Adaptive authorization: A new way for the early access of new drugs?

Dal-Ré, Rafael; Carné, Xavier
doi:10.1016/j.medcle.2014.06.005
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Maybe the most important challenge faced by society in relation to new medications is the capacity to develop them rapidly to facilitate their prompt availability to clinicians and patients&#44; without undermining confidence in clinical safety&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">1</span></a> The correct time to authorize the commercialisation of a medication should not unnecessarily delay patient access&#44; as relevant health benefits may be involved&#44; nor should it expose patients to a benefit&#47;risk balance that is still too uncertain&#46; Our regulatory environment &#40;European Medicines Agency &#91;EMA&#93;&#59; Spanish Agency of Medicines and Medical Devices &#91;<span class="elsevierStyleItalic">Agencia Espa&#241;ola de Medicamentos y Productos Sanitarios&#44; AEMPS</span>&#93;&#41; takes decisions based on a limited number of data and&#44; thus&#44; always assumes a particular level of uncertainty&#46; However&#44; it seems that the decisions taken to date are not only transparent but also reasonably correct&#44;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">2&#8211;4</span></a> although there are recent cases of medication withdrawals or important limitations on their use&#44; as in the cases of rofecoxib and rosiglitazone&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">5&#44;6</span></a> Regarding the promptness to commercialise a new medication&#44; some people support that the situation could be improved&#46; As a result&#44; an idea emerged some years ago&#58; progressive authorization &#40;PA&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">7</span></a> also known as adaptive or staged authorization&#44; which may provide an important change in the way society as a whole understands how the access to some new medications is regulated&#46; The definition of PA is shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Current commercialisation process of a medication</span><p id="par0010" class="elsevierStylePara elsevierViewall">The journey from the initiation of a clinical research of a new drug until its availability for use in actual clinical practice is lengthy and complex&#46; The role of medication regulatory agencies is to publicly guarantee that commercialised medicines meet certain standards for quality&#44; efficacy and safety&#46; Nowadays&#44; this mission involves a series of activities&#44; the most important of which is the decision to authorize the commercialisation of a medication for a particular indication and population based on the data provided by the manufacturer&#46; The assessment of clinical data&#44; mostly from controlled clinical trials &#40;CT&#41;&#44; is the critical part of the evaluation&#46; The clinical development of the medication has been described in correlative phases &#40;1&#44; 2 and 3&#41;&#44; so that&#44; in general&#44; no phase is started until the previous one has been successfully completed&#46; The clinical development of a new medication takes 6&#46;4 years on average&#44;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">9</span></a> with an additional year &#40;mean&#41; for regulatory agencies to authorize its use&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">10</span></a> When the regulatory agency authorizes its commercialisation&#44; there is another process that must be completed before it is available for prescription&#58; the decision on price&#44; reimbursement and conditions of use&#44; if the medication is included in the National Health System &#40;NHS&#41;&#46; In Spain&#44; this process can take up to 2 years after the technical authorization by the AEMPS&#46; This decision is taken based on the cost-efficacy ratio of the new medication compared to existing therapeutic alternatives&#46; In some countries&#44; after the cost-efficacy assessment&#44; the &#40;health&#41; technologies assessment agencies &#40;TAA&#41; &#8211; for example&#44; NICE in the United Kingdom and IQWIG in Germany&#8211;may or may not recommend their use for the NHS&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Progressive authorization&#58; the acting framework</span><p id="par0015" class="elsevierStylePara elsevierViewall">Nowadays&#44; until the new medication is launched on the market&#44; the only way for patient to be treated with that medication is by inclusion in a CT or with compassionate use&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">11</span></a> Currently&#44; regulatory agencies have systems that allow for rapid commercialisation of certain medications for patients without an available treatment&#58; the &#8220;conditional commercialisation authorization&#8221; and the &#8220;accelerated approval&#8221; of the European EMA and American Food and Drug Administration &#40;FDA&#41;&#46; The objective of the PA is for patients to have access to the new medication after an initial authorization that should be refined over time&#44; which would be possible by applying the current regulations for the EMA and the FDA&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">12</span></a> The general PA framework should be based on the 4 pillars described by De Jong et al&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">13</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">As the PA will assume there will be more uncertainty in the benefit&#47;risk ratio than when a new product is commercialised with the traditional model&#44; it seems obvious that the regulatory agencies shall communicate all decisions taken so that the public opinion is appropriately informed&#46; This is highly important considering that&#44; currently&#44; much of the population wrongly believes that the regulatory agencies only authorize new medications that are highly efficient and do not produce serious adverse effects&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">24</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">It is clear that the PA will also entail a new challenge for the decision-making process on financing and price-reimbursement&#46; The fact that the regulation and the decisions about medication access are unrelated does not really seem to make sense&#46; Common sense dictates that the development of the new medications should not only consider the demonstration of their efficacy and security but should also demonstrate their added value over available alternatives&#44; and thus facilitate the decision of the NHS and citizens to pay for that&#46; The achievement of this double objective requires improvements to the existent regulation of drug development&#44; which could be regulated in PA&#46; Furthermore&#44; it also requires the disclosure of information among the players involved in the process&#58; biopharmaceutical industry&#44; regulatory agencies and financial supporters &#40;the NHS in Spain&#41;&#46; This is a process that also entails certain difficulties because&#44; even if the commercialisation authorization tends to be increasingly global&#44; the decisions on financing and reimbursement are national in nature and&#44; sometimes&#44; pertain to regional administrations&#46; Thus&#44; it is crucial to know the funder&#39;s criteria and needs in the discussion of clinical development plans&#46; For example&#44; note that in less than half of the oncology drugs assessments carried out by the NICE did it recommended their use in the British NHS&#44; as approved by the British regulatory agency&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">25</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Information about progressive authorization</span><p id="par0030" class="elsevierStylePara elsevierViewall">The EMA has launched a pilot project so that interested companies can prospectively present the clinical development plans of new products in early developmental phases &#40;during or even before phase 2&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">8</span></a> In the discussions of this programme&#44; the goal is for the participation of not only the interested company and the EMA&#44; but also the NHS&#44; patients associations and scientific societies&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">8</span></a> In the near future&#44; we will witness the first steps of the PA in Europe&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">However&#44; there is a precedent of another PA programme called New Drug Development Paradigms &#40;NEWDIGS&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">26</span></a> This is an initiative launched by the Biomedical Innovation Centre of the Massachusetts Institute of Technology &#40;U&#46;S&#46;A&#46;&#41;&#44; that started in 2010 and where the regulatory agencies &#40;EMA&#44; FDA and others&#41;&#44; TAAs&#44; pharmaceutical agencies&#44; patients&#44; suppliers and academic researchers are represented&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">27</span></a> The project has assessed 12 products&#44; presented by 9 different companies&#44; out of which only 2 are considered real candidates for a PA&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">27</span></a> Meanwhile&#44; a theoretical analysis of 3 medications &#40;for melanoma&#44; multiple sclerosis and obesity&#41; has shown that the PA has clear advantages for companies&#44; regulatory agencies and patients&#59; it should be noted that financial supporters were not considered for this study&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">28</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">The conflicting aspects of progressive authorization</span><p id="par0040" class="elsevierStylePara elsevierViewall">While some authors propose the use of PA for any kind of medication&#44;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">7</span></a> others limit it to those medications that target unmet medical needs&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">16</span></a> Like the EMA in its pilot programme&#44;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">8</span></a> we understand that PA will be aimed at unresolved health problems&#44; among which there will undoubtedly be many low-prevalence diseases&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Although during recent years the EMA and FDA have increasingly requested post-authorization studies from biopharmaceutical companies&#44; the truth is that the most important effort related to clinical development is still done before drug commercialisation&#46; This should not be the case with PA&#44; as the commercialisation process would be developed in a more controlled and gradual manner&#46; Not only the regulatory agencies but also doctors and patients should be willing to accept that the uncertainty of the benefit&#47;risk ratio will be higher than now&#44; and that it should be reduced little by little as more data accumulate&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">7</span></a> In turn&#44; this will be criticised by those who are of the opinion that the commercialisation of a medication in a situation of greater uncertainty does nothing more than reduce current requirements and standards&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">16</span></a> The PA implies accepting that there is much to learn from the already commercialised medication&#44; especially from its safety profile&#44; and that will entail the need for better management of adverse reactions&#46; In this regard&#44; society should decide if current legislation is adequate to address the resolution of potential litigations derived from the emergence of serious adverse reactions in the clinical practice after PA&#46; It has been proposed that&#44; once the medication has been commercialised&#44; maybe the patients should be informed through specific information sheets and a process that involves informed consent&#44; which should <span class="elsevierStyleItalic">a priori</span> reduce the number of potential litigations due to safety issues&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">7</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">In the immediate post-commercialisation period&#44; there should be a use restriction on the new medication&#44; as is already done in certain &#8220;risk management plans&#8221;&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">29</span></a> A process like the one described above should be accepted by prescribing physicians and patients&#46; The objective would be that the medication should only be administered to those patients at whom it is targeted&#44; while avoiding its use in conditions other than those stated in the technical card &#40;off-label&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">7</span></a> without undermining the ethics commitment of the physician in the patient&#39;s best interest&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">30</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Biopharmaceutical companies should make a commitment to perform and complete post-commercialisation studies in due time and proper form &#40;something which currently does not always happen&#41;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">31</span></a> until the data agreed upon with the regulatory agencies and TAA have been collected&#46; The PA process should create tougher regulations to help avoid this kind of non-compliance&#46; In any case&#44; it must be acknowledged that post-PA studies will no longer need to be controlled trials&#44; and&#44; of course&#44; no placebo is involved&#46; In addition to pragmatic CT&#44; observational studies and data derived from records could be quite useful&#46; Early commercialisation will probably entail less availability of patients to participate in all types of CT&#46; Furthermore&#44; scientific data will also be obtained about the effects of the medications from overlapping studies in the standard medical care setting&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Some wonder whether the biopharmaceutical companies will be motivated enough to be a decisive part of the PA process&#44; which means a radical change of the rules of the game&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">16</span></a> This will soon be seen in the EMA&#39;s pilot programme&#46; The truth is that certain steps to facilitate the research and development of new medications&#44; and the transition to the PA&#44; are being proposed from the European business world&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">32</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusions</span><p id="par0065" class="elsevierStylePara elsevierViewall">It is then probable that as of 2014 we will be part of the emergence of an innovative way to assess and authorize new medications in the European Union&#46; The implementation of PA is expected to be slow&#44; careful and progressive&#44; and correctly communicated to the public opinion&#46; Some are already proposing its implementation in certain cases&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">33</span></a> It should be recognised that some unpleasant surprises might arise&#44; as is currently the case with rapid authorizations&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">34</span></a> All the parties involved&#44; especially patients and the NHS&#44; should participate in its development&#44; implementing imaginative solutions to resolve the multiple inconveniences that will gradually appear&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Conflict of interest</span><p id="par0070" class="elsevierStylePara elsevierViewall">The authors declare that there are no conflicts of interest&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "Current commercialisation process of a medication"
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        2 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Progressive authorization&#58; the acting framework"
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        3 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Information about progressive authorization"
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        4 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "The conflicting aspects of progressive authorization"
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        5 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Conclusions"
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          "titulo" => "Conflict of interest"
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    "fechaRecibido" => "2014-06-10"
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        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as&#58; Dal-R&#233; R&#44; Carn&#233; X&#46; Autorizaci&#243;n progresiva&#58; &#191;un nuevo camino hacia el acceso temprano de nuevos medicamentos&#63; Med Clin &#40;Barc&#41;&#46; 2015&#59;144&#58;275&#8211;278&#46;</p>"
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        "fuente" => "<span class="elsevierStyleItalic">Source</span>&#58; European Medicines Agency&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">18</span></a>"
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                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Progressive authorization can be defined as a prospective&#44; planned and flexible approximation to commercialise medications&#46; It begins with the authorization of an indication &#40;probably a &#8220;niche&#8221; indication&#41; for a medication&#46; Through repeated phases of evidence collection and consecutive adaptive authorizations about the initial authorized indication and the potential therapeutic uses of the medication in the future&#44; progressive authorization intends to maximise the positive impact of the new medications in the public health through the balance between the early access of the medication for patients and the need to provide correct information obtained on benefits and risks&#46;&nbsp;\t\t\t\t\t\t\n
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Also known as adaptive or staged authorization&#59; the European Medicines Agency uses the term <span class="elsevierStyleItalic">adaptive licensing&#46;</span></p>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Progressive authorization<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&#58; definition proposed by the European Medicines Agency&#46;</p>"
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          "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">TAA&#58; &#40;health&#41; technologies assessment agency&#59; EMA&#58; European Medicines Agency&#59; FDA&#58; Food and Drug Administration&#46;</p>"
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Basic pillars<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">13</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">How to implement them&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Organisation of data generation and requirements&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Use of the EMA&#39;s &#8220;scientific guidelines&#8221;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">14</span></a> adapted to progressive authorization&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Clinical trials&#58; use of adaptive designs<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">15</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Collection of controlled data after the medication authorization under restricted conditions<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">16</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Sharing of data between the biopharmaceutical companies and researchers<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">17&#44;18</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Clarity in the decision-making process on risks and benefits&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Development of innovative methods to assess the benefit&#47;risk ratio of the medications with multiple safety and efficacy criteria<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">19</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Use of simulation and clinical trial modelling methods<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">16</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Transparent communication of the regulatory agencies&#8217; decisions to the public&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Dialogue among the parties involved&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Redesign of the assessment procedure for biopharmaceutical companies by the regulatory agencies<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">20</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Presence of patients in the deliberations to take their preferences into consideration<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">13&#44;21</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Closer collaboration between the EMA and the FDA<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">16</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Consideration of TAA requirements&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Clinical development plans should be agreed upon between the regulatory agencies and the TAA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">The EMA has established a joint scientific advisory procedure with the TAA in several European countries<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">22&#44;23</span></a>&nbsp;\t\t\t\t\t\t\n
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      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
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            0 => array:3 [
              "identificador" => "bib0175"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Balancing early market access to new drugs with the need for benefit&#47;risk data&#58; a mounting dilemma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "H&#46;G&#46; Eichler"
                            1 => "F&#46; Pignatti"
                            2 => "B&#46; Flamion"
                            3 => "H&#46; Leufkens"
                            4 => "A&#46; Breckenridge"
                          ]
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                    0 => array:2 [
                      "doi" => "10.1038/nrd2664"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nat Rev Drug Discov"
                        "fecha" => "2008"
                        "volumen" => "7"
                        "paginaInicial" => "818"
                        "paginaFinal" => "826"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18787530"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0180"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Timing of new black box warnings and withdrawals for prescription medications"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "K&#46;E&#46; Lasser"
                            1 => "P&#46;D&#46; Allen"
                            2 => "S&#46;J&#46; Woolhandler"
                            3 => "D&#46;U&#46; Himmelstein"
                            4 => "S&#46;M&#46; Wolfe"
                            5 => "D&#46;H&#46; Bor"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "JAMA"
                        "fecha" => "2002"
                        "volumen" => "287"
                        "paginaInicial" => "2215"
                        "paginaFinal" => "2220"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11980521"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0185"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Safety-related regulatory actions for biologicals approved in the United States and the European Union"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "T&#46;J&#46; Giezen"
                            1 => "A&#46;K&#46; Mantel-Teeuwisse"
                            2 => "S&#46;M&#46; Straus"
                            3 => "H&#46; Schellekens"
                            4 => "H&#46;G&#46; Leufkens"
                            5 => "A&#46;C&#46; Egberts"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1001/jama.300.16.1887"
                      "Revista" => array:6 [
                        "tituloSerie" => "JAMA"
                        "fecha" => "2008"
                        "volumen" => "300"
                        "paginaInicial" => "1887"
                        "paginaFinal" => "1896"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18940975"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0190"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Safety-related regulatory actions for orphan drugs in the US and EU&#58; a cohort study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "H&#46;E&#46; Heemstra"
                            1 => "T&#46;J&#46; Giezen"
                            2 => "A&#46;K&#46; Mantel-Teeuwisse"
                            3 => "R&#46;L&#46; de Vrueh"
                            4 => "H&#46;G&#46; Leufkens"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2165/11319870-000000000-00000"
                      "Revista" => array:6 [
                        "tituloSerie" => "Drug Saf"
                        "fecha" => "2010"
                        "volumen" => "33"
                        "paginaInicial" => "127"
                        "paginaFinal" => "137"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20082539"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0195"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Failing the public health &#8211; Rofecoxib&#44; Merck&#44; and the FDA"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "E&#46;J&#46; Topol"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMp048286"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2004"
                        "volumen" => "351"
                        "paginaInicial" => "1707"
                        "paginaFinal" => "1709"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15470193"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0200"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The rosiglitazone decision process at FDA and EMA&#46; What should we learn&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "K&#46;B&#46; Pouwels"
                            1 => "K&#46; van Grootheest"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3233/JRS-2012-0559"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Risk Saf Med"
                        "fecha" => "2012"
                        "volumen" => "24"
                        "paginaInicial" => "73"
                        "paginaFinal" => "80"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22751189"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0205"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Adaptive licensing&#58; taking the next step in the evolution of drug approval"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "H&#46;G&#46; Eichler"
                            1 => "K&#46; Oye"
                            2 => "L&#46;G&#46; Baird"
                            3 => "E&#46; Abadie"
                            4 => "J&#46; Brown"
                            5 => "C&#46;L&#46; Drum"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/clpt.2011.345"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Pharmacol Ther"
                        "fecha" => "2012"
                        "volumen" => "91"
                        "paginaInicial" => "426"
                        "paginaFinal" => "437"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22336591"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0210"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Senior Medical Officer&#46; Pilot project on adaptive licensing&#46; EMA&#47;254350&#47;2012"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "European Medicines Agency"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Libro" => array:1 [
                        "fecha" => "2014&#44; March"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0215"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmaceutical innovation in the 21st century&#58; new drug approvals in the first decade&#44; 2000&#8211;2009"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "K&#46;I&#46; Kaitin"
                            1 => "J&#46;A&#46; DiMasi"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/clpt.2010.286"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Pharmacol Ther"
                        "fecha" => "2011"
                        "volumen" => "89"
                        "paginaInicial" => "183"
                        "paginaFinal" => "188"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21191382"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0220"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Regulatory review of novel therapeutics &#8211; comparison of three regulatory agencies"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "N&#46;S&#46; Downing"
                            1 => "J&#46;A&#46; Aminawung"
                            2 => "N&#46;D&#46; Shah"
                            3 => "J&#46;B&#46; Braunstein"
                            4 => "H&#46;M&#46; Krumholz"
                            5 => "J&#46;S&#46; Ross"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMsa1200223"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2012"
                        "volumen" => "366"
                        "paginaInicial" => "2284"
                        "paginaFinal" => "2293"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22591257"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0225"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nuevo real decreto de acceso a medicamentos en situaciones especiales"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "D&#46; Montero"
                            1 => "E&#46; Vargas"
                            2 => "C&#46; de la Cruz"
                            3 => "F&#46; Andr&#233;s-Trelles"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Med Clin &#40;Barc&#41;"
                        "fecha" => "2009"
                        "volumen" => "133"
                        "paginaInicial" => "427"
                        "paginaFinal" => "432"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0230"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Legal foundations of adaptive licensing"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "K&#46; Oye"
                            1 => "L&#46;G&#46; Baird"
                            2 => "A&#46; Chia"
                            3 => "S&#46; Hocking"
                            4 => "P&#46;B&#46; Hutt"
                            5 => "D&#46; Lee"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/clpt.2013.95"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Pharmacol Ther"
                        "fecha" => "2013"
                        "volumen" => "94"
                        "paginaInicial" => "309"
                        "paginaFinal" => "311"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23963219"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0235"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Appropriate evidence for adaptive marketing authorization"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "J&#46;P&#46; De Jong"
                            1 => "D&#46;E&#46; Grobbee"
                            2 => "B&#46; Flamion"
                            3 => "S&#46;R&#46; Forda"
                            4 => "H&#46;G&#46; Leufkens"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/nrd4114"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nat Rev Drug Discov"
                        "fecha" => "2013"
                        "volumen" => "12"
                        "paginaInicial" => "647"
                        "paginaFinal" => "648"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23989775"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0240"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "European Medicines Agency&#46; Clinical efficacy and safety guidelines&#46; Available from&#58; <a href="http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000085.jsp">http&#58;&#47;&#47;www&#46;ema&#46;europa&#46;eu&#47;ema&#47;index&#46;jsp&#63;curl&#61;pages&#47;regulation&#47;general&#47;general&#95;content&#95;000085&#46;jsp</a> &#91;accessed 01&#46;06&#46;14&#93;&#46;"
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0245"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nuevos dise&#241;os en investigaci&#243;n cl&#237;nica&#46; Desaf&#237;os y oportunidades"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "C&#46; Pontes"
                            1 => "J&#46; R&#237;os"
                            2 => "F&#46; Torres"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "LibroEditado" => array:4 [
                        "titulo" => "Luces y sombras en la investigaci&#243;n cl&#237;nica"
                        "paginaInicial" => "241"
                        "paginaFinal" => "268"
                        "serieFecha" => "2013"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0250"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Gatekeepers and enablers&#58; how drug regulators respond to a challenging and changing environment by moving toward a proactive attitude"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "F&#46; Ehmann"
                            1 => "M&#46; Papaluca Amati"
                            2 => "T&#46; Salmonson"
                            3 => "M&#46; Posch"
                            4 => "S&#46; Vamvakas"
                            5 => "R&#46; Hemmings"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/clpt.2013.14"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Pharmacol Ther"
                        "fecha" => "2013"
                        "volumen" => "93"
                        "paginaInicial" => "425"
                        "paginaFinal" => "432"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23549149"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0255"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:1 [
                      "titulo" => "Pharma firms pool and share cancer trial data"
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Nat Rev Drug Discov"
                        "fecha" => "2014"
                        "volumen" => "13"
                        "paginaInicial" => "323"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0260"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "US website is launched to share cancer trial data"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "M&#46; McCarthy"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "BMJ"
                        "fecha" => "2014"
                        "volumen" => "348"
                        "paginaInicial" => "g2742"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24727302"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0265"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "European Medicines Agency&#46; Benefit-risk methodology project&#46; Available from&#58; <a href="http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/document_listing/document_listing_000314.jsp">http&#58;&#47;&#47;www&#46;ema&#46;europa&#46;eu&#47;ema&#47;index&#46;jsp&#63;curl&#61;pages&#47;special&#95;topics&#47;document&#95;listing&#47;document&#95;listing&#95;000314&#46;jsp</a> &#91;accessed 01&#46;06&#46;14&#93;&#46;"
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0270"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "European Medicines Agency&#46; Scientific advice and protocol assistance&#46; Available from&#58; <a href="http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000049.jsp%26mid=WC0b01ac05800229b9">http&#58;&#47;&#47;www&#46;ema&#46;europa&#46;eu&#47;ema&#47;index&#46;jsp&#63;curl&#61;pages&#47;regulation&#47;general&#47;general&#95;content&#95;000049&#46;jsp&#8739;&#61;WC0b01ac05800229b9</a> &#91;accessed 01&#46;06&#46;14&#93;&#46;"
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0275"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Involving patients in drug licensing decisions"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "N&#46; Britten"
                            1 => "S&#46; Denford"
                            2 => "K&#46; Stein"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "BMJ"
                        "fecha" => "2013"
                        "volumen" => "347"
                        "paginaInicial" => "f4329"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23861411"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0280"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "EMA&#39;s parallel advice workshop bridges regulatory and reimbursement divide"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "S&#46; Elvidge"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/nrd4219"
                      "Revista" => array:5 [
                        "tituloSerie" => "Nat Rev Drug Discov"
                        "fecha" => "2014"
                        "volumen" => "13"
                        "paginaInicial" => "8"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24378785"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0285"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "EUnetHTA&#46; Available from&#58; <a href="http://www.eunethta.eu/">http&#58;&#47;&#47;www&#46;eunethta&#46;eu&#47;</a> &#91;accessed 01&#46;06&#46;14&#93;&#46;"
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0290"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Communicating uncertainties about prescription drugs to the public&#58; a national randomized trial"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "L&#46;M&#46; Schwartz"
                            1 => "S&#46; Woloshin"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1001/archinternmed.2011.396"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Intern Med"
                        "fecha" => "2011"
                        "volumen" => "171"
                        "paginaInicial" => "1463"
                        "paginaFinal" => "1468"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21911629"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0295"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "What is the value of oncology medicines&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "J&#46; Cohen"
                            1 => "W&#46; Looney"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/nbt1110-1160"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nat Biotechnol"
                        "fecha" => "2010"
                        "volumen" => "28"
                        "paginaInicial" => "1160"
                        "paginaFinal" => "1163"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21057481"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0300"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "MIT&#46; Center for Biomedical Innovation &#40;CBI&#41;&#46; NEW Drug Development ParaDIGmS &#40;NEWDIGS&#41;&#46; Available from&#58; <a href="http://cbi.mit.edu/research-overview/newdigshomepage/">http&#58;&#47;&#47;cbi&#46;mit&#46;edu&#47;research-overview&#47;newdigshomepage&#47;</a> &#91;accessed 01&#46;06&#46;14&#93;&#46;"
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0305"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Adaptive licensing&#58; creating a safe haven for discussions"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "L&#46; Baird"
                            1 => "G&#46; Hirsch"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Scrip Regul Affairs"
                        "fecha" => "2013"
                        "paginaInicial" => "10"
                        "paginaFinal" => "11"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib0310"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Comparison of stakeholders metrics for traditional and adaptive development and licensing approaches to drug development"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "L&#46;G&#46; Baird"
                            1 => "M&#46;R&#46; Trusheim"
                            2 => "H&#46;G&#46; Eichler"
                            3 => "E&#46;R&#46; Berndt"
                            4 => "G&#46; Hirsch"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Ther Innov Regul Sci"
                        "fecha" => "2013"
                        "volumen" => "47"
                        "paginaInicial" => "474"
                        "paginaFinal" => "483"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0315"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "European Medicines Agency&#46; Risk-management plans&#46; Available from&#58; <a href="http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000360.jsp">http&#58;&#47;&#47;www&#46;ema&#46;europa&#46;eu&#47;ema&#47;index&#46;jsp&#63;curl&#61;pages&#47;regulation&#47;document&#95;listing&#47;document&#95;listing&#95;000360&#46;jsp</a> &#91;accessed 01&#46;06&#46;14&#93;&#46;"
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0320"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
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                      "titulo" => "Novel licensure pathways for expeditious introduction of new tuberculosis vaccines&#58; a discussion of the adaptive licensure concept"
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                            4 => "Z&#46; Hindle"
                            5 => "G&#46; Steel"
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                        ]
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                    ]
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                      "titulo" => "The accelerated approval of oncology drugs&#58; lessons from ponatinib"
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                          "autores" => array:2 [
                            0 => "V&#46; Prasad"
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