this innovative treatment approach. What does it mean in practice? Personalized medicine is the movement towards rational treatment based on individual characteristics at a biologic level. The ultimate goal is to increase the pretest probability of a successful outcome for the patient. Broadly, this falls into two categories—better patient selection for a therapy, and more rational selection of a therapy that maximizes a chance of a positive outcome while minimizing expected toxicity. The term “targeted therapy” is often spoken of in the same sentence—the idea being that with better classification of the target, rational therapeutics will result. While personalized medicine is being explored across many different areas, this article focuses on its use in breast cancer. Chemotherapy is largely empiric from the earliest phases of drug development through the use of these agents in practice. That has certainly Personalized medicine is the movechanged in ment towards rational treatment drug developbased on individual characteristics at ment in recent a biologic level. The ultimate goal is years with therto increase the pretest probability of a apeutic targets successful outcome for the patient. isolated and drugs developed specifically against this target—as opposed to screening biologic compounds for activity in cancer cell lines. The ultimate example of this was the development of Imatinib— an oral agent that targets a specific gene mutation in patients with chronic myelogenous leukemia. This is one of the true “wonder” drugs in cancer. One of the first targeted therapies was tamoxifen—it works in patients who overexpress its target, the estrogen receptor. Thus treatment with this agent was never empiric; women whose cancer did not express the target would not respond to this agent, and thus the benefit/toxicity profile was easy to categorize. To date, traditional cytotoxic chemotherapy has not been personalized—drugs such as doxorubicin, Cytoxan, Paclitaxel and Docetaxel. Studies have tried to define which patients might respond to these agents preferentially, but selection of the appropriate agent is still largely empirical, integrating well-performed clinical trials in the decision making progress.

A major step forward was the identification of the receptor for erbb2, now known more commonly as HER2 (human epidermal growth factor receptor 2) and a monoclonal antibody targeted against this receptor, Herceptin (Trastuzumab). It is relatively easy to characterize which women will respond to this agent—those who overexpress the receptor. This changed the landscape dramatically for women with metastatic breast cancer where survival improved by years with this therapy. More recently, by giving Herceptin for a year following surgery to appropriately selected patients, the cure rate probably increases by 30% to 50%—a giant leap forward. A similar agent, Tykerb, was approved and targets both HER1 and HER2 and has been shown to work in patients who become resistant to Herceptin. The holy grail of personalized medicine would be a gene chip with impressive performance characteristics measuring DNA (or RNA or proteins) such that we could know exactly which agent(s) a woman with breast cancer should receive to maximize her chance of a cure. In the adjuvant setting, women have been found, through well-performed questionnaires and time-tradeoff methods, to be willing to undergo three to six months of chemotherapy for a perceived increase in cure rate of two to three percent. In this setting the number needed to treat—50—implies that the overwhelming majority of women receive chemotherapy with minimal or no benefit. In the future, it is hoped that we will be able to identify patients initially who are going to have their chance of cure increased by chemotherapy following surgery—and spare women who are likely to be cured already from undergoing unnecessary chemotherapy. We have made strides in this area but will continue to hope for better accuracy in our patient selection via personalized medicine. In practical terms, the idea is that you can take a patient’s breast cancer, analyze it using appropriate technology, and then determine if she should have chemotherapy, and if so, what agents should be chosen for maximum efficacy. Two more Food and Drug Administration (FDA) approved products exemplify personalized medicine—Oncotype Dx and MammaSite. These are genetic analyses of a woman’s breast cancer designed to be informative to a specific question—will this woman benefit from chemotherapy after surgery. In this example, both tests have been validated in patients whose breast cancer is estrogen receptor positive and has not spread to regional lymph nodes. Both tests give a score which the treating physician can interpret to determine if that woman will or will not benefit from chemotherapy. As with most diagnostic tests, there are grey areas, and the performance characteristics of 100% sensitivity and 100% specificity are not there—but these two diagnostic assays are widely used with confidence. Additional efforts in breast and other cancers are engineered around predicting pharmacology of cancer agents in vivo. In some examples, this is used to predict which patients might have a serious toxicity from a certain agent. In another recently approved product, the efforts are used to target


the pharmacologic dose of an agent based on an individual patients’ pharmacokinetics and pharmacodynamics (the way their body handles and metabolizes that drug). These are some examples, and the future of targeted treatment is very bright for our patients. Parallel developments in colon cancer and lung cancer are widely known and have become standards in clinical practice. With all these new developments towards improving our therapeutic outcomes and the advances seen so far in personalized medicine, the future of oncology treatments and successes holds great excitement. With the advent of personalized targeted therapies, will there still be a need for cost-effectiveness (CE) studies? Is it possible that knowing within a reasonable limit the likelihood of a patient responding to therapy will avoid unnecessary prescribing and maximize efficacy/toxicity, but none of the current targeted therapies approach a predictive value of 100% certainty of efficacy. If a target is identified that differentiates responders vs. non-responders (e.g., expression of wild type vs. mutant k-ras in colon cancer), then the therapy can immediately become more cost-effective, yet society will still study what an appropriate CE ratio will be for each of the cancer therapeutics. There will be continue to be competing therapies for each target which bear comparison; each with slightly different characteristics. Combining therapies against different targets might yield better efficacy through synergy—but the cost-effectiveness of this strategy needs to be worked out. Even the cost-effectiveness of the diagnostic technique used for patient selection for treatment or treatment selection is important to understand. Therefore, as targeted therapies become more and more refined, the overall cost-effectiveness will improve, but knowledge of the ratio to compare therapies, lines of therapy, or approval of therapy will still be paramount. For more information, please contact [email protected].

Improvement of the Patient Experience with Web-Based ePRO Studies via a Standardized User Interface Template By Sonya Eremenco, MA, e-PRO Manager; Sherilyn Notte, BS, Research Associate; Karin Coyne, PhD, Senior Research Leader, Center for Health Outcomes Research

As the use of electronic patient-reported outcome (ePRO) data collection grows, questions have arisen regarding the effect of format and style on patient interpretation of questions and responses. Several studies have shown that varied electronic questionnaire presentations can result in different patient responses.1,2,3 As a result, some questionnaire deve lopers are taking steps to ensure ePRO platforms will not

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affect the integrity of their previously validated instruments, such as requiring ePRO vendors to obtain device certification prior to data collection. As access to Web technology is rapidly expanding as a means of ePRO data collection, UBC sought to determine whether there is an optimal format to ensure clarity, ease of use, and data quality for Web-based questionnaire administration with the goal of developing and validating a standardized Web-based ePRO interface of common patient-reported outcome (PRO) question formats for use on a desktop or tablet PC. The goal was to create a template, minimizing response bias due to format, that could be easily implemented in future ePRO studies to administer study-specific questionnaires. A cross-sectional study, consisting of a general health survey followed by a cognitive debriefing interview to provide feedback on items, different ePRO platforms, format and usability, was conducted to evaluate face validity and feasibility of the Web template. Forty-seven participants (51% female; mean age 54.0 ± 13.0 years) were recruited from the general public with a variety of racial backgrounds and education levels (51% black; 41% white; 36% had completed some college). The Web-based application of standard ePRO questions was developed for both desktop and tablet PC platforms, consisting of 52 demographic and clinical questions representing Likert-type, dichotomous, visual analog scales (VAS) and numeric rating scales (NRS), as well as general health questions from the publicly available RAND-36.4 Participants first completed the questionnaires on either the desktop or tablet PC and reviewed the alternate platform during the interview. Interviews were conducted in three rounds to allow for changes to be made to the formatting or functionality of the system before the second and third rounds of interviews based on patient feedback. Slightly more than half of participants (53%) said they preferred the desktop to the tablet PC. Issues with the tablet PC included screen glare and difficulty using the touch screen or stylus. Importantly, almost all (97.8%) participants preferred either type of electronic administration over paper and pencil administration. Participants found most question formats easy to answer with only date, time and year entry requiring revisions and formatting. A keypad method of entry was preferred over drop-down or number-spinner formats, especially on the tablet, along with specific instructions on how to answer the questions. Two-thirds (66%) of the participants considered multiple items per screen to be acceptable. Participants were presented with several formatting options for the VAS items. The majority of participants (77%) preferred the VAS scales with hash marks every 10 units compared to the VAS scales with zero and 100 anchors alone. Most (83%) participants also preferred to have their continued on page 8


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Improvement of the Patient Experience with ePRO Studies

Time and Motion Studies: Opportunities and Challenges

continued from page 7

By Krista A. Payne, MEd, Research Scientist, Director of Health Care Data Capture; Karen Yeomans, BSc, Research Associate, Health Care Data Capture; Erwin DeCock, MSc, Senior Research Associate, Center for Health Economics & Science Policy

numerical selection displayed on the screen after clicking on the VAS line. When selecting their response on a VAS scale without hash marks but with a numerical pop-up in the first round, 24% of participants changed their answers after seeing their answer selection appear on the screen. However, when the VAS scale displayed hash marks every 10 units, no participants changed their answer after their numerical selection was shown. Thus, hash marks appear to be an important component in minimizing response bias in VAS formatting. Other formatting recommendations for Web-based applications based on participant feedback were to keep the screen simple and clean, limit …it is possible to develop a the number of single interface that functions the questions per same way on both a desktop and screen, avoid scrolling, use tablet computer with some of a larger font, programming adjustments… let participants manually advance from screen to screen rather than to have an autoadvance feature, and test visual presentation before launch. The ePRO template study established that it is possible to develop a single interface that functions the same way on both a desktop and tablet computer with some programming adjustments to accommodate the tablet. Participants with a wide range of health conditions, educational backgrounds and ages were able to use both platforms easily with the addition of instructional text on certain types of questions. Results of the interviews informed the development and final testing of a standardized interface that can be used across studies to facilitate rapid deployment of ePRO studies using Web technology. For more information, please contact [email protected], [email protected], or [email protected].

References Christian LM, Dillman DA. The Influence of Graphical and Symbolic Language Manipulations on Responses to Self-Administered Questions. Public Opinion Quarterly 2004; 68(1):57-58.

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Tourangeau R, Couper MP, Conrad F. Spacing, Position, and Order: Interpretive Heuristics for Visual Features of Survey Questions. Public Opinion Quarterly 2004; 68(3):368-393.

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Dillman DA, Smyth JD. Design Effects in the Transition to Webbased Surveys. Am J Prev Med 2007 May; 32(5 Suppl):S90-96.

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Ware JE, Jr., Sherbourne CD. The MOS 35-Item Short-Form Health Survey (SF-36). I. Conceptual Framework and Item Selection. Med Care 1992 June; 30(6):473-483.

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Time and Motion studies are designed to collect observational data to quantify the impact of medical interventions or procedures on dynamics of patient movement through the health care facility and resources consumed in terms of staff time and consumables. When the efficiency of a drug, medical device, or intervention is the outcome of interest, time and motion studies are typically warranted. Data obtained may inform activity-based costing and health care management by facility administrators,1 but also inform health economic analyses, including budget impact models.2,3,4 In the context of limited health care budgets, facility administrators are under increasing pressures to recognize the precise staffing levels and required equipment and resources, including medical devices, that optimize both patient care and net income.5 Moreover, as regulatory processes associated with the development and launch of medical devices become more stringent, the need for real-world effectiveness and efficiency data in support of these new and emerging products becomes increasingly important. Timing is everything… Time and Motion studies employ direct on-site observation and include manual timing techniques of events occurring over full episodes of care. Frequently, hand-held stop watches are used by observers not part of the current facility care team to measure how long pre-identified staff activities take to complete and, sometimes, in which order they occur. Resources allocated or consumed in relation to patient care are also carefully documented along the way. Although wholly naturalistic and prospective in nature, the inherent focus on movement, and multiple events performed by multiple people—all in real-time, contribute to both the uniqueness and associated challenges of this type of observational study. In contrast to prospective designs that employ interviews or questionnaires to gather data, data quality control in Time and Motion studies is much more difficult, unless the process of care and resource utilization is filmed. There is seldom, by design, a source document to refer back to. Practiced and well-trained observers, quick on their feet and attuned to care provision, are, therefore, essential components of a successful Time and Motion study. The following additional design and process elements which contribute to a successful Time and Motion study are also worth noting. trategic evidence matters. If it is intended that S study data will populate an economic model, it is critical that study variables map precisely to model


data requirements. While this seems intuitive, close monitoring of the evolution of the economic model and study design is essential as these are very dynamic development processes each in their own way, and it is likely that different teams of researchers are involved as different expertise is required.

to pre-identify the role each health care staff plays on the care team. This pre-knowledge and familiarization can contribute directly to the accuracy of timings by health care resource type that needs to be recorded by the observers. on’t let the data get cold. Data should be processed D immediately so that any gaps in the data can be communicated back to the observer or site-based study nurse within a reasonable recall period. Innovative approaches to communicating information to the study coordinating center, such as the use of tablet PCs to record study data, or the use of DataFax, which also facilitates rapid data transmittal, can dramatically reduce the time required for data processing and management.

ess is more. Study variables’ interest must be L carefully scrutinized to ensure that only the variables of utmost importance are included in the case report form (CRF). It is advisable to exclude from the CRF activities that happen infrequently or that are intertwined with other activities of less importance. The fewer the number of variables, the more likely that valid and complete study data will result. eep it simple. The CRF that observers will use to K record their data must be user-friendly. The formats should be designed with the predicted chronological order of health care events and resource utilization of interest in mind, along with the awareness that observers are likely juggling a writing instrument, a stop-watch, and a CRF. ind the common ground. Each activity to be F measured should be described on the CRF in the most accurate way, providing a clear and unambiguous indication of when to start and stop the clock. Especially in multi-country and multi-center Time and Motion studies, one should ensure that the activity definitions are applicable across all sites, despite highly variable facility types and local care processes. A common CRF is paramount for efficient and meaningful data analyses. Invest in local leadership. It is essential that participating study sites offer both a principal investigator and study nurse who are engaged and committed to the day-to-day management of the study. While patients may be pre-identified from facility schedules for enrollment into the study, it is likely not until the day of the treatment or procedure that the precise time of the observation period will be known. Also, last-minute changes to the health care staff on duty, as well as appointment delays and cancellations, are common occurrences in actual practice; thus, spontaneity, practicality, and common sense must prevail on observation days. It is essential that a seasoned study nurse, welltrained by the study design team, leads this effort. T raining is the key to success. In addition to the provision of detailed instructions for site study staff and observers alike, on-site training at the actual facility, in the treatment or procedure rooms where the observations will ultimately take place, is highly recommended. eam play—know your collaborators. At the beginT ning of each observation day, if feasible, it is suggested that observers meet the actual health care staff that will be providing care to the study subjects that day. This provides an opportunity for observers

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Main limitations of Time and Motion studies include risk of observers interfering with care patterns by their presence (Hawthorne Effect) and the precision of the study data given the possibility of human timing errors. Moving through time and space, while juggling a stop-watch, pen, and CRF, is indeed a challenge for the observers charged with the mandate to produce a complete and high quality dataset. The pressures observers face are significant. With a thoughtful design, careful planning, and an experienced study team, however, these studies can, nevertheless, result in meaningful and valid data that are extremely useful for a variety of purposes. While these studies are generally more complex with respect to logistics, there is an opportunity within Time and Motion research to be creative and innovative in both the delineation of the data points of interest, as well as the observation and data gathering techniques employed. Despite these challenges, those responsible for the empirical quantification of efficiency-related outcomes in support of a treatment or medical device are encouraged to consider this approach to evidence generation. It just may be that the time is now. For more information, please contact [email protected], [email protected], or [email protected].

References 1

Demeere N, Stouthuysen K, Roddhooft F. Time-Driven ActivityBased Costing in an Outpatient Clinic Environment: Development, Relevance and Managerial Impact. Health Policy 2009; 92:296-304.

2

Dioguardi J, Kausz A, Brenner L, El-Shahawy M, Bernardo M, Payne K. Costs of Administration of Intravenous Iron during Outpatient Hemodialysis: A Time and Motion Study. American Society of Nephrology, November 4-9, 2008, Philadelphia, PA.

3

Schiller B, Doss S, De Cock E, Del Aguila MA, Nissenson AR. Costs of Managing Anemia with Erythropoiesis-Stimulating Agents during Hemodialysis: A Time and Motion Study. Hemodial Int. 2008; 12(4):441-449.

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Saueressig U, Kwan JT, De Cock E, Sapède C. Healthcare Resource Utilization for Anemia Management: Current Practice with Erythropoiesis-Stimulating Agents and the Impact of Converting to Once-Monthly C.E.R.A. Blood Purif. 2008; 26(6):537-546.

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Beck DF, Depmsey J. Survival through Productivity Improvement. Health Care Superv. 1991 Sep; 10(1):1-13.


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Upcoming Presentations Canadian Cardiovascular Congress 2009 Oct 24–Oct 28 2009, Edmonton, Alberta, Canada Presentation Impact of Diffuse Vascular Disease History on Outcomes and Costs in Patients Diagnosed with Peripheral Artery Disease: Estimates from Saskatchewan Health Data Migliaccio-Walle K, Proskorovsky I, Stokes M, El-Hadi W, Popovici-Toma D

DIA’s Measuring Study Endpoints in Multinational Clinical Trials: Outcomes Reported from the Viewpoint of the Clinician, Patient, and Caregiver Oct 26–Oct 27 2009 New Orleans, LA, USA Program Committee Members Laurie Burke, MPH, RPh, Director, Study Endpoints and Labeling, Office of New Drugs, CDER, FDA; Nancy Kline Leidy, PhD, Senior Vice President, Scientific Affairs, United BioSource Corporation; Donald L. Patrick, PhD, MPH, Professor, Univ. of Washington; Jean Paty, PhD, Founder and SVP, Scientific, Quality and Regulatory Affairs, invivodata inc.; Jay D. Pearson, PhD, MA, Senior Director, Epidemiology, Merck & Company Inc.; John M. Weiler, MD, MBA, President, Compleware Corporation; Keith W. Wenzel, Senior Director Product Management, Perceptive Informatics Inc.

Tues., October 27, 8:30 a.m. – 10:00 a.m. SESSION 3—Evaluating and Demonstrating Content Validity— PART 1: What Have We Learned From PROs? Session Chairs: Nancy Kline Leidy, PhD, SVP, Scientific Affairs, United BioSource Corp.; Jean Paty, PhD, Founder and SVP, Scientific Quality & Regulatory Affairs, invivodata inc.

Oral Presentation Overview of Content Validity: What Is It? Why Is It Important? When Is It at Risk? Nancy Kline Leidy, PhD, SVP, Scientific Affairs, United BioSource Corp.

Tues., October 27, 10:30 a.m. – 12:00 p.m.

Is It What It Is? A Workshop on the Content Validity of PRO Instruments Instructors: Nancy Leidy, PhD, United BioSource Corp.; Julie McCormack, MA, United BioSource Corp.; Donald Patrick, PhD, University of Washington; Laurie Burke, MPH, FDA Advanced Psychometric Methods, Part 1: Use of Exploratory and Confirmatory Factor Analyses in PRO Instrument Development and Evaluation Instructors: Margaret Vernon, PhD, United BioSource Corp.; Donald Stull, PhD, United BioSource Corp. Wed., October 28, 1:30 p.m. - 4:30 p.m. Interpreting Change in Health-Related Quality of Life PatientReported Outcomes Measures Instructors: Kathleen Wyrwich, PhD, United BioSource Corp.; Ariane Kawata, PhD, United BioSource Corp. Advanced Psychometric Methods, Part 2: Executing and Interpreting Exploratory and Confirmatory Factor Analyses in PRO Instrument Development and Evaluation Instructors: Margaret Vernon, PhD, United BioSource Corp.; Donald Stull, PhD, United BioSource Corp.

Symposia Presentations Sat., October 31, 3:30 p.m. Advances in Health-Related Quality of Life Research: The PatientReported Outcomes Measurement Information System (PROMIS) Current Developments and Future Applications Development and Psychometric Analysis of PROMIS Pain Behavior and Impact Item Banks Dennis A. Revicki, PhD, United BioSource Corp.; Dagmar Amtmann, PhD, University of Washington; Wen-Hung Chen, PhD, United BioSource Corp.; Karon Cook, PhD, University of Washington Linking Patient Reported Quality of Life to the Neurobiology of Psychosis and Mood Disorder Impact of Mood States on Patient Reported Health-Related Quality of Life Dennis A. Revicki, PhD, United BioSource Corp.

SESSION 4 – Evaluating and Demonstrating Content Validity— PART 2: The Case of Caregiver and Clinician Reported Outcomes Session Chair: Nancy Kline Leidy, PhD, SVP, Scientific Affairs, United BioSource Corp.

Poster Presentations

Oral Presentations

Content Validity of Three Patient-Reported Outcome Measures in Men with Overactive Bladder (OAB) and Benign Prostatic Hyperplasia (BPH) Margolis MK, Coyne KS, Rodriquez J, Vats V

Content Validity in Pediatric Assessment Louis S. Matza, PhD, Research Scientist, Center for Health Outcomes Research, United BioSource Corp. Content Validity in Caregiver-Reported Outcomes for Cognitive Impairment Lori Frank, PhD, Executive Director, Center for Health Outcomes Research, United BioSource Corp.

Tues., October 27, 1:00 p.m. – 3:00 p.m. SESSION 5—Practical Considerations for Multi-National Clinical Trials Session Chairs: John M. Weiler, MD, MBA, President, Compleware Corp.; Keith W. Wenzel, Sr. Director, Product Management, Perceptive Informatics

Oral Presentation Instrument Development for Multi-National Application Ingela Wiklund, PhD, Senior Research Leader, Center for Health Outcomes Research, United BioSource Corp.

ISOQOL 16th Annual Conference Oct 28–Oct 31 2009, New Orleans, LA, USA Workshop Presentations Wed., October 28, 9:30 a.m. – 12:30 p.m. Moving Beyond Paper: Innovative Methods for Capturing Outcomes and Physiologic Data in the Electronic Age Instructors: Sonya Eremenco, MA, United BioSource Corp.; Ingela Wiklund, PhD, United BioSource Corp.; Shae Wilkins, Arrowhead Electronic Healthcare, LLC

Content Validation of a Daily Symptom Diary for Assessment of Heartburn Mody RR, DeLeon MC, O’Quinn SR, Dabbous O, Vernon MK

Development and Validation of an ePRO Interface Template for Web-Based Administration Eremenco S, Coyne K, Duran B, Leidy NK Mapping Qualitative Data to Items in Existing PRO Instruments Martin ML, Leidy NK, Patrick DL, Gandra SR, Wu A, Ware JE Qualitative Research in Castleman’s Disease: Exploring Patients’ Perspectives of Symptoms through Qualitative Interviews Vernon MK, Teschendorf B, Rhee V Variations on Energy Levels Reported by Patients with Type 2 Diabetes and Non-Dialysis Chronic Kidney Disease Related Anemia Brazg TN, Gandra SR, Leidy NK, Martin ML, Patrick DL, Ware JE, Wu AW When Does “Today” End? Implications for Shiftworkers Completing e-Diaries Eremenco S, Vernon M

CHEST 2009 Oct 31–Nov 5 2009, San Diego, CA, USA Poster Presentation Patient Preference for Maintenance Medications in Chronic Obstructive Pulmonary Disease Kawata AK, Kleinman L, Harding G, Ramachandran S


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By Sallyanne Williams, MBA, Clinical Program Director

number of Sponsors require that the CRO follow A their processes, SOPs, utilize their systems, etc. In strategic relationships, many CROs have found that they’ve lost productivity and efficiency due to the amount of time dedicated to educating staff on Sponsor processes and utilization of Sponsor systems.

In past years when outsourcing clinical trials, Sponsors have typically interacted with several service providers and have solicited bids from each provider. Once a Contract Research Organization (CRO) was selected to conduct the clinical trial, the CRO would be closely managed by the Sponsor in order to ensure smooth operations, adherence to timelines and standard operating procedures (SOPs), etc. In other words, the Sponsor would use the CRO as a labor pool while maintaining close day-to-day direct supervision.

In an effort to win business, CROs may overpromote their actual experience, and upon project execution, the Sponsor learns that the CRO is not capable of carrying out the agreed to scope of work for reasons such as lack of therapeutic expertise, lack of capacity, systems capability, etc. Consequently, the Sponsor finds that they’ve had to exert more effort to remediate gaps and prevent issues than initially anticipated to support the study.

CRO/Pharmaceutical Collaborations— A Winning Approach to Creating Successful Partnerships

Sponsor companies are now faced with significant internal capacity constraints resulting in increased pressure to conduct their clinical trials in the most efficient and cost-effective manner possible. As such, Sponsors continue to leverage use of external service providers and often form strategic relationships with a CRO or group of CROs. An April 2009 article in Specialty Pharma suggests that there is a current trend toward preferred partner announcements and indicates that “these types of partnerships are driven by the fact that despite significant increases in R&D spending, the number of new drug approvals is at a historic low.” These strategic relationships are established with the goal of capitalizing on efficiencies, such as a decrease in the amount of training required prior to study launch, more aggressive study timelines, etc. However, many issues with these relationships have been encountered; therefore, many relationships have failed with very little efficiency gained. Many of these strategic relationships fail as a result of the Sponsor placing a heavy emphasis on cost and frequently selecting the “lowest bidder” as the strategic partner of choice. This lowest bidder approach does not always achieve the original goal, and in the early stages of the relationship, the Sponsor may find themselves dealing with several challenges, such as the following. here is no discussion related to expectations at T the inception of the relationship. Many CROs launch studies early in the relationship with no clarity on whether they will follow their own SOPs or those of the Sponsor, which systems will be utilized, which decisions are to be made without Sponsor input, etc. ponsors have not been able to establish confidence S and trust in their partner, and as a result, the CRO finds that they are being micromanaged by the Sponsor rather than being allowed to function independently and liaise with the Sponsor for purposes of providing study status updates, problem solving and decision making.

If these challenges exist, what starts out as an exciting strategic relationship can soon become an adversarial relationship, ultimately ending in failure and, possibly, a tarnished reputation for the CRO. To avoid these pitfalls, it is imperative to work diligently early on in the process to establish good relationships with Sponsor partners. UBC has been fortunate to build strong relationships with most of the Sponsors with whom we have strategic relationships due to our dedication in providing excellent service and fostering open communication early in the process. Below are key issues in building successful partnerships. ll Sponsor/CRO relationships must have a senior A level management representative who is actively involved in the relationship. Sponsor feedback indicates that this dedication is imperative in the ability to allow for rapid decision making. When escalation is necessary, the Sponsor has direct access to the senior staff person, avoiding the need to work through several layers within the vendor organization to reach a decision or resolution. It is critical for the CRO and Sponsor to integrate at the conception of each relationship to discuss expectations as well as roles and responsibilities of both parties. This allows both parties to gain an understanding of expectations and obtain clarification on any areas of uncertainty prior to the launch of any studies, avoiding any potential negative impact on study operations. For example, UBC engages in governance meetings with all Sponsors, either biweekly or monthly. We review the status and financials of each active study, discuss any issues in need of escalation, identify additional work in the pipeline so that we may begin resource planning, etc. Having these meetings in a face-to-face environment is extremely beneficial to allow for greater transparency and enables a level of “bonding” that is not always continued on page 12


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CRO/Pharmaceutical Collaborations— continued from page 11

achievable with phone interactions, contributing to the strength of the relationship. lear identification of which processes and systems C are to be used—the Sponsor’s or the CRO’s—must be identified from the start. While a “hands off” approach by the Sponsor allows the CRO partner to use their own processes and enables rapid transitions and decreases time spent educating staff on Sponsor systems, some strategic partners mandate that their processes and systems are used. In these cases, a strong infrastructure to support these relationships is necessary, including a dedicated trainer assigned to the project. This dedicated trainer works with the project team to ensure training is completed in a timely manner as well as ensuring compliance with any updates during Access to the industry’s leading the course of the study to scientific experts is key to forming a which they successful, partnering relationship. are assigned. The experience and knowledge of a The trainer well-renowned and educated staff of is the main scientists and medical doctors enables point of project teams to have key resources contact for the Sponavailable to them when needed. sor for any questions or concerns regarding training and also participates in monthly training teleconferences with the Sponsor to discuss any issues and learn of any training updates. This person also serves as the subject matter expert on the client’s systems as well as serving as the internal point of escalation for issue resolution with the Sponsor subject matter experts. This approach has allowed UBC Project Managers to focus on the management of their studies and ensure a proper and timely launch, rather than focus time and effort on staff training and comprehension of Sponsor processes and system requirements. ccess to the industry’s leading scientific experts is A key to forming a successful, partnering relationship. The experience and knowledge of a well-renowned and educated staff of scientists and medical doctors enables project teams to have key resources available to them when needed. UBC project teams have relied on these expert staff resources for protocol input as well as assistance with problem solving. Sponsors have recognized us for this innovative approach which has allowed for much more creativity as well as demonstrated a proactive approach when providing services to our Sponsors.

pecific to UBC is the fact that we have such a S diversity of service offerings which has contributed to the success of our strategic relationships. With many strategic relationships, the Sponsor forms strategic relationships with multiple vendors for support services outside of project management, clinical monitoring, etc., and the CRO must work and coordinate with these vendors. While we can and do work in this environment, UBC also has a unique advantage in being able to offer a variety of different services across UBC business units, which can result in a decreased number of vendors to work with and manage, and increased efficiency and communication. Strategic relationships seem to be the wave of the future— and the present—and can lead to increased efficiencies that benefit both partners if managed well. It is important to recognize the challenges to these partnerships and address them from the beginning to build successful collaborations that lead to winning results. For more information, please contact [email protected].

Establishing Routine and Effective Communication with Sites is a Key to the Success of Large Simplified Trials By Traci Kruckemyer, MS, Clinical Program Director

What is it that makes a large, simplified trial ultimately successful, one might ask? After working on numerous large, simplified programs over the years, we’ve found that the secret lies in the management of the participating sites. By developing an effective site management model, your team will often find themselves positioned to develop rapport with those sites participating in the trial. To develop an effective and successful site management model, it is imperative to consider two key elements: The timing/frequency of site contacts, and he effectiveness of the communications being T delivered. As with any clinical trial, it is important to objectively review your site management model in a phased approach. Determine what objectives you need to meet during each phase of the trial and the amount of time realistically needed to be spent with each site to achieve those goals. In large, simplified trials, oftentimes we find that we may be dealing with “real-world” physicians who may have little to no research experience. These sites may require more


assistance than a typical research-savvy site during the start-up phase when regulatory documents and contracts are being collected; however, they may be constrained in the time they have available due to patient care obligations. During the start-up phase, we would want to plan for these types of scenarios and have sufficient time to provide sites with proper instruction on completion of the regulatory and contractual obligations for the trial. We would typically plan to spend more time with each site during the start-up phase in an effort to collect regulatory documents and contracts and ensure that sites are initiated and get started appropriately with enrollment. Once all sites are initiated and enrollment is progressing smoothly, site contact frequency may decrease depending on the duration of the enrollment timeline needed to meet the trial milestones. The same could be said with the end of the enrollment period. Once enrollment has been completed and sites have completed enrolling their complement of subjects/ patients, the number of contacts with sites may decrease again. Theoretically, if sites have kept up with their work during the course of the trial, one would anticipate the level of site management to decrease if the trial timelines allow for this. The key is establishing a rapport with your sites during the start-up period, appointing a central point of contact for the site, and outlining specifically what should be achieved during the site management calls in order to encourage the sites to be as prepared as possible. This may involve scripting the information to be collected or messages to be communicated. Once the site has established parameters for the trial and knows that their study contact will be following up to check with them at the defined intervals, the site is prepared and available to provide their updates when needed. The communication between the site and study team is much more effective when both parties are prepared. Frequent communication through a variety of modes is an effective method for keeping sites’ attention during large simplified trials. Busy physicians’ offices tend to occasionally get frustrated from too many phone contacts. To remedy this, it is important to discuss in advance with each site their preferred communication methods and the best times to reach them based on their schedules. In addition, you can capture their attention by sending out an eye-catching and informative mass fax, email or special edition newsletter. Large, bold prints, photos and clip art can help in designing communications that will stand out and grab sites’ attention. In addition, newsletters commonly feature a study coordinators’ or sites’ tips column which also helps to further engage study sites. Study Coordinator teleconferences that bring sites together to discuss study-specific issues, announcement, etc., are excellent forums that will help ensure that a large number of sites hear a consistent message. These conferences should be arranged at a preset mix of times to allow flexibility in attendance during the enrollment or other critical periods throughout a trial

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Regardless of timing of the site contacts, your study team should always be well informed of what is currently going on with the study. Here are a few tips to make your study team successful in site contacts: Always assign team members their own study sites. – This will create a sense of ownership among your team members, as well as help to develop a rapport with the sites. The sites and the team members will develop a connection during the course of the trial. – This will also help the Project Manager, from an accountability perspective, track site contacts made on a routine basis. nsure that team members are always up to date E with what is going on with the trial. Make sure your team members know what information can and cannot be shared with study sites. – Copy team members on updates with newsletters and general study updates that can be shared with study sites. rovide your team with guidance on what informaP tion should be disseminated to sites each week (i.e., enrollment updates, enrollment deadlines, query status, etc.) – Always determine the purpose of each communication that is made to a site. Are there any outstanding issues that require follow up at the time of the contact? Collect as much information and report as much information in one call as possible. Sites do not like to be called back repeatedly for the study multiple times in a short period of time. lways convey the value to the receiver/listener. Let A them know the importance of the communication. nsure that you hold internal team meetings on a E regular basis to provide updates to team members and meeting minutes for those who are unable to attend the meeting. Always follow up on outstanding issues. In summary, study teams can be most successful by establishing effective and routine contacts with study sites based on the phase of the study. By establishing a central point of contact for each study site, team members will develop a rapport with their own study sites over the duration of the trial. As sites tend to be very busy with patient care, it is important to not burden them with constant phone calls, yet find a balance with a variety of communication from phone calls, newsletters, mass faxes, etc., to help provide variety and ensure that sites are kept engaged throughout the duration of the trial. For more information, please contact [email protected].


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Study Quality Metrics By Jim Young, MS, Senior Principal Statistician

Study Quality Metrics (SQM) is a clinical study oversight strategy designed to monitor key aspects of accumulating data on a regular basis in relation to critical study objectives. The goal of SQM is to ensure that study hypotheses are not compromised and to take corrective action as early as possible to enhance or improve the quality of study data, thereby ensuring that study results are valid and credible.

have a different severity or type of disease than intended. The report described in Figure 1 shows that while Site 5 is falling slightly short of overall study median for this metric, an even larger percentage of subjects at Site 3 do not appear to meet the key eligibility criteria, and Site 3 has dropped below the minimum standard of 75%. Is this site receiving a large number of waivers for these eligibility criteria, might they misunderstand the requirements for enrollment, or are they feeling pressure to enroll borderline subjects? Pre-planned corrective action might include a recommendation to review the inclusion/exclusion criteria with site personnel, stressing the importance of enrolling a representative study population.

An SQM strategy is defined in a written plan developed by a team of stakeholders from various functional areas, including clinical, statistics, programming, and data management. The plan is formulated shortly after protocol finalization and defines procedures, roles and responsibilities, major data components, frequency of review, and measurement metrics. The primary output of an SQM plan is a panel of quality metric reports that are produced and reviewed by the study team on an ongoing basis. SQM reports are study-specific and are driven by the major objectives outlined in the study protocol. The first step in the process of developing SQM reports is to identify key study success factors. In identifying success factors, consideration should be given to the measurability of these factors, minimum performance standards for each metric, and how they can facilitate corrective action to study conduct if required. It is also imperative that the data required to support each report are available in the study database and can be obtained in a timely fashion. This ensures any problems and potential corrective actions can be monitored as close to real time as possible. SQM reports typically monitor aspects of study design, such as, adherence to inclusion and exclusion criteria, dosing and administration, and visit scheduling. These reports also identify potential inconsistencies in the assessment of safety signals across sites or regions and target key aspects of the primary efficacy endpoint, such as the amount of missing data and consistency of patient follow-up. Site monitors often examine these data elements for individual subjects during site visits, but SQM reports provide a higher level comparative overview based on all available data. Ideally, all the above takes place as a part of study startup activities, but can be implemented in ongoing studies as well. All team members are afforded the opportunity to provide input into the creation and definition of the various metrics. As a result, should the need for corrective action arise, emphasis is placed on maintaining overall study quality rather than individual functional area performance. Consider the following example. The consistent adherence to key inclusion and exclusion criteria as described in the protocol can be critical to the success of the study. If these criteria are not met, the enrolled population may no longer represent the target study population. This can potentially lead to a diminished treatment effect if the enrolled subjects

Figure 1. Percentage of Patients Meeting Key Eligibility Criteria

Figure 2. D ifference from Study Median in Number of Adverse Events Per Patient At Each Site

As another example, either under-or over-reporting of adverse events (AE) can result in an inaccurate safety profile for the study, so an early signal in this metric is worth investigating, especially when outside the expected threshold. The SQM report described in Figure 2 suggests that Site 2 is reporting fewer adverse events per subject than other sites in the study, and this difference has crossed the minimum standard for under reporting. Is there something about Site 2 that would reasonably explain the variation from other sites, or might this be indicative of a systematic problem such as not using a standard script to elicit adverse event information? Might the site be incorrectly grouping symptoms into higher level syndromes? If a problem is suspected, review of the guidelines for AE reporting and CRF completion with the site may be indicated.


Finally, suppose one were conducting a study with a timeto-event endpoint. Since events are often only recorded at clinic visits, imbalances in the visit schedule for subjects in the active and control arms can impact the reported time of the event, and may result in a scheduling bias towards longer event times in the arm with delayed visits. In Figure 3, note that while Site 5 has a slightly low percentage of visits within one week of expected timing in comparison to all sites combined, Site 1 has dropped below the minimum standard. Is this indicative of subjects experiencing drug intolerability resulting in earlier clinic visits? Are there scheduling problems with the subjects or the sites? These questions can be only be addressed once the problem has been identified, and the solution could be as simple as providing a transportation service for subjects enrolled at that site.

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to safety. From the standpoint of the FDA, data mining could allow for detection of safety signals early in clinical trial programs and drug-drug interactions with marketed drugs. However, data mining has broader implications for pharmaceutical, biotech, and medical device companies. For any given drug, biologic, or device that makes it to market, there will be multiple studies involved in establishing efficacy and safety. These studies, which are expensive to conduct, can contain a vast wealth of data that are useful beyond establishing safety, efficacy, and initial labeling claims. It is a relatively inexpensive endeavour (compared with collecting new data) to analyze existing trial data, and there are newer and more powerful methods that can be used to explore these data. Once trial data are collected, several possible data mining opportunities exist: sample size calculations based on responders from early trials to inform subsequent trials; refined inclusion/exclusion criteria for later trials; development of new patient-reported outcomes (PROs), or modification of previously used trial PROs; development of screening tools, diagnostic tools, or prognostic tools; additional product claims; product differentiation and market segmentation; examination of relationships among biologic, clinical and PRO endpoints; and scientific and promotional materials. Nearly all of these data mining opportunities fit with the spirit of the FDA’s Critical Path Initiative:

Figure 3. P ercentage of Patients With Time-to-Event Assessments Within +/– 1 Week of Expected Timing

Creation and review of SQM reports provide useful ongoing feedback to study teams regarding data quality and the ability to meet critical study objectives. An SQM reporting strategy allows for timely reaction to any developing data problems and leads to cleaner data, more credible results, and a greater likelihood for a successful study. For more information, please contact [email protected].

Data Mining Clinical Trial Databases: Gaining Value from Existing Data By Donald E. Stull, PhD, Senior Research Scientist; Ingela Wiklund, PhD, Senior Research Leader; and Dennis A. Revicki, PhD, Senior Vice President and Scientific Director, Center for Health Outcomes Research

The Center for Drug Evaluation and Research (CEDR) of the U.S. Food and Drug Administration (FDA) defines data mining as “a systematic process whereby large databases are searched (or mined) for combinations of variables that occur at a higher than expected frequency.”1 The goal, in this instance, is to use data-mining techniques to search for potential adverse event patterns in pre-market safety databases and explore possible subgroup differences related

The goal of critical path research is to develop new, publicly available scientific and technical tools—including assays, standards, computer modeling techniques, biomarkers, and clinical trial endpoints—that make the development process itself more efficient and effective and more likely to result in safe products that benefit patients.2 For example, early in clinical trial programs, analyses such as factor mixture models can be used to explore whether differential response to treatment (including placebo-responders) is more likely to be observed in patients with particular characteristics, or in specific regions, countries, or even clinical sites.3 Patients who are much less likely to be responsive to treatment or more likely to experience adverse events can be identified and their characteristics can be used to revise the inclusion/exclusion criteria in later clinical trials. Treatments can be targeted to those patients most likely to experience treatment benefit with the potential of reducing the risk of exposure to treatments that are toxic. Exploring trial data to examine the impact of baseline severity level for symptomatic conditions can help guide companies as to whether it is advisable to include all severity grades or just the more severe ones. This might require pooling trial data to explore the consequences of various severity levels or to replicate findings from one trial across several others. continued on page 18


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UBC Presents at ISPOR 12th Annual European Congress P aris , F rance 2 4 - 2 7 O ctober , 2 0 0 9

Saturday, 24 October Short Course 9:00 – 18:00 Discrete Event Simulation for Economic Analyses Faculty: J. Jaime Caro, MDCM, FRCPC, FACP, Adjunct Professor of Medicine, Adjunct Professor of Epidemiology and Biostatistics, McGill University and Senior Vice President, Health Care Analytics, United BioSource Corp.; Jorgen Möller, MSc Mech. Eng., Vice President, Modeling, United BioSource Corp.

Sunday, 25 October

Cost Effectiveness Analysis of Sunitinib, Bevacizumab + Interferon-Alfa and Temsirolimus as First-Line Therapy of Metastatic Renal Cell Carcinoma in Sweden Remak E, Vioix H, Sandin R, Harmenberg U, Ullen A, Sandstrom P

Cost-Effectiveness Analysis of Xolair Under Real Life Conditions in Belgian Patients with Severe Allergic Asthma Lecome P, Lee CS, Van Nooten FE, Thompson CL

Cost-Effectiveness of Combination Therapy for Treatment of Benign Prostatic Hyperplasia Baker TM, Black L, Bjerklund Johansen TE

Workshops – Session I 15:15 – 16:15 Quantifying the Risk in Risk Sharing: Collecting and Modeling Outcomes of the New Access Strategies

Cost-Effectiveness of Thalidomide Combined with Melphalan and Prednisone in Previously Untreated Multiple Myeloma in Wales

Discussion Leaders: J. Jaime Caro, MDCM, FRCPC, FACP, Senior Vice President, United BioSource Corp.; Zeba M. Khan, RPh, PhD, Vice President Pricing and Market Access, Celgene Corp.; Ian Joseph, BA, Research Associate, United BioSource Corp.

Joseph I, Facon T, Lewis P, Deniz HB, Caro JJ

Symptom Assessment in Clinical Trials— Bridging the Gap Between EMEA and FDA

Stokes ME, Shah M, Williams K, Reynolds MW, Rupnow MF, Hammond J

Discussion Leaders: Ingela Wiklund, PhD, Senior Research Leader, United BioSource Corp.; Olivier Chassany, MD, PhD, Medical Leader, Hopitaux de Paris; Alastair Glendenning, PhD, Health Economics and Outcomes Research, Novartis Pharma

Workshops – Session II 16:30 – 17:30 Ethical Implications of Resource Allocation in Situations of Extreme Scarcity, As in Pandemic Flu—Is There a Role for QALY? Discussion Leaders: Peter Kolominsky-Rabas, MD, PhD, Managing Director, Interdisciplinary Center for Public Health Studies, University of Erlangen-Nuremberg; Georgia Mitsi, PhD, MBA, MSc, Manager, United BioSource Corp.

Heterogeneity in Treatment Response: What It Is, Why It’s Important and How to Find It Discussion Leaders: Alastair Glendenning, PhD, HEOR, Novartis Pharma; Kathleen W. Wyrwich, PhD, Senior Research Scientist, United BioSource Corp.; Donald Stull, PhD, Senior Research Scientist, United BioSource Corp.

Posters – Session II 12:00 – 19:30 A Review of the Use of PROs in Submissions to NICE Lenderking WR

Applying Key Principles for Improved Health Technology Assessment: An Analysis of 14 HTA Organizations Neumann PJ, Drummond MF, Jonsson B, Luce B, Schwartz JS, Siebert U, Sullivan SD

Burden of Thrombocytopenia in Cancer Patients Undergoing Chemotherapy, 2000 – 2007 Nalysnyk L, Wu Y, Aravind S, Ranganathan G

Changing the Surgical Wound Closure Management Pathway: Time and Supplies with Prineo* vs. Standard of Care for Breast Reconstruction Surgery De Cock E, Van Nooten F, Raluy M, Muller K, Fabre J, Hargreaves J

Cost Effectiveness Analysis of Anastrozole Versus Tamoxifen in Adjuvant Therapy for Early Stage Breast Cancer Based on the 100-Month Analysis of the ATAC Trial From a German Perspective Kreif N, Benedict A, Lux MP, Wockel A, Klevesath MB

Costs of Bleeding Related Complications and Blood Product Transfusions Among Surgical Patients Development of a Preference-Based Algorithm to Report Utilities for Exacerbations of COPD From the EXACT Petrillo J, Cairns JA

Dose Delay Amongst Cancer Patients Undergoing Chemotherapy Nalysnyk L, Wu Y, Aravind S, Ranganathan G

“Patient Access Schemes”—The Use of Risk-Sharing in the UK Carroll SM, Wasiak R

Time and Supplies for Wound Management During and After Breast Reduction Surgery in Germany and the Netherlands: Prineo* vs. Standard of Care De Cock E, Van Nooten F, Raluy M, Muller K, Fabre J, Hargreaves J

Utility Library to Capture Utilities in the Area of Oncology Stafford MR, Van Hanswijck de Jonge P, Manson SC, Walker M

Validation of the SF-36 in Patients with Endometriosis Stull D, Wasiak R, Kreif N, Colligs A, Seitz C, Gerlinger C

Xolair Quality of Life Results as Measured in a Belgian Observational Study in Patients with Severe Allergic Asthma Lecomte P, See CS, Van Nooten FE, Rentz AM

Monday, 26 October

Educational Symposium Sponsored by Shire and UBC 7:00 – 8:00 Comparative Effectiveness: Can the Agencies’ Demands Be Met? Moderator: J. Jaime Caro, MDCM, FRCPC, FACP, Senior Vice President Health Economics, United BioSource Corp. Speakers: Kalipso Chalkidou, MD, PhD, Director NICE International, National Institute for Health and Clinical Excellence (NICE); Andreas Gerber, Dr. Med., Dipl.-Theol. (ev.), PhD, MD, MA, MSc, Head of Health Economics Department, Institut fur Qualitat und Wirtschaftlichkeit im Gesundheitswesen (IQWiG); Claire Le Jeunne, MD, Vice President, Haute Autorite de Sante (HAS)


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Podium Presentation – Session II 14:00 – 15:00 Bayesian Generalized Linear Modelling of the Relationship Between Health Assessment Questionnaire-Disability Index and Health Utilities Index Mark III in Early and Late Rheumatoid Arthritis: Data From the Premier and Armada Trials

Using Simulation to Boost Epidemiological Studies: It Saves the Day

Vanness D, Roy S, Benedict A, Cifaldi M

Workshop – Session IV 14:45 – 15:45 Methods of Pooling Data From Patient-Reported Outcome (PRO) Measures from Global Trials: Implementing Recommendations of the ISPOR Task Force

Podium Presentation – Session IV 16:30 – 17:30 When Does Value of Information Analysis Add Value? Ishak KJ, Getsios D, Caro JJ

Posters – Session II 8:00 – 19:00 Burden of Illness Study in Patients with Resistant Hypertension in UK Wasiak R, Kreif N, Stull D, Tyas DA

Cost-Effectiveness Analysis of Olanzapine Long-Acting Injection Compared with Risperidone Long-Acting Injection in the Treatment of Schizophrenia in Norway Carroll SM, Jemiai N, Suter B, O’Donohoe P, Skjoldborg U, Möller J, Kleivenes OK, Novick D

Cost Consequences of Reduced CVD Risk Through Improved SBP Control: A Comparative Analysis of Valsartan vs. Losartan Baker TM, Goh J, Dastani HB, Brede Y, Falvey H, Getsios D

Economic Evaluation of Ezetimibe Combined with Simvastatin for Treatment of Primary Hypercholesterolaemia Van Nooten F, Davies GM, Jukema JW, Liem AH, Hu XH

Impact of Chronic (CM) and Episodic Migraine (EM) on Work Presenteeism in 9 Countries Varon SF, Burk CT, Buse DC, Kawata AK, Payne KA, Blumenfeld A, Lipton RB

Overcoming the Challenges of Modelling Schizophrenia: A UK Case Study of the Cost-Effectiveness of Olanzapine Long-Acting Injection vs. Risperidone Long-Acting Injection Carroll SM, Jemiai N, Möller J, Novick D

Predicted Cost-Effectiveness of Achieving Multiple Optimal Lipid Values When Fenofibric Acid is Co-Administered with a Statin in Special Patient Populations with Mixed Dyslipidemia Webb SF, Sorensen SV, Williamson R

The Cost Effectiveness of Ambrisentan for the Treatment of Pulmonary Arterial Hypertension in Ireland Redmond S, Bozkaya D

Discussion Leaders: Georgia Mitsi, PhD, MBA, MSc, Manager, United BioSource Corp.; Bernd Bruggenjurgen, MD, MPH, Head, Alpha Care; J. Jaime Caro, MDCM, FRCPC, FACP, Senior Vice President Health Economics, United BioSource Corp.

Discussion Leaders: Asha Hareendran, PhD, Senior Research Scientist, United BioSource Corp.; Angela Williams, BSc, RGN, Pricing and Reimbursement Manager, ViroPharma Europe; Tara Symonds, PhD, Senior Director, Global Market Access, Outcomes Research, Pfizer Ltd.

Issue Panel – Session II 10:00 – 11:00 Estimating the Cost-Effectiveness of Vaccines—Is the Health Economist’s Standard Toolbox Sufficiently Equipped? Moderator: Stuart Carroll, BA (Hons), MSc, Research Associate and Policy Analyst, United BioSource Corp. Panelists: Philippe Beutels, BSc, MSc, PhD, Professor, Centre for HE Research & Modeling Infectious Diseases, Centre for the Evaluation of Vaccination, University of Antwerp; John Hutton, PhD, Professor of Health Economics, University of York; Carole Omnes, PharmD, MSc, HE Service Manager, Senior Market Access and HE, Europe, Sanofi Pasteur

Poster Presentations – Session III 8:00 – 16:00 Annual Costs of Chronic Hepatitis B Disease States in Portugal Raluy M, De Cock E, Marinho RT, Areias J, Calinas F, Carvalho A, Matos L, Rodrigues B, Macedo G, Velosa J, Perelman J

Budgetary Impact of Adding Doripenem to a Hospital Formulary in Germany Kongnakorn T, De Cock E, Kubitz N, Merchant S

Clinical History, Resource Utilization, and Other PatientReported Outcomes (PROs) in Migraineurs: An Adaptable Web-Based Methodology for the Design, Implementation and Conduct of a Multi-National Survey of Patients Payne KA, Wilcox TK, Yeomans K, Kawata AK, Varon SF, Burk CT, Lipton RB, Blumenfeld A

Cost-Effectiveness of Ustekinumab vs. Etanercept in Severe Plaque Psoriasis Patients: A Canadian Perspective Brazier N, Pan F, Shear N, Jivraj F, Schenkel B, Brown R

The Application of Discrete Event Simulation to Quantitative Risk Benefit Analysis Maguire A, Douglas I, Blak BT

Using ATLAS.TI as a Tool to Extract and Synthesize Data Obtained in Literature Reviewing Stafford M, Houghton K, Stull D

Tuesday, 27 October Workshops – Session III 8:30 – 9:30 Electronic Capture of PROs—ePROs— Status Today and Tomorrow? Discussion Leaders: Tara Symonds, PhD, Senior Director, Outcomes Research, Global Market Access, Pfizer Ltd.; Ingela Wiklund, PhD, Senior Research Leader, United BioSource Corp.; Alastair Glendenning, PhD, Health Economics and Outcomes Research, Novartis Pharma; Lucy Abraham, MSc, CPsychol, Associate Director, Outcomes Research, Pfizer Ltd.

P lease stop by B ooth 4 5 to meet Adam Barak and Lisbet Coulton, UBC's new International Pricing and Reimbursement leaders, as well as UBC experts in all areas of health economics and outcomes research.


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Data Mining Clinical Trial Databases continued from page 15

Data mining allows examination of treatment outcomes as a function of baseline severity levels: Do baseline levels tell us something about potential treatment response? Similarly, the severity or frequency of a symptom used as an inclusion criterion can be evaluated for its utility in detecting a treatment response. When developing clinical trial programs, there are often questions about whether particular symptoms or PROs should be included as endpoints in clinical trials. For example, should pain be included as an endpoint in gastroparesis clinical trials? If such measures are included in early phase trials, then data mining these early trials can permit researchers and sponsors to explore the predictive ability of symptom measures or PROs for establishing efficacy, for use as possible labelling claims, or early warnings about adverse events. If an analyst can identify participants who differentially respond to treatment and then establish the proportion of trial participants who respond to varying degrees, this information can aid in more precise sample size determinations for subsequent clinical trials. For example, knowing that 30% of trial participants show marked response, another 30% show marginal response, and the remaining show little or no response and identifying their characteristics can help with subsequent trial designs in terms of inclusion/exclusion criteria. Then, knowing that there is greater likelihood that the patients in the subsequent trials will be at least minimally responsive to treatment can reduce the overall sample size requirements and the costs for the trials. In addition to informing decisions about future trial designs, distinguishing subgroups of differential responders can provide insights into possible market segmentation. For instance, before starting reimbursement negotiations, a sponsor would benefit by understanding if there is subset of patients with a high unmet medical need in whom the treatment benefit is more pronounced, and how large that subset is, as a good fall-back position to secure the highest price possible in the largest population possible. Data are often collected at multiple time points in clinical trials. If the primary analyses have focused on pre-post treatment change, then there is a great deal of intermediate data not being used. These intermediate data points can be informative for understanding trajectories of change by treatment or responder group. Latent growth curve models can be used to explore onset of effect by including all intermediate points and noting where trajectories of treatment effect change the greatest.4 Data mining can allow analysts to explore key symptoms that can be used for screening or inclusion, or symptoms that represent a warning sign, if present, because they indicate a

higher likelihood of an adverse effect on treatment outcome. All of these can help ensure that maximal treatment benefit is being detected. Items used as inclusion/exclusion criteria can be evaluated in post hoc analyses for their potential as clinical screening instruments that have wider application than patient selection in clinical trials, resulting in a valuable addition to clinical practice. Of critical importance is the distinction between inclusion criteria that are based on physician assessment versus patient reports. Knowing that there is often a low correspondence between these two types of assessments,5, 6 if physician ratings are used for inclusion and a key endpoint is patient-reported, there may be a disconnect that potentially affects the outcome assessed. Secondary analysis of physician and patient-reported symptom data can help with understanding the magnitude of correspondence between the two data sources. Yet another application of data mining is to explore potential confounding variables that may adversely impact on treatment outcome (anxiety/depression in conditions such as irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD), and fibromyalgia, all being characterized as having a pronounced inherent psychosocial component. For instance, a previous analysis of pooled clinical trials data showed that in patients with endoscopy negative heartburn, patients with a low anxiety score at baseline displayed the expected beneficial dose-related response to proton pump inhibitors, whilst patients with a high anxiety score at baseline had a treatment response similar to patients on placebo treatment, clearly indicating the confounding impact of high anxiety levels.7 Subsequent analyses of trial data can permit examination of secondary endpoints for potential labelling or promotional claims or for manuscripts for dissemination of product benefits. For example, if PROs are used as secondary endpoints, data analyses can explore whether these are equally or more informative as primary endpoints for treatment efficacy. Further, are certain PRO domains or individual items more informative than others? The results of such analyses could lead to additional claims, and certainly can be used for dissemination purposes. Pooling data from clinical trials across multiple countries and languages can permit psychometric evaluation of PROs across different languages. Psychometric analyses can be conducted to assure that the measurement properties are consistent regardless of translation, lending confidence in the use of the PRO as an endpoint. Such an approach can help validate the conceptual framework across multiple languages and cultures. When more complex relationships among clinical and PRO endpoints are hypothesized, data mining existing trials can help explicate these conceptual models of disease progression. This may involve pooling data across trials to assure sufficient sample size or to explore whether the conceptual models are consistent across countries. At the least, using data from multiple trials allows for replication using multi-sample analytic designs.


Pooling of data across international, multi-center trials is also an issue and concern raised by the FDA, especially with the increasing trend in industry to more and more clinical trials into non-traditional countries such as Taiwan, the Philippines, China, India, South America, and Russia, to name a few, with different treatment and practice patterns, different cultures, a variety of languages within the same country (for instance 44 different language versions in India alone), lower literacy levels, and a much greater diversity in socioeconomic status. Differential Item Functioning tests can be used to explore to what extent the observed differences in treatment outcome are related to issues around translations, cross-cultural adaptation, or different salience of individual items within an instrument. These can guide sponsors about the appropriateness of pooling data and suggest which countries to select for future studies when PROs are primary or key secondary endpoints. The impact of differences in practice and treatment patterns across countries and regions can similarly be explored. Data from such an analysis would help in discussions with regulatory bodies by anticipating potential concerns about “translatability” of efficacy data derived in non-traditional countries to North America and Europe. Data mining has the potential of generating outcomes of great value at a cost that is only a fraction of those of original data collection. Given the tremendous amount of clinical trial data collected by companies and the powerful analytic techniques now available, exploring existing data can be done relatively quickly and inexpensively, with the potential of yielding additional insights and outcomes for a good value. For more information, please contact [email protected], [email protected], or [email protected].

References Center for Drug Evaluation and Research (CEDR), US FDA: http://www.fda.gov/AboutFDA/CentersOffices/CDER/ ucm101460.htm; downloaded 7 July 2009

1

Innovation or Stagnation? Challenge and Opportunity on the Critical Path to New Medical Products. March, 2004. U.S. Department of Health and Human Services.

2

Stull DE, Wyrwich KW. Identifying Subgroups of Differential Responders: Implications for Personalized Health Care. Evidence Matters 2009; 15(2):14-16.

3

Stull DE. Analyzing Growth and Change: Latent Variable Growth Curve Modeling with an Application to Clinical Trials. Qual Life Res 2008; 17:47-59.

4

McColl E, Junghard O, Wiklund I, Revicki DA. Assessing Symptoms in Gastroesophageal Reflux Disease: How Well Do Clinicians’ Assessments Agree with Those of Their Patients? Am J Gastroenterol 2005; 100:11–18.

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Patient-Reported Outcomes (PROs) in Product Labeling, 2006 to Present By Sajjad Khan, PhD, MSW, LCSW-C, Senior Research Associate and Andrew C. Palsgrove, BA, Research Associate, Center for Health Outcomes Research

Background Not long ago, it was understood that provision of sound research data to worldwide regulatory bodies was the highest hurdle for achieving market place access and reimbursement. Today, however, the evidence hurdle goes beyond the Food and Drug Adminstration (FDA), European Medicines Agency (EMEA), and other regulatory authorities and includes national health services and payer-based evaluative bodies, such as the Pharmaceutical Benefits Advisory Committee (PBAC) and National Institute for Clinical Excellence (NICE). In each case, there must be substantial evidence that demonstrates product value. For regulatory agencies, the focus of evidence is efficacy and safety, while the payer audience looks for key product differentiation and cost-effectiveness. Indeed, providing sound evidence, as well as the right evidence to the right audience, is more important now than ever. In many cases, one of the most important sources of data to understand treatment benefit is the patient. The importance of patient-reported outcomes (PROs) stems from the need for greater understanding of how medicines comprehensively benefit the patient using standardized assessment methods beyond the “traditional” physiologic or clinician-rated endpoints. The use of PROs provides another very important data point that substantiates the usefulness, efficacy, and tolerability of a given treatment intervention. Ultimately, PRO data are part of the constellation of clinical evidence that demonstrate treatment benefit and often serve as a product differentiator. The FDA’s Draft Guidance for Industry, Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims1 was designed to provide sponsors with the Agency’s initial thinking on the essential elements needed to support the inclusion of PRO information in product labels approved in the United States. There has been a growing interest in utilizing PRO measures in drug development with the goal of obtaining PRO label language and communicating this treatment benefit to payers, providers, and patients.

5

Chassany O, Le-Jeunne P, Duracinsky M, Schwalm MS, Mathieu M. Discrepancies Between Patient-Reported Outcomes and Clinician-Reported Outcomes in Chronic Venous Disease, Irritable Bowel Syndrome, and Peripheral Arterial Occlusive Disease. Value Health 2006; 9(1):39-46.

6

Wiklund I, Carlsson R, Carlsson J, Glise H. Anxiety as a Predictor of Treatment Response in Patients with Heartburn: A Pooled Analysis of Clinical Trials. Scand J Gastroenterol 2006; 41:288-293.

7

Issue A frequently asked question about PROs is what, if any, products have included PRO labeling language since the Draft Guidance appeared in 2006. We decided to address this question by identifying specific examples. The intent was not to perform an all-inclusive systematic review, but rather to provide a list of compounds to serve as examples of drugs that were granted PRO label language after the release of the 2006 FDA Draft Guidance. continued on page 20


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PROs in Product Labeling continued from page 19

musculoskeletal conditions (2007); and Pulmicort Flexhaler and Advair HFA for asthma (2006). Discussion

Approach We used the UBC PRO Labeling Database which is based on information gathered from. the Physicians’ Desk Reference (PDR) Electronic Library (Version 2009.1A)2 and Drugs@ FDA3, supplementing this source with new information from the www.drugs.com/newdrugs.html website. The UBC PRO Labeling Database contains information on over 220 labels with PRO language, 1994 to 2009. To offer greater insight into post-draft guidance PRO label activity, we decided to provide examples of products with new indications since 2006, excluding new formulations of existing products with pre-2006 PRO label language.

Each of the examples of pharmaceutical products with PRO labeling addresses the treatment of conditions characterized by substantial patient-experienced and patient-reported problems, such as pain; symptomatic conditions such as rhinitis, GERD, or nicotine withdrawal; and, physical function. Three of the labels included language around healthrelated quality of life (HRQL) benefits (Symbicort, Soliris, and Thyrogen). The amount of PRO information provided in the label varied. For example, some included the names of the instrument(s) used in the development program, while others did not. In all cases, PRO label language was found in the Clinical Studies section.

The extent to which the procedures used to develop PRO evidence to support these labels were consistent with the Examples FDA’s PRO Draft Guidance standards is unknown. It is likely A list of 18 products with PRO label language since 2006 is that all of the labels reviewed involved product development shown in Table 1. Three of the products were approved prior programs that were well underway or completed by the time to 2006, but had PRO label information for new indications the Draft Guidance was released, making it virtually imposapproved after 2006. Two products had multiple indications. sible for them to have followed the guidance “to the letter.” Together, these 18 products have 23 product labels with Sponsors of products in the early phases of development in PRO language. 2006 should benefit from the information contained in the Guidance. Assuming a Product Name (Date) Disease Area three to six Alvesco (2008) Cymbalta (2008) Seroquel (2006) Toviaz (2008) year developMajor Depressive Disorder Overactive Bladder Asthma (multiple disease areasb) ment program, Arcalyst (2008) Kapidex (2009) Soliris (2007) Veramyst (2008) it is likely that these new drug Cryopyrin-Associated Periodic Paroxysmal Nocturnal Seasonal and Perennial GERD Syndromes Hemoglobinuria Allergic Rhinitis applications Azilect (2006) Letairis (2007) Symbicort (2006) Vivitrol (2006) are only now Parkinson’s Disease Pulmonary Hypertension Asthma Alcohol Dependence reaching the Chantix (2006) Lyrica (2007) Thyrogen (2006) Voltaren Gel (2007) FDA’s desk Smoking Cessation Fibromyalgia Thyroid Cancer Diagnostic Osteoarthritis Pain for review and Clinoril (2006) Omnaris (2006) approval. (multiple disease areasa)

Seasonal and Allergic Rhinitis

It is important to note that we Osteoarthritis, Rheumatoid Arthritis, Ankylosing Spondylitis, Acute Painful Shoulder, and Acute Gouty Arthritis b did not search Fibromyalgia and Generalized Anxiety Disorder for examples of *A comprehensive table with verbatim PRO language is available on-line at http://unitedbiosource.com/pdfs/ PRO language pro-label-information.pdf. in biologic or device approvals. Clearly, licensed biologics and devices that have Although we decided to exclude products with existing PRO a therapeutic indication or patient-relevant benefit present an label language and new formulations from our list of examopportunity to capture patient-reported information during ples, it is of interest to note that the following supplemental testing, and such data points would likely add value to the new drug applications (sNDA) with PRO label language were body of evidence to understand benefit and support value. also approved during this time period: Emend Powder (IV) for acute and delayed nausea and vomiting associated with Conclusion initial and repeat courses of cancer chemotherapy (2008); The release of the FDA’s Draft Guidance in 2006 was an Ambien CR for insomnia characterized by difficulties with important milestone in the evolution of the PRO as a recsleep onset and/or sleep maintenance (2007); Amrix for ognized and integral endpoint in the evaluation of medical relief from muscle spasm associated with acute, painful

Table 1. Examples of Pharmaceutical Products with PRO Label Information, 2006 to Present* a


products. We pulled together examples of products with PRO label language since 2006 to address the frequently overheard comment that there have been “no” PRO instruments or language approved for label inclusion since the Draft Guidance was released. If you are aware of additional successes, please let us know and we will add this information to the posted table for all to see! For more information, please contact [email protected] or [email protected].

References 1

Draft Guidance for Industry on Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. Federal Register February 3, 2006; 71(23):58625863.

2

Physicians’ Desk Reference (2009). Thomson PDR, Montvale, NJ. Version 2009.1.0

3

U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Drugs@FDA: FDA Approved Drug Products. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/

UBC Experts Publish On Industry Issues Executing Postapproval Studies That Meet Timelines and Contain Costs by David Hufner, Traci Kruckemyer, and Peggy Schrammel September 2009, Life Science Leader Postapproval studies are typically initiated to gather additional product safety information, comply with a post marketing requirement (PMR), or support overall market access. Many times, these studies require enrolling very large numbers of patients at often research-naïve investigative sites to address pressing study objectives. Many sponsors and CROs erroneously believe that a phase III operational approach will meet all needs of a postapproval study. However, applying phase III processes can result in study delays, astronomical budgets, and dissatisfied study investigators. Streamlining all aspects of postapproval studies is key to overall success. Rethinking Randomized Clinical Trials for Comparative Effectiveness Research by Bryan Luce et al. August 2009, Annals of Internal Medicine While advances in medical science have led to continued improvements in medical care and health outcomes, evidence of the comparative effectiveness of alternative management options remains inadequate for informed medical care and health policy decision making. The result is frequently suboptimal and inefficient care as well as unsustainable costs. To enhance or at least maintain quality of care as health reform and cost containment occurs, better evidence of comparative clinical and cost-effectiveness is required. Evidence Generation is the Foundation to Optimal Product Positioning by Teresa Wilcox, RPh, PhD, Peter Marangos and Beth Hahn, PhD June 2009, Pharmaceutical Commerce Obtaining optimal product positioning and market uptake requires thoughtful planning and a fresh perspective in this turbulent global economy. While the need for product differentiation and comparative assessment has been a constant, there are increasing pressures from formulary decision makers and payers demanding evidence backed by an increasing level of scientific rigor. The economic environment is acting as a catalyst in the movement, truly signaling that it is time to provide value-based evidence data to support formulary positioning and product access. New Directions in Monitoring Post-Approval Drug Safety by Kelly Davis and Annette Stemhagen May 2009, Good Clinical Practice Journal In both Europe and the US, a heightened focus on drug safety and risk management has led to new regulations that will result in significant changes for the pharmaceutical industry, particularly during the post-approval phase of drug development. Regulators at both the European Medicines Agency (EMEA) and the Food and Drug Administration (FDA) have embarked on new initiatives to update and expand methodologies used to monitor product safety after approval. For the most updated list of current publications, visit http://www.unitedbiosource.com/news/press-coverage.aspx. For more information on any of these topics, email [email protected].

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SCIENCE SPOTLIGHT & POLICY ON SCIENCE OPINION

Recent Publications Beaton SJ, Robinson SB, Von Worley A, Davis HT, Boscoe AN, Ben-Joseph R, Okamoto LJ. “Cardiometabolic Risk and Health Care Utilization and Cost for Hispanic and Non-Hispanic Women.” Popul Health Manag 2009 Aug; 12(4):177-183. Becker MA, Schumacher HR, Benjamin KL, Gorevic P, Greenwald M, Fessel J, Edwards L, Kawata AK, Frank L, Waltrip R, Maroli A, Huang B, Sundy J. “Quality of Life and Disability in Patients with Treatment-Failure Gout.” J Rheumatol 2009 May; 36(5):1041-1048. [Epub 2009 Mar 30] Benedict A, Arellano J, De Cock E, Baird J. “Economic Evaluation of Duloxetine Versus Serotonin Selective Reuptake Inhibitors and Venlafaxine XR in Treating Major Depressive Disorder in Scotland.” J Affect Disord 2009 Jun 2 [Epub ahead of print] Bharmal M, Payne K, Atkinson MJ, Desrosiers MP, Morisky DE, Gemmen E. “Validation of an Abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9) Among Patients on Antihypertensive Medications.” Health Qual Life Outcomes 2009 Apr 27; 7:36. Black R, Greenberg B, Ryan JM, Posner H, Seeburger J, Amatniek J, Resnick M, Mohs R, Miller DS, Saumier D, Carrillo MC, Stern Y. “Scales as Outcome Measures for Alzheimer’s Disease.” Alzheimers Dement 2009 Jul; 5(4):324-339. Boudreau DM, Malone DC, Raebel MA, Fishman PA, Nichols GA, Feldstein AC, Boscoe AN, Ben-Joseph RH, Magid DJ, Okamoto LJ. “Health Care Utilization and Costs by Metabolic Syndrome Risk Factors.” Metab Syndr Relat Disord 2009 Aug; 7(4):305-314. Burnier M, Brown RE, Ong SH, Keskinaslan A, Khan ZM. “Issues in Blood Pressure Control and the Potential Role of Single-Pill Combination Therapies.” Int J Clin Pract 2009 May; 63(5):790-8. [Epub 2009 Feb 11] Busner J, Targum SD, Miller DS. “The Clinical Global Impressions Scale: Errors in Understanding and Use.” Compr Psychiatry 2009 May-June; 50(3):257-62. [Epub 2008 Oct 16] Calkins H, Reynolds MR, Spector P, Sondhi M, Xu Y, Martin A, Williams CJ, Sledge I. “Treatment of Atrial Fibrillation with Anti-Arrhythmic Drugs or Radio Frequency Ablation: Two Systematic Literature Review and Meta-Analyses.” Circ Arrhythmia Electrophysiol 2009 Jun 2 [Epub ahead of print]

Cappelleri JC, Bushmakin AG, Gerber RA, Leidy NK, Sexton CC, Karlsson J, Lowe MR. “Evaluating the Power of Food Scale in Obese Subjects and a General Sample of Individuals: Development and Measurement Properties.” Int J Obes (Lond) 2009 Aug; 33(8):913-922. [Epub 2009 Jun 9] Cappelleri JC, Bushmakin AG, Gerber RA, Leidy NK, Sexton CC, Lowe MR, Karlsson J. “Psychometric Analysis of the Three-Factor Eating Questionnaire-R21: Results from a Large Diverse Sample of Obese and NonObese Participants.” Int J Obes (Lond) 2009 Jun: 33(6):611-620. [Epub 2009 Apr 28] Caro JJ. “Methods of Economic Evaluation for the German Statutory Healthcare System.” Pharmacoeconomics 2009; 27(3):263-264. Caro J, Huybrechts K. “Case-Control Studies in Pharmacoeconomic Research: An Overview.” Pharmacoeconomics 2009; 27(8):627-634. Carroll S. “Is There Anything Nicer than NICE? A Question the Conservative Shadow Health Team is Right to Ask.” Value Health 2009 Jul/ Aug; 12(5):631-633. [Epub 2009 Apr 23] Cheak-Zamora NC, Wyrwich KW, McBride TD. “Reliability and Validity of the SF-12v2 in the Medical Expenditure Panel Survey.” Qual Life Res 2009 Aug; 18(6):727-735. [Epub 2009 May 8] Chen J, Bhatt DL, Dunn ES, Shi C, Caro JJ, Mahoney EM, Gabriel S, Jackson JD, Topol EJ, Cohen DJ. “Cost-Effectiveness of Clopidogrel plus Aspirin versus Aspirin Alone for Secondary Prevention of Cardiovascular Events: Results from the CHARISMA Trial.” Value Health 2009 Sep; 12(6):872-879. [Epub 2009 Mar 10] Chen WH, Revicki DA, Lai JS, Cook KF, Amtmann D. “Linking Pain Items from Two Studies onto a Common Scale Using Item Response Theory.” J Pain Symptom Manage 2009 Jul 2 [Epub ahead of print] Coons SJ, Gwaltney CJ, Hays RD, Lundy JJ, Sloan JA, Revicki DA, Lenderking WR, Cella D, Basch E, on behalf of the ISPOR ePRO Task Force. “Recommendations on Evidence Needed to Support Measurement Equivalence Between Electronic and Paper-Based PatientReported Outcome (PRO) Measures: ISPOR ePRO Good Research Practices Task Force Report.” Value Health 2009 Jun; 12(4):419-429. [Epub 2008 Nov 11] Coyne KS, Margolis MK, Thompson C, Kopp Z. “Psychometric Equivalence of the OAB-q in Danish, German, Polish, Swedish, and Turkish.” Value Health 2008 Dec; 11(7):1096-101. [Epub 2008 May 16]

Coyne KS, Matza LS, Brewster-Jordan J. “’We have to stop again?!’: The Impact of Overactive Bladder on Family Members.” Neurourol Urodyn 2009 Mar 19 [Epub ahead of print] Coyne KS, Sexton CC, Kopp ZS, Luks S, Gross A, Irwin D, Milsom I. “Rationale for the Study Methods and Design of the Epidemiology of Lower Urinary Tract Symptoms (EpiLUTS) Study.” BJU Int 2009 Aug; 104(3):348-351. [Epub 2009 Mar 9] Coyne KS, Sexton CC, Thompson CL, Milsom I, Irwin D, Kopp ZS, Chapple CR, Kaplan S, Tubaro A, Aiyer LP, Wein AJ. “The Prevalence of Lower Urinary Tract Symptoms (LUTS) in the USA, the UK and Sweden: Results from the Epidemiology of LUTS (EpiLUTS) Study.” BJU Int 2009 Aug; 104(3):352-360. [Epub 2009 Mar 5] Crean S, Boyd DM, Sercus B, Lahn M. “Safety of Multi-Targeted Kinase Inhibitors as Monotherapy Treatment of Cancer: A Systematic Review of the Literature.” Curr Drug Saf 2009 May; 4(2):143-154. Crean SM, Michels SL, Moschella K, Reynolds MW. “Bovine Thrombin Safety Reporting: An Example of Study Design and Publication Bias.” J Surg Res 2008 Oct 16 [Epub ahead of print] Crepey P, Getsios D. “Underestimation of Invasive Meningococcal Disease Case Fatality Rates.” Clin Infect Dis 2009 Oct 1; 49(7):11361137. Coudeville L, Van Rie A, Getsios D, Caro JJ, Crepey P, Nguyen VH. “Adult Vaccination Strategies for the Control of Pertussis in the United States: An Economic Evaluation Including the Dynamic Population Effects.” PLoS One 2009 Jul 16; 4(7):e6284. De Cock E, Krueger WA, Sorensen S, Baker T, Hardewig J, Duttagupta S, Müller E, Piecyk A, Reisinger E, Resch A. “Cost-Effectiveness of Linezolid versus Vancomycin in Suspected Methicillin-Resistant Staphylococcus Aureus Nosocomial Pneumonia in Germany.” Infection 2009 Apr; 37(2):123-132. [Epub 2009 Mar 9] De Cock E, Sorensen S, Levrat F, Besnier JM, Dupon M, Guery B, Duttagupta S. “CostEffectiveness of Linezolid versus Vancomycin for Hospitalized Patients with Complicated Skin and Soft-Tissue Infections in France.” Med Mal Infect 2009 May; 39(5):330-340. [Epub 2009 Mar 21] De Lissovoy G, Fraeman K, Hutchins V, Murphy D, Song D, Vaughn BB. “Surgical Site Infection: Incidence and Impact on Hospital Utilization and Treatment Costs.” Am J Infect Control 2009 Jun; 37(5):387-397. [Epub 2009 Apr 23]


De Lissovoy G, Fraeman K, Teerlink JR, Mullahy J, Salon J, Sterz R, Durtschi A, Padley RJ. “Hospital Costs for Treatment of Acute Heart Failure: Economic Analysis of the REVIVE II Study.” Eur J Health Econ 2009 Jul 7 [Epub ahead of print] Dworkin RH, Turk DC, Revicki DA, Harding G, Coyne KS, Peirce-Sandner S, Bhagwat D, Everton D, Burke LB, Cowan P, Farrar JT, Hertz S, Max MB, Rappaport BA, Melzack R. “Development and Initial Validation of an Expanded and Revised Version of the Short-Form McGill Pain Questionnaire (SF-MPQ-2).” Pain 2009 Jul; 144(1-2):35-42. [Epub 2009 Apr 7] Feltner D, Hill C, Lenderking W, Williams V, Morlock R. “Development of a Patient-Reported Assessment to Identify Placebo Responders in a Generalized Anxiety Disorder Trial.” J Psychiatr Res 2009 May 5 [Epub ahead of print] Friedman HS, Eid NS, Crespi S, Wilcox TK, Reardon G. “Retrospective Claims Study of Fluticasone Propionate / Salmeterol FixedDose Combination Use as Initial Asthma Controller Therapy in Children Despite Guideline Recommendations.” Clin Ther 2009 May; 31(5):1056-1063. Harding G, Coyne K, Barrett RJ, Pixton GC. “Modified Visual Analog Scale SymptomIntensity and Overall-Bother Measures for the Assessment of Symptoms in Studies of Pharmacologic Stress Agents.” Clin Ther 2009 Apr; 31(4):889-901. Harding G, Leidy NK, Meddis D, Kleinman L, Wagner S, O’Brien CD. “Interpreting Clinical Trial Results of Patient-Perceived Onset of Effect in Asthma: Methods and Results of a Delphi Panel.” Curr Med Res Opin 2009 Jun; 25(6):1563-1571. Hays RD, Bjorner JB, Revicki DA, Spritzer KL, Cella D. “Development of Physical and Mental Health Summary Scores from the PatientReported Outcomes Measurement Information System (PROMIS) Global Items.” Qual Life Res 2009 Sep; 18(7):873-880. [Epub 2009 Jun 19] Huang IC, Thompson LA, Chi YY, Knapp CA, Revicki DA, Seid M, Shenkman EA. “The Linkage Between Pediatric Quality of Life and Health Conditions: Establishing Clinically Meaningful Cutoff Scores for the PedsQL.” Value Health 2009 Jul/Aug; 12(5):773-781. [Epub 2009 Jan 9] Hunt T, Luce BR, Page MJ, Pokrzywinski R. “Willingness to Pay for Cancer Prevention.” Pharmacoeconomics 2009; 27(4):299-312. Huybrechts KF, Caro JJ, O’Brien JA. “Prevention and Management of Hyperphosphatemia with Sevelamer in Canada: Health and Economic Consequences.” Value Health 2009 Jan-Feb; 12(1):16-19. [Epub 2008 Jul 18]

Ishak KJ, Proskorovsky I, Guo S, Lin J, Caro JJ. “Persistence with Anti-Arrhythmics and its Impact on Atrial Fibrillation-Related Outcomes.” The American Journal of Pharmacy Benefits; [In Press] Jarbrink K, Kreif N, Benedict A, Locklear J. “Quality of Life and Drug Costs Associated with Switching Antipsychotic Medication to Once-Daily Extended Release Quetiapine Fumarate in Patients with Schizophrenia.” Curr Med Res Opin 2009 Feb 2 [Epub ahead of print] Jones P, Harding G, Berry P, Wiklund I, Leidy NK. “Development and First Validation of the COPD Assessment Test.” Eur Respir J 2009 Sep; 34(3):648-654. Jones P, Harding G, Wiklund I, Berry P, Leidy NK. “Improving the Process and Outcome of Care in COPD: Development of a Standardised Assessment Tool.” Prim Care Respir J 2009 Sep; 18(3):208-215. Khoury H, Merikle E, Roberts C, Wagner M, Johnson S. “Cost-Effectiveness of Atorvastatin 10 Mg Daily in the Primary Prevention of Major Cardiovascular Events in Patients with Type 2 Diabetes in Canada.” Canadian Journal of Diabetes; [In Press] Kongnakorn T, Ward A, Roberts CS, O’Brien JA, Proskorovsky I, Caro JJ. “Economic Evaluation of Atorvastatin for Prevention of Recurrent Stroke Based on the SPARCL Trial.” Value Health 2009; 12(6):880-887. Langford RM, Joshi GP, Gan TJ, Stoeckl Mattera M, Chen W-H, Revicki DA, Chen C, Zlateva G. “Reduction in Opioid-Related Adverse Events and Improvement in Function with Parecoxib followed by Valdecoxib Treatment after Non-Cardiac Surgery: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Trial.” Clin Drug Investig 2009; 29(9):577-590. Lloyd A, van Hanswijck de Jonge P, Doyle S, Cornes P. “Health State Utility Scores for Cancer-Related Anemia through Societal and Patient Valuations.” Value in Health 2008 Dec; 11(7):1178-1185. Luce B, Cohen RS. “Health Technology Assessment in the United States.” Int J Technol Assess Health Care 2009 Jul; 25 Suppl 1:3341. [Epub 2009 Jun 9] Luce BR, Kramer JM, Goodman SN, Connor J, Tunis S, Whicher D, Schwartz JS. “Rethinking Randomized Clinical Trials for Comparative Effectiveness Research: The Need for Transformational Change.” Ann Intern Med 2009 Aug 4; 151(3):206-209. [Epub 2009 Jun 30] Margolis MK, Fox KM, Cerulli A, Ariely R, Kahler KH, Coyne KS. “Psychometric Valida-

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tion of the Overactive Bladder Satisfaction with Treatment Questionnaire (OAB-SAT-q).” Neurourol Urodyn 2009; 28(5):416-422. Manson SC, Brown RE, Cerulli A, Vidaurre CF. “The Cumulative Burden of Oral Corticosteroid Side Effects and the Economic Implications of Steroid Use.” Respir Med 2009 Jul; 103(7):975994. [Epub 2009 Apr 15] Matza LS, Yu-Isenberg KS, Coyne KS, Park J, Wakefield J, Skinner EP, Wolever AR. “Further Testing of the Reliability and Validity of the ASK-20 Adherence Barrier Questionnaire in a Medical Center Outpatient Population.” Curr Med Res Opin 2008; 24(11):3197-3206. [Epub 2008 Oct 14] O’Brien JA, Ward A, Michels S, Tzivelekis S. “Economic Burden Associated with Parkinson Disease.” Drug Benefit Trends 2009; 21(6):179190. Ofosu FA, Crean SM, Reynolds MW. “A Safety Review of Topical Bovine Thrombin-Induced Generation of Antibodies to Bovine Proteins.” Clin Ther 2009 Apr; 31(4):679-691. Onukwugha E, Zuckerman IH, McNally D, Coyne KS, Vats V, Mullins CD. “The Total Economic Burden of Overactive Bladder in the United States: A Disease-Specific Approach.” Am J Manag Care 2009 Mar; 15(4 Suppl):S90-7. Pandina GJ, Garibaldi GM, Revicki DA, Kleinman L, Turkoz I, Kujawa MJ, Mahmoud RA. “Psychometric Evaluation of a Patient-Rated Most Troubling Symptom Scale for Depression: Findings from a Secondary Analysis of a Clinical Trial. Int Clin Psychopharmacol; [In Press] Pandina GJ, Revicki DA, Kleinman L, Turkoz I, Wu JH, Kujawa MJ, Mahmoud R, Gharabawi GM. “Patient-Rated Troubling Symptoms of Depression Instrument Results Correlate with Traditional Clinician- and Patient-Rated Measures: A Secondary Analysis of a Randomized, Double-Blind, Placebo-Controlled Trial.” J Affect Disord 2009 Mar 24 [Epub ahead of print] Paramore LC, Page MJ, Doshi D, Rupnow MFT. “Burden of Migraine in the Employer Setting.” Journal of Health and Productivity 2009; 4(1):3-9. Pelletier EM, Shim B, Ben-Joseph R, Caro JJ. “Economic Outcomes Associated with Microvascular Complications of Type 2 Diabetes Mellitus: Results from a US Claims Data Analysis.” Pharmacoeconomics 2009; 27(6):479-90. Petrillo J, Cairns J. “Converting ConditionSpecific Measures into Preference-Based Outcomes for Use in Economic Evaluation.” Expert Rev Pharmacoecon Outcomes Res 2008 Oct; 8(5):453-461. continued on page 24


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SPOTLIGHT ON SCIENCE


Rentz A, Flood E, Butler R, Christie B, Giangrande P, McCusker P, Wasserman J, Gorina E. “Psychometric Evaluation of a Patient-Reported Symptom Assessment Tool for Adults with Haemophilia (the HAEMOSYM).” Haemophilia 2009 Sep; 15(5):10391047. [Epub 2009 Jun 10] Revicki DA, Camilleri M, Kuo B, Norton NJ, Murray L, Palsgrove A, Parkman HP. “Development and Content Validity of a Gastroparesis Cardinal Symptom Index Daily Diary.” Aliment Pharmacol Ther 2009 Sep 15; 30(6):670-680. [Epub 2009 Jun 25] Revicki DA, Chen W-H, Harnam N, Cook K, Amtmann D, Callahan LF, Jensen MP, Keefe FJ. “Development and Psychometric Analysis of the PROMIS Pain Behavior Item Bank.” Pain 2009 Aug 14 [Epub ahead of print] Revicki DA, Kawata AK, Harnam N, Chen W-H, Hays RD, Cella D. “Predicting EuroQol (EQ-5D) Scores from the Patient-Reported Outcomes Measurement Information System (PROMIS) Global Items and Domain Item Banks in a United States Sample.” Qual Life Res 2009 Aug; 18(6):783-791. [Epub 2009 May 27] Robinson Jr. D, Aguilar D, Schoenwetter M, Dubois R, Russak S, Ramsey-Goldman R, Navarra S, Hsu B, Revicki D, Cella D, Rapaport MH, Renahan K, Ress R, Wallace D, Weisman M. “The Impact of Systemic Lupus Erythematosus on Health, Family and Work: The Patient Perspective.” Arthritis Care Res; [In Press] Robinson D, Zhao N, Gathany T, Kim LL, Cella D, Revicki D. “Health Perceptions and Clinical Characteristics of Relapsing-Remitting Multiple Sclerosis Patients: Baseline Data From an International Clinical Trial.” Curr Med Res Opin 2009 May; 25(5):1121-1130. Roehrborn CG, Albertsen P, Stokes ME, Black L, Benedict A. “First-Year Costs of Treating Prostate Cancer: Estimates from SEER-Medicare Data.” Prostate Cancer Prostatic Dis 2009 May 26 [Epub ahead of print] Rofail D, Abetz L, Viala M, Gait C, Baladi JF, Payne K. “Satisfaction and Adherence in Patients with Iron Overload Receiving Iron Chelation Therapy as Assessed by a Newly Developed Patient Instrument.” Value Health 2009 Jan/Feb; 12(1):109-117. [Epub 2008 Jul 11] Rothman M, Burke L, Erickson P, Leidy NK, Patrick D, Petrie C. “Use of Existing PRO Instruments and Their Modification: Good Research Practices for Evaluating and Documenting Content Validity.” Value Health; [In Press]

Sexton CC, Coyne KS, Cats V, Kopp ZS, Irwin DE, Wagner TH. “Impact of Overactive Bladder on Work Productivity in the United States: Results from EpiLUTS.” Am J Manag Care 2009 Mar; 15(4Suppl):S98-S107. Sorensen SV, Baker T, Fleurence R, Dixon J, Roberts C, Haider S, Hughes D. “Cost and Clinical Consequence of Antibiotic NonAdherence in Acute Exacerbations of Chronic Bronchitis.” Int J Tuberc Lung Dis 2009 Aug; 13(8):945-954. Sorensen SV, Dewilde S, Singer DE, Goldhaber SZ, Monz BU, Plumb JM. “Cost-Effectiveness of Warfarin: Trial Versus ‘Real-World’ Stroke Prevention in Atrial Fibrillation.” Am Heart J 2009 Jun; 157(6):1064-1073.

Van Nooten FE, Koolman X, Brouwer WB. “The Influence of Subjective Life Expectancy on Health State Valuations Using a 10 Year TTO.” Health Econ 2009 May; 18(5):549-558. Vernon M, Leidy NK, Nacson A, Nelsen L. “Measuring Cough Severity: Perspectives From the Literature and from Patients with Chronic Cough.” Cough 2009 Mar 19; 5:5. Vernon MK, Rentz AM, Wyrwich KW, White MV, Grienenberger A. “Psychometric Validation of Two Patient-Reported Outcome Measures to Assess Symptom Severity and Changes in Symptoms in Hereditary Angioedema.” Qual Life Res 2009 Sep; 18(7):929-939. [Epub 2009 Jul 14]

Sorensen SV, Frick KD, Wade A, Simko R, Burge R. “Model-Based Simulation to Explore the Cost-Effectiveness of Following Practice Guidelines for Triglyceride and Low-Density Lipoprotein Cholesterol Control Among Patients with Diabetes Mellitus and Mixed Dyslipidemia.” Clin Ther 2009 Apr; 31(4):862-879.

Wagner M, Goetghebeur M, Merikle E, Pandya A, Chu P, Taylor DC. “Cost-Effectiveness of Intensive Lipid Lowering Therapy with 80mg of Atorvastatin, versus 10 mg of Atorvastatin, for Secondary Prevention of Cardiovascular Disease in Canada.” Can J Clin Pharmacol 2009 Summer; 16(2):e331-345. [Epub 2009 Jun 16]

Spector P, Reynolds MR, Calkins H, Sondhi M, Xu Y, Martin A, Williams CJ, Sledge I. “Meta-Analysis of Ablation of Atrial Flutter and Supraventricular Tachycardia.” Am J Cardiol 2009 Sep 1; 104(5):671-677.

Wasiak R, Young AE, Dunn KM, Cote P, Gross D, Heymans M, von Korff M. “Back Pain Recurrence – An Evaluation of Existing Indicators and Direction for Future Research.” Spine 2009 April 20; 34(9):970-977.

Stafford M, Gavriel S, Lloyd A. “Patient-Reported Outcomes Measurement in Epilepsy.” Expert Rev Pharmacoecon Outcomes Res 2007 Aug; 7(4):373-384.

Wild D, Eremenco S, Mear I, Martin M, Houchin C, Gawlicki M, Hareendran A, Wiklund I, Chong LY, von Maltzahn R, Cohen L, Molsen E. “Multinational Trials – Recommendations on the Translations Required, Approaches to Using the Same Language in Different Countries, and the Approaches to Support Pooling the Data: The ISPOR Patient-Reported Outcomes Translation and Linguistic Validation Good Research Practices Task Force Report.” Value Health 2009 Jun; 12(4):430-440. [Epub 2008 Nov 12]

Stull DE, Gavriel S. “Use of, Satisfaction with, and Willingness to Switch Prescription and Over-The-Counter Treatments for Chronic Urticaria: An Online Survey.” Patient 2009; 2(3):151-157. Stull DE, Schaefer M, Crespi S, Sandor DW. “Relative Strength of Relationships of Nasal Congestion and Ocular Symptoms with Sleep, Mood and Productivity.” Curr Med Res Opin 2009 Jul; 25(7):1785-1792. Sundaram M, Smith MJ, Revicki DA, Elswick B, Miller LA. “Rasch Analysis Informed the Development of a Classification System for a Diabetes-Specific Preference-Based Measure of Health.” J Clin Epidemiol 2009 Aug; 62(8):845-856. Van der Heijde DM, Revicki DA, Gooch KL, Wong RL, Kupper H, Harnam N, Thompson C, Sieper J, Atlas Study Group T. “Physical Function, Disease Activity and Health-Related Quality-of-Life Outcomes After 3 years of Adalimumab Treatment in Patients with Ankylosing Spondylitis.” Arthritis Res Ther 2009 Aug 17; 11(4):R124 [Epub ahead of print]

Wyrwich K, Harnam N, Revicki DA, Locklear JC, Svedsäter H, Endicott J. “Assessing Health-Related Quality of Life in Generalized Anxiety Disorder Using the Quality of Life Enjoyment and Satisfaction Questionnaire.” Int Clin Psychopharmacol 2009 Aug 22 [Epub ahead of print] Yang Y, Brazier J, Tsuchiya A, Coyne K. “Estimating a Preference-Based Single Index from the Overactive Bladder Questionnaire.” Value Health 2009 Jan/Feb; 12(1):159-166. [Epub 2008 Jul 18] Yu O, Boudreau DM, Buist DS, Miglioretti DL. “Statin Use and Female Reproductive Organ Cancer Risk in a Large Population-Based Setting.” Cancer Causes Control 2009 Jul; 20(5):609-616. [Epub 2008 Nov 30]


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Recent Presentations

Oral Presentations

ACR / ARHP Scientific Meeting 09 Oct 16–Oct 21 2009, Philadelphia, PA, USA

Formatting Tips and Techniques for Printable Excel Tables Created with the SAS Excel XP ODS Tagset and PROC REPORT Fraeman KH

Poster Presentation

European Respiratory Society Annual Congress 2009 Sep 12–Sep 16 2009, Vienna, Austria

Relationships Between Presence, Severity, and Location of Prevalent Vertebral Fractures and Health Related Quality of Life (HRQoL) Silverman S, Viswanathan H, Yang Y, Eis SR, Fardellone P, Gilchrist N, Lips P, Nevitt M, Palacios S, Pavelka K, Revicki D, Simon J, Macarios D, Siris E

NEI/FDA Endpoints Symposium—Use of PatientReported Outcomes in Medical Product Development Oct. 13, 2009, Bethesda, MD, USA Oral Presentation Practical Issues in Instrument Development: An Instrument Developer’s Perspective Nancy Kline Leidy, PhD, SVP, Scientific Affairs, United BioSource Corp.

MAGI’s 2009 Clinical Research Conference—West Oct 4–Oct 7 2009, San Diego, CA, USA Oral Presentation Clinical Trial Agreements Outside the United States: How do Clinical Trial Agreements and Processes Differ Outside the U.S.? Speaker: Gina Morton, MBA, CRCP, Senior Contracts Manager, United BioSource Corp.

2nd Annual Risk Management and Drug Safety Summit Oct 1–Oct 2 2009 Washington, DC, USA Oral Presentation Thursday, October 1, 1:00 p.m. – 1:45 p.m. How Do We Know That REMS Are Effective? A Guide to Evaluating Risk Management Strategies Annette Stemhagen, DrPH, FISPE, Senior Vice President, Safety, Epidemiology, Registries & Risk Management, United BioSource Corp.

Panel Discussions Friday, October 2, 9:00 a.m. – 10:00 a.m. & 10:00 a.m. – 11:00 a.m. Developing REMS Early in the Life Cycle – Can Patient Understanding of Risks Be Determined During Clinical Trials? Panel Moderator: Gerald Faich, MD, MPH, FISPE, Senior Vice President, Safety, Epidemiology, Registries & Risk Management, United BioSource Corp.

All Rolled Up Into One: Using SAS to Generate Patient-Level Analysis Files from Insurance Claims Data Fraeman KH

Ecommunication Assessing COPD Health: What do Patients and Physicians Consider? Harding G, Roberts L, Gavriel S, Murray L, Berry P, Wiklund I, Leidy NK, Jones P

22nd European College of Neuropsychopharmacology (ECNP) Sep 12–Sep 16 2009, Istanbul, Turkey UBC Sponsored Satellite Symposium Monday, September 14, 2009 Title: The Failure of Multi-National Placebo-Controlled Studies Session Chair: Professor Norman Sartorius, MD, PhD, University of Geneva Session Co-Chair: Professor Heinz Grunze, MD, PhD, Newcastle University Ensuring Data Quality in Multi-National Clinical Trials Speaker: Professor Cyril Höschl, MD, PhD, Charles University in Prague, Czech Republic Evaluating the Relationship Between Severity and Efficacy in Placebo-Controlled Trials Speaker: Professor Stuart A. Montgomery, MD, Imperial College of Medicine University of London Designing and Implementing Global CNS Development Programs: Disease-Specific Considerations Speaker: Professor W. Wolfgang Fleischacker, MD, Medical University Innsbruck, Austria. Symposium contact: Adam Butler

Poster Presentations Patterns in European and Rest of World Use of Doctorate Level Raters in Bipolar and Schizophrenia Clinical Trials Authors: Daniel D, Bartko J, Sartorius N, Vieta E, Butler A, Moya G Global Surveillance Program Monitoring Raters’ Administration and Scoring of the ADAS-Cog Authors: McNamara C, Miller D, Jones A, Samuelson P, Moya G, Butler A

ISPOR 2nd Latin America Conference Sep 10–Sep 12 2009, Rio de Janeiro, Brazil Podium Presentations Fri., September 11, 12:00 p.m. – 1:00 p.m.

Achieving Predictability and Transparency in REMS Panelist: Mark Ammann, PharmD, Vice President, Regulatory Affairs, United BioSource Corp.

The Cost and Health Consequences of Subcutaneous Immunotherapy Plus Beclomethasone Dipropionate in Colombian Children with Moderate and Severe Asthma Hernandez L, Castillo M, Garcia E

Joint ECCO 15-34th ESMO Multidisciplinary Congress Sep 20–Sep 24 2009, Berlin, Germany

Literature Review and Product Label Claim Review of PRO Measures for Benign Prostatic Hyperplasia Angalakuditi M, Pokrzywinski R, Currie B, Lenderking W

Poster Presentations Impact of Ipilimumab on the Health-Related Quality of Life (HRQL) of Patients With Previously Treated Unresectable Stage III or IV Melanoma Revicki D, Kotapati S, Villanueva I, Van Baardewiljk M Patients Experience with Treatments of Chemotherapy Induced Anemia (CIA) and Myelodysplastic Syndromes (MDS) Cong Z, Ireland A, Stull D, McGarvey N, Brooks A, Kleinman L Risk of Mortality in Patients with Cancer Experiencing Febrile Neutropenia Lyman GH, Michels SL, Tomic K, Yu J, Reynolds MW, Barron R

22nd NorthEast SAS Users Group (NESUG) Educational Conference Sep 13–Sep 16 2009, Burlington, VT, USA

Sat., September 12, 10:45 a.m. – 11:45 a.m. How and Why Automated Medical Databases Should be Used to Create Background Occurrences for Drug Outcomes and Safety Studies: Glaucoma in THIN (UK) Maguire A, Blak BT

Workshop Presentation Fri., September 11, 4:15 p.m. – 5:15 p.m. The New German Methods for Economic Evaluation: Are They Applicable in Latin America Discussion Leaders: J. Jaime Caro, MDCM, FRCPC, FACP, Adjunct Professor, McGill University and Senior VP Health Economics, United BioSource Corporation; Charalabos-Markos Dintsios, MA, MPH, Research Fellow, Pharmaceutical Products Evaluation, Institute for Quality and Efficiency in Health Care (IQWiG) continued on page 26


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14th International Headache Congress Sep 10–Sep 13 2009, Philadelphia, PA, USA Poster Presentations Disability Status of Chronic and Episodic Migraineurs Globally Blumenfeld A, Goadsby PJ, Lipton RB, Kawata AK, Wilcox TK, Manack A, Buse D, Varon SF Global Impact of Chronic Migraine (CM) Compared to Episodic Migraine (EM) on Health-Related Quality of Life (HRQol), Depression and Anxiety. Buse D, Lipton RB, Kawata AK, Varon SF, Manack A, Wilcox TK, Goadsby PJ, Blumenfeld A Health Care Resource Utilization Patterns Among Individuals with Chronic Migraine (CM) and Episodic Migraine (EM) Varon SF, Blumenfeld A, Lipton RB, Manack A, Buse D, Wilcox TK, Goadsby PJ, Kawata AK

International Psychogeriatric Association 14th International Congress (IPA) Sep 1–Sep 5 2009, Montreal, Canada Oral Presentations

A Novel Method for Assessing Dose-Response Relationships Using Meta-Analytic Techniques Williams CJ, Reynolds MW, Luo W, Fahrbach K, Collins J Off-Label Use of Oncology Drugs in a Community Oncology EMR Database Stephen R, Knopf K, Reynolds MW, Luo W, Fraeman K Systematic Process for Coding Definition / Algorithm Development in Database Analyses LoCasale B, Metha V, Alderton L, Bortnichak E, Reynolds MW, Stephen R, Jones N, Ware C

Tues., August 18, 8:30 a.m. – 6:00 p.m. Epidemiology of Glaucoma and Drug Utilization in UK Primary Care Maguire A, Thompson M

Wed., August 19, 8:30 a.m. – 2:00 p.m. Defining Mild Cognitive Impairment: Disparity of Incidence and Prevalence Estimates with Variable Operationalized Definitions Ward A, Michels S, Cedarbaum J, Arrighi HM Drug Utilization Patterns in a Community Oncology Electronic Medical Record (EMR) Database in Response to Clinical Trial Evidence and Drug Availability Stephen R, George J, Knopf K, Jones N, Reynolds MW

Identifying Capable Raters for Global Alzheimer’s Disease Clinical Trials: Challenges and Potential Solutions Miller D, Samuelson P, Foulds K, Wesnes K

American Academy of Dermatology (AAD) Summer Academy Meeting Jul 29–Aug 2 2009, Boston, MA, USA

The Cost Effectiveness of Donepezil in the Treatment of Alzheimer’s Disease in the UK: Estimates Based on Updated Evidence and Microsimulation Techniques Getsios D, Blume S, Ishak J, Maclaine G

Poster Presentation

Screening and Treatment of Alzheimer’s Disease with Donepezil: Cost-Effectiveness Estimates for the UK Getsios D, Blume S, Ishak J, Maclaine G

25th International Conference on Pharmacoepidemiology and Therapeutic Risk Management Aug 16–Aug 19 2009, Providence, RI, USA Symposium Mon., August 17, 3:30 p.m. – 5:00 p.m.

Once Daily Application of a Fixed Combination Clindamycin Phosphate (1.2%) and Benzoyl Peroxide (2.5) Gel Results in Clinically Meaningful Improvements in Health Related Quality of Life (HRQL) in Patients with Moderate to Severe Acne Vulgaris Kimball A, Thiboutot D, Chen D Merikle E

Alzheimer’s Association 2009 International Conference on Alzheimer’s Disease (ICAD) Jul 11–Jul 16 2009, Vienna, Austria Featured Research Symposium Conducting Global Clinical Trials in Alzheimer’s Disease-Challenges and Potential Solutions Chair: Miller D Speakers: Mohs R, Sugishita M, Tomaszewski Farias S, Seely L, Broich K

Can Registries Deliver? The Methods and Use of Registries for Biologics Sean Zhao, Nancy Dreyer, Alex Cole, Annette Stemhagen, Nils Feltelius, Joanna Haas

Poster Presentations

Workshop Wed., August 19, 10:30 a.m. – 12:00 p.m.

Screening for Alzheimer’s Disease: Health Economic Projections of the Impact of Earlier Diagnosis and Treatment Getsios D, Blume S, Ishak J, Maclaine G

RMP, RiskMAP and REMS: The Challenges of Epidemiology Patricia Saddier, Susana Perez-Gutthann, Annette Stemhagen, Rekha Garg, Stella Blackburn, Gerald Dal Pan

Oral Presentations Mon., August 17, 10:30 a.m. – 10:45 a.m.

Analysis of ADAS-Cog Constructional Praxis Scoring Errors McNamara C, Samuelson P, Miller D, Jones A, Moya G

Updated Cost-Effectiveness Projections for Donepezil in the Treatment of Patients with Mild to Moderately Severe Alzheimer’s Disease in the UK Getsios D, Blume S, Ishak J, Maclaine G

Reliability and Validity of the Caregiver-Perceived Burden Questionnaire (CPBQ) in Alzheimer’s Disease Erder MH, Wilcox T, Understanding the Prescribing Patterns of Lipid-Lowering Agents Chen W-H, Setyawan J, O’Quinn S, Saxton J in the United States and Canada Matthew W. Reynolds, Yola Defining Mild Cognitive Impairment: Disparity of Incidence and Moride Prevalence Estimates with Variable Operationalized Definitions Ward Tues., August 18, 11:45 a.m. to 12:00 p.m. A, Michels S, Cedarbaum J, Arrighi HM Quantification of Patient Population Impact of Contra-Indications: Glaucoma Therapy Andrew Maguire, Sharon MacLachlan International Liver Transplantation Society (ILTS)

Poster Presentations Mon., August 17, 8:30 a.m. – 6:00 p.m. Case Reports of Suspected Adverse Drug Reactions: An Evaluation of the Efficiency of Search Strategies in MEDLINE and EMBASE Michels S, Ward A Comparison of Treatment Utilization of Intravenous Bisphosphonates (IVBIS) in an Electronic Medical Records (EMR) and Administrative Claims Database Mehta V, LoCasale B, Wentworth C, Stephen R, Nordstrom B, Fraeman K Meta-Analysis for Drug Development and Risk Management Reynolds MW, Lasky T

15th Annual Congress Jul 8–Jul 11 2009, New York, NY, USA Poster Presentations

Degree of Thrombocytopenia as an Indicator of Severity of Liver Disease in Patients Awaiting and Following Liver Transplantation Brown RS, Odeh-Ramadan R, Afdhal NH, Curry MP, Reddy R, Poordad F, Schiano TD, Charlton MR, Han S-HB, Theodore D, Grotzinger K, Ishak J, Payne K, Lordan N Medical Procedures in Patients with Chronic Liver Disease (CLD): Thrombocytopenia and Transfusion Use Curry MP, Afdhal NH, Brown RS, Odeh-Ramadan R, Reddy R, Poordad F, Schiano TD, Charlton MR, Han S-HB, Theodore D, Grotzinger K, Ishak J, Payne K


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SCIENCE NEWS & POLICY BRIEFSOPINION

UBC Hires New Pricing and Reimbursement Experts to Expand International Capabilities UBC has expanded its international offerings with the addition of two senior strategists in the area of pricing and reimbursement, both located in UBC’s UK office in London. Adam Barak joins UBC as the Head of International Pricing and Reimbursement. Mr. Barak is an international expert in health care pricing, reimbursement and market access, having had senior positions at both pharmaceutical companies and consulting companies over a 13 year span. After an early career in automotives, where Mr. Barak was responsible for pricing at General Motors Europe, in 1997 he headed GlaxoWellcome’s European pricing function, developing pricing and market access strategies for multi-million pound portfolios, including a number of household name brands. Mr. Barak was subse quently responsible for global pricing and reimbursement (P&R) for biotech company Oxford GlycoSciences, before pursuing a career in consultancy in which he created the companies ABPPC Ltd and the international P&R expert group PharmaPrice International (PPi) to offer drug, device and diagnostics companies truly global support for strategy development and implementation. Most recently, Mr. Barak was Vice President at PPi associate Boston Healthcare Associates, Inc. Mr. Barak has experience with a multitude of therapeutic areas, has had several articles published on health care pricing, has presented at conferences across the world and provided training in international P&R for both industry and government stakeholders. Mr. Barak is a Chartered Marketer. Lisbet Coulton, with over 25 years in the health care market, joins UBC as Director of International Pricing and Reimbursement. Ms. Coulton’s expertise focuses on market assessments, product commercialization, and international strategic planning and communications. She also brings with her extensive understanding of the global health care market, specializing in issues relevant to market access and reimbursement in the UK. Before joining UBC, Ms. Coulton ran her own consultancy company, and she has also worked for major pharmaceutical companies in the past, such as GSK [SmithKline & French Laboratories Ltd.], BMS [ER Squibb & Sons Ltd.], and Aventis [Merrell Dow Pharmaceuticals Ltd.], and subsequently for GR Micro

Ltd., a contract research company specializing in medical and environmental microbiology. In a consulting capacity, Ms. Coulton has had a major role in PharmaPrice International and has also worked for medical device and diagnostic companies as well as independent service providers. Ms. Coulton’s therapeutic experience includes pricing and reimbursement projects in oncology, neurology, gastroenterology, ophthalmology, anti-infectives, cardiovascular disease, respiratory care, and at-home services. “We are excited to have Mr. Barak and Ms. Coulton join UBC, allowing us to significantly expand our collective ability to provide comprehensive, market access solutions to our clients,” said Lynn J. Okamoto, General Manager, UBC Health Care Analytics. “As health care regulations and needs continue to evolve, the importance of demonstrating product value and optimizing new product launches and life cycle development becomes even more vital. The vast experience and strong leadership of these two new team members will be invaluable in continuing to strengthen our international capabilities and presence.” For more information on UBC’s international pricing and reimbursement services, or to contact Mr. Barak or Ms. Coulton, please email [email protected].

UBC Announces Acquisition of Cognitive Drug Research Ltd. UBC has acquired Cognitive Drug Research, Ltd. (CDR), the leader in computerized cognitive testing for clinical trials. The CDR System is the most widely used computerized cognitive testing system in the world: it is used in more than 1000 trials encompassing approximately 50 different disease areas, validated in over 60 languages, and cited in more than 700 publications and abstracts. Additionally, CDR maintains the industry’s largest healthy subject, patient, and drug databases of cognitive effects, providing the standard for establishing the clinical relevance of compounds. Computerized cognitive testing facilitates standardized administration, measurement precision, and the reliability of cognitive endpoints. Importantly, it enables the assessment of major aspects of cognitive function that are otherwise overlooked by traditional methods. The CDR System has demonstrated unparalleled sensitivity to cognitive enhancements as well as to impairments in a broad range of disorders. Increased sensitivity translates into significant cost savings as fewer study subjects are required to reach statistical significance. “Our experience with both computerized cognitive testing and the measurement of clinician- and patient-reported outcomes has reinforced the need for a fully integrated solution continued on page 28


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NEWS BRIEFS


to reliably assess cognitive function,” said Catherine Spear, Sr. Vice President at UBC. “CDR offers a solution no one else in the industry can provide; more than 20 years of clinical trial experience together with the largest, most comprehensive cognitive effects database encompassing tens of thousands of patients.” “The premier evidence base, reliability, and global reach of the CDR System coupled with UBC’s validated rater training, assessment, and rater surveillance methods will provide an unprecedented opportunity for improved signal detection in the measurement of cognition and clinically subjective endpoints,” said Ethan Leder, CEO of UBC. “The addition of Professor Keith Wesnes, to the UBC scientific team and our integrated offerings will provide sponsor companies with the broadest, most seamless capabilities available.” “We are excited to join the UBC family and take cognitive testing to the next level,” said Professor Wesnes, Chief Executive and founder of CDR. “Combining the CDR System with UBC’s industry-leading solutions for standardizing the administration and scoring of clinically subjective outcomes measures offers pharmaceutical and medical device companies the unique ability to cost-effectively integrate computerized cognitive testing, rater training, and data quality monitoring to generate accurate, clinically relevant data in even the very largest, most complex development programs,” stated Professor Wesnes.

UBC Expands Global Drug Safety Capabilities UBC has acquired HPM (Geneva) SA, a Geneva, Switzerland-based provider of drug safety and pharmacovigilance services, further extending UBC’s reach into the European market. The acquisition of HPM (Healthcare Project Management) represents a strategic expansion of UBC’s marketleading safety and risk management services, which include comprehensive safety reporting, case processing, and integrated pharmacovigilance services. “We are very excited to add the vast experience and services of the HPM team to the UBC family and equally pleased to enhance our growing global presence with our first office in Switzerland, from which we intend to offer the portfolio of UBC’s evidence-generating offerings,” said Ethan Leder, CEO of United BioSource Corporation. Leder added, “HPM has deep experience and offers sophisticated solutions in the operational and regulatory requirements related to drug safety, particularly with regard to the specific needs of European agencies.” The Geneva office is led by Executive Director Véronique Basch, PharmD, and is operating as part of UBC’s global safety and risk management group. Following a

successful career in drug safety with a major pharmaceutical company, Dr. Basch was responsible for establishing HPM’s drug safety operations. “We are very pleased to be part of UBC,” said Pierre-André Lauener, MD, Managing Director and co-founder of HPM. “After building HPM for the past 12 years, we wanted to find a company with the same commitment to excellence in drug safety that has made HPM successful. With their expertise in REMS, late stage studies, and proven operational expertise, UBC is an ideal fit in that regard. We look forward to supporting our long-established clients with outstanding service and an even broader set of capabilities.” UBC’s global drug safety and risk management services include the development and implementation of risk evaluation and mitigation systems (REMS) programs, performancelinked access systems (PLAS), periodic safety update reporting (PSUR), risk management plans, case processing, and integrated pharmacovigilance services. These services are provided with dedicated and integrated resources around the globe.

UBC Consolidates Leadership in Pharmaceutical Risk Management UBC continues to meet the growing demand for consulting and implementation of risk management programs with the acquisition of Gigamoto Technology Partners, Inc. (Gigamoto), a Pennsylvania-based software development company providing leading-edge technology solutions in support of drug safety and risk management programs for the life sciences industry. The acquisition is part of UBC’s strategy of building integrated capabilities in risk management and drug safety by combining leading-edge technology with world class scientific, consulting and operational expertise. Gigamoto software powers several high-profile and highly complex risk management programs, including the largest and longest operating FDA mandated program—iPLEDGE. The program is an interactive, computer based distribution center that monitors pregnancy in women on isotretinoin therapy, also known by the brand name of Accutane, which has been known to cause birth defects. iPLEDGE was made mandatory by the FDA in 2006 and the most recent public data shows that this complex risk management system has registered multiple stakeholders including wholesalers, over 40,000 pharmacies, over 16,000 prescribers and over 300,000 patients, and today continues the ongoing successful enrollment and re-enrollment of patients. Gigamoto software has set the standard for integrating voice and web technologies to deliver risk management programs that link pharmacies, physicians, patients and payers to support pre-


scription drug therapies with the goal of providing medication to patients who can most benefit from them, while at the same time ensuring risk reduction. “Managing drug safety for increasingly complex drugs and biologicals requires world class scientific expertise, strong operations and demands state of the art technology,” said Ethan Leder, CEO of United BioSource. “The acquisition of Gigamoto enhances and accelerates our technology platform to include more top notch FDA approved technology solutions for complex post-approval programs.” Leder added, “Gigamoto’s experience with performance-linked access programs has ‘set the bar’ for high risk, data intensive programs.” UBC’s global drug safety and risk management services include the development and implementation of risk evaluation and mitigation (REMS) programs, including those with Elements to Assure Safe Use (ETASU), periodic safety update reporting (PSUR), European risk management plans, case processing, and integrated pharmacovigilance services. These services are provided with dedicated and integrated resources around the globe. Gigamoto provides further scale and commercial website functionality to UBC’s multi-stakeholder risk management systems. “We are very excited to be part of UBC,” said Jason Leedy, founder of Gigamoto. “After building the best technology platform in the industry, we are ready to join the industryleading provider of comprehensive safety and risk management programs.” Leedy added that, “We have always had the conviction that dedication, know-how and commitment to customer service would best serve our clients; we can now do so across the entire scientific program and not only the technology component.”

UBC Scientists’ Presentation of Burden of Disease Report Covered by C-SPAN Drs. Greg de Lissovoy, Vice President of Health Technology, and Bryan Luce, Senior Vice President of Science Policy, for UBC presented the findings of a recent report on burden of disease at the National Press Club in Washington, DC, August 31, 2009. The report titled “The Burden of Disease: The Economic Case for Investment in Quality Improvement and Medical Progress—A Literature Review and Synthesis” was prepared for the Advanced Medical Technology Association (AdvaMed). The study had two objectives: 1) to quantify the burden on the national economy that is attributable to lost productivity (“indirect costs”) associated with selected chronic and acute conditions that most affect working-age adults; and 2) discuss and seek to quantify potential gains in GDP from improvements in the prevention, detection, and

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treatment of various conditions. Taken together, the findings demonstrate the large economic payoff from improving the quality of our nation’s health care and continuing the remarkable progress we have made in developing better treatments and cures. The study report was authored by UBC researchers, including Greg de Lissovoy, PhD, MPH; Feng Pan, PhD; Steve Siak, PhD; Valerie Hutchins, BA; and Bryan Luce, PhD, MBA. To see C-SPAN’s coverage of the presentation, visit the UBC website: http://www.unitedbiosource.com/news/press-coverage.aspx, and to receive a copy of the full report, please email [email protected].

UBC Welcomes New Senior Biostatistician arilyn Stolar, PhD, has joined UBC as a Senior BiostatM istician. Dr. Stolar has over 15 years of experience, working at various research units at Yale School of Public Health, the V.A. Medical Center (Northeast Program Evaluation Center), and Pfizer’s Clinical Pharmacology and Neuroscience/Psychiatry departments. Most recently, Dr. Stolar supported pre-clinical and clinical research for the Cognitive Impairment Associated with Schizophrenia area at Pfizer, where she contributed to study design, protocol development, analysis planning and execution, as well as reporting. Her statistical expertise includes random/mixed effects models, longitudinal data analysis with missing data, structural equation models, analysis of observational data, and CART.

European Experts Join UBC as Visiting Scientists rofessor Vincenzo Atella is joining UBC’s Center for P Health Economics and Science Policy as a Visiting Scientist. Professor Atella holds a master’s degree in economics from Stanford University; he is an associate professor of economics at the Department of Economics at the University of Rome Tor Vergata and an adjunct associate of the Center for Health Policy at Stanford. Currently, he is a member of the Committee for the Strategic Evaluation of the Italian Drug Agency (AIFA) and a member of SIVEAS (National Monitoring System of Health Care Services) of the Ministry of Health. He is also a member of the Committee of Experts advising IQWiG (the German Agency for Health Care) on setting national guidelines for economic evaluation in the health sector. Recently, Professor Atella served as senior economist in the Italian Regional Agency for Health Care Services; advisor for the National Institute of Health continued on page 30


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NEWS BRIEFS


on a project aimed at monitoring Italian public pharmaceutical expenditures; member of the Italian Committee for Drug Price appointed by the Ministry of Treasury; and a consultant for WHO and the World Bank. His interests on health economics range from health-related income inequality, to drug cost containment policies, to the determinants of health care service demand. eter Fayers, PhD, Professor of Medical Statistics at the P University of Aberdeen, is joining UBC’s Center for Health Outcomes Research as a Visiting Scientist. Professor Fayers’ main research interest is in the area of patient-reported outcomes and subjective indicators, particularly in quality of life research, and he has written four books on this subject. He has been involved in developing and modifying the QLQ-C30 and developing new instruments for use in patients with gastric, oesophageal, head and neck, and colorectal cancers; patients in palliative care; patients receiving home parenteral nutrition; assessment of pain (in palliative care); and body image (in colorectal cancer). Professor Fayers served as president of the International Society for Quality of Life Research (ISOQOL) from 20052006, was the associate editor of Quality of Life Research from 1998 and is currently a member of the journal’s editorial board. He chaired the Quality of Life Group of the European Organisation for Research and Treatment of Cancer (EORTC) for four years ending in 2003. Among his many publications, Professor Fayers is the co-author of a leading book on quality of life assessment (Fayers P, Machin D. Quality of Life: The Assessment, Analysis and Interpretation of Patient-reported Outcomes, 2nd Ed., 2007, Wiley) and a co-editor of a leading book on assessing quality of life in clinical trials (Fayers PM, Hays RD. Assessing Quality of Life in Clinical Trials: Methods and Practice, 2nd Ed., 2005, Oxford University Press, Oxford). In addition, he is co-author (with David Machin) of a forthcoming book, Randomized Clinical Trials: Design, Practice and Reporting, Wiley-Blackwell, 2010.

UBC Announces the Addition of Bengt Winblad, MD, PhD, to Its European Scientific Advisory Board for CNS Trials UBC announced this summer at ICAD 2009 that Bengt Winblad, MD, PhD, has joined its European Scientific Advisory Board for CNS Clinical Trials. Professor Winblad is one of the world’s leading Alzheimer’s disease researchers and currently serves as Professor of Geriatric Medicine and Chief Physician at the Karolinska University Hospital, Huddinge, and the Karolinska Institute in Stockholm, Sweden. Prof. Winblad will work with UBC and its European Scientific Advisory Board

to support their ongoing efforts to develop new approaches to ensure data quality in CNS clinical trials. Since its inception in 2008, UBC’s European Scientific Advisory board has contributed to new research regarding the methodological challenges in CNS research. Professor Winblad’s experience in Alzheimer’s disease gives the board an opportunity to continue its work of improving outcome measurement by addressing such key challenges as increasing placebo response rates and cultural variance associated with large, multi-national trials.

Greg de Lissovoy, PhD, Named as Exceptional Reviewer Dr. Greg de Lissovoy, Vice President, Health Technology and Senior Research Scientist for UBC, has achieved the distinction of “Exceptional Reviewer” for 2007-2008 for Medical Care. Top reviewers were chosen on the basis of quality, timeliness, and number of reviews performed, and the list included approximately the top five percent of all Medical Care peer reviewers. Medical Care is one of North America’s leading outlets for peer-reviewed health services research. Since 2000, Medical Care has been ranked by the Institute of Scientific Information as either the top or one of the top five journals in the Health Care Sciences and Services category, a category that includes over 50 different peerreviewed journals.

UBC Gives Back Staff members across UBC organized this year to provide their personal time and energy to giving back to those in need. These efforts highlight the commitment of UBC staff to making a positive impact in the world across all areas of their lives. Here are highlights of what was accomplished this year. AIDS Walk American Cancer Society – Jeans for the Cure American Red Cross - Blood Drive - Adopt a Family Earth Hour for Environmental Awareness Habitat for Humanity Holy Family School Funding Langhorne Family Services School Supply Drives LiveStrong Challenge Philadelphia Bike Ride

The Omega Centre (subsidized apartments for people with mental disabilities) One Warm Coat Foundation Relay for Life for Cancer Research St. Baldrick’s Childhood Cancer Research “Hair Shaving” St. Barnabas Cancer Research Walk St. Jude’s Kick-A-Thon for Childhood Cancer Research and Support Susan B. Komen Foundation Passionately Pink Campaign Tub of Love and DonorsChoose

Make-A-Wish Foundation Bike Ride Walk for Ovarian Cancer NStar Walk for Children’s Hospital

Yale Cancer Center CT Challenge


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F ederal policy updates on what is impactin g our research and your business

SCIENCE&POLICY SCIENCE POLICYCORNER OPINION Congress returns from a raucous recess ready to scrimmage… After an August recess full of lively debate and colorful criticism, Congress resumed session ready to overcome partisan and policy obstacles and achieve major health care reform. The Chairman of the Senate Finance Committee, Sen. Max Baucus, D-Mont., released a framework document in early September reflecting the compromises and policy positions of the Committee’s bipartisan working group. The “Framework for Comprehensive Health Care Reform” advocates for reform in the following general areas: “(1) Immediate Relief for Families and Small Businesses; (2) Ensuring Affordable Health Coverage; (3) Promoting Disease Prevention and Wellness; (4) Improving the Quality and Efficiency of Health Care; (5) Transparency and Program Integrity; (6) Fraud, Waste, and Abuse; and (7) Revenue Provisions.” This framework reflects the substantive core of the Chairman’s Mark, expected for public release and markup by the end of September. The House health care proposal, H.R. 3200, is a combined effort of the Committees on Ways and Means, Energy and Commerce, and Education and Labor, and has favorably passed each of these Committees. This legislation includes provisions to address the cost of health care, the “shared responsibility” of public health, a public option to expand coverage access, affordability of insurance options, prevention and wellness, and investments to expand the health care workforce. After the three committees marked up the bill in July, legislators remain in agreement on about 85 percent of the bill, according to Majority Leader Steny Hoyer, D-Md. As of press time, the legislation had not yet been scheduled for floor consideration. Comparative effectiveness research is in the starting lineup… Comparative effectiveness research remains a key component of health care reform proposals in both the Senate and the House. The Senate Finance Committee’s framework fulfills the elements of the Patient-Centered Outcomes Research Act of 2009 (S. 1213), which includes establishing a non-profit institute governed by a board with broad stakeholder representation, which would be funded by a mix of mandatory appropriations, Medicare trust funds, and a fee on health insurance plans. The House’s legislation, H.R. 3200, establishes a Center for Comparative Effectiveness Research within the Agency for Healthcare Research and Quality (AHRQ) that would be financed by a tax on accident and health insurance policies. Both chambers agree on the importance of the health care research, yet compromise must be reached on how to pay for it and how to use the research optimally and appropriately. And important international health care policy activity is advancing down the field… In July 2009, the UK government announced plans to allow highly innovative drugs to be made available on the National Health Service (NHS) for a limited period without being subjected to the National Institute for Health and Clinical Excellence (NICE) appraisal process. The new initiative called the NHS Innovation Pass will be piloted for a three-year period. Monitoring the implementation and progress of this new initiative will be important to better understand which products might be eligible for the Innovation Pass. In addition to the NHS Innovation Pass, the findings from the NICE study into the value of innovation—headed by Professor Sir Ian Kennedy—were published in late July 2009. Comprising 37 written submissions and two open workshops, the Kennedy study principally considered the following key questions: hat approach should be adopted by NICE to ensure that innovation is properly taken into account when W establishing the value of new health technologies? Should particular forms of value be considered more important than others? continued on back page

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F ederal policy updates on what is impactin g our research and your business SCIENCE POLICY CORNER


How should innovation in health technologies be defined? What is the relationship between innovation and value? The resulting report makes 25 recommendations, including the need for NICE to improve the communication of its work and purpose; for NICE to work more closely with local NHS commissioners and budget holders to identify divestment opportunities; and for the pharmaceutical industry to better engage with the NICE process and actually prove innovation rather than hypothesize about product potential. Importantly, the Kennedy report essentially advises against any move towards the societal perspective and thereby the inclusion of wider societal costs and benefits. In 2008, the European Commission (EC) published its preliminary report on the competition inquiry into the pharmaceutical industry. The inquiry takes its legal basis from Article 17 of Regulation 1/2003 of EC Treaty competition rules. Understanding the implications of this inquiry, and what it means for pricing and reimbursement activities, constitutes an important strategic consideration moving forward. The EC launched its inquiry in the light of market information suggesting that pharmaceutical competition may be restricted or distorted in Europe, indicated by a decline in innovation and novel medicines. From 1995 to 1999, on average, 40 novel molecular entities were launched per year, compared with 27 in the period from 2000 to 2007. Other indications included delayed market entry of generic medicines, reduced research and development activity and decreasing pharmaceutical supply. Representative bodies consulted included individual companies, the European Federation of Pharmaceutical Industries and Associations (EFPIA), and the European Generic Medicines Association (EGA). The main focus of the inquiry is competition amongst originator companies (those developing new products) and competition between originator companies and generic companies (those manufacturing equivalents when products come off patent). Key provisional findings include: he European market is not as competitive as it should be. The report cites evidence of originator companies T delaying or stultifying market entry; nti-competitive practices such as multiple patent applications for the same product, defensive patents, A litigation disputes and intervention prior to regulatory approval are widespread; and, A significant decline in innovation and new product development. The EC has so far concluded that these practices are responsible for adding significant costs to national health care budgets. Phase One of the inquiry is now complete. The provisional findings have been put out for public consultations and stakeholder feedback. A final report is scheduled for publication in late 2009. Depending on the findings of the inquiry, the result could be new EC directives and legislation to advance competition, and therefore shape the way in which pharmaceutical companies operate. A change in competition legislation could have consequences for pharmaceutical development, regulatory approval, and market access.

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