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

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"tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "275" "paginaFinal" => "278" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Rafael Dal-Ré, Xavier Carné" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Rafael" "apellidos" => "Dal-Ré" "email" => array:1 [ 0 => "Rafael.dalre@fuam.uam.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Xavier" "apellidos" => "Carné" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Investigación Clínica, Programa BUC (Biociencias UAM+CSIC), Centro de Excelencia Internacional, Universidad Autónoma de Madrid, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Farmacología Clínica, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Departamento de Anatomía Patológica, Farmacología y Microbiología, Universidad de Barcelona, Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Autorización progresiva: ¿un nuevo camino hacia el acceso temprano de nuevos medicamentos?" ] ] "textoCompleto" => "IntroductionMaybe 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, without undermining confidence in clinical safety.<a class="elsevierStyleCrossRef" href="#bib0175">1</a> The correct time to authorize the commercialisation of a medication should not unnecessarily delay patient access, as relevant health benefits may be involved, nor should it expose patients to a benefit/risk balance that is still too uncertain. Our regulatory environment (European Medicines Agency [EMA]; Spanish Agency of Medicines and Medical Devices [Agencia Española de Medicamentos y Productos Sanitarios, AEMPS]) takes decisions based on a limited number of data and, thus, always assumes a particular level of uncertainty. However, it seems that the decisions taken to date are not only transparent but also reasonably correct,<a class="elsevierStyleCrossRefs" href="#bib0180">2–4</a> although there are recent cases of medication withdrawals or important limitations on their use, as in the cases of rofecoxib and rosiglitazone.<a class="elsevierStyleCrossRefs" href="#bib0195">5,6</a> Regarding the promptness to commercialise a new medication, some people support that the situation could be improved. As a result, an idea emerged some years ago: progressive authorization (PA),<a class="elsevierStyleCrossRef" href="#bib0205">7</a> also known as adaptive or staged authorization, which may provide an important change in the way society as a whole understands how the access to some new medications is regulated. The definition of PA is shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Current commercialisation process of a medicationThe 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. The role of medication regulatory agencies is to publicly guarantee that commercialised medicines meet certain standards for quality, efficacy and safety. Nowadays, this mission involves a series of activities, 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. The assessment of clinical data, mostly from controlled clinical trials (CT), is the critical part of the evaluation. The clinical development of the medication has been described in correlative phases (1, 2 and 3), so that, in general, no phase is started until the previous one has been successfully completed. The clinical development of a new medication takes 6.4 years on average,<a class="elsevierStyleCrossRef" href="#bib0215">9</a> with an additional year (mean) for regulatory agencies to authorize its use.<a class="elsevierStyleCrossRef" href="#bib0220">10</a> When the regulatory agency authorizes its commercialisation, there is another process that must be completed before it is available for prescription: the decision on price, reimbursement and conditions of use, if the medication is included in the National Health System (NHS). In Spain, this process can take up to 2 years after the technical authorization by the AEMPS. This decision is taken based on the cost-efficacy ratio of the new medication compared to existing therapeutic alternatives. In some countries, after the cost-efficacy assessment, the (health) technologies assessment agencies (TAA) – for example, NICE in the United Kingdom and IQWIG in Germany–may or may not recommend their use for the NHS.Progressive authorization: the acting frameworkNowadays, until the new medication is launched on the market, the only way for patient to be treated with that medication is by inclusion in a CT or with compassionate use.<a class="elsevierStyleCrossRef" href="#bib0225">11</a> Currently, regulatory agencies have systems that allow for rapid commercialisation of certain medications for patients without an available treatment: the “conditional commercialisation authorization” and the “accelerated approval” of the European EMA and American Food and Drug Administration (FDA). 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, which would be possible by applying the current regulations for the EMA and the FDA.<a class="elsevierStyleCrossRef" href="#bib0230">12</a> The general PA framework should be based on the 4 pillars described by De Jong et al.<a class="elsevierStyleCrossRef" href="#bib0235">13</a> (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>As the PA will assume there will be more uncertainty in the benefit/risk ratio than when a new product is commercialised with the traditional model, it seems obvious that the regulatory agencies shall communicate all decisions taken so that the public opinion is appropriately informed. This is highly important considering that, currently, 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.<a class="elsevierStyleCrossRef" href="#bib0290">24</a>It is clear that the PA will also entail a new challenge for the decision-making process on financing and price-reimbursement. The fact that the regulation and the decisions about medication access are unrelated does not really seem to make sense. 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, and thus facilitate the decision of the NHS and citizens to pay for that. The achievement of this double objective requires improvements to the existent regulation of drug development, which could be regulated in PA. Furthermore, it also requires the disclosure of information among the players involved in the process: biopharmaceutical industry, regulatory agencies and financial supporters (the NHS in Spain). This is a process that also entails certain difficulties because, even if the commercialisation authorization tends to be increasingly global, the decisions on financing and reimbursement are national in nature and, sometimes, pertain to regional administrations. Thus, it is crucial to know the funder's criteria and needs in the discussion of clinical development plans. For example, 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, as approved by the British regulatory agency.<a class="elsevierStyleCrossRef" href="#bib0295">25</a>Information about progressive authorizationThe EMA has launched a pilot project so that interested companies can prospectively present the clinical development plans of new products in early developmental phases (during or even before phase 2).<a class="elsevierStyleCrossRef" href="#bib0210">8</a> In the discussions of this programme, the goal is for the participation of not only the interested company and the EMA, but also the NHS, patients associations and scientific societies.<a class="elsevierStyleCrossRef" href="#bib0210">8</a> In the near future, we will witness the first steps of the PA in Europe.However, there is a precedent of another PA programme called New Drug Development Paradigms (NEWDIGS).<a class="elsevierStyleCrossRef" href="#bib0300">26</a> This is an initiative launched by the Biomedical Innovation Centre of the Massachusetts Institute of Technology (U.S.A.), that started in 2010 and where the regulatory agencies (EMA, FDA and others), TAAs, pharmaceutical agencies, patients, suppliers and academic researchers are represented.<a class="elsevierStyleCrossRef" href="#bib0305">27</a> The project has assessed 12 products, presented by 9 different companies, out of which only 2 are considered real candidates for a PA.<a class="elsevierStyleCrossRef" href="#bib0305">27</a> Meanwhile, a theoretical analysis of 3 medications (for melanoma, multiple sclerosis and obesity) has shown that the PA has clear advantages for companies, regulatory agencies and patients; it should be noted that financial supporters were not considered for this study.<a class="elsevierStyleCrossRef" href="#bib0310">28</a>The conflicting aspects of progressive authorizationWhile some authors propose the use of PA for any kind of medication,<a class="elsevierStyleCrossRef" href="#bib0205">7</a> others limit it to those medications that target unmet medical needs.<a class="elsevierStyleCrossRef" href="#bib0250">16</a> Like the EMA in its pilot programme,<a class="elsevierStyleCrossRef" href="#bib0210">8</a> we understand that PA will be aimed at unresolved health problems, among which there will undoubtedly be many low-prevalence diseases.Although during recent years the EMA and FDA have increasingly requested post-authorization studies from biopharmaceutical companies, the truth is that the most important effort related to clinical development is still done before drug commercialisation. This should not be the case with PA, as the commercialisation process would be developed in a more controlled and gradual manner. Not only the regulatory agencies but also doctors and patients should be willing to accept that the uncertainty of the benefit/risk ratio will be higher than now, and that it should be reduced little by little as more data accumulate.<a class="elsevierStyleCrossRef" href="#bib0205">7</a> In turn, 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.<a class="elsevierStyleCrossRef" href="#bib0250">16</a> The PA implies accepting that there is much to learn from the already commercialised medication, especially from its safety profile, and that will entail the need for better management of adverse reactions. In this regard, 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. It has been proposed that, once the medication has been commercialised, maybe the patients should be informed through specific information sheets and a process that involves informed consent, which should a priori reduce the number of potential litigations due to safety issues.<a class="elsevierStyleCrossRef" href="#bib0205">7</a>In the immediate post-commercialisation period, there should be a use restriction on the new medication, as is already done in certain “risk management plans”.<a class="elsevierStyleCrossRef" href="#bib0315">29</a> A process like the one described above should be accepted by prescribing physicians and patients. The objective would be that the medication should only be administered to those patients at whom it is targeted, while avoiding its use in conditions other than those stated in the technical card (off-label),<a class="elsevierStyleCrossRef" href="#bib0205">7</a> without undermining the ethics commitment of the physician in the patient's best interest.<a class="elsevierStyleCrossRef" href="#bib0320">30</a>Biopharmaceutical companies should make a commitment to perform and complete post-commercialisation studies in due time and proper form (something which currently does not always happen)<a class="elsevierStyleCrossRef" href="#bib0325">31</a> until the data agreed upon with the regulatory agencies and TAA have been collected. The PA process should create tougher regulations to help avoid this kind of non-compliance. In any case, it must be acknowledged that post-PA studies will no longer need to be controlled trials, and, of course, no placebo is involved. In addition to pragmatic CT, observational studies and data derived from records could be quite useful. Early commercialisation will probably entail less availability of patients to participate in all types of CT. Furthermore, scientific data will also be obtained about the effects of the medications from overlapping studies in the standard medical care setting.Some wonder whether the biopharmaceutical companies will be motivated enough to be a decisive part of the PA process, which means a radical change of the rules of the game.<a class="elsevierStyleCrossRef" href="#bib0250">16</a> This will soon be seen in the EMA's pilot programme. The truth is that certain steps to facilitate the research and development of new medications, and the transition to the PA, are being proposed from the European business world.<a class="elsevierStyleCrossRef" href="#bib0330">32</a>ConclusionsIt 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. The implementation of PA is expected to be slow, careful and progressive, and correctly communicated to the public opinion. Some are already proposing its implementation in certain cases.<a class="elsevierStyleCrossRef" href="#bib0335">33</a> It should be recognised that some unpleasant surprises might arise, as is currently the case with rapid authorizations.<a class="elsevierStyleCrossRef" href="#bib0340">34</a> All the parties involved, especially patients and the NHS, should participate in its development, implementing imaginative solutions to resolve the multiple inconveniences that will gradually appear.Conflict of interestThe authors declare that there are no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:8 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Current commercialisation process of a medication" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Progressive authorization: the acting framework" ] 3 => array:2 [ "identificador" => "sec0020" "titulo" => "Information about progressive authorization" ] 4 => array:2 [ "identificador" => "sec0025" "titulo" => "The conflicting aspects of progressive authorization" ] 5 => array:2 [ "identificador" => "sec0030" "titulo" => "Conclusions" ] 6 => array:2 [ "identificador" => "sec0035" "titulo" => "Conflict of interest" ] 7 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-06-10" "fechaAceptado" => "2014-06-17" "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Dal-Ré R, Carné X. Autorización progresiva: ¿un nuevo camino hacia el acceso temprano de nuevos medicamentos? Med Clin (Barc). 2015;144:275–278." ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Source: European Medicines Agency.<a class="elsevierStyleCrossRef" href="#bib0260">18</a>" "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \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, planned and flexible approximation to commercialise medications. It begins with the authorization of an indication (probably a “niche” indication) for a medication. 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, 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. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab959087.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Also known as adaptive or staged authorization; the European Medicines Agency uses the term adaptive licensing." ] ] ] "descripcion" => array:1 [ "en" => "Progressive authorization<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a>: definition proposed by the European Medicines Agency." ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "TAA: (health) technologies assessment agency; EMA: European Medicines Agency; FDA: Food and Drug Administration." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \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">13</a> \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 \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 \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's “scientific guidelines”<a class="elsevierStyleCrossRef" href="#bib0240">14</a> adapted to progressive authorization \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"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Clinical trials: use of adaptive designs<a class="elsevierStyleCrossRef" href="#bib0245">15</a> \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"> \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">16</a> \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"> \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">17,18</a> \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"></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 \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/risk ratio of the medications with multiple safety and efficacy criteria<a class="elsevierStyleCrossRef" href="#bib0265">19</a> \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"> \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">16</a> \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"> \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’ decisions to the public \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"></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Dialogue among the parties involved \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">20</a> \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"> \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">13,21</a> \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"> \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">16</a> \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"></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Consideration of TAA requirements \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 \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"> \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 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