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ABCD: first aid sequence that includes A: opening the airway, B: ventilation, C: circulatory support and D: differential diagnosis; CPA: cardiopulmonary arrest; ROSC: recovery of spontaneous circulation; CPR: cardiopulmonary resuscitation.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Luis Alberto Pallás Beneyto, Olga Rodríguez Luis, Vicente Miguel Bayarri" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Luis Alberto" "apellidos" => "Pallás Beneyto" ] 1 => array:2 [ "nombre" => "Olga" "apellidos" => "Rodríguez Luis" ] 2 => array:2 [ "nombre" => "Vicente Miguel" "apellidos" => "Bayarri" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775316304924" "doi" => "10.1016/j.medcli.2016.10.001" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775316304924?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020616307975?idApp=UINPBA00004N" "url" => "/23870206/0000014700000012/v1_201702040025/S2387020616307975/v1_201702040025/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2387020616307902" "issn" => "23870206" "doi" => "10.1016/j.medcle.2016.12.042" "estado" => "S300" "fechaPublicacion" => "2016-12-16" "aid" => "3748" "copyright" => "Elsevier España, S.L.U." "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Med Clin. 2016;147:547-53" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review</span>" "titulo" => "Fibrous dysplasia. Clinical review and therapeutic management" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "547" "paginaFinal" => "553" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Displasia fibrosa. Revisión clínica y abordaje terapéutico" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2374 "Ancho" => 3330 "Tamanyo" => 481139 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Patient with McCune–Albright syndrome. (A) “Coffee-with-milk” spots. (B) The bone scintigraphy shows a hypercaptation in facial mass, proximal and middle third of the right femur and right tibial diaphysis. (C) Radiograph of the proximal third of the right femur with inflatable lesions in “dull glass” with sclerosing contours and slight thickening of the cortical, with plate osteosynthesis. (D) Computed tomography scan showing sclerotic and cystic changes at the base of the skull, right orbit, nasal fossa, and right paranasal sinuses. The superior orbital fissure and the optic canal on the right side have a reduced size.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Helena Florez, Pilar Peris, Núria Guañabens" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Helena" "apellidos" => "Florez" ] 1 => array:2 [ "nombre" => "Pilar" "apellidos" => "Peris" ] 2 => array:2 [ "nombre" => "Núria" "apellidos" => "Guañabens" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775316303839" "doi" => "10.1016/j.medcli.2016.07.030" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775316303839?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020616307902?idApp=UINPBA00004N" "url" => "/23870206/0000014700000012/v1_201702040025/S2387020616307902/v1_201702040025/en/main.assets" ] "en" => array:15 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Special article</span>" "titulo" => "The reliability of clinical trials. The risky way towards drug deregulation" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "554" "paginaFinal" => "557" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Juan Erviti López, Luis Carlos Saiz Fernández, Javier Garjón Parra" "autores" => array:3 [ 0 => array:4 [ "nombre" => "Juan" "apellidos" => "Erviti López" "email" => array:1 [ 0 => "jervitil@navarra.es" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Luis Carlos" "apellidos" => "Saiz Fernández" ] 2 => array:2 [ "nombre" => "Javier" "apellidos" => "Garjón Parra" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Sección de Evaluación, Asesoría del Medicamento e Investigación, Servicio Navarro de Salud-Osasunbidea, Pamplona, Navarra, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Fiabilidad de los ensayos clínicos. El peligroso camino de la desregulación de los medicamentos" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Thalidomide was a drug marketed from 1957 to 1963 for the treatment of nausea during the first 3 months of pregnancy. Its use was associated with serious teratogenic effects, particularly, phocomelia, and it was withdrawn from the market. Spain was one of the last countries to suspend its commercialization.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Until then, there was no regulation on drug authorization that required an acceptable benefit-risk ratio based on the results of properly designed studies. From the thalidomide disaster, Western governments began to require randomized and controlled clinical trials to obtain evidence of acceptable quality as a requirement for making the most appropriate regulatory decisions.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Quality standards in conducting clinical trials were increasing until the 1980s. Thereafter, a series of practices and turns in the policy of drug approval have been leading to softening the clinical trial design requirements and accelerating the marketing of new drugs, sometimes to detriment of the patients’ safety.</p><p id="par0020" class="elsevierStylePara elsevierViewall">But before tackling these issues it should be noted that falsifying results is a real problem and much more usual than it may seem. For example, a head of an Anesthesiology Service at a US hospital made up 21 studies that never existed on celecoxib,<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">1</span></a> presumably intended to promote the use of this drug. This phenomenon even involves highly prestigious medical journals. In recent years, The Lancet has retracted at least 3 articles after finding out that the published trials were partially or totally false.<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">2–4</span></a> A Japanese anesthetist, Yoshitaka Fujii, invented data from over 172 studies, of which 126 were clinical trials.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">5</span></a> In a study on the 742 papers retracted in English-language medical journals from 2000 to 2010, it was found that data falsification was an important and growing concern.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">6</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">We must be aware that doctors, researchers and patients are in a situation of major defenselessness. When a new drug is marketed, the company provides information to regulatory agencies and this information is not always complete and truthful. Global data from the European Medicines Agency (EMA) for each drug are known as the clinical study report. This is the main extensive report on a clinical trial that the sponsor must submit to the regulatory authority for detailed examination. This document can contain around 10,000 pages. However, the information on the results released in the medical journals is summarized in about 10–12 pages only, with the subsequent uncertainty about the process leading to the selection and disposal of contents.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">7</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">There are currently very few people with access to the clinical study report. An initiative called Restoring invisible and abandoned trials<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">8</span></a> has recently been launched, which consists of accessing the actual data of a study, comparing it with those published in medical journals, contacting the original authors when the discrepancies are striking, and finally “restoring” the publication. That is, rewrite the paper to objectively show the real effects of the drug over the population studied. The first case published on the ‘restoration’ of a clinical trial was the so-called “329 study”. In the original publication, the authors concluded that imipramine (at high doses) and paroxetine antidepressants were effective and safe in the treatment of depression in adolescents. However, when the data from the clinical study report was accessed, it was observed that, in that study, both antidepressants had similar effectiveness compared to placebo, whereas the incidence of adverse effects was higher in adolescents treated with antidepressants. In fact, 7 cases of suicidal or self-injurious behavior were concealed in the group treated with antidepressants.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">9</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">All this confirms that the information available on the medicines we use is scarce and potentially manipulative.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Leaving aside these clearly fraudulent situations, a deregulation of clinical trials was initiated in the 1980s until today. During that decade, several Western countries began to harmonize their drug regulations. In April 1990 the International Conference on Harmonisation was created, later renamed as International Council on Harmonisation. This is a group consisting of the regulatory agencies of USA, Europe and Japan, together with representatives from the pharmaceutical industry in these countries and other observer members, including the World Health Organization. This group makes important decisions regarding changes in the regulation of medicines, which are then transposed to the guidelines of each region. It is striking that the pharmaceutical industry is involved in drug regulation, as striking as a student actively participating in the examination proposal that he has to overcome.</p><p id="par0045" class="elsevierStylePara elsevierViewall">The changes performed in guidelines during the last decades have had to do with softening conditions on drug approval. Let's have a look at some examples. The creation of the “non-inferiority trials” figure is full of controversy. It used to be required that a drug showed whether it was better or worse than the comparator. At one point, it was accepted that in order to authorize new drugs versus a reference drug (comparator), it was enough to show that they were not worse than the comparator. The problem lies in what we mean by “non-inferiority.” It is accepted that the evaluated drug is inferior to a certain point (known as a ‘delta’) and it is assumed that this difference is not clinically relevant. This margin of confidence is variable and is usually determined by the researcher subjectively. There are many cases in the medical literature where drugs objectively worse are accepted as “non-inferior” due to a “generous” definition of the non-inferiority margin. For example, in a non-inferiority trial of linagliptin versus glimepiride, the latter was statistically more effective than linagliptin in reducing glycosylated hemoglobin (HbA1c). However, the authors chose such an extensive non-inferiority margin that they concluded that linagliptin was “not inferior” compared to glimepiride.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">10</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">It is also worth reflecting on the “indirect comparisons”, widely used in network meta-analysis, which can give a sense of security by facilitating decision-making. However, it does not solve the underlying problem on the lack of relevant studies comparing efficacy versus safety of various drugs.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Another important factor is the Risk Management Plan. Now commercializing medicines that, in their development phase, show signs of serious security problems is accepted. Regulatory agencies suggest measures to minimize risks and conduct phase IV studies that confirm or deny the problems detected. The truth is that, in most cases, these studies are not usually conducted.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">11</span></a> A recent example is the umeclidinium/vilanterol association (Anoro<span class="elsevierStyleSup">®</span>) for COPD. Signs of increased incidence of cardiovascular and cerebral events have been detected due to the use of this combination. The EMA approved the drug (Spain and Italy voting against it) and, in the Risk Management Plan, it was determined that phase IV studies should be conducted to clarify these risks. The deadline for the company to submit the results was the third quarter of 2024, i.e. 10 years after its authorization, when the patent has expired and the company probably has no further interest in promoting this drug.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Another regulatory deficiency is that it is allowed that drugs compared only to placebo are marketed in diseases where there is clearly a reference drug. For example, safinamide is a new drug authorized as a supplementary treatment for Parkinson's disease. It has been shown to be slightly superior to placebo, but no data is available on its effectiveness compared to other adjunctive drugs in this indication. In practice, it involves the authorization of a drug that is very likely to be inferior to some other existing alternatives.</p><p id="par0065" class="elsevierStylePara elsevierViewall">Another remarkable aspect is the approval of drugs depending on the results of the clinical trials on surrogate variables of doubtful or null clinical value. In the case of diabetes, for example, patients want the use of drugs to be associated with lower morbidity and mortality, including lower risk of cardiovascular events. Many antidiabetics are authorized simply because they reduce HbA<span class="elsevierStyleInf">1c</span> by approximately 0.5%. It is not at all clear that this implies any clinical advantage. Moreover, drugs such as rosiglitazone have been withdrawn from the market because they are shown to cause increased risk of myocardial infarction despite reducing HbA<span class="elsevierStyleInf">1c</span>. As a result, major regulatory agencies have established as a requirement for marketing that antidiabetics should not increase cardiovascular risk by over 30%. They are not even required to minimize cardiovascular risk! But the requirements are increasingly softer and now the FDA authorizes medications that reduce HbA<span class="elsevierStyleInf">1c</span> by only 0.3%.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">12</span></a> In practical terms, the use of drugs that may cause adverse effects to patients is encouraged, with the highly improbable expectation that they will confer some beneficial clinical effect.</p><p id="par0070" class="elsevierStylePara elsevierViewall">Also the duration of the clinical trials is a controversial subject. For those drugs for chronic use we should require data from long-term clinical trials. Drugs usually have some effect within 12 to 24 weeks, but thereafter they lose effectiveness. Following the example of diabetes, recently a drug called empagliflozin has been marketed. The reduction of HbA<span class="elsevierStyleInf">1c</span> within 12 weeks compared to placebo was by 0.60%. However, at the end of the study (2.6 years), the HbA<span class="elsevierStyleInf">1c</span> dropped only by 0.24%.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">13</span></a> Drugs of chronic use should not be approved based on such short-term results and that rely on surrogate variables of questionable usefulness.</p><p id="par0075" class="elsevierStylePara elsevierViewall">Another important fact is that, sometimes, regulatory agencies make important decisions based on favorable outcomes observed in post hoc groups or subgroups of patients not previously defined. This is methodologically unacceptable, but the regulatory authorities end up accepting it as an argument for approving medicines or new indications. This is the case, for example, of most drugs indicated for reducing hip fractures.</p><p id="par0080" class="elsevierStylePara elsevierViewall">Apart from all of the aforementioned, it should be added that many trials have biases in their design to favor one of the drugs under study, such as, for example, the choice of an inadequate comparator, the use of inappropriate doses in the comparator, the use of incorrect combination variables, etc.</p><p id="par0085" class="elsevierStylePara elsevierViewall">The last step that regulatory agencies are taking is the definition of different types of drug authorization, with fewer and fewer requirements of scientific evidence. Until a few years ago, there was only one type of authorization, which was obtained once the drug showed a favorable benefit-risk ratio based on the results of phase III pivotal clinical trials.</p><p id="par0090" class="elsevierStylePara elsevierViewall">With the excuse of accelerating the development of drugs for rare diseases or in case of no other alternatives, 2 additional types of authorization were created. Approval “under exceptional circumstances” applies mainly to orphan medicinal products. It is assumed that, because the number of patients affected is small, the studies may be of poorer quality (smaller sample size, less consistent observational designs, case series, etc.). Thus, it is accepted that efficacy and safety data will be limited at the time of drug authorization and that there is little likelihood of obtaining better information in the future.</p><p id="par0095" class="elsevierStylePara elsevierViewall">The other type of license released a few years ago is “conditional authorization”. This time it is a question of facilitating quick access to the market of medicines indicated for life-threatening or seriously debilitating diseases. Marketing these drugs is allowed based on the results of phase II studies in surrogate variables and with very few patients. First, they should be required to subsequently provide evidence from phase III trials to confirm that the benefit-risk ratio is actually favorable.</p><p id="par0100" class="elsevierStylePara elsevierViewall">Most medicines approved by conditional authorization belong to the field of oncohematology. Many drugs are being rapidly marketed, but it is far from clear that the overall effect is beneficial. In an article prepared by the EMA's oncology department, which belongs to various European drug agencies,<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">14</span></a> it can be observed that the time to be marketed has been significantly shortened. However, patients have not obtained any relevant advantages regarding the availability of drugs with an added therapeutic value compared to the existing drugs.</p><p id="par0105" class="elsevierStylePara elsevierViewall">The last step intended by the EMA on deregulation is implementing the “adaptive licensing” or adaptive pathways. In practice, it would be a question of applying the conditional licensing approach to all medicines. Thus, any drug could be authorized based on data from phase II trials and observational studies. Therefore, in the future more robust evidence might be provided (phase III and IV studies) to prove that its benefit-risk ratio is favorable. This would be very bad news for physicians and patients, since the number of marketed drugs with uncertain effects on our patients would be progressively increased.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">15</span></a> In fact, a prestigious public institution such as the German technology assessment agency IQWiG has publicly reported its reluctance to adopt the adaptive licensing approach.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">16</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Regarding the initial reflections on concealing the information and lack of transparency of some pharmaceutical companies, some measures are being taking in the right direction. The European Parliament, aware of the seriousness of this situation, adopted some guidelines according to which the results of the clinical trials will be made public unless the confidentiality of the information can be justified for reasons of marketing data protection or patient personal data, among other causes.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">17</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">In line with the guidelines of the European Commission, the EMA has taken important steps toward better transparency and has decided to make public the information contained in the clinical study report since September 2016.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">18</span></a> The pharmaceutical industry has reacted to this situation demanding, in accordance with the trade agreement known as Transatlantic Trade and Investment Partnership between USA and Europe, that the European Parliament approve a directive of industrial secrecy. This European directive<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">19</span></a> was finally approved on 26 April 2016. It might be understood that industrial secrecy affects clinical trials, which would be a major setback to the transparency policy on clinical trials initiated by the EMA, although this issue is not entirely clear. On 20 October, 2016 the EMA announced that the first two clinical study reports of two recently marketed drugs, Kyprolis (carfilzomib) for multiple myeloma and Zurampic (lesinurad) for gout would be made public. This is very good news and we will have to verify thoroughly if the EMA continues to publish the rest of authorized medicines and if the information offered is complete and uncensored.</p><p id="par0120" class="elsevierStylePara elsevierViewall">In addition to moving toward transparency and publication of all clinical trial results, it is important to be aware of the ongoing process of deregulation we are experiencing, as well as the importance of reversing it. We must require that drugs be approved based on well-designed, implemented and evaluated clinical trials and that the results of the drugs in clinically relevant robust variables be reported.</p><p id="par0125" class="elsevierStylePara elsevierViewall">For this purpose, many things should be modified at a political and regulatory level that are not directly accessible to doctors and patients. However, they can undertake some other very valuable actions. For example, it would be highly desirable for scientific societies to disengage their funding from the pharmaceutical industry in order to be able to defend freely the interests of the patients they care for. In this regard, unfortunately there are no shortcuts. Freedom of prescription should begin with a commitment to the intellectual and financial independence from the drug industry.</p><p id="par0130" class="elsevierStylePara elsevierViewall">On the other hand, the authorization of medicines is a supranational competence that depends on the European Union. However, the National Health System could not fund or use drugs with insufficient evidence, in response to this dangerous deregulation.</p><p id="par0135" class="elsevierStylePara elsevierViewall">Physicians could also commit themselves to not using drugs that were approved with poor data as long as there was no minimally acceptable evidence to justify their use. And, finally, patients should be well informed, letting them know that restricting the use of certain drugs may sometimes be necessary to protect the health of the population above any trading interest.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflict of interests</span><p id="par0140" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflict of interests" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-10-03" "fechaAceptado" => "2016-10-09" "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Erviti López J, Saiz Fernández LC, Garjón Parra J. 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