The Importance of Quality-of-Life Research
Clinical studies involving HRQOL endpoints have remained a niche pursuit over the past several decades owing to a variety of conceptual and methodological challenges. Enhanced interest in such studies is now driven by several powerful factors, including patient consumerism, product marketing, health economics, regulatory evolution and recent study results that have revealed how predictive HRQOL measures can be. New information technologies are available that can support cost-effective deployment of HRQOL studies longitudinally over large populations. Leading outcomes research organizations are creating new collaborative associations to increase the speed and efficiency of HRQOL clinical research.
Clinical versus experiential data
Clinical trials have traditionally utilized measures of morbidity and mortality as primary endpoints, with therapeutic efficacy assessed in terms of clinical findings such as physical exams, lab results, radiographic images and physician-assessed patient functional states. The late 1970s witnessed the beginnings of quality-of-life studies, in which psychometric tools were used to quantify patient attitudes, symptoms, preferences and functional status directly from self-reported patient information.
Collection techniques for these data subsequently evolved from structured interviews into formalized questionnaires of two primary types: lengthy multidimensional general health surveys (e.g. the SF-36 (1)), and focused disease-specific questionnaires (e.g. the Seattle Angina Questionnaire (2)). Depending on the specific instrument, both types of questionnaire generate both raw scores and calculated ‘scales’, which are often normalized to a 0–100 range. In addition, ‘utility’ measures (3) have been developed to assess patient preferences by posing choices between hypothetical health status alternatives (e.g. the ‘standard gamble’ and ‘time tradeoff’ measures). Utility measures are reported on a scale of 0–1 and, when coupled with lifeexpectancy data, yield quality-adjusted life years (4), which are used in cost-effectiveness calculations.
Questions of performance, validity and meaning
Some substantive conceptual challenges lurk behind this conversion of subjective patient attitudes into objective numeric values. The process of self-reporting leaves the interpretation of questions up to the literacy, comprehension and whim of the patient. The degree of fresh attention the patient brings to each performance of the questionnaire depends on its length and complexity. If the instrument is very long, the patient may skip through it, while if it is short, the patient might ‘learn’ his/her responses and tend to repeat them. Because sequentially administered HRQOL questionnaires are usually given at intervals of 2 weeks or more, the temporal granularity of the phenomena they measure is quite coarse. Even optimally completed questionnaires must be rigorously validated against external measurements in order for patient scores to be meaningful. In particular, the magnitude of change that gives clinical significance requires specific determination during validation (5).
HRQOL measures also face daunting methodological and logistical challenges. When responding to paper form questionnaires, patients can easily omit responses to questions or mark multiple responses when only one is appropriate. Error detection and correction either occurs late via a patient callback, which introduces bias, or by the use of a missing-value imputation algorithm, which introduces a different bias. Calculation of dimension/scale scores can involve complicated, error-prone algorithms requiring special staff expertise. The distribution and collection of paper forms involves many steps, causing increased costs. Data transcription into a computer database requires either expensive data-entry staff or scanning and optical character-recognition systems, both of which are subject to errors. If not assiduously countered, these logistical problems can cause HRQOL evaluations to be not only subjective and hard to interpret, but also fundamentally flawed and misleading.
Niche applications of HRQOL
Despite—or perhaps because of—these challenges, HRQOL research has occupied a small, but growing, niche in the clinical research world. Current MEDLINE data reveal that quality-of-life publications constituted 0.1% of all indexed publications in 1980, 0.4% in 1990 and still only about 0.9% now (6). Much of the literature describes the development of new questionnaires and their use in descriptive, cross-sectional and cohort studies to characterize populations defined by geographic, demographic or diagnostic criteria. More recently, randomized, interventional studies using HRQOL measures have joined the literature, constituting about 3% of all HRQOL studies now (6). Although the growth rate of published HRQOL research is somewhat higher than that of general publications, the absolute number of studies remains fairly low.
Reasons behind increased HRQOL research
Several ongoing developments are increasing the level of interest in HRQOL research.
Pharmaceutical and device manufacturers
In the current aggressively competitive marketplace, manufacturers have unprecedented need to differentiate their products from those of their competitors. This is most apparent in ‘lifestyle’ drug categories such as antidepressants, ulcer medications and anti-inflammatory agents. To this end, product manufacturers are adding HRQOL information to marketing campaigns, particularly those directed at the consumer (DTC advertising). HRQOL data also often form part of the pitch to large purchasers such as managed care organizations and pharmacy benefits managers. HRQOL data have typically been collected—though often not analyzed if the primary endpoints were significant— during studies for new drug applications (NDAs). The fact that one new technology (laser transmyocardial revascularization) won US Food and Drug Administration (FDA) approval due in a large part to the HRQOL data collected suggests that such data will likely play a larger role in future NDAs.
Faced with pressure from product manufacturers to accept HRQOL data for advertising and labeling claims, the FDA and the European Agency for the Evaluation of Medicinal Products are in the process of formulating new guidance statements. FDA policy will likely stipulate standards for how HRQOL instruments are designed and validated, how HRQOL measures are integrated and analyzed with other data, and how specific HRQOL results are converted into labeling claims (7) (8).
Spurred by DTC advertisements and empowered by Internet consumer health sites, patients are seeking out more information on therapeutic products and are wielding that information during treatment discussions with their physicians. The HRQOL benefits of products frequently assume much greater importance in patients’ decision making than standard clinical measures. Patients will increasingly demand to know quantitatively and precisely how they can expect to be impacted by the therapeutics they take.
Employers, insurers and the government increasingly look for detailed economic analyses of the healthcare products and services they purchase. Quality-adjusted life-year calculations from utility measures are used to form key components of cost-effectiveness and cost-utility analyses (4).
Physicians are beginning to realize the value of collecting performance measures and patient outcomes data to generate quality indicators for use during contract negotiations and marketing campaigns. HRQOL data collected longitudinally in a physician’s patient population could constitute powerful evidence of the quality of care the physician provides. However, revenue models to support such data collection are currently not clear, and until they are, physicians are unlikely to perform such studies in their practices. The new crop of disease-management companies that contract for the care of specialized patient populations based on diagnostic ‘carve-outs’ do have a compelling need to quantify their program’s cost-effectiveness for both marketing and internal program management purposes. HRQOL studies could form important components of such return-on-investment metrics.
Recent work has shown how remarkably predictive carefully validated disease-specific HRQOL instruments can be in tracking patient health status responsively and reliably. The Seattle Angina Questionnaire (2) (9) and Kansas City Cardiomyopathy Questionnaire (10) are demonstrably as reproducible (or more so) for heart patients as some of the traditional ‘hard data’ measures relied upon by cardiologists (e.g. treadmill tests and ejection fractions). They can accurately identify high-risk and high-cost patient subpopulations (11). Next-generation developments in HRQOL instrument design include minimizing the length of questionnaires to reduce measurement burden, controlling for language and cultural variables, and defining dynamic, computer-adaptive testing algorithms (12). The incorporation of such validated instruments into central endpoints of international, long-term randomized controlled trials such as the COURAGE trial (a comparison of percutaneous coronary revascularization to medical therapy) (13) is raising the profile of HRQOL measures in such research.
Demand for large-scale, repeated assessment of HRQOL data thus appears to be emerging in a wide variety of contexts, from traditional clinical trial settings to clinical practice facilities where clinical research might not previously have been performed.
Using information technology in HRQOL research
The traditional interview- and paper form-based methods of HRQOL research do not scale well because of the high costs, logistical complexity and risk of errors involved. Most organizations lack the infrastructure and the large number of trained staff required by standard techniques. Fortunately, a palette of new information technologies makes innovative solutions possible that increase the ease, speed and reliability of HRQOL studies, while cutting their cost.
Numerous vendors offer methods by which HRQOL data can be scanned into a digital format for importation into a database. More complete solutions include tools for form creation, remote scanning and e-mail transport, and scanning-error detection and adjudication. These systems reduce data entry time but provide no mechanism to reduce errors introduced by patients.
Automated telephone systems
Various programmable telephone systems are available to collect HRQOL data in an oral interview fashion. By using the virtually ubiquitous telephone, these systems can reach nearly any patient (as long as the patient is not deaf). Patient responses keyed in via the telephone can be digitally captured without additional effort. However, HRQOL questions consisting of multiple-choice responses impose a potentially excessive burden on patients’ short-term memories. Unless the instrument has been validated for this use, the data may be suspect, or at least not directly comparable to those derived from other methods (14).
Many experimental and commercial systems using personal computers—often with a touch-screen monitor to simplify user interactivity via a kiosk format—have been created (15) (16) (17) (18) (19) (20) (21). Error detection and correction routines are typically part of these programs, as is support for complex instruments with skip logic and visual scales (such as some utility measures). Published evaluations uniformly confirm the ease, speed and accuracy with which these systems collect digital data. However, supporting these PC systems may be a more complicated task than many sites can handle, and many facilities find that on-site patient use of PCs imposes objectionable logistical bottlenecks to smooth patient flow. Further, multi-site deployments are not well served by separate stand-alone PCs, nor do they allow system access by patients in their homes.
Several experimental and commercial systems using hand-held computers exist (22). These vendors primarily target professional data-entry staff with ‘electronic case report form’ products, but data collection tools for direct patient use are also available.
Numerous custom and commercial Internet-based clinical trial tools exist (13) (23) (24) (25) (26) (27) (28), and many consumer-oriented health sites provide access to HRQOL instruments as well. These solutions offer all the interactivity and error-control advantages of PC systems, plus they decentralize test administration so that patients can perform the tests wherever and whenever it is convenient to do so. The collection of large, geographically distributed data-sets directly into study databases is thus possible, as is near-realtime data analysis. However, despite the recent rapid increase in the number of people with Internet access, many important subpopulations remain unconnected. The ill, elderly and enfeebled—likely the most important subjects of clinical research—are typically the ones least likely to be on the right side of the ‘digital divide’. These patients will be more easily queried via telephone and mailed forms.
Clearly, no one system is yet ideal, but all have a useful role in certain contexts. This table charts each alternative against important criteria to consider when collecting HRQOL data. Over time, the accelerating convergence within telecommunication and computing technologies will no doubt radically shape the evolution of available solutions.
|Feature||Paper forms||Scanned forms||Automated telephone||PC||Palm-top||Internet|
|Decentralized point of data collection||Yes||Yes||Yes||No||Maybe||Yes|
|Patient error/omission detection and correction||No||No||Yes||Yes||Yes||Yes|
|Digital data conversion error risk||High||Medium||Low||Low||Low||Low|
|Setup costs||Low||Medium||High (build), Medium (buy)||Medium–high||Medium–high||High (build), Medium (buy)|
|Organizational infrastructural sophistication||Low||Medium||Low||Low||Low||High|
|Organizational support capabilities||High||Medium–high||Low||Medium–high||Medium–high||Low|
Emerging collaborative outcomes research organizations
Harnessing innovative information technologies to deliver cost-effective data is only part of the solution, however. Long-term, longitudinal measurement of the broader effects of therapeutic interventions will draw from areas of patient referral much larger than those of individual academic medical centers or contract research organizations. Timely recruiting and retention of adequate numbers of appropriate patients will require new processes and procedures. Performing these studies will be best accomplished by site management organizations with national scope or innovative ‘virtual’ collaborative groups such as the new Cardiovascular Outcomes Research Consortium (CORC). CORC brings together the outcomes research sections of most of the principal leaders in US cardiac HRQOL studies, including Yale (CT), Emory (GA), Stanford (CA), Northwestern (IL), Duke (NC), the University of Texas, Case Western Reserve University (OH), Mid America Heart Institute (MO), the University of Missouri- Kansas City and the University of Iowa. CORC’s goal is to create an information infrastructure through which its members can solve the remaining conceptual and methodological problems with HRQOL research. CORC expects its efforts to elevate the discipline to new levels of authoritativeness and influence.
Several decades of small-scale health-related quality-of-life studies have revealed that, despite certain conceptual issues, HRQOL data can produce vital information about patients’ interaction with illness and their response to treatment. Current integration of HRQOL data into central endpoints of randomized controlled clinical trials is now possible due to the creation and validation of reliable disease-specific instruments. Rapidly evolving information technologies will support cost-effective performance of HRQOL research at a scope previously unthinkable. Innovative new collaborations among visionary investigators will direct the discipline’s evolution toward a ‘technology of patient experience’ (29).
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Created: January 12, 2009 16:19; Last updated: February 07, 2009 12:31