An investment appraisal approach to clinical trial design.

In this paper, a general investment appraisal model is presented which shows how pharmaceutical companies could take profit considerations into account when making decisions about the design of randomized controlled trials. A general model is presented based on the net present value method of investment appraisal. The approach is illustrated with a hypothetical example which shows how optimal (net present value maximizing) designs can be determined based on choices about sample size and endpoint measurement. The method could be extended to accommodate considerations about other trial design features, and could be used to determine a portfolio of studies which maximizes the expected return on a given development or trial budget. Furthermore, the approach could be used by pharmaceutical companies to evaluate the incremental costs and benefits of incorporating non-clinical objectives into trials, such as quality of life research and economic evaluation studies. A number of practical difficulties would need to be overcome to utilize the approach. Directions for further research are therefore highlighted centred on the key components of the model: a trial cost function, a product demand function, innovation diffusion processes and Bayesian approaches to trial design.

Economic evaluation of antiviral therapy for the treatment of herpes zoster in immunocompetent adults.

Shingles (herpes zoster) affects 20% of the population at some stage during their lives. The economic consequences can be significant. For example, in the UK, the costs of post-herpetic neuralgia, a complication that affects between 10 and 14% of patients with shingles, have been estimated between 4.8 million and 17.9 million pounds sterling (Pounds). This study is the first formal assessment of the cost-effectiveness of the 2 most commonly used oral antiviral treatments that have proven efficacy in patients with shingles: famciclovir and aciclovir (acyclovir). It shows that the clinical advantages of famciclovir over aciclovir are accompanied by potential economic advantages in the form of savings in direct costs to the UK National Health Service of between 2.04 pounds and 16.85 pounds per patient treated. Future economic research to validate the benefits of antiviral treatment should focus on prospective assessments alongside controlled trials incorporating resource use analysis, quality-of-life appraisal, assessments of pain severity, and long term follow-up with continuation protocols.

Synthetic surfactant for rescue treatment of respiratory distress syndrome in premature infants weighing from 700 to 1350 grams: impact on hospital resource use and charges.

To determine the impact of the use of synthetic surfactant on hospital resource use and charges, we analyzed the economic data from a multicenter, randomized, placebo-controlled clinical trial of synthetic surfactant in infants with neonatal respiratory distress syndrome and birth weights between 700 and 1350 gm. Two 5 ml/kg doses of a synthetic surfactant (Exosurf Neonatal) or air placebo were administered to 419 infants who were receiving mechanical ventilation and had an arterial/alveolar oxygen tension ratio < 0.22. In addition to the clinical endpoints for safety and efficacy, data were collected on length of hospital stay, days in the neonatal intensive care unit, days of mechanical ventilation, days of oxygen supplementation, and hospital charges until the infant reached 1 year adjusted age. Growth and development of infants who received synthetic surfactant therapy in the study and survived to 1 year adjusted age were equivalent to those of the survivors in the air placebo group. For 1-year survivors, synthetic surfactant reduced the average length of stay at the different levels of care needed during the hospitalization such as neonatal intensive care unit days, days of mechanical ventilation, and days of oxygen supplementation. For nonsurvivors, synthetic surfactant increased the average length of stay, especially at more intense levels of care. Total hospital charges for the initial hospitalization and through 1 year adjusted age for a hypothetic cohort of 100 infants treated with synthetic surfactant were, on average, the same as those for a comparable cohort of infants in the air placebo group. These results indicate that rescue therapy with synthetic surfactant in infants with respiratory distress syndrome and birth weights from 700 to 1350 gm can result in significantly improved survival without significant increases in hospital charges.

Economic outcomes of colfosceril palmitate rescue therapy in infants weighing 1250g or more with respiratory distress syndrome: results from a randomised trial.

An analysis of the economic data from a multicentre, randomised, placebo-controlled clinical trial of colfosceril palmitate in infants with neonatal respiratory distress syndrome (NRDS) and birthweights of 1250g or more is presented. Two 5 ml/kg (67.5 mg/kg) doses of a synthetic surfactant (colfosceril palmitate) or air placebo were administered to 1237 infants who were receiving mechanical ventilation and had an arterial/alveolar oxygen tension ratio of less than 0.22. In addition to the clinical end-points for safety and efficacy, data were collected on length of hospital stay, days in the neonatal intensive care unit, days on mechanical ventilation, days on oxygen, and hospital charges until the child reached 1-year adjusted age. One-year adjusted age is attained when the time elapsed since birth is equal to 365 days plus the number of days of prematurity. Rescue treatment with synthetic surfactant therapy has been shown to reduce the incidence of complications of NRDS. Growth and development of infants who received colfosceril palmitate therapy in the study and survived to 1-year adjusted age were equivalent to those of the survivors in the air placebo group. For the cohort of treated infants, colfosceril palmitate reduced the average length of stay at 2 levels of care needed during both the initial hospitalisation (a reduction of 8 days overall and 5 days in intensive care) and all first year hospitalisations (a reduction of 9 days overall and 5 days in intensive care). Total hospital charges for the initial hospitalisation and through 1-year adjusted age for a hypothetical cohort of 100 infants treated with colfosceril palmitate were less than those for a comparable cohort in the air placebo group. The results would, therefore, suggest that rescue therapy with colfosceril palmitate in infants with NRDS and birthweights over 1250g can result in substantial reductions in hospital resource utilisation and charges in addition to the clinical benefits associated with its use.

International cross-section analysis of the determination of mortality.

An essential ingredient in the evaluation of policies concerning health services is knowledge of the impact of health services and other factors on the health of the population. One method of obtaining this information is from the regression analysis of international cross-section data on mortality rates, health service provision, income levels, consumption patterns, and other variables hypothesised to affect population health. The investigation of the determinants of population health is in many ways akin to the estimation of production functions which describe the relationship between the output of goods or services and the mix of inputs used in their production. The purpose of our paper is to use this analogy to discuss, and provide examples of, the problems which arise with the statistical investigation of mortality rates. Issues raised include simultaneous equation bias, multicollinearity, selection of explanatory variables, omitted variable bias, definition and measurement of variables, functional forms, lagged relationships and temporal stability. These problems are illustrated by replication and re-analysis, using new data, of the well known study by Cochrane, St Leger and Moore.