[The European Medicines Agency rejects the authorization of aducanumab for Alzheimer's disease]. / La Agencia Europea de Medicamentos rechaza la autorización del aducanumab para la enfermedad de Alzheimer.

TITLE: La Agencia Europea de Medicamentos rechaza la autorización del aducanumab para la enfermedad de Alzheimer.

[Aducanumab approval for Alzheimer's disease in the USA: the surrender of science]. / Aprobación del aducanumab para la enfermedad de Alzheimer en Estados Unidos: la claudicación de la ciencia.

TITLE: Aprobación del aducanumab para la enfermedad de Alzheimer en Estados Unidos: la claudicación de la ciencia.

Potential predatory journals are colonizing the ICMJE recommendations list of followers.

BACKGROUND: The International Committee of Medical Journal Editors (ICMJE) has expressed its concerns about predatory journals using the list of ICMJE Recommendations (ICMJE-R) followers to "gain the appearance of legitimacy." We assessed the presence of potential predatory journals on the ICMJE-R list and their adherence to ICMJE recommendations. METHODS: A random sample of 350 journals from the estimated 3,100-3,200 biomedical journals listed as ICMJE-R followers was chosen. Data collected from the ICMJE and journal webpages in English were: adherence to six ICMJE-R policies/requirements, year of journal's listing as ICMJE-R follower, discipline covered, publisher and its country of origin and existence of article processing charge. Potential predatory journal was considered as one open access journal not being a member of a recognized listing in COPE, DOAJ, OASPA, AJOL and/or INASP. RESULTS: Thirty-one percent of journals were considered to be potentially predatory; 94% of them were included in the ICMJE-R list in 2014-2018. Half were published in the United States and 62% were devoted to medicine. Adherence to five of the six policies/requirements was infrequent, ranging from 51% (plagiarism) to 7% (trial registration). Seventy-two percent of journals mentioned a policy on authors' conflicts of interest. Information on article processing charge was available for 76% journals and could not be found for 22%. Authorship policy/ instructions were significantly more present in journals with publishers from India than from the USA (53% vs 30%; p = 0.047), with no differences in the other five policies. CONCLUSION: Predatory journals should be deleted from the ICMJE-R list of followers to prevent misleading authors. ICMJE-R following journals need to be reevaluated with pre-defined published criteria.

[Easing access to all information should be mandatory to medical journals]. / Facilitar el acceso a toda la informacion debe ser una obligacion para las revistas medicas.

TITLE: Facilitar el acceso a toda la informacion debe ser una obligacion para las revistas medicas.

[Patients organizations and new drug approval in the US. Eteplirsen and Duchenne muscular dystrophy case]. / Asociaciones de pacientes y autorizacion de nuevos farmacos en Estados Unidos. El caso del eteplirseno para la distrofia muscular de Duchenne.

INTRODUCTION: In 2016 the US Food and Drug Administration (FDA) granted the marketing authorization for eteplirsen for Duchenne muscular dystrophy. This has been a very controversial decision since it happened after a negative assessment from both the Advisory Committee and the technical FDA evaluation team. The FDA's Center for Drug Evaluation and Research (CDER) director was who ultimately approved the product, while the FDA Commissioner did not overrule that decision. AIM: To report about the most relevant events regarding the approval of eteplirsen by the US FDA. DEVELOPMENT: All relevant facts that occurred during the clinical development and evaluation phase following 'accelerated approval' procedure of eteplirsen are discussed in detail. The technical FDA evaluation team reasons supporting that the drug has not proven clinical benefit, the attitude of patient advocacy groups and the post-approval FDA requirements to the marketing authorization holder are discussed. Finally, we reflect on what is the situation Spanish patients face once eteplirsen is on the US market. CONCLUSIONS: This is a unique case in the history of drug authorizations in western countries, that shows the difficulties that current regulations on accelerated approval of new medicines could have when interpreting scarce and low quality clinical development data, when dealing with rare diseases with no available therapies.

TITLE: Asociaciones de pacientes y autorizacion de nuevos farmacos en Estados Unidos. El caso del eteplirseno para la distrofia muscular de Duchenne.Introduccion. En 2016, la Agencia de Medicamentos y Alimentos (FDA) estadounidense autorizo la comercializacion del eteplirseno para el tratamiento de la distrofia muscular de Duchenne. Este hecho ha sido muy controvertido, por cuanto la autorizacion se produjo tras una evaluacion negativa por parte del comite asesor de la FDA y de sus propios tecnicos. Fue la directora del Centro de Investigacion y Evaluacion de Farmacos quien autorizo el medicamento, decision que no revoco el director de la FDA. Objetivo. Informar sobre los acontecimientos mas relevantes que han conducido a la autorizacion del eteplirseno por la FDA. Desarrollo. En el articulo se exponen pormenorizadamente los hechos relevantes que acontecieron durante el desarrollo clinico y la evaluacion reguladora del eteplirseno siguiendo la via de la 'autorizacion acelerada'. Se comentan las razones por las que los tecnicos de la FDA entienden que este medicamento no ha mostrado producir beneficio clinico, la actitud de las asociaciones de pacientes y las exigencias postautorizacion que la FDA ha impuesto a la compañia propietaria del medicamento. Por ultimo, se reflexiona sobre la situacion en que quedan los pacientes espanoles una vez que el eteplirseno esta comercializado en Estados Unidos. Conclusiones. Este caso, unico en la historia de autorizacion de medicamentos en el mundo occidental, pone de manifiesto las dificultades que las regulaciones actuales de autorizacion acelerada de nuevos medicamentos pueden tener en la interpretacion de datos del desarrollo clinico, cuando estos son escasos y de poca calidad, y cuando se trata de enfermedades raras sin terapias disponibles.

The cohabitation of academia and industry: What position do the medical journals take regarding opinion articles? / La cohabitación de la academia y la industria: ¿qué postura toman las revistas médicas en relación con los artículos de opinión?

Should medical journals publish editorials and educational articles written by authors who have financial conflicts of interest with pharmaceutical and biotechnology industries on whose products (or their competitors) they discuss? In the last 18 months, a controversy was sparked between The New England Journal of Medicine and BMJ, who took 2 opposite positions: the former stated that the negative bias against authors with conflicts of interest with industry is excessive and therefore accept articles from any expert, ensuring that they have the minimum possible bias. BMJ, in contrast, prohibits the publication of these types of article by authors who have financial conflicts of interest with industry. This article discusses the approaches of the 2 journals (and those of others) and reflects on this type of conflict in the medical profession.

If the results of an article are noteworthy, read the entire article; do not rely on the abstract alone. / Si le llaman la atención los resultados de un artículo, léalo completo, no se fíe solo del resumen.

Clinicians typically update their knowledge by reading articles on the Internet. Easy access to the articles' abstracts and a lack of time to access other information sources creates a risk that therapeutic or diagnostic decisions will be made after reading just the abstracts. Occasionally, however, the abstracts of articles from clinical trials that have not obtained statistically significant differences in the primary study endpoint have reported other positive results, for example, of a secondary endpoint or a subgroup analysis. The article, however, correctly reports all results, including those of the primary endpoint. In the abstract, the safety information of the experimental treatment is usually deficient. The whole article should be read if a clinical decision is to be made.

Management and return of incidental genomic findings in clinical trials.

Whole-genome/exome sequencing used in clinical trials (CTs) to identify 'druggable' mutations and targets uncovers incidental findings unrelated to the trial objectives but of value for participants, although ethically challenging. To be disclosed to trial participants, the analytical validity, clinical validity, clinical utility, clinical relevance and actionability of incidental genomic findings (IGFs) must be established. Special considerations should be taken with minors to disclose only those findings related to early-onset conditions or diseases and in cases where early implementation of measures is necessary to prevent the occurrence of diseases. A plan for disclosing incidental findings that classifies the types that can be found, and who, when and how these findings will be disclosed to participants, should be included in the trial protocol to be approved by the relevant institutional review board. IGFs in CTs raise new ethical challenges that must be discussed by CT stakeholders, professional associations and patient advocates.

Therapeutic misconception in clinical trials: fighting against it and living with it. / El equívoco terapéutico en los ensayos clínicos: combatirlo y convivir con él.

A clinical trial seeks information for the benefit of future patients and not necessarily for those who participate in the study. However, there are patients who believe that they will receive a direct therapeutic benefit by participating in a clinical trial, the so-called «therapeutic misconception¼. In this article, we describe the nature and extent of therapeutic misconception, which researchers can also experience. Its presence is especially important in phase 1 oncology trials and those with placebo group. To limit its occurrence, investigators have to ensure that participant information sheet are well written and to establish an effective and transparent discussion during the process of obtaining informed consent so that patients understand all aspects of their participation in the research and appreciate what this participation entails.

Clinical trials with drugs? Based on 2 projects in Alzheimer's disease and malaria.

The biomedical research act (BRA) regulates clinical research in humans, but not that related to clinical trials with medicinal products. This article describes the scientific and regulatory foundations supporting 2 projects which could be observed as clinical trials, can follow the BRA requirements. One is a positron emission tomography study with radiopharmaceutical to determine the presence of amyloid-ß protein deposition in certain areas of the brain of cognitively healthy adults. The other is a study on controlled malaria infection in healthy volunteers using the inoculation of aseptic, purified and cryopreserved Plasmodium falciparum sporozoites. Since in both studies subjects undergo invasive procedures, the BRA requires the approval of the study by the relevant regional health authorities. These 2 studies have been the first ones that have used this regulatory procedure in Catalonia.

Association of common genetic variants with risperidone adverse events in a Spanish schizophrenic population.

Risperidone non-compliance is often high due to undesirable side effects, whose development is in part genetically determined. Studies with genetic variants involved in the pharmacokinetics and pharmacodynamics of risperidone have yielded inconsistent results. Thus, the aim of this study was to investigate the putative association of genetic markers with the occurrence of four frequently observed adverse events secondary to risperidone treatment: sleepiness, weight gain, extrapyramidal symptoms and sexual adverse events. A series of 111 schizophrenia inpatients were genotyped for genetic variants previously associated with or potentially involved in risperidone response. Presence of adverse events was the main variable and potential confounding factors were considered. Allele 16Gly of ADRB2 was significantly associated with a higher risk of sexual adverse events. There were other non-significant trends for DRD3 9Gly and SLC6A4 S alleles. Our results, although preliminary, provide new candidate variants of potential use in risperidone safety prediction.

Ethical problems arising from the use of placebo in clinical trials with drugs for migraine. Their analysis by the moral deliberation method.

INTRODUCTION: Migraine is characterised as episodes of headache plus a variety of accompanying symptoms. Its pharmacological control remains unsatisfactory for some patients. The use of placebo in drug clinical trials on migraine commonly leads to numerous ethical uncertainties. METHODS: The purpose of this paper is to illustrate how the deliberation method helps in analysing the issues and finding solutions to selected ethical problems. Ethical decisions that try to solve conflicts arising from placebo use in clinical trials may be adopted using the moral deliberation method. Thus, the conflict is systematically assessed by identifying the following: Relevant facts; Values in conflict; Duties, or in other words, possible courses of action. Moral duty is following the optimal course of action. To identify this, it is recommended to state extreme courses of action, then intermediate courses of action, and then to proceed to the optimal course(s) of action. RESULTS AND CONCLUSIONS: In this paper, the application of this method is shown in several conflicting situations arising in two placebo-controlled clinical trials with drugs under development for the prophylaxis and acute treatment of migraine.

Prevalence of HLA-B*5701 in HIV-infected patients in Spain (results of the EPI Study).

BACKGROUND: A hypersensitivity reaction (HSR) is associated with abacavir (ABC), a nucleoside reverse transcriptase inhibitor. Genetic association of ABC HSR with the presence of HLA-B*5701 has been demonstrated in PREDICT-1 study, showing a prevalence of 5.6% in HIV-infected population. However the prevalence of this allele in HIV-infected patients in Spain has not been established yet. METHOD: This is a cross-sectional epidemiological study that included 1,198 patients in 74 centers that serve the HIV-infected population of Spain. HLA-B*5701 was checked both in the hospital lab and one central lab, showing an overall prevalence of this allele of 6%. RESULTS: HLA-B*5701 was most prevalent in Caucasian population (6.5%). Concordance between the local and central lab was very high for positive and negative results (95.7% and 99.3%, respectively). CONCLUSION: These aspects define this test as a useful tool for the management of HIV-infected patients.

Drug development: assessment of pharmacogenetic studies by Spanish research ethics committees.

The decision taken by research ethics committees (RECs) while assessing pharmacogenetic (PGx) substudies as part of international clinical trials is almost unknown. A total of 255 applications of 36 PGx substudies embedded in clinical trials (12 phase 2, 24 phase 3) were submitted to 72 RECs in 2006-2007 by GlaxoSmithKline in Spain. These were trials of 17 different compounds, aimed to be conducted in the five continents. Of the 255 applications, 226 (89%) were directly approved by RECs without raising any queries to the sponsor; 1% (3/255) were plainly rejected by two RECs. The rest (10%) were followed by 64 queries asked by 16 RECs on 25 PGx substudies. Following responses from the sponsor, all but two applications were approved. Thus, the RECs involved finally approved 98% (250/255) of the submitted applications. The requirements specifically raised by two RECs (PGx samples to be transferred to a public biobank or alternatively destroyed immediately, or storage permitted only 5 years after the trial is concluded) could not be met by the sponsor. It can be inferred from the results obtained that ethical and scientific standards implemented by the sponsor in the design, conduct and sample management of PGx substudies satisfied the vast majority (70/72; 97%) of RECs involved in this study.

Factors impacting on length of stay and mortality of community-acquired pneumonia.

A 1-year retrospective multicentre study was performed to identify factors influencing hospital length of stay (LOS) and mortality of patients (n = 3233) admitted to hospital because of community-acquired pneumonia (CAP). Pneumonia severity index (PSI) high-risk classes (IV and V), positive blood culture, admission to an intensive care unit (ICU), multi-lobar involvement and alcohol consumption were associated independently with prolonged LOS. Tobacco smoking was associated with a reduced LOS. The LOS varied markedly among centres. Only PSI high-risk class, admission to ICU and multi-lobar involvement were associated with early, late and global mortality. Positive blood cultures, antimicrobial therapy according to treatment guidelines and the establishment of an aetiological diagnosis were linked to reduced late and global mortality. These data suggest that early mortality associated with CAP is highly dependent on the clinical status of the patient at presentation. Conversely, late mortality seems to be associated more closely with clinical management factors; hence, an aetiological diagnosis and compliance with appropriate therapeutic guidelines have a significant influence on outcome.

When should re-consent of subjects participating in a clinical trial be requested? A case-oriented algorithm to assist in the decision-making process.

Investigators, sponsors, and institutional review boards have to decide when re-consent of clinical trials' participants must be obtained when new information becomes available. We present an algorithm to help in the decision-making process, which takes into consideration the kind of new information, the risk of exposure (patients could be on the treatment or in the follow-up phases), and the possibility of managing the case. Re-consent should be obtained in three of the eight possible situations.