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José A Sacristán,1 Alfonso Aguarón,2 Cristina Avendaño-Solá,3 Pilar Garrido,4 Juan Carrión,5 Alipio Gutiérrez,6 Robert Kroes,7 Angeles Flores11Medical Department, Lilly Spain, 2Myeloma Patients Europe, 3Research Ethics Committee, University Hospital Puerta de Hierro, 4Oncology Department, Hospital Ramón y Cajal, 5FEDER (Spanish Federation for Rare Diseases), 6National Association of Health Journalists, Madrid, Spain; 7Clinical Open Innovation, Lilly Europe, Amsterdam, the Netherlands Abstract: The development of a patient-centered approach to medicine is gradually allowing more patients to be involved in their own medical decisions. However, this change is not happening at the same rate in clinical research, where research generally continues to be carried out on patients, but not with patients. This work describes the why, when, and how of more active patient participation in the research process. Specific measures are proposed to improve patient involvement in 1) setting priorities, 2) study leadership and design, 3) improved access to clinical trials, 4) preparation and oversight of the information provided to participants, 5) post-study evaluation of the patient experience, and 6) the dissemination and application of results. In order to achieve these aims, the relative emphases on the ethical principles underlying research need to be changed. The current model based on the principle of beneficence must be left behind, and one that upholds the ethical principles of autonomy and non maleficence should be embraced. There is a need to improve the level of information that patients and society as a whole have on research objectives and processes; the goal is to promote the gradual emergence of the expert patient.Keywords: patients, research, clinical trials, bioethics, engagement

Tatiana Dilla,1 Luís Lizan,2 Silvia Paz,2 Pilar Garrido,3 Cristina Avendaño,4 Juan J Cruz-Hernández,5 Javier Espinosa,6 José A Sacristán1 1Medical Department, Lilly, Madrid, 2Outcomes’10, Jaime I University, Castellón, 3Medical Oncology Department, University Hospital Ramon y Cajal, Madrid, 4Clinical Pharmacology Department, Puerta de Hierro-Majadahonda Hospital, Madrid, 5Salamanca Institute for Biomedical Research, University Hospital of Salamanca, Salamanca, 6Medical Oncology Department, General Hospital Ciudad Real, Ciudad Real, Spain Background: In oncology, establishing the value of new cancer treatments is challenging. A clear definition of the different perspectives regarding the drivers of innovation in oncology is required to enable new cancer treatments to be properly rewarded for the value they create. The aim of this study was to analyze the views of oncologists, health care policy makers, patients, and the general population regarding the value of new cancer treatments. Methods: An exploratory and qualitative study was conducted through structured interviews to assess participants’ attitudes toward cost and outcomes of cancer drugs. First, the participants were asked to indicate the minimum survival benefit that a new treatment should have to be funded by the Spanish National Health System (NHS). Second, the participants were requested to state the highest cost that the NHS could afford for a medication that increases a patient’s quality of life (QoL) by twofold with no changes in survival. The responses were used to calculate incremental cost-effectiveness ratios (ICERs). Results: The minimum improvement in patient survival means that justified inclusions into the NHS were 5.7, 8.2, 9.1, and 10.4 months, which implied different ICERs for oncologists (€106,000/quality-adjusted life year [QALY]), patients (€73,520/QALY), the general population (€66,074/QALY), and health care policy makers (€57,471/QALY), respectively. The costs stated in the QoL-enhancing scenario were €33,167, €30,200, €26,000, and €17,040, which resulted in ICERs of €82,917/QALY for patients, €75,500/QALY for the general population, €65,000/QALY for oncologists, and €42,600/QALY for health care policy makers, respectively. Conclusion: All estimated ICER values were higher than the thresholds previously described in the literature. Oncologists most valued gains in survival, whereas patients assigned a higher monetary value to treatments that enhanced QoL. Health care policy makers were less likely to pay more for therapeutic improvements compared to the remaining participants. Keywords: oncology, cost, cost-effectiveness, cost-effectiveness threshold, ICER, clinically meaningful outcomes, Spain

Background: A cascade of events follows initial antidepressant selection which includes the subsequent antidepressant use pattern, resultant clinical outcomes, and associated health care expenditures., Purpose: The purpose of this study using data from a clinical practice setting was to test whether the pattern of antidepressant use was correlated with patients' treatment response as measured by the score on the Clinical Global Impression-Improvement scale., Data and Methods: A retrospective dataset of patients who initiated therapy on fluoxetine, fluvoxamine, paroxetine, or sertraline in a primary care setting in Spain was used. A Cox proportional hazard analysis was used to predict the likelihood of treatment response based upon the pattern of initial antidepressant use, while minimizing the influence of other factors., Results: After controlling for other observed baseline characteristics including initial disease severity, (a) patients who remained on their initial antidepressant therapy for at least 2 months with no switching, augmentation, or upward dose titration were 1.63 times more likely to experience a treatment response than patients who had an adjustment to therapy; and (b) patients who initiated therapy on sertraline were 0.46 times as likely to experience a treatment response as patients who initiated therapy on the most common study antidepressant, fluoxetine., Conclusion: The pattern of antidepressant use is an important determinant of treatment response among patients initiating therapy on the newer antidepressants in clinical practice.

Although cost considerations traditionally have not been important in cancer treatment decision making, there is increasing concern worldwide about the economic impact of therapeutic alternatives in the field of oncology. In particular, there is greater pressure for pharmaceutical companies to assess the economic value of new products. We have investigated and compared the clinical outcomes and corresponding cost savings of a novel nucleoside analog, gemcitabine, with other chemotherapy options in three different health care settings: Germany, the United States, and Spain. To date, most of the work with gemcitabine has been done in non-small cell lung cancer. Most non-small cell lung cancer patients present with advanced disease that is unsuitable for surgery and, in many cases, unsuitable for potentially curative chemotherapy. Chemotherapy for the majority of patients is therefore administered with palliative intent. For this reason, the comparative agents chosen for the economic models were palliative treatments (cisplatin/etoposide and ifosfamide/etoposide). As is customary with oncolytics, gemcitabine was investigated first as a single agent in noncomparative trials. Since data were not available from a comparator trial, we estimated comparative data from the literature sources and expert opinion (German and Spanish cost models) and from retrospective chart reviews (US cost model). In all three models, the efficacy was assumed to be equal, so a cost-minimization approach was used. Gemcitabine monotherapy showed cost savings compared with both cisplatin/etoposide and ifosfamide/etoposide in all treatment settings. The majority of these savings were due to differences in hospitalization for drug administration, and the incidence and treatment of nausea and vomiting and febrile neutropenia.

Objective: To validate the use of successive salivary caffeine tests in evaluating how long inducer drugs affect hepatic metabolism. The time course of the inducer effect of rifampin found in other studies using different methodologies was chosen as the time course of reference., Design: Open-label, prospective, longitudinal study., Setting: A university hospital., Participants: Five healthy volunteers., Main Outcome Measures: Rifampin 600 mg/d was administered for 21 days. Anhydrous caffeine 300 mg was concurrently administered on each study day. Salivary caffeine tests were carried out on the following days: predose (baseline), and days 1, 5, 9, 13, and 17. Salivary tests were performed for up to 13 days after the last dose of rifampin (study days 21, 25, 29, and 33)., Results: The mean systemic caffeine clearance was increased for up to 17 days after the intake of rifampin, reaching the maximum inducer effect between days 5 and 9, and returning to previous values progressively during several days after rifampin was discontinued., Conclusions: Our results suggest that successive salivary caffeine measurements could be a safe, reliable, noninvasive, and suitable test for exploring the time course of the inducer effect of drugs on hepatic metabolism activity.

In clinical practice is very important to know the time course of the inhibitory effects of drugs to avoid side effects when several agents are taken concomitantly. We attempted to validate the effectiveness of successive salivary caffeine tests establishing the time for cimetidine to inhibit hepatic metabolism. The time of cimetidine's inhibitory effect as reported in other studies was chosen as the reference. In this open-label, prospective longitudinal, 16-day study, five healthy volunteers were treated with cimetidine 1 g/day for 5 days. After the intake of caffeine 300 mg, salivary caffeine tests were carried out on days -1 (control value), 1, 4, 8, 12, and 16. The mean systemic caffeine clearance was decreased after 24 hours of cimetidine. The drug's maximum inhibitory effect was reached after 5 days of administration, returning to previous values progressively 1-7 days after discontinuing cimetidine. No change occurred in the apparent volume of distribution. The time course of cimetidine's inhibitory effect was similar to that described with other methodologies. Although this was a pilot trial and the results have to be confirmed, it seems that successive salivary caffeine measurements could be a safe, reliable, noninvasive test for exploring the time course of the inhibitory effects of drugs on hepatic metabolism.

On the basis of reports that diltiazem may bind to the hepatic microsomal enzymes and inhibits the metabolism of some co-administered drugs, and to determine the effects of diltiazem on theophylline pharmacokinetics in patients with bronchospastic airway disease, we have investigated the effect of a 180-mg daily dose of oral diltiazem during 5 days on theophylline clearance in eight patients with that disease. Theophylline half-life increased 24%, from 5.7 +/- 1 to 7.5 +/- 1.8 h (p < 0.05), and total body theophylline clearance showed a decrease of 22%, from 87.3 +/- 20 to 68.3 +/- 18.6 ml/min (p < 0.05) after diltiazem therapy. The apparent volume of distribution was unchanged. This reduction in theophylline clearance is likely produced by inhibition of its metabolism by diltiazem. A clinically important drug interaction may occur with theophylline when diltiazem therapy is given concurrently in patients with bronchospastic airway disease.

Twelve hospitalized adult patients received 300 mg of oral caffeine 1 h before a diagnostic lumbar puncture. Caffeine concentrations were determined simultaneously in saliva, plasma, and cerebrospinal fluid (CSF). Mean caffeine concentrations in plasma, saliva, and CSF were 5.9 +/- 2.1, 4.4 +/- 1.5, and 2.9 +/- 1.1 micrograms/ml, respectively, with coefficients of correlation plasma-saliva, saliva-CSF, and plasma-CSF of 0.89, 0.79, and 0.77, respectively, all statistically significant (p < 0.001).

We present the case of a woman undergoing treatment with acenocoumarol for deep vein thrombosis, who maintained an international normalized ratio (INR) of between 2.5 and 4 for 2 months. Seven days after the introduction of amoxycillin (500 mg/8 h) for a probable respiratory infection, the patient developed spontaneous bruising, with an INR of 7.1. Treatment with amoxycillin was discontinued, and 3 weeks later the INR had returned to previous values. In this case, the increase in the INR value with associated bruising after the addition of amoxycillin suggests a drug interaction between acenocoumarol and amoxycillin, other possible causes having been eliminated.

We have compared the whole blood concentrations of parent cyclosporin A (CsA) using monoclonal fluorescence polarization immunoassay (FPIA) and radioimmunoassay (RIA) as well as polyclonal FPIA in kidney, heart, and bone marrow transplant patients (n = 89). A good correlation was found between monoclonal FPIA and monoclonal RIA (r = 0.96) and a slightly worse one between polyclonal and monoclonal FPIA (r = 0.90). The interassay coefficient of variation was satisfactory for all the methods-less than 5% for monoclonal FPIA. The monoclonal FPIA assay with Abbott TDx appears to provide rapid, precise, and accurate measurement of parent CsA. It is therefore useful for therapeutic monitoring of CsA in whole blood in kidney, heart, and bone marrow transplant patients.

The TDx digoxin II immunoassay was used in controls and in patients not taking digoxin or any other cardiac glycoside. We report the frequency of interference thought to be caused by digoxin-like factors (DLFs). We found a high incidence of false-positive results in 15 patients with severe hepatic disease (60% false-positive results). In newborn infants we found false-positive results both when their blood was drawn from a peripheral vein (89% false-positive results) and, more strikingly (100% false-positive results), when it was obtained from an umbilical cord vein (p less than 0.001). Compared to a control group, no statistically significant false-positive results were found in patients with mild to moderate chronic renal failure (n = 21) or in pregnant women (n = 15). In patients with chronic renal failure undergoing hemodialysis six of 25 had false-positive results. These results suggest that digoxin levels must be interpreted carefully in patients with chronic liver disease and chronic renal failure and in newborns until new methods that eliminate the interference caused by DLFs become readily available.