Implementing pharmacogenetics in clinical trials: considerations about current methodological, ethical, and regulatory challenges.

INTRODUCTION: The implementation of pharmacogenetic analysis within clinical trials faces methodological, ethical, and regulatory challenges, as well as tackling the difficulty in obtaining actionable information with a sufficient level of evidence to enable its integration into routine clinical practice. AREAS COVERED: We discuss the current status of pharmacogenetics integration in clinical trials, underscore the associated challenges, and make some suggestions on the aspects to address in any clinical trial including a pharmacogenetic evaluation. We conducted a literature review, thoroughly reviewed the applicable regulations and available guidelines, and assessed the application dossiers submitted for evaluation to the Ethics committee of Hospital La Paz (Madrid, Spain) to extract information related to inclusion of pharmacogenetics evaluations. EXPERT OPINION: The integration of pharmacogenetics into clinical trials is becoming increasingly common. However, several regulatory, methodological and ethical aspects involved are insufficiently addressed. There is a need for specific and transparent guidelines that establish unified and compliant criteria for methodology, proper handling of samples in compliance with regulations, and the protection of data privacy and confidentiality. Participants should receive complete and appropriate information regarding the purpose, handling, storage, and transfer of their samples and data, and should have the right to decide about their processing.

Clinical research and drug regulation in the challenging times of individualized therapies: A pivotal role of clinical pharmacology.

Since the 1980s, medical specialists in Clinical Pharmacology have been playing a crucial role in the development of drug regulation in Spain. In this article we report on the activities carried out and the prospects for development in three very relevant areas from the regulatory perspective: 1) the development of stable public infrastructures to facilitate non-commercial clinical research with medicines, 2) the regulatory aspects of individual access to medicines in special situations, beyond their regular access after marketing approval and funding by the National Health System, and 3) the challenges of development and access to advanced therapies, with special reference to the figure of the hospital exemption.

Acute Poisoning Readmissions to an Emergency Department of a Tertiary Hospital: Evaluation through an Active Toxicovigilance Program.

The aim of this study is to investigate hospital readmissions during 1 year after acute poisoning cases (APC), analyze the temporal behavior of early readmissions (ER) (in the month after the index episode) and predict possible ER. A descriptive analysis of the patients with APC assisted between 2011 and 2016 in the Emergency Department of Hospital La Paz is presented, and various methods of inferential statistics were applied and confirmed by Bayesian analysis in order to evaluate factors associated with total and early readmissions. Out of the 4693 cases of APC included, 968 (20.6%) presented, at least one readmission and 476 (10.1%) of them were ER. The mean age of APC with readmission was 41 years (12.7 SD), 78.9% had previous psychiatric pathology and 44.7% had a clinical history of alcohol addiction. Accidental poisoning has been a protective factor for readmission (OR 0.50; 0.26-0.96). Type of toxin ("drug of abuse" OR 8.88; 1.17-67.25), history of addiction (OR 1.93; 1.18-3.10) and psychiatric history (OR 3.30; 2.53-4.30) are risk factors for readmissions during the first year. Women showed three or more readmissions in a year. The results of the study allow for identification of the predictors for the different numbers of readmissions in the year after the index APC, as well as for ERs.

Experience of a Strategy Including CYP2C19 Preemptive Genotyping Followed by Therapeutic Drug Monitoring of Voriconazole in Patients Undergoing Allogenic Hematopoietic Stem Cell Transplantation.

Many factors have been described to contribute to voriconazole (VCZ) interpatient variability in plasma concentrations, especially CYP2C19 genetic variability. In 2014, Hicks et al. presented data describing the correlation between VCZ plasma concentrations and CYP2C19 diplotypes in immunocompromised pediatric patients and utilized pharmacokinetic modeling to extrapolate a more suitable VCZ dose for each CYP2C19 diplotype. In 2017, in our hospital, a clinical protocol was developed for individualization of VCZ in immunocompromised patients based on preemptive genotyping of CYP2C19 and dosing proposed by Hicks et al., Clinical Pharmacogenetics Implementation Consortium (CPIC) clinical guidelines, and routine therapeutic drug monitoring (TDM). We made a retrospective review of a cohort of 28 immunocompromised pediatric patients receiving VCZ according to our protocol. CYP2C19 gene molecular analysis was preemptively performed using PharmArray®. Plasma trough concentrations were measured by immunoassay analysis until target concentrations (1-5.5 µg/ml) were reached. Sixteen patients (57.14%) achieved VCZ trough target concentrations in the first measure after the initial dose based on PGx. This figure is similar to estimations made by Hicks et al. in their simulation (60%). Subdividing by phenotype, our genotyping and TDM-combined strategy allow us to achieve target concentrations during treatment/prophylaxis in 90% of the CYP2C19 Normal Metabolizers (NM)/Intermediate Metabolizers (IM) and 100% of the Rapid Metabolizers (RM) and Ultrarapid Metabolizers (UM) of our cohort. We recommended modifications of the initial dose in 29% (n = 8) of the patients. In RM ≥12 years old, an increase of the initial dose resulted in 50% of these patients achieving target concentrations in the first measure after initial dose adjustment based only on PGx information. Our experience highlights the need to improve VCZ dose predictions in children and the potential of preemptive genotyping and TDM to this aim. We are conducting a multicenter, randomized clinical trial in patients with risk of aspergillosis in order to evaluate the effectiveness and efficiency of VCZ individualization: VORIGENIPHARM (EudraCT: 2019-000376-41).

Health Care Workers' Reasons for Choosing Between Two Different COVID-19 Prophylaxis Trials in an Acute Pandemic Context: Single-Center Questionnaire Study.

BACKGROUND: In April 2020, two independent clinical trials to assess SARS-CoV-2 prophylaxis strategies among health care workers were initiated at our hospital: MeCOVID (melatonin vs placebo) and EPICOS (tenofovir disoproxil/emtricitabine vs hydroxychloroquine vs combination therapy vs placebo). OBJECTIVE: This study aimed to evaluate the reasons why health care workers chose to participate in the MeCOVID and EPICOS trials, as well as why they chose one over the other. METHODS: Both trials were offered to health care workers through an internal news bulletin. After an initial screening visit, all subjects were asked to respond to a web-based survey. RESULTS: In the first month, 206 health care workers were screened and 160 were randomized. The survey participation was high at 73.3%. Health care workers cited "to contribute to scientific knowledge" (n=80, 53.0%), followed by "to avoid SARS-CoV-2 infection" (n=33, 21.9%) and "the interest to be tested for SARS-CoV-2" (n=28, 18.5%), as their primary reasons to participate in the trials. We observed significant differences in the expected personal benefits across physicians and nurses (P=.01). The vast majority of volunteers (n=202, 98.0%) selected the MeCOVID trial, their primary reason being their concern regarding adverse reactions to treatments in the EPICOS trial (n=102, 69.4%). CONCLUSIONS: Health care workers' reasons to participate in prophylaxis trials in an acute pandemic context appear to be driven largely by their desire to contribute to science and to gain health benefits. Safety outweighed efficacy when choosing between the two clinical trials.

Inhaled Methoxyflurane Provides Greater Analgesia and Faster Onset of Action Versus Standard Analgesia in Patients With Trauma Pain: InMEDIATE: A Randomized Controlled Trial in Emergency Departments.

STUDY OBJECTIVE: The objective of the InMEDIATE study was to evaluate the change in intensity of traumatic pain over the first 20 min in adult patients treated with methoxyflurane versus standard analgesic treatment in Spain. This the first randomized, active-controlled, multicenter trial of methoxyflurane in the emergency setting in Europe. METHODS: This was a randomized, controlled study that enrolled adult patients with acute moderate to severe (score ≥4 on the 11-point Numeric Rating Scale) trauma-associated pain in 14 Spanish emergency departments. Patients were randomized 1:1 to methoxyflurane (up to 2×3 mL) or standard analgesic treatment. Coprimary endpoints were the change from baseline in Numeric Rating Scale pain intensity score during the first 20 minutes of treatment and time to first pain relief. RESULTS: Three hundred five patients were randomized (methoxyflurane 156; standard analgesic treatment 149). Most patients in the standard analgesic treatment group (70%) received intravenous first-step analgesics and 9.4% of patients were treated with opioids. Mean decrease from baseline in Numeric Rating Scale pain intensity score was greater for methoxyflurane than standard analgesic treatment at all points, with a significant treatment difference overall up to 20 minutes (repeated-measures model 2.47 versus 1.39; treatment difference 1.00; 95% confidence interval 0.84 to 1.32). Median time to first pain relief was significantly shorter for methoxyflurane than standard analgesic treatment (3 versus 10 minutes). Methoxyflurane achieved better patient and clinician ratings for pain control and comfort of treatment than standard analgesic treatment and exceeded patient and clinician expectations of treatment in, respectively, 77% and 72% of cases compared with 38% and 19% for standard analgesic treatment. CONCLUSION: These results support consideration of methoxyflurane as a nonnarcotic, easy-to-administer, rapid-acting, first-line alternative to currently available analgesic treatments for trauma pain.

Eficiencia en el diagnóstico y tratamiento de la intoxicación aguda por paracetamol: análisis de costeefectividad a través de un programa de toxicovigilancia activa hospitalario / Efficient diagnosis and treatment of acute paracetamol poisoning: cost-effectiveness analysis of approaches based on a hospital toxicovigilance program

OBJETIVO: Evaluar la eficiencia de cinco estrategias diagnóstico-terapéuticas posibles ante la sospecha de intoxicación aguda (IA) por paracetamol (PCT) a través de un análisis coste-efectividad, según la perspectiva del financiador en un hospital universitario terciario dotado de un programa de toxicovigilancia activa validado (SAT-HULP). MÉTODO: Estudio de análisis de coste-efectividad (ACE) de cinco alternativas diagnóstico-terapéuticas consideradas en el abordaje de los pacientes atendidos en el servicio de urgencias hospitalario (SUH) con intoxicación por PCT mediante un modelo de árbol de decisión. La población estudiada fueron los pacientes atendidos en un SUH detectados por el SAT-HULP, entre el 1/04/2011 y el 31/01/2015. Las alternativas diagnóstico-terapéuticas consideradas fueron: 1) administración sistemática de Nacetilcisteína; 2) administración del tratamiento según la dosis confirmada; 3) tratamiento según el nomograma de Rümack Matthew; 4) tratamiento según test de orina confirmado con posterior test en sangre; y 5) tratamiento según el cálculo de la semivida. Los datos correspondientes a probabilidades fueron obtenidos del programa SAT-HULP y publicaciones sobre la validación de las pruebas diagnósticas. Se realizaron análisis de sensibilidad determinístico y probabilístico. RESULTADOS: Las opciones "Tratar según dosis comunicada" y "Tratar según el nomograma" son las que muestran mejor coste-efectividad. Al compararlas, la razón coste-efectividad incremental es de 5.985,37 Euros para la primera. El análisis de sensibilidad mostró una importante dependencia del modelo a la variación de las variables principales. En el análisis de sensibilidad probabilístico la estrategia "Tratar a todos los casos" respecto a "Cálculo de semivida" obtuvo una razón coste-efectividad incremental de unos 25.111,06 Euros (DE: 1.534.420,16; intervalo: -42.136,03 a 92.358,75), resultando esta última la más eficiente. CONCLUSIONES: La estrategia "Tratar según el nomograma" es la alternativa más eficiente en el diagnóstico y tratamiento de la intoxicacióna aguda por Paracetamol en nuestro medio, no así para un escenario de mayor prevalencia e incertidumbre, donde la opción "Cálculo de semivida" se muestra como la más eficiente

OBJECTIVE: To evaluate 5 diagnostic-therapeutic strategies for suspected acute paracetamol poisoning in terms of cost-effectiveness in a tertiary university hospital with an active, validated poisoning surveillance program (SAT-HULP). METHODS: Cost-effectiveness analysis of the 5 diagnostic-therapeutic alternatives considered when attending patients with suspected paracetamol poisoning. The alternatives were chosen by means of a decision tree. We studied patients detected by the SAT-HULP program between April 1, 2011, and January 31, 2015. The diagnostic-therapeutic alternatives were as follows: 1) systematic treatment of all patients with N-acetylcysteine (NAC), 2) NAC treatment according to the reported dose; 3) NAC treatment according to a Rümack-Matthew nomogram; 4) NAC treatment according to urine test results confirmed by a blood test, and 5) treatment according to elimination half-life calculation. Probability data were obtained from the SAT-HULP program and validation studies corresponding to the diagnostic tests. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: The approaches that were most cost-effective were those guided by reported doses and nomograms. The incremental cost-effectiveness of treatment according to reported dose was Euros 5985.37. The sensitivity analysis showed that the model was highly dependent on variations in the main variables; the probabilistic sensitivity analysis indicated an incremental cost-effectiveness of Euros 25 111.06 (SD, Euros 1 534 420.16; range, Euros 42 136.03-Euros 92 358.75) between the first approach (treat all cases) and last (calculate elimination half-life); half-life calculation was the more efficient. CONCLUSIONS: Treating according to nomogram was the most efficient diagnostic-therapeutic approach to treating paracetamol poisoning in our hospital. However, when the prevalence of paracetamol poisoning is higher and uncertainty is greater, it would be more efficient to treat based on calculating the half-life

Efficient diagnosis and treatment of acute paracetamol poisoning: cost-effectiveness analysis of approaches based on a hospital toxicovigilance program. / Eficiencia en el diagnóstico y tratamiento de la intoxicación aguda por paracetamol: análisis de costeefectividad a través de un programa de toxicovigilancia activa hospitalario.

OBJECTIVES: To evaluate 5 diagnostic-therapeutic strategies for suspected acute paracetamol poisoning in terms of cost-effectiveness in a tertiary university hospital with an active, validated poisoning surveillance program (SAT-HULP). MATERIAL AND METHODS: Cost-effectiveness analysis of the 5 diagnostic-therapeutic alternatives considered when attending patients with suspected paracetamol poisoning. The alternatives were chosen by means of a decision tree. We studied patients detected by the SAT-HULP program between April 1, 2011, and January 31, 2015. The diagnostic-therapeutic alternatives were as follows: 1) systematic treatment of all patients with N-acetylcysteine (NAC), 2) NAC treatment according to the reported dose; 3) NAC treatment according to a Rümack-Matthew nomogram; 4) NAC treatment according to urine test results confirmed by a blood test, and 5) treatment according to elimination half-life calculation. Probability data were obtained from the SAT-HULP program and validation studies corresponding to the diagnostic tests. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: The approaches that were most cost-effective were those guided by reported doses and nomograms. The incremental cost-effectiveness of treatment according to reported dose was €5985.37. The sensitivity analysis showed that the model was highly dependent on variations in the main variables; the probabilistic sensitivity analysis indicated an incremental cost-effectiveness of €25 111.06 (SD, €1 534 420.16; range, €42 136.03-€92 358.75) between the first approach (treat all cases) and last (calculate elimination half-life); half-life calculation was the more efficient. CONCLUSION: Treating according to nomogram was the most efficient diagnostic-therapeutic approach to treating paracetamol poisoning in our hospital. However, when the prevalence of paracetamol poisoning is higher and uncertainty is greater, it would be more efficient to treat based on calculating the half-life.

OBJETIVO: Evaluar la eficiencia de cinco estrategias diagnóstico-terapéuticas posibles ante la sospecha de intoxicación aguda (IA) por paracetamol (PCT) a través de un análisis coste-efectividad, según la perspectiva del financiador en un hospital universitario terciario dotado de un programa de toxicovigilancia activa validado (SAT-HULP). METODO: Estudio de análisis de coste-efectividad (ACE) de cinco alternativas diagnóstico-terapéuticas consideradas en el abordaje de los pacientes atendidos en el servicio de urgencias hospitalario (SUH) con intoxicación por PCT mediante un modelo de árbol de decisión. La población estudiada fueron los pacientes atendidos en un SUH detectados por el SAT-HULP, entre el 1/04/2011 y el 31/01/2015. Las alternativas diagnóstico-terapéuticas consideradas fueron: 1) administración sistemática de Nacetilcisteína; 2) administración del tratamiento según la dosis confirmada; 3) tratamiento según el nomograma de Rümack- Matthew; 4) tratamiento según test de orina confirmado con posterior test en sangre; y 5) tratamiento según el cálculo de la semivida. Los datos correspondientes a probabilidades fueron obtenidos del programa SAT-HULP y publicaciones sobre la validación de las pruebas diagnósticas. Se realizaron análisis de sensibilidad determinístico y probabilístico. RESULTADOS: Las opciones "Tratar según dosis comunicada" y "Tratar según el nomograma" son las que muestran mejor coste-efectividad. Al compararlas, la razón coste-efectividad incremental es de 5.985,37 € para la primera. El análisis de sensibilidad mostró una importante dependencia del modelo a la variación de las variables principales. En el análisis de sensibilidad probabilístico la estrategia "Tratar a todos los casos" respecto a "Cálculo de semivida" obtuvo una razón coste-efectividad incremental de unos 25.111,06 € (DE: 1.534.420,16; intervalo: ­42.136,03 a 92.358,75), resultando esta última la más eficiente. CONCLUSIONES: La estrategia "Tratar según el nomograma" es la alternativa más eficiente en el diagnóstico y tratamiento de la intoxicacióna aguda por Paracetamol en nuestro medio, no así para un escenario de mayor prevalencia e incertidumbre, donde la opción "Cálculo de semivida" se muestra como la más eficiente.

Limited sampling strategies for tacrolimus exposure (AUC0-24) prediction after Prograf(®) and Advagraf(®) administration in children and adolescents with liver or kidney transplants.

To develop limited sampling strategies (LSSs) to predict total tacrolimus exposure (AUC0-24 ) after the administration of Advagraf(®) and Prograf(®) (Astellas Pharma S.A, Madrid, Spain) to pediatric patients with stable liver or kidney transplants. Forty-one pharmacokinetic profiles were obtained after Prograf(®) and Advagraf(®) administration. LSSs predicting AUC0-24 were developed by linear regression using three extraction time points. Selection of the most accurate LSS was made based on the r(2) , mean error, and mean absolute error. All selected LSSs had higher correlation with AUC0-24 than the correlation found between C0 and AUC0-24 . Best LSS for Prograf(®) in liver transplants was C0_1.5_4 (r(2)  = 0.939) and for kidney transplants C0_1_3 (r(2)  = 0.925). For Advagraf(®) , the best LSS in liver transplants was C0_1_2.5 (r(2)  = 0.938) and for kidney transplants was C0_0.5_4 (r(2)  = 0.931). Excluding transplant type variable, the best LSS for Prograf(®) is C0-1-3 (r(2)  = 0.920) and the best LSS for Advagraf(®) was C0_0.5_4 (r(2)  = 0.926). Considering transplant type irrespective of the formulation used, the best LSS for liver transplants was C0_2_3 (r(2)  = 0.913) and for kidney transplants was C0_0.5_4 (r(2)  = 0.898). Best LSS, considering all data together, was C0_1_4 (r(2)  = 0.898). We developed several LSSs to predict AUC0-24 for tacrolimus in children and adolescents with kidney or liver transplants after Prograf(®) and/or Advagraf(®) treatment.

Conversion from Prograf to Advagraf in stable paediatric renal transplant patients and 1-year follow-up.

BACKGROUND: The conversion from Prograf to Advagraf on a 1:1 (mg:mg) basis has been questioned in light of the publication of studies showing a decrease in tacrolimus blood concentrations after the administration of Advagraf. METHODS: The bioavailability of Prograf and Advagraf was evaluated in an open-label conversion study in 21 stable renal transplant paediatric patients. Serial blood samples for determining tacrolimus levels were collected during a 24-h period before (on Prograf) and after (on Advagraf) conversion. Tacrolimus pharmacokinetic parameters were calculated using a non-compartmental approach and the relative bioavailability calculated. Clinical and analytical data were obtained at 30, 90, 180 and 360 days after study enrolment. RESULTS: The mean ratio and 90 % confidence interval (CI) for peak plasma drug concentration (C(max)) and the area under the time-concentration curve during the first 24 h (AUC(0-24)) were 81.54 (95 % CI 71.6-92.87) and 87.19 (95 % CI 79.91-95.13), respectively. Renal glomerular filtration rate remained stable over the course of the follow-up. Two patients presented clinical events unrelated to tacrolimus. Tacrolimus levels decreased in the first month, the dose/level ratio increased between months 1 and 6 and slight dose adjustments were required during the follow-up period. CONCLUSIONS: Our results show that Advagraf bioequivalence cannot be ensured in this population. Significant changes in tacrolimus levels and dose were observed on long-term follow-up.

Conversion from Prograf to Advagraf in adolescents with stable liver transplants: comparative pharmacokinetics and 1-year follow-up.

The recommended dose of Advagraf for conversion from Prograf is considered to be 1:1 on a milligram basis. However, the long-term equivalence of Prograf and Advagraf has been questioned. The relative bioavailability of Advagraf and Prograf was evaluated in a single-center, open-label study of Prograf-to-Advagraf conversion in 20 patients, ranging in age from 12 to 18 years, who had a stable liver transplant and were receiving Prograf. After the supervised administration of Prograf for 7 days, the patients were converted to Advagraf. On days 7 and 14, serial blood samples were obtained for tacrolimus determinations. The pharmacokinetic parameters were calculated with a noncompartmental approach, and the relative bioavailability of both formulations was calculated according to standard statistical methods. Polymorphisms in cytochrome P450 3A5 (rs776746), adenosine triphosphate-binding cassette B1 (rs1045642), POR*28 (rs1057868), and POR (rs2868177) were determined with standard methods. The clinical and analytical data from a 1-year follow-up period were collected for all patients 30, 90, 180, and 360 days after conversion. The mean ratios for Cmax and AUC0-24 were 96.9 (90% confidence interval = 85.37-110.19) and 100.1 (90% confidence interval = 90.8-112.1), respectively. No relationship was found between the patients' genotypes and the pharmacokinetic tacrolimus values. During the follow-up, biochemical parameters (aspartate aminotransferase, alanine aminotransferase, bilirubin, cystatin C, and creatinine) did not change significantly; 3 patients presented with relevant clinical events, but no event was considered to be related to tacrolimus. A decrease in tacrolimus blood levels and an increase in dose/level ratios were observed 3 and 6 months after conversion, but they returned to basal levels by month 12. In conclusion, conversion from Prograf to Advagraf with a 1:1 dose equivalence is appropriate as an initial guideline. Our 1-year follow-up showed a transient decrease in tacrolimus levels, so closer monitoring of tacrolimus levels may be required after conversion.

Outcome trials of COX-2 selective inhibitors: global safety evaluation does not promise benefits.

BACKGROUND: Gastrointestinal toxicity is the most frequent adverse effect associated with nonsteroidal anti-inflammatory drug use. The most clinically relevant side effects of this toxicity are ulcer complications, including perforation, obstruction, or bleeding. Selective cyclooxygenase (COX-2) inhibitors (coxibs) have been proposed as a safer alternative to traditional, nonsteroidal anti-inflammatory drugs and they are currently widely used in clinical practice. The aim of this review was to analyze the available evidence and then critically evaluate the outcome trials supporting the use of coxibs in terms of their clinical gastrointestinal benefits and global safety. METHODS: All published clinical trials on selective COX-2 inhibitors were identified by searching Medline, the World Wide Web (WWW), and abstracts in Congress proceedings. From these, we selected randomized trials that clinically evaluated relevant safety outcome measures. Papers only describing endoscopic evaluation were excluded. RESULTS: Our search yielded three outcome trials and two pooled safety analyses. The outcome studies supporting the gastrointestinal and global safety of coxibs were found to be biased in their design, analysis, and dissemination, and interpretation of a clinical benefit. Cost considerations would make the use of coxibs acceptable only in patients at high gastrointestinal risk. CONCLUSIONS: The association of the reduced gastroerosive potential of coxibs with improved meaningful outcomes is debatable. Bias in the design of the trials, selection of outcome measures, post-hoc changes in analysis and the variables used, as well as flaws in the publication and reporting of trial results cast serious doubts on the gastrointestinal and global safety profile of coxibs. In addition, their high cost and the lack of clear identification of patients that would benefit most from treatment means the effectiveness of these drugs is uncertain at the moment.