Real World Data in Adaptive Biomedical Innovation: A Framework for Generating Evidence Fit for Decision-Making.

Analyses of healthcare databases (claims, electronic health records [EHRs]) are useful supplements to clinical trials for generating evidence on the effectiveness, harm, use, and value of medical products in routine care. A constant stream of data from the routine operation of modern healthcare systems, which can be analyzed in rapid cycles, enables incremental evidence development to support accelerated and appropriate access to innovative medicines. Evidentiary needs by regulators, Health Technology Assessment, payers, clinicians, and patients after marketing authorization comprise (1) monitoring of medication performance in routine care, including the materialized effectiveness, harm, and value; (2) identifying new patient strata with added value or unacceptable harms; and (3) monitoring targeted utilization. Adaptive biomedical innovation (ABI) with rapid cycle database analytics is successfully enabled if evidence is meaningful, valid, expedited, and transparent. These principles will bring rigor and credibility to current efforts to increase research efficiency while upholding evidentiary standards required for effective decision-making in healthcare.

Comparative efficacy and effectiveness: an opportunity for clinical pharmacology.

Over the past 10 or more years, the drug development paradigm has shifted radically as a consequence of the availability of generic formulations for many important drugs and the growing influence of major payers in controlling reimbursement of new medicines. The demand for health care in an aging and increasingly information-seeking population is steadily outstripping society's ability to pay for all possible treatments. Regulatory approval of new drugs is necessary but no longer sufficient for market access in many countries, including the United States.

Smoking, smoking cessation and smoking relapse patterns: a web-based survey of current and former smokers in the US.

AIM: The aim of this study was to characterise the natural course of smoking cessation behaviour in a web-based survey of current and former cigarette smokers (CS and FS) in the United States. METHODS: A web-based survey of CS and FS was conducted in April 2009; demographic and socioeconomic characteristics and smoking history (including the number of lifetime and length of latest quit attempts, aids used and time to relapse) were collated. The surveyed cohort was selected from prescreened CS and FS panellists and matched for age, race and education, to be representative of the US population. Descriptive statistics and time-to-event analyses using Kaplan-Meier curves were applied in the analysis of this report. RESULTS: The final cohort comprised 512 CS and 566 FS (n = 1078). A larger proportion of FS than CS reported a longest smoke-free period of > 1 year (78.8% vs. 22.4%, respectively). As a greater variety of smoking cessation products became available over time, the proportion of unassisted quit attempts decreased from 76.1% prior to 1983 to 43.9% after 2006 for CS and from 79.3% to 50.3% for FS. The cumulative proportion of subjects relapsing was 31.3% by 1 week and 79.3% by 6 months. The estimated median time to next quit attempt was approximately 360 days. CONCLUSIONS: These data confirm that relapse is common and that as the variety of cessation modalities increase, the proportion of unassisted quit attempts decreases. Self-help or cold-turkey methods still provide significant alternatives even when pharmacotherapy is available. This study provides data related to the smoking history and smoking cessation patterns of a large, nationally representative sample of CS and FS.

Comparison of length of hospital stay for patients with known or suspected methicillin-resistant Staphylococcus species infections treated with linezolid or vancomycin: a randomized, multicenter trial.

STUDY OBJECTIVE: To compare hospital length of stay (LOS), weekly discharges, and days of antibiotic treatment with linezolid (intravenous with oral follow-up) and vancomycin (intravenous only). DESIGN: Multinational, randomized, phase III trial. SETTINGS: Hospitals in North America, Latin America, and Europe. PATIENTS: Four hundred sixty hospitalized patients with infections of known or suspected methicillin-resistant Staphylococcus species. INTERVENTION: Administration of linezolid or vancomycin. MEASUREMENTS AND MAIN RESULTS: For linezolid recipients, median LOS was 5 and 8 days shorter (p=0.05 and 0.003) in the complicated skin and soft tissue infection intent-to-treat (230 patients) and clinically evaluable (144) samples, and slightly but not significantly shorter in the overall intent-to-treat (460) and clinically evaluable (254) samples. In all samples, linezolid recipients had more discharges in the first week of treatment and fewer days of intravenous therapy than vancomycin recipients. CONCLUSION: Our results support linezolid's ability to reduce medical resource use.

A comparison of scoring weights for the EuroQol derived from patients and the general public.

OBJECTIVE: General health state classification systems, such as the EuroQol instrument, have been developed to improve the systematic measurement and comparability of health state preferences. In this paper we generate valuations for EuroQol health states using responses to this instrument's visual analogue scale made by patients enrolled in a randomized clinical trial evaluating tirilazad mesylate, a new drug used to treat subarachnoid haemorrhage. We then compare these valuations derived from patients with published valuations derived from responses made by a sample from the general public. METHODS: The data were derived from two sources: (1) responses to the EuroQol instrument from 649 patients 3 months after enrollment in the clinical trial, and (2) from a published study reporting a scoring rule for the EuroQol instrument that was based upon responses made by the general public. We used a linear regression model to develop an additive scoring rule. This rule enables direct valuation of all 243 EuroQol health states using patients' scores for their own health states elicited using a visual analogue scale. We then compared predicted scores generated using our scoring rule with predicted scores derived from a sample from the general public. RESULTS: The predicted scores derived using the additive scoring rules met convergent validity criteria and explained a substantial amount of the variation in visual analogue scale scores (R(2)=0.57). In the pairwise comparison of the predicted scores derived from the study sample with those derived from the general public, we found that the former set of scores were higher for 223 of the 243 states. Despite the low level of correspondence in the pairwise comparison, the overall correlation between the two sets of scores was 87%. CONCLUSIONS: The model presented in this paper demonstrated that scoring weights for the EuroQol instrument can be derived directly from patient responses from a clinical trial and that these weights can explain a substantial amount of variation in health valuations. Scoring weights based on patient responses are significantly higher than those derived from the general public. Further research is required to understand the source of these differences.

Relationship between CD4 count, viral burden, and quality of life over time in HIV-1-infected patients.

BACKGROUND: Although surrogate markers such as CD4 counts and viral burden (HIV-1 RNA) are predictive of AIDS-related disease progression, little is known about the relationship between changes in surrogate markers and health-related quality of life (HRQOL) outcomes. This study investigated how changes in CD4/mm3 and viral burden (RNA copies/mL) are related to changes in HRQOL as indexed by the Medical Outcomes Study HIV Health Survey (MOS-HIV-30). METHODS: Subjects were HIV-1-infected patients with CD4 counts <300/mm3 enrolled in a double-blind, randomized clinical trial of delavirdine. As part of the clinical protocol, patients completed the MOS-HIV-30, from which the Physical Health (PHS) and Mental Health (MHS) summary scores were used for analyses. HRQOL and surrogate marker data assessed up to 2 years after randomization were analyzed for a total of 1,112 patients. RESULTS: Individual patients' initial status (intercepts) and rates of change (slopes) over time for log CD4, log RNA, PHS, and MHS were estimated with the use of empirical Bayes. Early response to treatment correlated with HRQOL better for RNA than for CD4. However, the relationship between weekly change and HRQOL was stronger for CD4 than for RNA. CONCLUSIONS: Surrogate markers are significantly associated with HRQOL outcomes. Improvements in HRQOL over time are associated with lower initial viral load and with increases in CD4 counts. Limitations concerning the restricted variability of the change scores are addressed.

Towards a composite scoring solution for the Neurobehavioral Functioning Inventory.

Little research has been conducted towards the development and evaluation of a measure of quality of life specific to head/brain injury populations. Accordingly, we examined responses to the Neurobehavioral Functioning Inventory in the context of a clinical trial for head injury patients (n = 655) conducted in 14 countries. To reduce the 66 item scale into a smaller number of composite scales, principal components analysis was conducted. Scales were constructed assessing four categories of symptoms: cognitive deficits, depression, aggression and somatization. The internal reliabilities (alpha coefficient) of the four scales were generally acceptable (range = 0.79-0.92). Scores on all four scales correlated significantly with patient-rated overall quality of life and all but the aggression scale correlated significantly with overall clinical severity. The need for more formal evaluation of this and other disease-specific measures is discussed.

A comparison of preference assessment instruments used in a clinical trial: responses to the visual analog scale from the EuroQol EQ-5D and the Health Utilities Index.

OBJECTIVES: To compare preference assessments that were made by using the EuroQol EQ-5D and the Health Utilities Index Mark II. SUBJECTS: 561 patients in a randomized trial of tirilazad mesylate for aneurysmal subarachnoid hemorrhage. MEASURES: Three preference assessments (a value score for the EuroQol instrument and value and utility scores for the Health Utilities Index) made three months after randomization. The averages for each of the three scores, stratified by clinical outcomes and attributes of the Health Utilities Index health status classification system, were compared. To evaluate potential sources of difference between the instruments, the authors estimated two alternative Health Utilities Index scoring rules that were based on patient responses to the EuroQol instrument. RESULTS: Patients' ratings of their current health made by using the 100-point visual analog scale from the EuroQol instrument were more similar to the utility scores for the Health Utilities Index than they were to the value scores for the Health Utilities Index. The biggest differences between the visual analog scores for the EuroQol instrument and the utility scores for the Health Utilities index were seen at higher levels of functioning. CONCLUSION: For states representing higher levels of functioning, differences were seen between patients' self-ratings obtained by using the EuroQol instrument and the patients' utility scores on the Health Utilities Index; for states representing lower levels of functioning, substantial agreement was observed between these two scores. Differences observed at the higher levels of functioning suggest that further research is needed to determine whether the Health Utility Index's assignment of a score of 1.0 to the reference state representing being healthy is appropriate.

An international comparison of the reliability and responsiveness of the Duke Health Profile for measuring health-related quality of life of patients treated with alprostadil for erectile dysfunction.

OBJECTIVES: It is important that health measures are both reliable and responsive to clinical change. The aim of this study was to assess the reliability and responsiveness of the physical, mental, and social health scales of the Duke Health Profile (DUKE). METHODS: Impotent males self-administered the Duke Health Profile before and during treatment with alprostadil for erectile dysfunction during a 19-month period. Subjects were 490 patients in the United States and 583 patients in 12 other countries. Each of the three basic Duke Health Profile scales has only five items, and each is heterogeneous because each measures more than one health concept. RESULTS: Cronbach's alpha reliability estimates were: physical health, 0.68 for United States and 0.64 for other countries; mental health, 0.62 and 0.52, respectively; and social health, 0.53 and 0.47, respectively. Alprostadil was expected to improve mental health primarily, and results of the study were consistent with this hypothesis. For example, at approximately 14 months from therapy onset, mental health improved for patients both in the United States (standardized response mean, SRM, = 0.17) and other countries (mean SRM = 0.30), whereas physical health worsened in the United States and was unchanged in other countries, and social health was unchanged in the United States and improved in other countries. Maximum responsiveness was shown for mental health in the other countries, where the mean standardized response means at four follow-ups during a 19-month period were 0.11, 0.21, 0.30, and 0.36. CONCLUSIONS: This study provides support for the responsiveness of the Duke Health Profile mental health scale.

Patient acceptability and satisfaction with Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension).

The results from a User Satisfaction Questionnaire, Treatment Assessment Questionnaire, and Global Well-Being Schedule questionnaire administered to women participating in an open-labeled, nonrandomized, parallel, controlled study comparing a new monthly injectable contraceptive containing 25 mg of medroxyprogesterone acetate (MPA) and 5 mg of estradiol cypionate (E2C) (MPA/E2C) (Lunelle Monthly Contraceptive Injection) and a triphasic norethindrone (0.5, 0.75, 1.0 mg)/0.035 mg ethinyl estradiol (NET/EE) oral contraceptive (Ortho-Novum 7/7/7) are reviewed. Approximately 85% of all 1103 women enrolled in the comparative trial completed their initial and final questionnaires. To better assess the comparison of a new and extant method of contraception, outcome data were divided among MPA/E2C users and new and previous oral contraceptive (OC) users. Despite the inherent inequalities in comparing an injectable to an oral method of contraception, few treatment assessment and satisfaction outcomes were significantly different when comparing MPA/E2C users to new OC (NET/EE) users. More women in the MPA/E2C study group reported discomfort with their method than women in either NET/EE study group; however, only 19.4% of MPA/E2C users rated the administration of their contraceptive to be moderately uncomfortable or worse, compared to 11.7% of new NET/EE users and 13.4% of previous OC users. Among MPA/E2C users, 86.3% reported no interference with social activities compared with 90.4% of new NET/EE users. MPA/E2C and new NET/EE users were also similar in their responses recommending their respective contraceptive method to friends, with > 90% of both groups stating that they had a very favorable experience and would definitely recommend their method to a friend. In general, MPA/E2C was well accepted by women in the study group. Their attitudes and perceptions are similar to those of women who were starting OCs for the first time. These data support the premise that MPA/E2C may become a well accepted, first-line contraceptive option for women in the US.

PIP: The results of a user satisfaction questionnaire, treatment assessment questionnaire, and global well being schedule questionnaire administered to women participating in an open-labeled, nonrandomized, parallel, controlled study is reported in this paper. The study compared a new monthly injectable contraceptive containing 25 mg medroxyprogesterone acetate (MPA) and 5 mg estradiol cypionate (E2C) with a triphasic norethindrone (0.5, 0.75, 1.0 mg)/0.035 mg ethinyl estradiol (NET/EE) oral contraceptive. Approximately 85% of 1103 women enrolled in the comparative trial completed their initial and final questionnaires. Despite the inherent inequalities in comparing an injectable to oral contraception, few treatment assessment and satisfaction outcomes were significantly different when comparing MPA/E2C users to new NET/EE users. More women in the MPA/E2C group reported discomfort with their method compared to the women in either the new or previous NET/EE user group. However, only 19.4% of MPA/E2C users rated the administration of their contraceptive to be moderately uncomfortable or worse, compared to 11.7% of new NET/EE users and 13.4% of previous NET/EE users. Among MPA/E2C users, 86.3% reported no interference with social activities compared with 90.4% of new NET/EE users. MPA/E2C and new NET/EE users were also similar in their responses recommending their respective contraceptive method to friends. These data support the premise that MPA/E2C may become the well-accepted, first-line contraceptive option for women in the US.

Resource costing for multinational neurologic clinical trials: methods and results.

We present the results of a multinational resource costing study for a prospective economic evaluation of a new medical technology for treatment of subarachnoid hemorrhage within a clinical trial. The study describes a framework for the collection and analysis of international resource cost data that can contribute to a consistent and accurate intercountry estimation of cost. Of the 15 countries that participated in the clinical trial, we collected cost information in the following seven: Australia, France, Germany, the UK, Italy, Spain, and Sweden. The collection of cost data in these countries was structured through the use of worksheets to provide accurate and efficient cost reporting. We converted total average costs to average variable costs and then aggregated the data to develop study unit costs. When unit costs were unavailable, we developed an index table, based on a market-basket approach, to estimate unit costs. To estimate the cost of a given procedure, the market-basket estimation process required that cost information be available for at least one country. When cost information was unavailable in all countries for a given procedure, we estimated costs using a method based on physician-work and practice-expense resource-based relative value units. Finally, we converted study unit costs to a common currency using purchasing power parity measures. Through this costing exercise we developed a set of unit costs for patient services and per diem hospital services. We conclude by discussing the implications of our costing exercise and suggest guidelines to facilitate more effective multinational costing exercises.

Estimating country-specific cost-effectiveness from multinational clinical trials.

Because costs and outcomes of medical treatments may vary from country to country in important ways, decision makers are increasingly interested in having data based on their own country's health care situations. This paper proposes methods for estimating country-specific cost-effectiveness ratios from data available from multinational clinical trials. It examines how clinical and economic outcomes interact when estimating treatment effects on cost and proposes empirical methods for capturing these interactions and incorporating them when making country-specific estimates. We use data from a multinational phase III trial of tirilazad mesylate for the treatment of subarachnoid haemorrhage to illustrate these methods. Our findings suggest that it is possible for meaningful country-by-country differences to be found in such trial data. These differences can be useful in informing reimbursement, utilization, and other decisions taken at the country level.

Economic analysis of tirilazad mesylate for aneurysmal subarachnoid hemorrhage. Economic evaluation of a phase III clinical trial in Europe and Australia.

This study used data from a multinational phase III randomized, double-blind, vehicle-controlled trial to evaluate the cost-effectiveness of tirilazad mesylate (Freedox) in the treatment of aneurysmal subarachnoid hemorrhage. In men, therapy with 6 mg/kg per day of tirilazad mesylate was associated with significantly increased survival, increased cost of care, and ratios of cost per death averted that compare favorably with the ratios of other life and death interventions. In women, it appeared to have no effects on costs or survival. Further clinical studies may provide additional information about the cost-effectiveness of this intervention.

Comparison of the use of medical resources and outcomes in the treatment of aneurysmal subarachnoid hemorrhage between Canada and the United States.

OBJECTIVE: Using data from a randomized trial of tirilazad mesylate, we assessed the differences between Canada and the United States in the use of medical resources and outcomes in the treatment of aneurysmal subarachnoid hemorrhage during the first 90 days after admission to the hospital. METHODS: Of the 877 patients for whom economic data were available, 194 were enrolled in Canada and 683 were enrolled in the United States. The differences between the countries in patient characteristics, use of medical resources, and outcomes were analyzed by comparing means and the 95% confidence intervals (CIs) around the differences in means. These differences also were predicted with use of multivariable regression analysis. RESULTS: The average hospital stay was 4.2 days longer (95% CI, 1.3 to 7.1 days) in Canada, but most of the extra stay was among patients admitted to the study in poor neurological condition. In general, however, hospital stays in Canada were substantially less intensive. Patients treated in Canada spent 3.7 fewer days (95% CI, 1.2 to 6.1 days) in nursing homes and rehabilitation centers than did patients in the United States. No statistically significant differences were seen for Glasgow Outcome Scale score, death, and occurrence of vasospasm. CONCLUSIONS: For patients admitted to the study in good neurological condition, the apparent difference in length of stay between Canada and the United States was caused by a shift in the sites of formal care rather than to the length of this care. For those admitted in poor neurological condition, both the length and sites of care differed between the two countries. No significant difference in outcomes appeared to justify these differences in the use of medical resources.

Quality of life effects of alprostadil therapy for erectile dysfunction: results of a trial in Europe and South Africa.

OBJECTIVES: Quality of life (QOL) data were used to evaluate the effects of self-administered intracavernosal injection of alprostadil for erectile dysfunction, when used for up to 18 months during a 13 country Phase III clinical trial. METHODS: The Duke Health Profile was used to measure patients' physical and psychosocial QOL at baseline, 3, 6, 12 and 18 months. Changes from baseline were measured using paired t-tests, with additional analyses by cause of dysfunction, starting dosage, and prior treatment. RESULTS: Patients displayed significant improvements in mental and social health and self-esteem at six months (P < 0.01, n = 570), with greater improvements at 12 and 18 months. Anxiety and depression measures also improved significantly at 12 and 18 months, as did the summary general health score. Worse pain scores were observed in the first year but not at 18 months. Those with a starting dosage of 10-20 micrograms, those with psychogenic causes of dysfunction, and those with no prior treatment for erectile dysfunction generally showed the greatest improvements. CONCLUSION: In this study, the clinical improvements in erectile function due to intracavernosal alprostadil therapy were complemented by QOL improvements, particularly in the mental health, of many patients.

Construction of scales for the Center for Marital and Sexual Health (CMASH) Sexual Functioning Questionnaire.

The objective of this study was to identify a set of scales for summarizing the results of the Center for Marital and Sexual Health Sexual Functioning Questionnaire (CMASH SFQ). Scales for this instrument were constructed using patients' responses to the CMASH SFQ in a recent clinical trial of prostaglandin E1 (PGE1, alprostadil), an injectable vasodilator used to treat erectile dysfunction. A set of items was identified as a scale if they met predetermined standards of internal consistency, discriminant validity, and convergent validity. The reproducibility of the scales was then evaluated, and the extent to which the scales reliably measured change in treatment-related quality of life was assessed. Reliable and responsive scales for four domains related to sexual functioning were identified. Items in these scales were generally internally consistent; items in the scales and the scores for the scales generally satisfied criteria of discriminant validity; and the scales generally satisfied the standard for convergent validity. Evaluating patients' responses to the CMASH SFQ with scores for four reliable and responsive scales allows easier summarization of patients' sexual functioning and increases the statistical power of evaluations of the effects of interventions designed to improve sexual functioning.

Quality of life effects of alprostadil therapy for erectile dysfunction.

PURPOSE: We evaluated the quality of life effects of self-administered intracavernosal injection of alprostadil sterile powder for erectile dysfunction when used by patients for up to 18 months. MATERIALS AND METHODS: Clinical and self-reported measurements were used to assess physiological and psychological status at baseline, and at 3, 6, 12 and 18 months for 579 patients who entered the self-injection phase of an open label, flexible dose clinical trial. Quality of life was measured using the Center for Marital and Sexual Health Sexual Functioning Questionnaire, which focuses on the psychosocial and physical dimensions of erectile dysfunction; the Brief Symptom Inventory, which measures mental health, and the Duke Health Profile, which measures general quality of life. The primary evaluations were quality of life changes from baseline to post-initiation periods and reasons for treatment discontinuation. RESULTS: The Center for Marital and Sexual Health Sexual Functioning Questionnaire displayed improvements at all post-initiation periods in 10 questions (p < 0.001, Student's paired t-tests) grouped into scales representing frequency of sexual activity, erection, orgasm and satisfaction domains. On the Brief Symptom Inventory interpersonal sensitivity, anxiety and depression as well as global scores improved (p < 0.001). Overall mental health as measured by the Duke Health Profile also improved (p < 0.01) between baseline and 6 months. The reasons most frequently cited for treatment discontinuation were nonfirm erections and injection site pain. CONCLUSIONS: Clinical improvements in erectile function due to alprostadil therapy were associated with improvements in sexual activity, sexual satisfaction and overall mental health.

Confidence intervals for cost-effectiveness ratios: a comparison of four methods.

We evaluated four methods for computing confidence intervals for cost-effectiveness ratios developed from randomized controlled trials: the box method, the Taylor series method, the nonparametric bootstrap method and the Fieller theorem method. We performed a Monte Carlo experiment to compare these methods. We investigated the relative performance of each method and assessed whether or not it was affected by differing distributions of costs (normal and log normal) and effects (10% absolute difference in mortality resulting from mortality rates of 25% versus 15% in the two groups as well as from mortality rates of 55% versus 45%) or by differing levels of correlation between the costs and effects (correlations of -0.50, -0.25, 0.0, 0.25 and 0.50). The principal criterion used to evaluate the performance of the methods was the probability of miscoverage. Symmetrical miscoverage of the intervals was used as a secondary criterion for evaluating the four methods. Overall probabilities of miscoverage for the nonparametric bootstrap method and the Fieller theorem method were more accurate than those for the other the methods. The Taylor series method had confidence intervals that asymmetrically underestimated the upper limit of the interval. Confidence intervals for cost-effectiveness ratios resulting from the nonparametric bootstrap method and the Fieller theorem method were more dependably accurate than those estimated using the Taylor series or box methods. Routine reporting of these intervals will allow individuals using cost-effectiveness ratios to make clinical and policy judgments to better identify when an intervention is a good value for its cost.

Re-engineering drug development: integrating pharmacoeconomic research into the drug development process.

Pharmacoeconomic research will be an increasingly important aspect of drug development as providers, third-party payers, and worldwide government health agencies use cost-effectiveness and quality-of-life data to assist in making decisions on optimal pharmaceutical treatment protocols, formulary listings, and reimbursement. It is in the best interest of pharmaceutical companies to have an established, well-integrated pharmacoeconomic research program that can respond to the dynamic health-care environment and proactively plan a program to optimize patient care. The new paradigm for pharmacoeconomic research will require establishment and successful management of many internal and external customer relationships. This article discusses one company's organization of these relationships and how they are integrated into the drug development process during each stage of the product life cycle.

Assessing the validity of the geographic practice cost indexes.

Data on physician practice inputs were used to test the degree to which the geographic practice cost indexes (GPCIs) of the Medicare physician payment schedule reflect geographic variation in input prices. For purposes of this study, input quantity information was collected through the American Medical Association's Socioeconomic Monitoring System survey in 1990 and 1991. These data, along with practice expense information, were used to construct unit input prices. The GPCIs were correlated with input prices; however, "real" or GPCI-adjusted prices varied significantly across locations. We conclude that the GPCIs are useful, but imperfect measures of geographic differences in physician practice input prices.