Clinical pharmacology facing the real-world setting: Pharmacovigilance, pharmacoepidemiology and the economic evaluation of drugs.

Traditionally, clinical pharmacology has focused its activities on drug-organism interaction, from an individual or collective perspective. Drug efficacy assessment by performing randomized clinical trials and analysis of drug use in clinical practice by carrying out drug utilization studies have also been other areas of interest. From now on, Clinical pharmacology should move from the analysis of the drug-individual interaction to the analysis of the drug-individual-society interaction. It should also analyze the clinical and economic consequences of the use of drugs in the conditions of normal clinical practice, beyond clinical trials. The current exponential technological development that facilitates the analysis of real-life data offers us a golden opportunity to move to all these other areas of interest. This review describes the role that clinical pharmacology has played at the beginning and during the evolution of pharmacovigilance, pharmacoepidemiology and economic drug evaluations in Spain. In addition, the challenges that clinical pharmacology is going to face in the following years in these three areas are going to be outlined too.

Clinical research and medical care: towards effective and complete integration.

BACKGROUND: Despite their close relationship, clinical research and medical care have become separated by clear boundaries. The purpose of clinical research is to generate generalizable knowledge useful for future patients, whereas medical care aims to promote the well-being of individual patients. The evolution towards patient-centered medicine and patient-oriented research, and the gradual standardization of medicine are contributing to closer ties between clinical research and medical practice. But the integration of both activities requires addressing important ethical and methodological challenges. DISCUSSION: From an ethical perspective, clinical research should evolve from a position of paternalistic beneficence to a situation in which the principle of non-maleficence and patient autonomy predominate. The progressive adoption of "patient-oriented informed consent", "patient equipoise", and "altruism-based research", and the application of risk-based ethical oversight, in which the level of regulatory scrutiny is adapted to the potential risk for patients, are crucial steps to achieve the integration between research and care. From a methodological standpoint, careful and systematic observations should have greater relevance in clinical research, and experiments should be embedded into usual clinical practice. Clinical research should focus on individuals through the development of patient-oriented research. In a complementary way, the integration of experiments into medical practice through the systematic application of "point of care research" could help to generate knowledge for the individuals and for the populations. SUMMARY: The integration of clinical research and medical care will require researchers, clinicians, health care managers, and patients to reevaluate the way they understand both activities. The development of an integrated learning health care system will contribute to generating and applying clinically relevant medical knowledge, producing benefits for present and future patients.

Long-acting olanzapine versus long-acting risperidone for schizophrenia in Spain - a cost-effectiveness comparison.

BACKGROUND: In schizophrenia, medication adherence is critical to achieve better patient outcomes and to avoid relapses, which are responsible for a significant proportion of total healthcare costs for this chronic illness. The aim of this study was to assess the cost-effectiveness of olanzapine long-acting injection (OLAI) compared with risperidone long-acting injection (RLAI) in patients with schizophrenia in Spain. METHODS: A discrete event simulation (DES) model was developed from a Spanish healthcare system perspective to estimate clinical and economic outcomes for patients with schizophrenia over a five-year period. Patients who had earlier responded to oral medication and have a history of relapse due to adherence problems were considered. Identical model populations were treated with either OLAI or RLAI. In the absence of a head-to-head clinical trial, discontinuation and relapse rates were obtained from open-label studies. The model accounted for age, gender, risks of relapse and discontinuation, relapse management, hospitalization, treatment switching and adverse events. Direct medical costs for the year 2011 and outcomes including relapse avoided, life years (LYs), and quality-adjusted life years (QALYs) were discounted at a rate of 3%. RESULTS: When comparing RLAI and OLAI, the model predicts that OLAI would decrease 5-year costs by €2,940 (Standard Deviation between replications 300.83), and result in a QALY and LY gains of 0.07 (SD 0.019) and 0.04 (SD 0.025), respectively. Patients on OLAI had fewer relapses compared to RLAI (1.392 [SD 0.035] vs. 1.815 [SD 0.035]) and fewer discontinuations (1.222 [SD 0.031] vs. 1.710 [SD 0.039]). Sensitivity analysis indicated that the study was robust and conclusions were largely unaffected by changes in a wide range of parameters. CONCLUSIONS: The present evaluation results in OLAI being dominant over RLAI, meaning that OLAI represents a more effective and less costly alternative compared to RLAI in the treatment of patients with schizophrenia in the Spanish setting.

Patient-centered medicine and patient-oriented research: improving health outcomes for individual patients.

BACKGROUND: Patient-centered medicine is developing alongside the concepts of personalized medicine and tailored therapeutics. The main objective of patient-centered medicine is to improve health outcomes of individual patients in everyday clinical practice, taking into account the patient's objectives, preferences, values as well as the available economic resources. DISCUSSION: Patient-centered medicine implies a paradigm shift in the relationship between doctors and patients, but also requires the development of patient-oriented research. Patient-oriented research should not be based on the evaluation of medical interventions in the average patient, but on the identification of the best intervention for every individual patient, the study of heterogeneity and the assignment of greater value to observations and exceptions. The development of information-based technologies can help to close the gap between clinical research and clinical practice, a fundamental step for any advance in this field. SUMMARY: Evidence-based medicine and patient centered medicine are not contradictory but complementary movements. It is not possible to practice patient-centered medicine that is not based on evidence, nor is it possible to practice evidence-based medicine at a distance from the individual patient.

Exploratory trials, confirmatory observations: a new reasoning model in the era of patient-centered medicine.

BACKGROUND: The prevailing view in therapeutic clinical research today is that observational studies are useful for generating new hypotheses and that controlled experiments (i.e., randomized clinical trials, RCTs) are the most appropriate method for assessing and confirming the efficacy of interventions. DISCUSSION: The current trend towards patient-centered medicine calls for alternative ways of reasoning, and in particular for a shift towards hypothetico-deductive logic, in which theory is adjusted in light of individual facts. A new model of this kind should change our approach to drug research and development, and regulation. The assessment of new therapeutic agents would be viewed as a continuous process, and regulatory approval would no longer be regarded as the final step in the testing of a hypothesis, but rather, as the hypothesis-generating step. The main role of RCTs in this patient-centered research paradigm would be to generate hypotheses, while observations would serve primarily to test their validity for different types of patients. Under hypothetico-deductive logic, RCTs are considered "exploratory" and observations, "confirmatory". SUMMARY: In this era of tailored therapeutics, the answers to therapeutic questions cannot come exclusively from methods that rely on data aggregation, the analysis of similarities, controlled experiments, and a search for the best outcome for the average patient; they must also come from methods based on data disaggregation, analysis of subgroups and individuals, an integration of research and clinical practice, systematic observations, and a search for the best outcome for the individual patient. We must look not only to evidence-based medicine, but also to medicine-based evidence, in seeking the knowledge that we need.

Individual point-of-care trials: a new approach to incorporate patient's preferences into personalized pragmatic clinical trials.

Although Evidence-based medicine (EBM) and Patient-centered medicine (PCM) are often perceived as two conflicting paradigms that speak the language of populations and the language of individuals, respectively, both share the common objective of improving the care of individual patients. As physicians should not practice an EBM that is away from the individual patient nor a PCM that is not based on the best available evidence, it is crucial to connect and combine both movements, promoting the fruitful and natural interaction between research and care. Achieving such interaction requires developing new individual-patient centric research methods. In this commentary, we propose an innovative clinical research design oriented to personalize point-of-care trials-integrating clinical research and medical care-through the incorporation of individual patients' preferences to build personalized research protocols. Building on the framework of N-of-1 studies, in "individual point-of-care trials," each protocol could be personalized for each patient so that the therapeutic objectives, the outcome variables analyzed, and the (operationalization of the) compared interventions would be based not only on the clinical and biological characteristics of each patient but also on their individual preferences, goals, and values. If patient preferences are being progressively integrated into medical practice, it makes sense that they also are incorporated into clinical trials embedded in care delivery. The proposal to perform individual point of care trials may be an optimal way to combine EBM and PCM while preserving their foundational principles, and to ensure the connection between "personalized" and "personal" care.

Treat-To-Target and Treat-To-Budget in Rheumatoid Arthritis: Measuring the Value of Individual Therapeutic Interventions.

Treat-to-target (T2T) and dose tapering after obtaining the therapeutic objective (called "treat-to-budget"-T2B-in this Commentary) are the two most commonly used therapeutic strategies in rheumatoid arthritis. In theory, both strategies could add value to the healthcare system, although they are focused on different objectives: T2T strategy improves outcomes but increases short-term costs, while the cost savings obtained through T2B are associated with higher relapse rates. The systematic implementation of both strategies must be founded on solid evidence of their effectiveness and efficiency. However, the level of evidence between guidelines and individual studies is inconsistent for both strategies and the number and the quality of cost-effectiveness analyses is scarce. Raising the level of evidence requires a move from generalization to individualization by conducting randomized clinical trials that assess each of the many strategies that fall under the umbrella of the overall T2T and T2B concepts. In addition, such studies should consider the therapeutic goals and impact of the disease from the perspective of individual patients, which is only possible by promoting shared decision-making. FUNDING: Lilly Spain.

Should clinically meaningful outcomes in cancer be based on individual survival rather than median overall survival?

AIM: To assess whether the use of median overall survival to define clinically meaningful outcomes in the area of oncology could yield different decisions compared with those obtained with a more realistic measure such as individual survival. METHODS: Two scenarios that offered equivalent health gains/money spent were presented: 'median overall survival' scenario (new treatment provided small clinical benefits for the average population) and 'individual survival'scenario (new treatment provided substantial clinical benefits for a small percentage of the patients and no benefits for the rest). Responses from both scenarios were compared. RESULTS: Responses between the two scenarios were different for oncologists, healthcare policy makers and patients (p < 0.05). 'Individual survival' scenario obtained higher percentage of positive answers compared with 'median overall survival'. CONCLUSION: Expressing the benefits of new oncologic treatments in terms of 'individual survival' may yield to different healthcare decisions compared with the widely used median overall survival.

Patient involvement in clinical research: why, when, and how.

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.

Do new cancer drugs offer good value for money? The perspectives of oncologists, health care policy makers, patients, and the general population.

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.

Perceptions of Oncologists, Healthcare Policy Makers, Patients and the General Population on the Value of Pharmaceutical Treatments in Oncology.

INTRODUCTION: The purpose of this study was to explore the main factors explaining the relative weight of the different attributes that determine the value of oncologic treatments from the different perspectives of healthcare policy makers (HCPM), oncologists, patients and the general population in Spain. METHODS: Structured interviews were conducted to assess: (1) the importance of the attributes on treatment choice when comparing a new cancer drug with a standard cancer treatment; (2) the importance of survival, quality of life (QoL), costs and innovation in cancer; and (3) the most worrying side effects related to cancer drugs. RESULTS: A total of 188 individuals participated in the study. For all participants, when choosing treatments, the best rated characteristics were greater efficacy, greater safety, treatment adaptation to patients' individual requirements and the rapid reincorporation of patients to their daily activities. There were important differences among participants in their opinion about survival, QoL and cost. In general, oncologists, patients, and the general population gave greater value to gains in QoL than healthcare policy makers. Compared to other participants healthcare policy makers gave greater importance to the economic impact related to oncology treatments. CONCLUSIONS: Gains in QoL, survival, safety, cost and innovation are perceived differently by different groups of stakeholders. It is recommended to consider the perspective of different stakeholders in the assessment of a new cancer drugs to obtain more informed decisions when deciding on the most appropriate treatment to use. FUNDING: Eli Lilly & Co, Madrid (Spain).

What is the value of social values? The uselessness of assessing health-related quality of life through preference measures.

BACKGROUND: The use of preference-based measures in the evaluation of health outcomes has extended considerably over the last decade. Their alleged advantage over other types of general instruments in the evaluation of health related quality of life (HRQOL), supposedly lies in the fact that preference measures incorporate values or utilities that reflects the value of social preferences through health states. The objective of this study was to determine whether the use of social preference weights or utilities makes any real difference when calculating scores for the Euroqol (EQ5-D) questionnaire, a HRQOL preference-based measure. METHODS: Responses to the EQ5-D of a sample of 10,972 patients from 10 countries enrolled in an observational study of the treatment of schizophrenia in Europe were used for this purpose. Two different methods of scoring the EQ-5D where compared: 'weighting the items' of the questionnaire through the UK official weight coefficients, and 'non-weighting the items'. Pearson's, Spearman's, and two-way mixed parametric intraclass correlation coefficients were used to estimate the association of the scores obtained in both ways. RESULTS: The association between weighted and unweighted Euroqol scores was extremely high (Pearson's r = 0.91), as was the association between their ranks (Spearman's rho = 0.93). The intraclass correlation coefficient obtained (0.89) also suggested that the concordance between the score distributions was prominent. CONCLUSIONS: A non-weighted approach to score the EQ5-D is enough to explain a high proportion of variance in scores obtained through the use of utilities. The differential contribution of weights based on population preference values is therefore minimal and, in our opinion, negligible.

Problems and solutions in calculating quality-adjusted life years (QALYs).

The quality-adjusted life-year (QALY) is a measure of the value of health outcomes. Since health is a function of length of life and quality of life, the QALY was developed as an attempt to combine the value of these attributes into a single index number. The QALY calculation is simple: the change in utility value induced by the treatment is multiplied by the duration of the treatment effect to provide the number of QALYs gained. QALYs can then be incorporated with medical costs to arrive at a final common denominator of cost/QALY. This parameter can be used to compare the cost-effectiveness of any treatment. Nevertheless, QALYs have been criticised on technical and ethical grounds. A salient problem relies on the numerical nature of its constituent parts. The appropriateness of the QALY arithmetical operation is compromised by the essence of the utility scale: while life-years are expressed in a ratio scale with a true zero, the utility is an interval scale where 0 is an arbitrary value for death. In order to be able to obtain coherent results, both scales would have to be expressed in the same units of measurement. The different nature of these two factors jeopardises the meaning and interpretation of QALYs. A simple general linear transformation of the utility scale suffices to demonstrate that the results of the multiplication are not invariant. Mathematically, the solution to these limitations happens through an alternative calculation of QALYs by means of operations with complex numbers rooted in the well known Pythagorean theorem. Through a series of examples, the new calculation arithmetic is introduced and discussed.

[Cost-effectiveness of drotrecogin alpha [activated] in the treatment of severe sepsis in Spain]. / Coste-efectividad de drotrecogina alfa (activada) en el tratamiento de la sepsis grave en España.

INTRODUCTION: The PROWESS clinical trial has shown that treatment with drotrecogin alpha (activated) in patients with severe sepsis is associated with a reduction in the absolute risk of death compared with standard treatment. The aim of the present study was to assess the cost-effectiveness of drotrecogin alpha (activated) versus that of standard care in the treatment of severe sepsis in Spain. PATIENTS AND METHODS: A decision analysis model was drawn up to compare costs to hospital discharge and the long-term efficacy of drotrecogin alpha (activated) versus those of standard care in the treatment of severe sepsis in Spain from the perspective of the health care payer. Most of the information for creating the model was obtained from the PROWESS clinical trial. A two-fold baseline analysis was performed: a) for all patients included in the PROWESS clinical trial and b) for the patients with two or more organ failures. The major variables for clinical assessment were the reduction in mortality and years of life gained (YLG). Cost-effectiveness was expressed as cost per YLG. A sensitivity analysis was applied using 3% and 5% discount rates for YLG and by modifying the patterns of health care, intensive care unit costs, and life expectancy by initial co-morbidity and therapeutic efficacy of drotrecogin alpha (activated). RESULTS: Treatment with drotrecogin alfa (activated) was associated with a 6.0% drop in the absolute risk of death (p = 0.005) when all of the patients from the PROWESS trial were included and with a 7.3% reduction (p = 0.005) when the analysis was restricted to patients with two or more organ failures. The cost-effectiveness of drotrecogin alfa (activated) was 13,550 euros per YLG with respect to standard care after analysing all of the patients and 9,800 euros per YLG in the group of patients with two or more organ failures. In the sensitivity analysis, the results ranged from 7,322 to 16,493 euros per YLG. The factors with the greatest impact on the results were the change in the efficacy of drotrecogin alfa (activated), adjustment of survival by initial co-morbidity and the application of discount rates to YLG. CONCLUSIONS: Treatment with drotrecogin alfa (activated) presents a favorable cost-effectiveness ratio compared with other health care interventions commonly used in Spain.

Which nontraditional outcomes should be measured in healthcare decision-making in schizophrenia? A systematic review.

PURPOSE: This article aims to define the utility of nontraditional outcomes (NTOs) in healthcare decision-making in schizophrenia. DESIGN AND METHODS: A systematic review of studies published between January 1, 1996, and December 31, 2008, was performed. A 10-point evidence-based utility index (UI) was used to assess the utility of NTOs: high (UI: 7.5-10), medium (UI: ≥ 5 to <7.5), and low (UI: <5) utility. FINDINGS: Of 736 citations identified, 94 met inclusion criteria. One hundred ninety-four NTOs were identified (patient reported outcomes [38.7%] and economic outcomes [61.3%]). Of these, 68 (35.1%) were appropriate for decision making. PRACTICE IMPLICATIONS: Numerous NTOs with low utility in schizophrenia are being used for healthcare policy and clinical care by policy makers, managers, and healthcare professionals. Medium and low utility NTOs should be used with caution.