Editorial
Why is it necessary to produce a BCG strain in Spain?
¿Por qué es necesario tener una cepa de BCG fabricada en España?
a Comité Científico del Ensayo Clínico ENCORE-01
b Laboratorio Mixto de Investigación Traslacional en Cáncer de Próstata, CICbioGUNE-Basurto, IIS Biobizkaia
c CIBERONC
d Dirección Oficina de Relaciones con la Administración Sanitaria de la AEU
e Servicio de Urología, Hospital Universitario Virgen de las Nieves, Granada, Spain
f Universidad de Granada, Granada, Spain
g Servicio de Urología, Hospital Universitario Puerta del Mar, Cádiz, Spain
h Presidencia de la Asociación Española de Urología (AEU)
i Presidencia de la Fundación para la Investigación en Urología de la AEU
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The latter are defined as those having any of the following characteristics: Invading lamina propria (T1) and having highly undifferentiated cells (high grade, GIIb/GIII), with or without associated carcinoma in situ (CIS), isolated CIS without associated papillary, low grade Ta/T1 that also has all three risk factors: multiple, recurrent and >3 cm, high grade Ta that meets two of the above risk factors, low grade T1 with at least two of the risk factors.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In this scenario, and in the absence of more data from clinical trials being conducted with new molecules, BCG is the adjuvant treatment of choice after transurethral resection.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In April 2012, SANOFI-PASTEUR -the world's largest BCG producing center- ceased production of its Connaught strain of BCG, following an FDA inspection visit to its Toronto manufacturing facility. Considering that 80% of the world's production came from these facilities, this caused a worldwide shortage of unsuspected dimensions. Due to this fact, the biopharmaceutical companies that produced other strains tried to increase their production in order to cover the deficit generated. However, the results were uneven due to the difficulty involved in the manipulation of live organisms.</p><p id="par0020" class="elsevierStylePara elsevierViewall">The situation in Spain was similar to other countries without companies marketing their own BCG strain. The availability of BCG strains authorized by the Spanish Agency of Medicines and Health Products (AEMPS) and manufactured outside our borders was very variable as many countries had to be supplied and stock-outs had to be solved. As a result, the AEMPS decided to import strains that were unauthorized for marketing in Spain.</p><p id="par0025" class="elsevierStylePara elsevierViewall">This problem, which would initially have lasted only a few months, has persisted for more than 10 years. During this time, BCG availability in Spain has varied enormously. It has depended on the production of the different biopharmaceutical companies that produce it and on the worldwide demand, with the aggravating circumstance that only the unconsumed surplus in the country of origin could be acquired, as was the case in Japan. To alleviate the negative consequences of the lack of BCG on patients treated in our hospitals, the Spanish Association of Urology (AEU) guided the AEMPS to publish recommendations for the use of BCG, followed by all hospitals and Hospital Pharmacy Services in Spain, including alternatives available at that time.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,7</span></a> This absolute BCG shortage did not allow patients to receive adequate treatment according to the available scientific evidence. In face of this situation, the AEU contacted BIOFABRI Biopharmaceuticals, which had the necessary technology and facilities authorized by the AEMPS for the manufacture of product batches under Good Manufacturing Practices (GMP) conditions, to produce BCG in their facilities with some of the strains marketed in other countries, even though they were not authorized in Spain. The strain chosen was MOREAU RJ, developed in Brazil because of their experience in vaccine format and in intravesical treatment of NMIBT. This strain, similar to the Tokyo strain marketed mainly in Japan, is not capable of synthesizing PDIM (Phthiocerol Dimycocerosate), one of the most important lipids involved in its virulence, thus its safety could be guaranteed.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Several comparative studies have been carried out between the Moreau strain and other strains, but these have been mainly retrospective and with few patients. D'Andrea published their results comparing BCG-Moreau with BCG-TICE strains in intermediate or high-risk non-muscle-invasive bladder cancer. The authors found no differences in either recurrence-free or progression-free survival.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> In this context, the Research Institute (IDI-URO) of the AEU is conducting a prospective clinical trial<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> ENCORE-01 (NCT03982797), in patients with high-risk NMIBC with or without associated carcinoma in situ or carcinoma in situ without associated papillary carcinoma. The trial uses the MOREAU-RJ strain developed by BIOFABRI (Porriño-Pontevedra) after undergoing a manufacturing quality and batch stability audit.</p><p id="par0030" class="elsevierStylePara elsevierViewall">The CUETO risk calculator<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> is used to stratify risk. Additionally, the protocol establishes all patients undergo a second transurethral resection to confirm the absence of disease when BCG instillations are started. Patients are instilled with 80 mg of IMUNO BCG Moreau-RJ. There are 6 instillations on induction phase (once per week) and a one-year maintenance phase with 3 instillations per week at 3, 6 and 12 months. The primary objective is to assess progression-free survival and the secondary objectives are to analyze disease-free survival, quality of life measured with the Functional Assessment of Cancer Therapy-Bladder questionnaire (FACT-BL version 4), adverse reactions and the drop-out rate due to toxicity. As an exploratory objective, the immune response is measured by cytokine analysis.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Fifteen centers committed to recruiting 306 patients, starting in 2019. Due to various reasons, including the pandemic, recruitment in most centers has not been as good as expected. <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">An independent data monitoring committee has been set up, and its report will be sent to the AEMPS for a preliminary evaluation that may allow the Agency's approval of the investigated strain. This would constitute an important milestone in public hospitals, since we would no longer depend on other countries and their availability for supply of BCG.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0040" class="elsevierStylePara elsevierViewall">The ENCORE-01 clinical trial has been funded by BIOFABRI SL.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflicts of interest</span><p id="par0045" class="elsevierStylePara elsevierViewall">The authors are members of the Scientific Committee of the ENCORE-01 Clinical Trial.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Funding" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Conflicts of interest" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1523 "Ancho" => 2956 "Tamanyo" => 318847 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Recruitment status as of October 2023.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:12 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparative outcomes of primary, recurrent, and progressive high-risk non-muscle-invasive bladder cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "F. 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