Tips and tricks for successfully conducting a multicenter study | Gastroenterología y Hepatología (English Edition)

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"apellidos" => "Rodríguez-Gandía" ] 7 => array:2 [ "nombre" => "Juan" "apellidos" => "Turnes" ] 8 => array:2 [ "nombre" => "Manuel" "apellidos" => "Romero-Gomez" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2444382424000932?idApp=UINPBA00004N" "url" => "/24443824/0000004700000006/v2_202409200854/S2444382424000932/v2_202409200854/en/main.assets" ] "en" => array:16 [ "idiomaDefecto" => true "cabecera" => "Special article" "titulo" => "Tips and tricks for successfully conducting a multicenter study" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "649" "paginaFinal" => "660" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Javier P. Gisbert, María Chaparro" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Javier P." "apellidos" => "Gisbert" "email" => array:1 [ 0 => "javier.p.gisbert@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "María" "apellidos" => "Chaparro" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Aparato Digestivo, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Universidad Autónoma de Madrid (UAM), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Reglas y consejos para desarrollar con éxito un estudio multicéntrico" ] ] "textoCompleto" => "IntroductionA multicentre study is a collaborative effort that involves more than one research site in the inclusion and follow-up of patients, uses a common protocol and standardised procedures and then performs a centralised analysis of the data.<a class="elsevierStyleCrossRefs" href="#bib0005">1,2</a> Multicentre studies play a crucial role in research and the advancement of knowledge in a variety of different fields, and in medicine in particular, where they provide support for application to clinical practice. Their importance lies in their ability to address complex and challenging questions that could not be resolved by single-centre studies.Multicentre research can be applied to most study designs, from purely observational to randomised clinical trials. However, not all research questions require a cooperative study to be answered. Although with definite advantages, multicentre studies are obviously more complex and costly (in terms of time and effort) than studies in which only one site is taking part. It is therefore necessary to be clear when, how and why we should conduct this type of study.Advantages of multicentre studiesMulticentre studies have numerous advantages, as summarised in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>, and may be necessary for a number of different reasons.<a class="elsevierStyleCrossRefs" href="#bib0015">3–9</a> The main reason is usually the need to recruit an adequate (larger) number of participants in a reasonable (shorter) time. A larger sample size improves statistical precision and the ability to identify discrete benefits, subtle relationships or rare effects.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Another reason for carrying out a multicentre study is that it helps us obtain a more generalisable sample of the population to be studied. With collaboration between multiple research centres in different geographical locations, multicentre studies provide a broader and more diverse representation of the patient population under study; this in turn increases the external validity and applicability of the results obtained and, also therefore, enables their more direct application to clinical practice.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> Another potential advantage of multicentre studies is that, with standardised protocols, investigators at multiple sites tend to be less prone to different biases that might affect the study, especially if their design is not blinded. In contrast, participants from a single site, all under the supervision of a principal investigator who may be "committed" to the hypothesis to be demonstrated, could be at much greater risk of bias.<a class="elsevierStyleCrossRef" href="#bib0045">9</a>Additionally, a multicentre study makes it possible for investigators with similar interests to work together on a common problem. Collaborative research teams involving members of various professions or disciplines incorporate multiple perspectives, which introduce new knowledge to improve medical care.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> By sharing resources and experience between sites, efficiency in data collection and analysis is increased, saving both time and resources.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> Collaboration networks are then established or consolidated, which can have a very beneficial effect when conducting future studies.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> It is clear that the successful completion of a multicentre study in the past is the best guarantee of future success in the organisation of the next one.Thanks to the high-quality results that tend to be generated, authors who carry out multicentre studies tend to publish in more prestigious journals (although it is true that what matters is not the stature of the journal, but that of the actual study), which often leads to more effective dissemination of the study results.<a class="elsevierStyleCrossRef" href="#bib0060">12</a>In summary, multicentre studies are essential for addressing complex questions, obtaining more robust and applicable results, and significantly contributing to scientific progress and the improvement of medical care. The most effective strategy for increasing both the quantity and, in particular, the quality of research is collaboration between institutions and networks of investigators.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> It cannot be denied that teamwork produces great results.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> Coming together gives us strength, and this is especially true in research.<a class="elsevierStyleCrossRefs" href="#bib0035">7,16</a> However, conducting a multicentre study presents important challenges and difficulties that have to be effectively addressed to guarantee success.Aims of this manuscriptWe have discussed the fact that, although there are numerous advantages, conducting multicentre studies is complex. The fundamental aim of this article is to share our experience with investigators who are considering taking on the challenge of setting up a multicentre study. We review a series of tricks and tips which, in our opinion, are essential for successfully reaching port and not sinking in the attempt. That said, we do not set out merely to list a set of theoretical recommendations, but to offer some personal suggestions based on our own experience, which are therefore of a highly practical nature.Leadership by the principal investigatorA multicentre trial has to have an identifiable leader, a principal investigator, who must be able to effectively direct collaborators and keep the project on track and under control. Some might think that the best way to lead a multicentre study is to have a large group of people, to form a large committee. However, experience shows that this strategy tends not to be very successful.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> Concrete and solid leadership (from one or very few people) is essential for successfully conducting multicentre studies. Being a good leader (of a multicentre study or indeed of any company) requires a combination of management, communication, organisation and empathy skills. Ideally, a leader of a multicentre study should be communicative, organised, adaptable, motivating, decisive, collaborative, empathetic, an informed decision maker, resilient, a constant learner, ethical, time-efficient and visionary. Honesty and integrity are the most valuable and valued qualities of a leader.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> Leaders have (and communicate) a clear vision and choose (and articulate) a precise direction. Leaders think and talk about solutions, whereas followers focus on problems. Good leaders inspire, encourage and, only when necessary, impose discipline.<a class="elsevierStyleCrossRefs" href="#bib0080">16,17</a>The principal investigator/coordinator of a multicentre study does not have to occupy a senior position in a scientific body or society. Although that may be a "political" advantage, it may also make it difficult for the person to dedicate the time required to properly coordinate a study of this type on a day-to-day basis.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> A fundamental characteristic of a good principal investigator is clearly previous experience in the area to be studied and recognition as an expert by the rest of the group. Even more important, however, are perseverance and dedication, two essential requirements that shape and channel the passion for research. As Zig Ziglar rightly pointed out, “Your attitude, not your aptitude, will determine your altitude”.<a class="elsevierStyleCrossRef" href="#bib0080">16</a>Perseverance and discipline will help you to maintain a high rate of work and scientific output for long periods of time, which is the key to lasting success in the world of research. Our capacity for resistance is particularly put to the test when coordinating a multicentre clinical trial, when it often takes longer than initially estimated to enrol fewer patients than hoped for, and unforeseen obstacles always arise.<a class="elsevierStyleCrossRef" href="#bib0090">18</a> We must not allow the numerous bureaucratic barriers, which often represent a real challenge in our path as investigators, to discourage us. Even a small observational, retrospective study involves a long list of requirements, including the approval of the Independent Ethics Committee and eventually the signing of contracts with the participating sites. For clinical trials in particular, logistical complications can turn an exciting idea into a seemingly impossible mission.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> However, we should not be discouraged by problems that arise before or during the study. Tenacity and perseverance are key for our project to be brought to a successful conclusion.Even the most successful principal investigator has experienced moments of crisis coordinating a multicentre clinical trial and questioned whether all the effort is worth it. At such times, when we feel on the verge of giving up and are considering throwing in the towel, is precisely when we should look back and remember what our motivation was for starting in the first place.<a class="elsevierStyleCrossRef" href="#bib0080">16</a>Lastly, we believe that the best way to be successful in leading a multicentre study is to try to replicate the qualities which, if we were to be collaborators (recruiters) in a study, would convince us to participate in one and not another. We need to remember that a large number of multicentre studies are now being conducted and competition can be fierce, and also that, unfortunately, many such studies which do start, having invested both time and energy, are not brought to a successful conclusion. Certainly, as contributors to the study, we would agree to participate if the coordinator offers us assurance (usually based on their leadership, reputation and previous successes) that the study will be relevant, successfully completed and result in a first rate publication.Definition of clear, viable and relevant objectivesThe objectives are one of the most important parts of a research proposal. They are goals that the investigator sets in relation to the aspects they wish to investigate and learn about. The objectives act as pillars that guide the research and direct the search for answers throughout the journey. Properly defining the objectives in a multicentre study is fundamental in ensuring that the results are relevant and the impact of the research maximised.The principal investigator is usually the person who formulates the initial research question and is the architect of the protocol. Although formulating research questions may seem to be a simple process, in reality it is far from easy. It is not uncommon to come across research projects that are confused, answer questions that have not been adequately posed, or fail to address questions that should have been asked from the start.<a class="elsevierStyleCrossRef" href="#bib0095">19</a>As a preliminary consideration, to accurately establish the objectives of our study it is obviously essential to have a clear understanding of the hypothesis and the research question.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> Our study's objectives must be clear (crystal clear), specific (beginners often tend to pose questions that are too broad), assessable (measurable), viable (achievable) and relevant (of social, health or scientific interest).<a class="elsevierStyleCrossRefs" href="#bib0050">10,19–21</a> Defining clear objectives in a multicentre study involves establishing specific and measurable goals that are relevant, achievable and with a defined time frame. The use of the PICO format (Patient/Intervention/Comparison/Outcome) can help us formulate a clear and precise research question.When we are developing a research project, particularly to qualify for possible funding, and especially if it is multicentre in nature, one aspect must be perfectly clear and carefully expressed in the proposal: its feasibility.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> This element is essential to ensure confidence and the maximum rating from the assessors. Feasibility implies coherence between the objectives and methodology of the study, including the work plan, distribution of tasks, available resources and the requested budget. While the ideal is to present a proposal that is both innovative and ambitious, it must also be credible in terms of content and timeline.<a class="elsevierStyleCrossRef" href="#bib0095">19</a>Clear and detailed protocol designOur research project must include a detailed written plan that covers all the scientific, ethical and logistical aspects of the study we are preparing to conduct. The objective of the protocol is to present and describe in detail what is going to be investigated, the conceptual theoretical basis, the methodological components and the human, technical and financial resources that will be necessary to carry out the research.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> The protocol is the culmination of all the work we have done in the research planning phase, and becomes a reference for the investigators during the conduct of the study.<a class="elsevierStyleCrossRef" href="#bib0110">22</a> Also, as mentioned in the previous section, it must contain sufficient information so that others (investigators or assessors) can assess its feasibility.<a class="elsevierStyleCrossRef" href="#bib0095">19</a>Putting together a quality protocol requires considerable effort and time, but it is worth it, as it is the main guarantee that you will successfully achieve your objectives.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> Of particular importance, the methodology section should provide a thorough description of the planned actions: how, when and where.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> However, this section should not be limited to a simple list of the techniques to be used, but rather is about establishing a logical connection between the formulated objectives and the outlined methodological approach. The fundamental purpose of the methodology section in a research project is to clearly explain the design of the study and the procedures that the investigators will follow to address each of the stated objectives.<a class="elsevierStyleCrossRef" href="#bib0095">19</a>If we wish to conduct a study at multiple sites, we need to make a concerted effort to guarantee uniformity across the board.<a class="elsevierStyleCrossRefs" href="#bib0115">23–25</a> Given that any difference in the way the protocol is interpreted can negatively affect the final uniformity of the study, for multicentre studies where, by definition, very diverse investigators will be participating, the interpretation must be particularly clear and detailed. Precise and unambiguous protocol design, in addition to standardisation of procedures, is therefore vital because it guarantees the consistency, quality and reliability of the data collected and the results obtained.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> Depending on the type of study, the preparation of a detailed protocol may not be enough, with training and qualification of the research staff at each site sometimes required.<a class="elsevierStyleCrossRefs" href="#bib0040">8,11,27–30</a> This reduces variability and minimises bias that could arise due to differences in local practices, minimising the risk of uncontrolled factors distorting the results.<a class="elsevierStyleCrossRefs" href="#bib0055">11,29,30</a> The standardisation of procedures in a multicentre study also simplifies coordination and communication between sites, as all of them will be adhering to the same methodology. This saves time and resources by avoiding misunderstandings in how to interpret procedures.Especially when it is a clinical trial, the study should be registered on a specific platform approved for the registration of clinical studies (such as ClinicalTrials.gov or EudraCT) before the inclusion of the first patient in the study.Sometimes it may be useful to initially propose a preliminary or pilot study, before launching into organising a complex multicentre study with everything it entails. A pilot study can help us better develop the final protocol of our definitive clinical trial, for example, by polishing aspects of the design or more reliably estimating the sample size. It can also give us very important information about the feasibility of the study, the realistic recruitment rate and the expected loss rate. Furthermore, carrying out a pilot study will help us confirm whether or not the Case Report Form (CRF) or other study procedures work correctly. A pilot study will also be very useful to more accurately estimate the cost of our final study. In another vein, having results (or even publications) from a pilot study makes it easier to obtain the funding necessary to conduct the full study in the various public and private calls for research projects, as it demonstrates to the assessors our previous experience in the subject and the feasibility of the proposal. It is also important to recognise that, if the study sample size can be reasonably estimated from previous publications and it is considered that logistical barriers will be limited, a pilot study may not contribute substantially to developing the final multicentre study protocol, while it will probably involve a not insignificant cost in terms of time and money. Lastly, it may be a good idea to include in the protocol the planning of an interim analysis when a certain percentage of the sample size is reached, so that, in the event of obtaining a negative or inconclusive result, a futility analysis could be performed to indicate the advisability of ending the study early.<a class="elsevierStyleCrossRef" href="#bib0145">29</a>Careful selection of sites and investigatorsOne of the most important decisions a principal investigator has to make concerns which investigators are going to participate in their multicentre study, as reaching recruitment targets and maintaining quality standards and, hence, obtaining valid results sufficient for making rigorous conclusions, will all be dependent on the people selected. Choosing the right investigators in a multicentre study is therefore one of the most important factors for a project to be carried through and, more importantly, completed successfully. We would like to share with the reader the following series of tips which, in our experience, can be useful when making this selection.<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0100">a)Selecting a broad range and a large number (while being sensible) of different sites is an important aspect in our opinion. When considering carrying out a multicentre study, it should be considered that very often the organisational work will be almost as arduous whether we restrict ourselves to a small group of local sites (for example, in the same city) or expand it nationally, involving multiple regions. Obviously, this is not always the case, but often making that extra effort to expand our borders is worth it, as we can obtain faster results and, even more importantly, increased relevance and scientific impact. The really difficult factor is devising a good research idea. We need to think "big" and not let the fear of expanding the scope of our study detract from its chances of success. That said, it is important to point out that careful selection of study collaborators is obviously essential. There are those who maintain that "the success of a research project is usually inversely related to the number of people on whom it depends".<a class="elsevierStyleCrossRef" href="#bib0150">30</a> What is clear is that, in most cases, the quality (of the investigators) is more important than the quantity. We will return to this point when sharing the last of our tips: selecting committed investigators.</li><li class="elsevierStyleListItem" id="lsti0105">b)Ideally we should choose sites with research experience, especially if specifically related to the proposed study, and with adequate resources and infrastructure to carry it out. This requirement will obviously depend on the type of project; a simple epidemiological/observational study (in which all that is essentially required is to recruit patients who suffer from the disease under study) is not the same as a double-blind randomised clinical trial (in which the organisational aspects will be important) or another of a more basic nature (where the correct processing of the samples by the laboratory staff of each site is the crucial factor). The availability of a study coordinator at the site to be included is essential in multicentre studies of reasonable complexity (for example, a clinical trial with medicinal products). When we do not know the potential capacity of some sites to participate (typically, when the study does not simply involve including patients in the clinic or reviewing medical records, but calls for a more complex infrastructure), it may be useful to use a feasibility questionnaire prior to selecting the participants.</li><li class="elsevierStyleListItem" id="lsti0110">c)Geographical and demographic diversity should be taken into consideration when selecting sites, to ensure the representative nature of the population included in the study and the subsequent generalisation of the results.</li><li class="elsevierStyleListItem" id="lsti0115">d)Searching for alternatives to failed sites quickly is essential, especially in studies where reaching the predefined sample size is important; for example, in comparative clinical trials.<a class="elsevierStyleCrossRef" href="#bib0155">31</a> It should not be forgotten that, on average, less than half of the sites that participate in a multicentre study manage to meet their recruitment targets.<a class="elsevierStyleCrossRefs" href="#bib0160">32,33</a> Inability to reach the calculated sample size may result in biased studies without sufficient statistical power to reach a reliable conclusion.<a class="elsevierStyleCrossRefs" href="#bib0155">31,34,35</a> Therefore, when problems arise (repeated delays in responding to various requests, failure to complete different tasks) that are clear warning signs, we should try to resolve them as soon as possible. If this is not possible, we need to identify alternative sites/investigators early, as the administrative process of including new candidates takes at least a few months.</li><li class="elsevierStyleListItem" id="lsti0120">e)Although we have a Contract Research Organisation (CRO) - a company that provides clinical trial management services - the principal investigator should select all participating investigators. CROs typically base their selection on information obtained from feasibility questionnaires, including, for example, the number of patients the participating investigator thinks they will include. However, this information is not sufficiently reliable and is often far removed from reality (i.e., the actual recruitment rate at the end of the study). For all these reasons, we honestly believe that we, the principal investigators ourselves, know best who may be the most appropriate candidates to participate in each study.</li><li class="elsevierStyleListItem" id="lsti0125">f)Having national coordinators, one in each country, in international studies can be of great help. Their main functions, in addition to providing us with different organisational or logistical support, would be to initially help us in selecting investigators from that country and, subsequently, to continuously stimulate their inclusion of patients.</li><li class="elsevierStyleListItem" id="lsti0130">g)Encouraging investigators from other sites to lead a sub-analysis derived from the overall project can motivate their collaboration. This is especially feasible in projects in which multiple biological samples are obtained from patients as, for example, this would allow various diagnostic techniques to be performed on them.</li><li class="elsevierStyleListItem" id="lsti0135">h)We have left the key factor for last, the one we consider essential: the commitment of the investigator. Generally, what matters, more than the site itself, is the enthusiasm or passion of the investigator at the site.<a class="elsevierStyleCrossRef" href="#bib0180">36</a> Commitment is a very personal quality, and is only demonstrated by example. Commitment and having fulfilled expectations in a previous study are the best predictors of future success in another.<a class="elsevierStyleCrossRefs" href="#bib0045">9,37,38</a> The dedication of time is essential here. In fact, one of the main barriers to proper participation in a multicentre study is the investigator's lack of availability/dedication.<a class="elsevierStyleCrossRef" href="#bib0195">39</a> The professional or academic hierarchy of the potential investigator is therefore of little relevance here. Highly reputable scientists (who could certainly add prestige to a study) are not always successful in collaborative ventures like the ones we are discussing here. A head of department may or may not be a good candidate to participate in a multicentre study, as it all depends on their commitment and the amount of time they are able and willing to dedicate.<a class="elsevierStyleCrossRef" href="#bib0200">40</a> However, relatively unspecialised professionals who work in regional hospitals may be very willing to participate in this type of study and be very effective collaborators. In short, we need to choose committed investigators, with the confidence that they will fulfil the initial agreements (such as, for example, recruiting the agreed number of patients). It is clear that this commitment is not always easy to honour because it depends on a number of factors, some of which are beyond our control. However, it is crucial to select collaborators who have a realistic perception of their capabilities, as, if they ultimately cannot deliver as agreed, they could jeopardise the viability of the project. A typical example is the process of including patients in a clinical trial. The mistake is often made of trying to participate in multiple (too many) (competing) studies at the same time and committing to a number of patients that is not realistic or feasible. In fact, inclusion rates in multicentre clinical trials have decreased dramatically in recent years.<a class="elsevierStyleCrossRef" href="#bib0195">39</a> One of the main reasons for this is the exponential increase in the number of these types of studies around the world, many of which compete in terms of inclusion criteria and target patient population.<a class="elsevierStyleCrossRef" href="#bib0205">41</a></li></ul>Meticulous designing of the case report formThe use of a CRF, usually electronic, in multicentre studies is essential due to its numerous benefits in terms of speed, precision, standardisation, quality and efficiency.<a class="elsevierStyleCrossRefs" href="#bib0210">42,43</a> The electronic CRF also facilitates remote monitoring and early detection of any errors. The data can be reviewed continuously, which helps to identify inconsistencies or deviations, enabling rapid intervention and prevention of such problems. Therefore, an additional challenge faced by the principal investigator in the early stages of a multicentre study is developing such a CRF. Although it may not seem so important, this phase is in fact crucial and has a very significant impact on the quality of the final results. In other words, a poorly designed CRF will inevitably collect low-quality data.The introduction of the electronic CRF has been a milestone in the field of data collection. It seems pertinent here to highlight the role of REDCap (Research Electronic Database Capture, <a href="https://www.project-redcap.org/">https://www.project-redcap.org/</a>).<a class="elsevierStyleCrossRef" href="#bib0220">44</a> This platform includes computer software that enables the design, development and management of electronic CRFs in research studies. This tool is characterised by its ease of use for both investigators and monitors, and offers functions and services superior to most private providers. Moreover, it provides the tools necessary for efficient data analysis, online statistics generation, monitoring, collecting data on mobile devices and a multitude of extra functions. The REDCap platform significantly reduces the costs associated with traditional CRFs and so encourages the development of projects driven by investigators, outside the interests of private industry (it is important to highlight that the use of this software is limited exclusively to non-commercial research).<a class="elsevierStyleCrossRefs" href="#bib0215">43,45</a>The CRF can be designed by a CRO, but we are convinced that it is most effective (and efficient) for it to be developed by the research team itself. No one knows the ideal way to include information in a CRF better than the investigators responsible for the study. These people have detailed knowledge of the disease being studied and, at the same time, will appreciate like no one else the clarity and simplicity that a CRF should have.When designing the CRF, we must strive to select all the data relevant to the study, but only the essential data.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> This is the cardinal rule for the CRF designer and, although it may seem over-dramatic, we have to be prepared to adhere to that rule, as we will almost certainly be tempted to break it (either ourselves or because of external requests). In this field, quantity and quality are frequently not compatible. It is essential to avoid unnecessary questions or repetitions. We should not ask for data that can be extrapolated from others already included. The language used must be clear and simple, with concise, unambiguous sentences, minimising the use of abbreviations as far as possible.Lastly, it is essential that the CRF be reviewed by several members of the research team (in addition to the principal investigator), including monitors and statisticians, before considering it final. Making significant changes to the CRF once the study is underway is costly and risky, and this justifies the initial investment in time to design it carefully.<a class="elsevierStyleCrossRefs" href="#bib0215">43,46</a>Effective and centralised project management: the importance of the coordinating siteOne of the main challenges of any multicentre study is the coordination between the multiple participating centres, each with its own infrastructure, personnel and procedures. Centralised management in multicentre studies plays a critical role in the coordination and success of collaborative research. Maintaining effective and efficient collaboration, standardising different procedures and ensuring consistency in data collection and handling requires careful planning and supervision; and for this it is essential to have a well-organised coordinating centre and a functional governance mechanism.<a class="elsevierStyleCrossRefs" href="#bib0115">23,35,47–49</a>The management of a multicentre study is more intricate than one might imagine, as it involves multiple stakeholders (for example, sponsors, investigators, study coordinators, ethics committees, health authorities, legal departments, monitors and patients).<a class="elsevierStyleCrossRef" href="#bib0250">50</a> In addition, it is essential to adhere to good clinical practice, a series of requirements that guarantee protection of the rights, safety and well-being of the study subjects, as well as the reliability of the results. In particular, the logistics of coordinating ethical and regulatory approvals across multiple sites are often complicated and time-consuming.<a class="elsevierStyleCrossRef" href="#bib0255">51</a> Synchronising deadlines and managing required documentation are critical for avoiding delays. The administrative burden for the investigators at the different centres needs to be kept to a minimum and, to do so, assistance needs to be provided from the coordinating centre.Centralised management allows for closer supervision and rigorous quality control at all the participating centres. This means procedures and protocols can be uniform and followed consistently, resulting in comparable and reliable data. Additionally, an effective coordinating centre facilitates fluid, two-way communication between the coordinating research team and individual sites, allowing challenges to be addressed and problems resolved quickly and efficiently.Generally, the administrative management of studies is entrusted to a CRO, which functions as an intermediary between the sponsor and the other parties involved in conducting the study.<a class="elsevierStyleCrossRefs" href="#bib0235">47,52,53</a> The services provided by a CRO vary depending on the phase the study is in. The start-up phase includes developing the research protocol, adapting documentation to Spanish legislation, obtaining the necessary approvals from ethics committees and the health authorities, designing the CRF, selecting investigators and negotiating contracts with the sites. Once approval is obtained and the study is underway, the CRO provides monitoring and, if necessary, pharmacovigilance services. Lastly, the CRO takes charge of managing the data obtained by the study, generating reports and overseeing and archiving documentation.<a class="elsevierStyleCrossRef" href="#bib0215">43</a>An attractive alternative, although with a certain degree of complexity in terms of organisation, is to have personnel within the research team itself trained to carry out all the above-mentioned tasks applied to the independent research studies that group leads.<a class="elsevierStyleCrossRef" href="#bib0215">43</a> The main advantage of this option is that these people, being part of the research group, will be familiar with the disease under study, the routine procedures and the idiosyncrasies of the team, and this should guarantee excellent coordination with that team. This approach is particularly productive and profitable when the research group does continuous and sustained research activities over time. In our experience, training personnel on the group's previous projects has a very positive impact on future projects, with their efficiency gradually increasing. This obviously involves an initial investment in human resources and requires having the capacity to hire the specialised personnel and keep them on in the medium-to-long term.<a class="elsevierStyleCrossRef" href="#bib0215">43</a>Finally, an aspect that deserves particular attention is the monitoring of data quality. This is particularly important in multicentre studies, where there are highly likely to be significant differences between the different sites.<a class="elsevierStyleCrossRefs" href="#bib0130">26,27</a> Evaluation and continuous improvement are essential to ensure the quality, effectiveness and validity of the results in a multicentre study. Quality monitoring ensures regulatory compliance in each phase of the study. Monitoring visits to the sites facilitates the evaluation of patient recruitment, as well as the quality, integrity and validity of the data included.<a class="elsevierStyleCrossRefs" href="#bib0120">24–27</a> It is advisable to conduct the initial monitoring visits shortly after the inclusion of the first patients at the corresponding site. Early detection of any problems means corrective measures can be implemented to prevent them from continuing.<a class="elsevierStyleCrossRefs" href="#bib0135">27,54,55</a> Being flexible and able to adapt are essential tools for overcoming obstacles and successfully concluding a multicentre study.In general, the best way to evaluate the quality of a site is with an in-person visit, where the study monitor reviews all signed informed consent forms, official documents and ethics approvals, and then compares the information included in the CRF with that in the medical records, to identify any discrepancies.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> Nonetheless, telematic or remote monitoring reduces costs and improves the efficiency of the process, especially in multicentre studies. The implementation of hybrid designs (in-person and telematic) can be very useful, combining the advantages of efficiency and simplicity (not only from the perspective of the coordinating centre, but also, very importantly, of the investigator at each centre).<a class="elsevierStyleCrossRef" href="#bib0195">39</a>Effective and fluid communication with the investigatorsMany of the problems that arise in a multicentre study are caused by inadequate communication between the principal investigator and the co-investigators from the different sites. Therefore, fluid communication among the investigators plays a fundamental role in the success of collaborative research, especially when, as is often the case, the sites are geographically far apart.<a class="elsevierStyleCrossRef" href="#bib0280">56</a> Effective and constant communication is essential for several reasons.<a class="elsevierStyleCrossRef" href="#bib0280">56</a> First of all, it establishes a solid foundation for understanding the objectives, protocol and expectations of the study at all participating sites; this ensures uniform and consistent implementation of procedures, reducing variability in data collection and improving comparability of results. Secondly, constant communication allows challenges and potential obstacles to be identified as they arise, which facilitates early resolution of problems, minimising delays. Thirdly, regular interaction with investigators promotes a sense of community and collaboration between the different sites. In addition, feedback and the exchange of experiences allow shared learning and joint adaptation to changes during the course of the study. Last but not least, effective communication keeps investigators informed about targets achieved, interim results and pending objectives. Communication is the basis of fidelity in research studies<a class="elsevierStyleCrossRef" href="#bib0280">56</a>; we can hardly demand that the participants in our study act quickly and effectively if we do not show our interest and keep them periodically informed. All of this stimulates the collaboration, commitment and motivation of investigators, who feel valued and in tune with the objectives of the research project; communication between investigators becomes the “glue” that effectively bonds the various components of a successful multicentre study.There are many different and complementary means of communicating with investigators, mainly involving telephone calls, emails and newsletters. It may also sometimes be a good idea, or even necessary, to organise face-to-face meetings<a class="elsevierStyleCrossRef" href="#bib0285">57</a>; to do this, we could take advantage of the scientific events that many of these professionals attend. Remote meetings, by videoconference, can be sufficient in most cases, and are also much more convenient and economical (especially in multinational studies), although the communicative effectiveness of face-to-face meetings is undeniable.<a class="elsevierStyleCrossRef" href="#bib0270">54</a> In addition to group meetings, it is often necessary to hold other personal meetings with the investigator from a specific site, for example, when a problem at that site is identified. In meetings with investigators, whether in-person or remote, open communication should be encouraged, where they can ask questions, express concerns and offer suggestions. For example, a site that is particularly effective in recruiting patients could share its experience and so help inclusion by other investigators.Newsletters enable periodic (for example, monthly) updates on study status, progress, milestones reached and next steps. It is recommended that they be brief, concise, specific and also intuitive, with a predominance of figures and graphs over written information. These iconographic bulletins are especially useful for providing updates on the sites' progress in patient recruitment; publicly sharing this information can have an incentive effect stimulated by healthy competition. Public recognition and appreciation of investigators' contributions as the study progresses can also be encouraging.An essential aspect of an effective communication strategy is the dissemination of study results and the celebration of various achievements.<a class="elsevierStyleCrossRef" href="#bib0290">58</a> Sharing results with investigators in a multicentre study is of utmost importance, as it strengthens transparency, promotes collaboration and maximises the impact of the research. Dissemination of results can lead to new discoveries, innovative approaches and additional scientific advances, amplifying the value of the investment made in the initial multicentre study. Dissemination also reinforces the prestige of the participating sites and the reputation of their investigators in particular. In light of the above, it is essential to design a good communication plan to share the results of the study both within the scientific community and with the general public.In relation to the dissemination of the study results in scientific forums, the preparation of abstracts and their presentation at conferences is essential. This allows the early dissemination of the study, well before the complete article that will eventually be published in a scientific journal can be finalised, especially when it comes to preliminary results or interim analyses. Although this involves additional work for the principal investigator, it is worthwhile as, for the co- investigators, this is obvious confirmation that the study is on the right track or that it has even come to a successful conclusion. The preparation and publication of the full article in a scientific journal will be discussed in the next section.Finally, celebrating the achievements of a multicentre study has a very positive influence on the motivation and cohesion of investigators. Recognising and commemorating milestones achieved is not only personally rewarding, but also has a positive impact on the quality and success of the project. The celebration of achievements recognises the hard work, dedication and commitment of all the investigators involved at the different sites. This creates a positive environment, fosters a sense of belonging to the group and strengthens team morale, which in turn increases motivation and job satisfaction. Anyone who has even minimal responsibility in managing or coordinating human teams knows perfectly well that a motivated team tends to be more productive and more willing to face up to challenges with determination.Clear (and generous) authorship policy and commitment to publishMulticentre studies increase the complexity of determining authorship of the resulting publications, which can pose unique practical and ethical challenges.<a class="elsevierStyleCrossRef" href="#bib0295">59</a> Authorship in multicentre studies therefore requires careful planning to meet ethical standards, promote a fair distribution of credit and avoid potential conflict. It is essential to clearly establish a priori the rules of authorship and publication, in order to guarantee transparency, equity and credibility in the dissemination of the results. The criteria on which the selection of authors will be based must be made clear from the beginning (for example, defining a minimum number of patients recruited). Naturally, this order can only be specified at the end of the study, when the relative contributions can be accurately assessed.<a class="elsevierStyleCrossRef" href="#bib0300">60</a> In any case, the final order of authorship should be clearly determined before starting to write the first draft of the manuscript.<a class="elsevierStyleCrossRefs" href="#bib0305">61,62</a>To start with, the concept of authorship must be clearly established.<a class="elsevierStyleCrossRefs" href="#bib0305">61–63</a> The International Committee of Medical Journal Editors (ICMJE) states that authors must be active contributors to the study, participate in the preparation of the manuscript, approve the final content and accept responsibility for its publication. That said, our philosophy is to try to provide the maximum possible representation, being generous (as well as fair) with the investigators, who are fully deserving of it. We try, as far as possible, to include the maximum number of authors who have made a significant contribution to the study and that the journal allows. When there is a large number of authors and they cannot all be included on the front page of the manuscript, the rest of the investigators (usually called collaborators) should be included in a list as an addendum, linked by an asterisk located after the name of the research group at the end of the list of main authors. In this case, it is important to confirm with the editor of the journal in which the article is to be published that all authors included in this appendix will be linked to the manuscript's PubMed reference, so they are identified as co-authors when searching for this manuscript in that search engine; this is the only way these authors will have a contribution equivalent to being a signatory of the article in terms of including it on their curriculum vitae.Journal embargo and copyright rules often prevent dissemination of results before manuscript publication. Therefore, the research team needs to carefully plan the best strategy to disseminate these results through traditional media (for example, television or newspapers), social networks, webinars, podcasts or blogs once they have been published.<a class="elsevierStyleCrossRef" href="#bib0090">18</a>Last of all, it is essential to comply with reasonable publication deadlines.<a class="elsevierStyleCrossRef" href="#bib0135">27</a> Our role as coordinators must be to guide the project to a successful conclusion, and this means not only the successful completion of the study, but also the prompt and appropriate publication of the results. Unfortunately, this is not always achieved. An analysis of 244 randomised clinical trials funded by a research agency showed that only 57% of the results of these studies were published within 30 months after the trial ended.<a class="elsevierStyleCrossRef" href="#bib0320">64</a> Furthermore, for many of these funded projects, no publication deriving from their results was ever generated.<a class="elsevierStyleCrossRef" href="#bib0320">64</a> The following is a series of tips we want to share with the reader, which, in our experience, can be useful for guaranteeing appropriate and timely publication of the results of a multicentre study.<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0140">a)First of all, we should plan at an early stage when the article (or more frequently articles) deriving from the study will be published.</li><li class="elsevierStyleListItem" id="lsti0145">b)Initially, it is practical to publish the study protocol, particularly the methodology aspects, as this can have several benefits: it is usually quick to write (as much of the information should already be in the initial study protocol); it facilitates subsequent publication of the full article (among other things because it will save space, if necessary, as different aspects of methodology can be referenced); and it serves as encouragement for the investigators, who can see how their hard work is beginning to bear fruit.</li><li class="elsevierStyleListItem" id="lsti0150">c)We can begin writing the introduction section of the manuscript even before the study is completed and the results have been analysed. We have already seen that the methods section will be all but finalised after the publication of the protocol. The literature review should have already been carried out in the initial stages of the study, so it should be quick and easy to organise the articles to be included using a bibliographic reference manager.</li><li class="elsevierStyleListItem" id="lsti0155">d)Once we have written the draft of the manuscript, we should circulate it amongst the rest of the investigators, giving the co-authors a reasonable, but relatively short, period of time to review it and make their suggestions. In our experience, if we do not hear back from an investigator within a couple of weeks, we are probably not going to, so we think that time frame may be sensible.</li><li class="elsevierStyleListItem" id="lsti0160">e)If the article is rejected by one journal, we should submit it to another as soon as possible, getting over the disappointment quickly to avoid unnecessary delays. In most cases, the article can be resubmitted as it is to another journal, since the "major" items of criticism received by the first would be difficult to correct, given they were the reason for the unconditional rejection. Only if there are indisputable comments from reviewers that can be feasibly and realistically implemented is it worth including them. We should remember that it is not uncommon for the suggestions of the first journal's reviewer to be completely different from those of a second journal's reviewer, so it is probably not worth wasting time making changes that may be unnecessary.</li><li class="elsevierStyleListItem" id="lsti0165">f)Lastly, if the article is potentially accepted (typically, when we are asked for "major changes"), we should strive to submit the revised version as soon as possible, ideally within a few weeks (not months), unless new analyses of the data or substantial modifications are required.<a class="elsevierStyleCrossRef" href="#bib0325">65</a> We should not allow ourselves to procrastinate, but tackle the often arduous task of responding to the reviewers as soon as possible and so make sure that the article is finally accepted.</li></ul>ConclusionsMulticentre studies generate quality, generalisable medical data that can change clinical practice, which is why they are considered the backbone of evidence-based medical care. There is no doubt that there are many benefits associated with these studies, but to conduct them, solid leadership, detailed planning, constant and meticulous coordination, multidisciplinary collaboration and an effective communication strategy are required; and, above all, a strong commitment from the entire research team. In this manuscript we have shared with the reader a series of recommendations that we consider important to successfully conduct a multicentre study, which are summarised in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>. We hope that these suggestions will encourage some investigators to carry out such studies and, in doing so, we can all improve the quality of research and its application to clinical practice. Finally, we would like to conclude this article by sincerely thanking all the investigators who have collaborated with generosity and commitment to the various multicentre studies that we have had the privilege of coordinating, as well as the staff of our local research team for their outstanding competence and dedication.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Conflicts of interestJ.P. Gisbert has provided scientific advice and support for research and/or training activities for MSD, Abbvie, Pfizer, Kern Pharma, Biogen, Mylan, Takeda, Janssen, Roche, Sandoz, Celgene/Bristol Myers, Gilead/Galapagos, Lilly, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, Norgine, Vifor Pharma, Mayoly, Allergan, Diasorin, Gebro Pharma and Richen.M. Chaparro has provided scientific advice and support for research and/or training activities for: MSD, Abbvie, Hospira, Pfizer, Takeda, Janssen, Ferring, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma and Lilly." "textoCompletoSecciones" => array:1 [ "secciones" => array:16 [ 0 => array:3 [ "identificador" => "xres2247045" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1879526" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2247044" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1879527" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Advantages of multicentre studies" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Aims of this manuscript" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Leadership by the principal investigator" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Definition of clear, viable and relevant objectives" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Clear and detailed protocol design" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Careful selection of sites and investigators" ] 11 => array:3 [ "identificador" => "sec0040" "titulo" => "Meticulous designing of the case report form" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Effective and centralised project management: the importance of the coordinating site" ] ] ] 12 => array:3 [ "identificador" => "sec0050" "titulo" => "Effective and fluid communication with the investigators" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "Clear (and generous) authorship policy and commitment to publish" ] ] ] 13 => array:2 [ "identificador" => "sec0060" "titulo" => "Conclusions" ] 14 => array:2 [ "identificador" => "sec0065" "titulo" => "Conflicts of interest" ] 15 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1879526" "palabras" => array:5 [ 0 => "Clinical trial" 1 => "Success" 2 => "Researcher" 3 => "Investigation" 4 => "Multicenter" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1879527" "palabras" => array:5 [ 0 => "Ensayo clínico" 1 => "Éxito" 2 => "Investigador" 3 => "Investigación" 4 => "Multicéntrico" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Multicenter studies play a crucial role in medical research and advancement, facilitating the application of new knowledge to clinical practice. These studies are associated with multiple benefits but are more complex than those involving a single center. With the philosophy that most of the qualities required to lead a multicenter study depend on attitude and can be learned, developed, and improved, in this manuscript, we share with the reader a series of recommendations that we consider important for successfully conducting such studies. The tips and tricks that will be discussed in detail are as follows: effectively leading the project; clearly defining viable and relevant objectives; designing a clear and detailed protocol; carefully selecting centers and collaborating investigators; meticulously designing the case report form; centrally managing the project efficiently; maintaining fluent communication with investigators; and, finally, designing a clear authorship policy and ensuring the appropriate publication of the study results. We hope that these suggestions encourage potential researchers to conduct multicenter studies, thereby collectively enhancing the quality of research and its application to clinical practice." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Los estudios multicéntricos desempeñan un papel crucial en la investigación y el avance de la medicina, favoreciendo la aplicación de los nuevos conocimientos a la práctica clínica. Estos estudios se asocian con múltiples beneficios, pero son más complejos que aquellos en los que participa un único centro. Con la filosofía de que la mayoría de las cualidades que se requieren para liderar un estudio multicéntrico dependen de la actitud, y pueden aprenderse, desarrollarse y mejorarse, en el presente manuscrito compartimos con el lector una serie de recomendaciones que consideramos importantes para llevar a cabo con éxito este tipo de estudios. Las reglas y consejos que se tratarán con detalle son las siguientes: liderar eficazmente el proyecto; definir claramente unos objetivos viables y relevantes; diseñar un protocolo claro y detallado; seleccionar cuidadosamente los centros y los investigadores colaboradores; diseñar minuciosamente el cuaderno de recogida de datos; gestionar, de forma centralizada, eficazmente el proyecto; mantener una comunicación fluida con los investigadores; y, finalmente, diseñar una política de autorías clara y garantizar la adecuada publicación de los resultados del estudio. Esperamos que estas sugerencias animen a los potenciales investigadores a llevar a cabo este tipo de estudios multicéntricos y, al hacerlo, mejoremos entre todos la calidad de la investigación y su aplicación a la práctica clínica." ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "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-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">•Make it easier to address complex issues</li><li class="elsevierStyleListItem" id="lsti0010">•Enable inclusion of a larger number of patients (and consequently increase the statistical power)</li><li class="elsevierStyleListItem" id="lsti0015">•Are able to include patients more quickly</li><li class="elsevierStyleListItem" id="lsti0020">•Allow greater generalisation of the results</li><li class="elsevierStyleListItem" id="lsti0025">•Facilitate applicability to clinical practice</li><li class="elsevierStyleListItem" id="lsti0030">•Reduce the risk of bias</li><li class="elsevierStyleListItem" id="lsti0035">•Optimise data collection and analysis</li><li class="elsevierStyleListItem" id="lsti0040">•Encourage collaboration between different investigators</li><li class="elsevierStyleListItem" id="lsti0045">•Promote the development of future research studies</li><li class="elsevierStyleListItem" id="lsti0050">•Increase academic recognition</li><li class="elsevierStyleListItem" id="lsti0055">•Facilitate the publication of the results in scientific journals</li></ul> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3662063.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Advantages of multicentre studies." ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "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-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0060">•Lead the project effectively</li><li class="elsevierStyleListItem" id="lsti0065">•Clearly define viable and relevant objectives</li><li class="elsevierStyleListItem" id="lsti0070">•Design a clear and detailed protocol</li><li class="elsevierStyleListItem" id="lsti0075">•Carefully select collaborating sites and investigators</li><li class="elsevierStyleListItem" id="lsti0080">•Design the case report form meticulously</li><li class="elsevierStyleListItem" id="lsti0085">•Manage the project centrally and effectively</li><li class="elsevierStyleListItem" id="lsti0090">•Maintain fluid communication with investigators</li><li class="elsevierStyleListItem" id="lsti0095">•Design a clear authorship policy and guarantee the proper publication of the study results</li></ul> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3662062.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Tips and tricks for successfully conducting a multicentre study." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:65 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Multicentre clinical trials: Bradford Hill’s contributions and some subsequent developments" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "J.L. 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Tips and tricks for successfully conducting a multicenter study

Reglas y consejos para desarrollar con éxito un estudio multicéntrico

Javier P. Gisbert

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javier.p.gisbert@gmail.com

Corresponding author.

, María Chaparro

Servicio de Aparato Digestivo, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Universidad Autónoma de Madrid (UAM), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0100" class="elsevierStylePara elsevierViewall">A multicentre study is a collaborative effort that involves more than one research site in the inclusion and follow-up of patients&#44; uses a common protocol and standardised procedures and then performs a centralised analysis of the data&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> Multicentre studies play a crucial role in research and the advancement of knowledge in a variety of different fields&#44; and in medicine in particular&#44; where they provide support for application to clinical practice&#46; Their importance lies in their ability to address complex and challenging questions that could not be resolved by single-centre studies&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Multicentre research can be applied to most study designs&#44; from purely observational to randomised clinical trials&#46; However&#44; not all research questions require a cooperative study to be answered&#46; Although with definite advantages&#44; multicentre studies are obviously more complex and costly &#40;in terms of time and effort&#41; than studies in which only one site is taking part&#46; It is therefore necessary to be clear when&#44; how and why we should conduct this type of study&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Advantages of multicentre studies</span><p id="par0110" class="elsevierStylePara elsevierViewall">Multicentre studies have numerous advantages&#44; as summarised in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#44; and may be necessary for a number of different reasons&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#8211;9</span></a> The main reason is usually the need to recruit an adequate &#40;larger&#41; number of participants in a reasonable &#40;shorter&#41; time&#46; A larger sample size improves statistical precision and the ability to identify discrete benefits&#44; subtle relationships or rare effects&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0115" class="elsevierStylePara elsevierViewall">Another reason for carrying out a multicentre study is that it helps us obtain a more generalisable sample of the population to be studied&#46; With collaboration between multiple research centres in different geographical locations&#44; multicentre studies provide a broader and more diverse representation of the patient population under study&#59; this in turn increases the external validity and applicability of the results obtained and&#44; also therefore&#44; enables their more direct application to clinical practice&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Another potential advantage of multicentre studies is that&#44; with standardised protocols&#44; investigators at multiple sites tend to be less prone to different biases that might affect the study&#44; especially if their design is not blinded&#46; In contrast&#44; participants from a single site&#44; all under the supervision of a principal investigator who may be &#34;committed&#34; to the hypothesis to be demonstrated&#44; could be at much greater risk of bias&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Additionally&#44; a multicentre study makes it possible for investigators with similar interests to work together on a common problem&#46; Collaborative research teams involving members of various professions or disciplines incorporate multiple perspectives&#44; which introduce new knowledge to improve medical care&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> By sharing resources and experience between sites&#44; efficiency in data collection and analysis is increased&#44; saving both time and resources&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Collaboration networks are then established or consolidated&#44; which can have a very beneficial effect when conducting future studies&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> It is clear that the successful completion of a multicentre study in the past is the best guarantee of future success in the organisation of the next one&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Thanks to the high-quality results that tend to be generated&#44; authors who carry out multicentre studies tend to publish in more prestigious journals &#40;although it is true that what matters is not the stature of the journal&#44; but that of the actual study&#41;&#44; which often leads to more effective dissemination of the study results&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">In summary&#44; multicentre studies are essential for addressing complex questions&#44; obtaining more robust and applicable results&#44; and significantly contributing to scientific progress and the improvement of medical care&#46; The most effective strategy for increasing both the quantity and&#44; in particular&#44; the quality of research is collaboration between institutions and networks of investigators&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> It cannot be denied that teamwork produces great results&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Coming together gives us strength&#44; and this is especially true in research&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;16</span></a> However&#44; conducting a multicentre study presents important challenges and difficulties that have to be effectively addressed to guarantee success&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Aims of this manuscript</span><p id="par0135" class="elsevierStylePara elsevierViewall">We have discussed the fact that&#44; although there are numerous advantages&#44; conducting multicentre studies is complex&#46; The fundamental aim of this article is to share our experience with investigators who are considering taking on the challenge of setting up a multicentre study&#46; We review a series of tricks and tips which&#44; in our opinion&#44; are essential for successfully reaching port and not sinking in the attempt&#46; That said&#44; we do not set out merely to list a set of theoretical recommendations&#44; but to offer some personal suggestions based on our own experience&#44; which are therefore of a highly practical nature&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Leadership by the principal investigator</span><p id="par0140" class="elsevierStylePara elsevierViewall">A multicentre trial has to have an identifiable leader&#44; a principal investigator&#44; who must be able to effectively direct collaborators and keep the project on track and under control&#46; Some might think that the best way to lead a multicentre study is to have a large group of people&#44; to form a large committee&#46; However&#44; experience shows that this strategy tends not to be very successful&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Concrete and solid leadership &#40;from one or very few people&#41; is essential for successfully conducting multicentre studies&#46; Being a good leader &#40;of a multicentre study or indeed of any company&#41; requires a combination of management&#44; communication&#44; organisation and empathy skills&#46; Ideally&#44; a leader of a multicentre study should be communicative&#44; organised&#44; adaptable&#44; motivating&#44; decisive&#44; collaborative&#44; empathetic&#44; an informed decision maker&#44; resilient&#44; a constant learner&#44; ethical&#44; time-efficient and visionary&#46; Honesty and integrity are the most valuable and valued qualities of a leader&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> Leaders have &#40;and communicate&#41; a clear vision and choose &#40;and articulate&#41; a precise direction&#46; Leaders think and talk about solutions&#44; whereas followers focus on problems&#46; Good leaders inspire&#44; encourage and&#44; only when necessary&#44; impose discipline&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#44;17</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">The principal investigator&#47;coordinator of a multicentre study does not have to occupy a senior position in a scientific body or society&#46; Although that may be a &#34;political&#34; advantage&#44; it may also make it difficult for the person to dedicate the time required to properly coordinate a study of this type on a day-to-day basis&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> A fundamental characteristic of a good principal investigator is clearly previous experience in the area to be studied and recognition as an expert by the rest of the group&#46; Even more important&#44; however&#44; are perseverance and dedication&#44; two essential requirements that shape and channel the passion for research&#46; As Zig Ziglar rightly pointed out&#44; &#8220;Your attitude&#44; not your aptitude&#44; will determine your altitude&#8221;&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Perseverance and discipline will help you to maintain a high rate of work and scientific output for long periods of time&#44; which is the key to lasting success in the world of research&#46; Our capacity for resistance is particularly put to the test when coordinating a multicentre clinical trial&#44; when it often takes longer than initially estimated to enrol fewer patients than hoped for&#44; and unforeseen obstacles always arise&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> We must not allow the numerous bureaucratic barriers&#44; which often represent a real challenge in our path as investigators&#44; to discourage us&#46; Even a small observational&#44; retrospective study involves a long list of requirements&#44; including the approval of the Independent Ethics Committee and eventually the signing of contracts with the participating sites&#46; For clinical trials in particular&#44; logistical complications can turn an exciting idea into a seemingly impossible mission&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> However&#44; we should not be discouraged by problems that arise before or during the study&#46; Tenacity and perseverance are key for our project to be brought to a successful conclusion&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Even the most successful principal investigator has experienced moments of crisis coordinating a multicentre clinical trial and questioned whether all the effort is worth it&#46; At such times&#44; when we feel on the verge of giving up and are considering throwing in the towel&#44; is precisely when we should look back and remember what our motivation was for starting in the first place&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Lastly&#44; we believe that the best way to be successful in leading a multicentre study is to try to replicate the qualities which&#44; if we were to be collaborators &#40;recruiters&#41; in a study&#44; would convince us to participate in one and not another&#46; We need to remember that a large number of multicentre studies are now being conducted and competition can be fierce&#44; and also that&#44; unfortunately&#44; many such studies which do start&#44; having invested both time and energy&#44; are not brought to a successful conclusion&#46; Certainly&#44; as contributors to the study&#44; we would agree to participate if the coordinator offers us assurance &#40;usually based on their leadership&#44; reputation and previous successes&#41; that the study will be relevant&#44; successfully completed and result in a first rate publication&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Definition of clear&#44; viable and relevant objectives</span><p id="par0165" class="elsevierStylePara elsevierViewall">The objectives are one of the most important parts of a research proposal&#46; They are goals that the investigator sets in relation to the aspects they wish to investigate and learn about&#46; The objectives act as pillars that guide the research and direct the search for answers throughout the journey&#46; Properly defining the objectives in a multicentre study is fundamental in ensuring that the results are relevant and the impact of the research maximised&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">The principal investigator is usually the person who formulates the initial research question and is the architect of the protocol&#46; Although formulating research questions may seem to be a simple process&#44; in reality it is far from easy&#46; It is not uncommon to come across research projects that are confused&#44; answer questions that have not been adequately posed&#44; or fail to address questions that should have been asked from the start&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">As a preliminary consideration&#44; to accurately establish the objectives of our study it is obviously essential to have a clear understanding of the hypothesis and the research question&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Our study&#39;s objectives must be clear &#40;crystal clear&#41;&#44; specific &#40;beginners often tend to pose questions that are too broad&#41;&#44; assessable &#40;measurable&#41;&#44; viable &#40;achievable&#41; and relevant &#40;of social&#44; health or scientific interest&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;19&#8211;21</span></a> Defining clear objectives in a multicentre study involves establishing specific and measurable goals that are relevant&#44; achievable and with a defined time frame&#46; The use of the PICO format &#40;Patient&#47;Intervention&#47;Comparison&#47;Outcome&#41; can help us formulate a clear and precise research question&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">When we are developing a research project&#44; particularly to qualify for possible funding&#44; and especially if it is multicentre in nature&#44; one aspect must be perfectly clear and carefully expressed in the proposal&#58; its feasibility&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> This element is essential to ensure confidence and the maximum rating from the assessors&#46; Feasibility implies coherence between the objectives and methodology of the study&#44; including the work plan&#44; distribution of tasks&#44; available resources and the requested budget&#46; While the ideal is to present a proposal that is both innovative and ambitious&#44; it must also be credible in terms of content and timeline&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Clear and detailed protocol design</span><p id="par0185" class="elsevierStylePara elsevierViewall">Our research project must include a detailed written plan that covers all the scientific&#44; ethical and logistical aspects of the study we are preparing to conduct&#46; The objective of the protocol is to present and describe in detail what is going to be investigated&#44; the conceptual theoretical basis&#44; the methodological components and the human&#44; technical and financial resources that will be necessary to carry out the research&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> The protocol is the culmination of all the work we have done in the research planning phase&#44; and becomes a reference for the investigators during the conduct of the study&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Also&#44; as mentioned in the previous section&#44; it must contain sufficient information so that others &#40;investigators or assessors&#41; can assess its feasibility&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">Putting together a quality protocol requires considerable effort and time&#44; but it is worth it&#44; as it is the main guarantee that you will successfully achieve your objectives&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Of particular importance&#44; the methodology section should provide a thorough description of the planned actions&#58; how&#44; when and where&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> However&#44; this section should not be limited to a simple list of the techniques to be used&#44; but rather is about establishing a logical connection between the formulated objectives and the outlined methodological approach&#46; The fundamental purpose of the methodology section in a research project is to clearly explain the design of the study and the procedures that the investigators will follow to address each of the stated objectives&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">If we wish to conduct a study at multiple sites&#44; we need to make a concerted effort to guarantee uniformity across the board&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#8211;25</span></a> Given that any difference in the way the protocol is interpreted can negatively affect the final uniformity of the study&#44; for multicentre studies where&#44; by definition&#44; very diverse investigators will be participating&#44; the interpretation must be particularly clear and detailed&#46; Precise and unambiguous protocol design&#44; in addition to standardisation of procedures&#44; is therefore vital because it guarantees the consistency&#44; quality and reliability of the data collected and the results obtained&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> Depending on the type of study&#44; the preparation of a detailed protocol may not be enough&#44; with training and qualification of the research staff at each site sometimes required&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;11&#44;27&#8211;30</span></a> This reduces variability and minimises bias that could arise due to differences in local practices&#44; minimising the risk of uncontrolled factors distorting the results&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;29&#44;30</span></a> The standardisation of procedures in a multicentre study also simplifies coordination and communication between sites&#44; as all of them will be adhering to the same methodology&#46; This saves time and resources by avoiding misunderstandings in how to interpret procedures&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Especially when it is a clinical trial&#44; the study should be registered on a specific platform approved for the registration of clinical studies &#40;such as ClinicalTrials&#46;gov or EudraCT&#41; before the inclusion of the first patient in the study&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">Sometimes it may be useful to initially propose a preliminary or pilot study&#44; before launching into organising a complex multicentre study with everything it entails&#46; A pilot study can help us better develop the final protocol of our definitive clinical trial&#44; for example&#44; by polishing aspects of the design or more reliably estimating the sample size&#46; It can also give us very important information about the feasibility of the study&#44; the realistic recruitment rate and the expected loss rate&#46; Furthermore&#44; carrying out a pilot study will help us confirm whether or not the Case Report Form &#40;CRF&#41; or other study procedures work correctly&#46; A pilot study will also be very useful to more accurately estimate the cost of our final study&#46; In another vein&#44; having results &#40;or even publications&#41; from a pilot study makes it easier to obtain the funding necessary to conduct the full study in the various public and private calls for research projects&#44; as it demonstrates to the assessors our previous experience in the subject and the feasibility of the proposal&#46; It is also important to recognise that&#44; if the study sample size can be reasonably estimated from previous publications and it is considered that logistical barriers will be limited&#44; a pilot study may not contribute substantially to developing the final multicentre study protocol&#44; while it will probably involve a not insignificant cost in terms of time and money&#46; Lastly&#44; it may be a good idea to include in the protocol the planning of an interim analysis when a certain percentage of the sample size is reached&#44; so that&#44; in the event of obtaining a negative or inconclusive result&#44; a futility analysis could be performed to indicate the advisability of ending the study early&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Careful selection of sites and investigators</span><p id="par0210" class="elsevierStylePara elsevierViewall">One of the most important decisions a principal investigator has to make concerns which investigators are going to participate in their multicentre study&#44; as reaching recruitment targets and maintaining quality standards and&#44; hence&#44; obtaining valid results sufficient for making rigorous conclusions&#44; will all be dependent on the people selected&#46; Choosing the right investigators in a multicentre study is therefore one of the most important factors for a project to be carried through and&#44; more importantly&#44; completed successfully&#46; We would like to share with the reader the following series of tips which&#44; in our experience&#44; can be useful when making this selection&#46;<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0100"><span class="elsevierStyleLabel">a&#41;</span><p id="par0215" class="elsevierStylePara elsevierViewall">Selecting a broad range and a large number &#40;while being sensible&#41; of different sites is an important aspect in our opinion&#46; When considering carrying out a multicentre study&#44; it should be considered that very often the organisational work will be almost as arduous whether we restrict ourselves to a small group of local sites &#40;for example&#44; in the same city&#41; or expand it nationally&#44; involving multiple regions&#46; Obviously&#44; this is not always the case&#44; but often making that extra effort to expand our borders is worth it&#44; as we can obtain faster results and&#44; even more importantly&#44; increased relevance and scientific impact&#46; The really difficult factor is devising a good research idea&#46; We need to think &#34;big&#34; and not let the fear of expanding the scope of our study detract from its chances of success&#46; That said&#44; it is important to point out that careful selection of study collaborators is obviously essential&#46; There are those who maintain that &#34;the success of a research project is usually inversely related to the number of people on whom it depends&#34;&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> What is clear is that&#44; in most cases&#44; the quality &#40;of the investigators&#41; is more important than the quantity&#46; We will return to this point when sharing the last of our tips&#58; selecting committed investigators&#46;</p></li><li class="elsevierStyleListItem" id="lsti0105"><span class="elsevierStyleLabel">b&#41;</span><p id="par0220" class="elsevierStylePara elsevierViewall">Ideally we should choose sites with research experience&#44; especially if specifically related to the proposed study&#44; and with adequate resources and infrastructure to carry it out&#46; This requirement will obviously depend on the type of project&#59; a simple epidemiological&#47;observational study &#40;in which all that is essentially required is to recruit patients who suffer from the disease under study&#41; is not the same as a double-blind randomised clinical trial &#40;in which the organisational aspects will be important&#41; or another of a more basic nature &#40;where the correct processing of the samples by the laboratory staff of each site is the crucial factor&#41;&#46; The availability of a study coordinator at the site to be included is essential in multicentre studies of reasonable complexity &#40;for example&#44; a clinical trial with medicinal products&#41;&#46; When we do not know the potential capacity of some sites to participate &#40;typically&#44; when the study does not simply involve including patients in the clinic or reviewing medical records&#44; but calls for a more complex infrastructure&#41;&#44; it may be useful to use a feasibility questionnaire prior to selecting the participants&#46;</p></li><li class="elsevierStyleListItem" id="lsti0110"><span class="elsevierStyleLabel">c&#41;</span><p id="par0225" class="elsevierStylePara elsevierViewall">Geographical and demographic diversity should be taken into consideration when selecting sites&#44; to ensure the representative nature of the population included in the study and the subsequent generalisation of the results&#46;</p></li><li class="elsevierStyleListItem" id="lsti0115"><span class="elsevierStyleLabel">d&#41;</span><p id="par0230" class="elsevierStylePara elsevierViewall">Searching for alternatives to failed sites quickly is essential&#44; especially in studies where reaching the predefined sample size is important&#59; for example&#44; in comparative clinical trials&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> It should not be forgotten that&#44; on average&#44; less than half of the sites that participate in a multicentre study manage to meet their recruitment targets&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;33</span></a> Inability to reach the calculated sample size may result in biased studies without sufficient statistical power to reach a reliable conclusion&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">31&#44;34&#44;35</span></a> Therefore&#44; when problems arise &#40;repeated delays in responding to various requests&#44; failure to complete different tasks&#41; that are clear warning signs&#44; we should try to resolve them as soon as possible&#46; If this is not possible&#44; we need to identify alternative sites&#47;investigators early&#44; as the administrative process of including new candidates takes at least a few months&#46;</p></li><li class="elsevierStyleListItem" id="lsti0120"><span class="elsevierStyleLabel">e&#41;</span><p id="par0235" class="elsevierStylePara elsevierViewall">Although we have a Contract Research Organisation &#40;CRO&#41; - a company that provides clinical trial management services - the principal investigator should select all participating investigators&#46; CROs typically base their selection on information obtained from feasibility questionnaires&#44; including&#44; for example&#44; the number of patients the participating investigator thinks they will include&#46; However&#44; this information is not sufficiently reliable and is often far removed from reality &#40;i&#46;e&#46;&#44; the actual recruitment rate at the end of the study&#41;&#46; For all these reasons&#44; we honestly believe that we&#44; the principal investigators ourselves&#44; know best who may be the most appropriate candidates to participate in each study&#46;</p></li><li class="elsevierStyleListItem" id="lsti0125"><span class="elsevierStyleLabel">f&#41;</span><p id="par0240" class="elsevierStylePara elsevierViewall">Having national coordinators&#44; one in each country&#44; in international studies can be of great help&#46; Their main functions&#44; in addition to providing us with different organisational or logistical support&#44; would be to initially help us in selecting investigators from that country and&#44; subsequently&#44; to continuously stimulate their inclusion of patients&#46;</p></li><li class="elsevierStyleListItem" id="lsti0130"><span class="elsevierStyleLabel">g&#41;</span><p id="par0245" class="elsevierStylePara elsevierViewall">Encouraging investigators from other sites to lead a sub-analysis derived from the overall project can motivate their collaboration&#46; This is especially feasible in projects in which multiple biological samples are obtained from patients as&#44; for example&#44; this would allow various diagnostic techniques to be performed on them&#46;</p></li><li class="elsevierStyleListItem" id="lsti0135"><span class="elsevierStyleLabel">h&#41;</span><p id="par0250" class="elsevierStylePara elsevierViewall">We have left the key factor for last&#44; the one we consider essential&#58; the commitment of the investigator&#46; Generally&#44; what matters&#44; more than the site itself&#44; is the enthusiasm or passion of the investigator at the site&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> Commitment is a very personal quality&#44; and is only demonstrated by example&#46; Commitment and having fulfilled expectations in a previous study are the best predictors of future success in another&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;37&#44;38</span></a> The dedication of time is essential here&#46; In fact&#44; one of the main barriers to proper participation in a multicentre study is the investigator&#39;s lack of availability&#47;dedication&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> The professional or academic hierarchy of the potential investigator is therefore of little relevance here&#46; Highly reputable scientists &#40;who could certainly add prestige to a study&#41; are not always successful in collaborative ventures like the ones we are discussing here&#46; A head of department may or may not be a good candidate to participate in a multicentre study&#44; as it all depends on their commitment and the amount of time they are able and willing to dedicate&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> However&#44; relatively unspecialised professionals who work in regional hospitals may be very willing to participate in this type of study and be very effective collaborators&#46; In short&#44; we need to choose committed investigators&#44; with the confidence that they will fulfil the initial agreements &#40;such as&#44; for example&#44; recruiting the agreed number of patients&#41;&#46; It is clear that this commitment is not always easy to honour because it depends on a number of factors&#44; some of which are beyond our control&#46; However&#44; it is crucial to select collaborators who have a realistic perception of their capabilities&#44; as&#44; if they ultimately cannot deliver as agreed&#44; they could jeopardise the viability of the project&#46; A typical example is the process of including patients in a clinical trial&#46; The mistake is often made of trying to participate in multiple &#40;too many&#41; &#40;competing&#41; studies at the same time and committing to a number of patients that is not realistic or feasible&#46; In fact&#44; inclusion rates in multicentre clinical trials have decreased dramatically in recent years&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> One of the main reasons for this is the exponential increase in the number of these types of studies around the world&#44; many of which compete in terms of inclusion criteria and target patient population&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a></p></li></ul></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Meticulous designing of the case report form</span><p id="par0255" class="elsevierStylePara elsevierViewall">The use of a CRF&#44; usually electronic&#44; in multicentre studies is essential due to its numerous benefits in terms of speed&#44; precision&#44; standardisation&#44; quality and efficiency&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">42&#44;43</span></a> The electronic CRF also facilitates remote monitoring and early detection of any errors&#46; The data can be reviewed continuously&#44; which helps to identify inconsistencies or deviations&#44; enabling rapid intervention and prevention of such problems&#46; Therefore&#44; an additional challenge faced by the principal investigator in the early stages of a multicentre study is developing such a CRF&#46; Although it may not seem so important&#44; this phase is in fact crucial and has a very significant impact on the quality of the final results&#46; In other words&#44; a poorly designed CRF will inevitably collect low-quality data&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">The introduction of the electronic CRF has been a milestone in the field of data collection&#46; It seems pertinent here to highlight the role of REDCap &#40;Research Electronic Database Capture&#44; <a href="https://www.project-redcap.org/">https&#58;&#47;&#47;www&#46;project-redcap&#46;org&#47;</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> This platform includes computer software that enables the design&#44; development and management of electronic CRFs in research studies&#46; This tool is characterised by its ease of use for both investigators and monitors&#44; and offers functions and services superior to most private providers&#46; Moreover&#44; it provides the tools necessary for efficient data analysis&#44; online statistics generation&#44; monitoring&#44; collecting data on mobile devices and a multitude of extra functions&#46; The REDCap platform significantly reduces the costs associated with traditional CRFs and so encourages the development of projects driven by investigators&#44; outside the interests of private industry &#40;it is important to highlight that the use of this software is limited exclusively to non-commercial research&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">43&#44;45</span></a></p><p id="par0265" class="elsevierStylePara elsevierViewall">The CRF can be designed by a CRO&#44; but we are convinced that it is most effective &#40;and efficient&#41; for it to be developed by the research team itself&#46; No one knows the ideal way to include information in a CRF better than the investigators responsible for the study&#46; These people have detailed knowledge of the disease being studied and&#44; at the same time&#44; will appreciate like no one else the clarity and simplicity that a CRF should have&#46;</p><p id="par0270" class="elsevierStylePara elsevierViewall">When designing the CRF&#44; we must strive to select all the data relevant to the study&#44; but only the essential data&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> This is the cardinal rule for the CRF designer and&#44; although it may seem over-dramatic&#44; we have to be prepared to adhere to that rule&#44; as we will almost certainly be tempted to break it &#40;either ourselves or because of external requests&#41;&#46; In this field&#44; quantity and quality are frequently not compatible&#46; It is essential to avoid unnecessary questions or repetitions&#46; We should not ask for data that can be extrapolated from others already included&#46; The language used must be clear and simple&#44; with concise&#44; unambiguous sentences&#44; minimising the use of abbreviations as far as possible&#46;</p><p id="par0275" class="elsevierStylePara elsevierViewall">Lastly&#44; it is essential that the CRF be reviewed by several members of the research team &#40;in addition to the principal investigator&#41;&#44; including monitors and statisticians&#44; before considering it final&#46; Making significant changes to the CRF once the study is underway is costly and risky&#44; and this justifies the initial investment in time to design it carefully&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">43&#44;46</span></a></p><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Effective and centralised project management&#58; the importance of the coordinating site</span><p id="par0280" class="elsevierStylePara elsevierViewall">One of the main challenges of any multicentre study is the coordination between the multiple participating centres&#44; each with its own infrastructure&#44; personnel and procedures&#46; Centralised management in multicentre studies plays a critical role in the coordination and success of collaborative research&#46; Maintaining effective and efficient collaboration&#44; standardising different procedures and ensuring consistency in data collection and handling requires careful planning and supervision&#59; and for this it is essential to have a well-organised coordinating centre and a functional governance mechanism&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;35&#44;47&#8211;49</span></a></p><p id="par0285" class="elsevierStylePara elsevierViewall">The management of a multicentre study is more intricate than one might imagine&#44; as it involves multiple stakeholders &#40;for example&#44; sponsors&#44; investigators&#44; study coordinators&#44; ethics committees&#44; health authorities&#44; legal departments&#44; monitors and patients&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> In addition&#44; it is essential to adhere to good clinical practice&#44; a series of requirements that guarantee protection of the rights&#44; safety and well-being of the study subjects&#44; as well as the reliability of the results&#46; In particular&#44; the logistics of coordinating ethical and regulatory approvals across multiple sites are often complicated and time-consuming&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> Synchronising deadlines and managing required documentation are critical for avoiding delays&#46; The administrative burden for the investigators at the different centres needs to be kept to a minimum and&#44; to do so&#44; assistance needs to be provided from the coordinating centre&#46;</p><p id="par0290" class="elsevierStylePara elsevierViewall">Centralised management allows for closer supervision and rigorous quality control at all the participating centres&#46; This means procedures and protocols can be uniform and followed consistently&#44; resulting in comparable and reliable data&#46; Additionally&#44; an effective coordinating centre facilitates fluid&#44; two-way communication between the coordinating research team and individual sites&#44; allowing challenges to be addressed and problems resolved quickly and efficiently&#46;</p><p id="par0295" class="elsevierStylePara elsevierViewall">Generally&#44; the administrative management of studies is entrusted to a CRO&#44; which functions as an intermediary between the sponsor and the other parties involved in conducting the study&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">47&#44;52&#44;53</span></a> The services provided by a CRO vary depending on the phase the study is in&#46; The start-up phase includes developing the research protocol&#44; adapting documentation to Spanish legislation&#44; obtaining the necessary approvals from ethics committees and the health authorities&#44; designing the CRF&#44; selecting investigators and negotiating contracts with the sites&#46; Once approval is obtained and the study is underway&#44; the CRO provides monitoring and&#44; if necessary&#44; pharmacovigilance services&#46; Lastly&#44; the CRO takes charge of managing the data obtained by the study&#44; generating reports and overseeing and archiving documentation&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a></p><p id="par0300" class="elsevierStylePara elsevierViewall">An attractive alternative&#44; although with a certain degree of complexity in terms of organisation&#44; is to have personnel within the research team itself trained to carry out all the above-mentioned tasks applied to the independent research studies that group leads&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> The main advantage of this option is that these people&#44; being part of the research group&#44; will be familiar with the disease under study&#44; the routine procedures and the idiosyncrasies of the team&#44; and this should guarantee excellent coordination with that team&#46; This approach is particularly productive and profitable when the research group does continuous and sustained research activities over time&#46; In our experience&#44; training personnel on the group&#39;s previous projects has a very positive impact on future projects&#44; with their efficiency gradually increasing&#46; This obviously involves an initial investment in human resources and requires having the capacity to hire the specialised personnel and keep them on in the medium-to-long term&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a></p><p id="par0305" class="elsevierStylePara elsevierViewall">Finally&#44; an aspect that deserves particular attention is the monitoring of data quality&#46; This is particularly important in multicentre studies&#44; where there are highly likely to be significant differences between the different sites&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#44;27</span></a> Evaluation and continuous improvement are essential to ensure the quality&#44; effectiveness and validity of the results in a multicentre study&#46; Quality monitoring ensures regulatory compliance in each phase of the study&#46; Monitoring visits to the sites facilitates the evaluation of patient recruitment&#44; as well as the quality&#44; integrity and validity of the data included&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#8211;27</span></a> It is advisable to conduct the initial monitoring visits shortly after the inclusion of the first patients at the corresponding site&#46; Early detection of any problems means corrective measures can be implemented to prevent them from continuing&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27&#44;54&#44;55</span></a> Being flexible and able to adapt are essential tools for overcoming obstacles and successfully concluding a multicentre study&#46;</p><p id="par0310" class="elsevierStylePara elsevierViewall">In general&#44; the best way to evaluate the quality of a site is with an in-person visit&#44; where the study monitor reviews all signed informed consent forms&#44; official documents and ethics approvals&#44; and then compares the information included in the CRF with that in the medical records&#44; to identify any discrepancies&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Nonetheless&#44; telematic or remote monitoring reduces costs and improves the efficiency of the process&#44; especially in multicentre studies&#46; The implementation of hybrid designs &#40;in-person and telematic&#41; can be very useful&#44; combining the advantages of efficiency and simplicity &#40;not only from the perspective of the coordinating centre&#44; but also&#44; very importantly&#44; of the investigator at each centre&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a></p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Effective and fluid communication with the investigators</span><p id="par0315" class="elsevierStylePara elsevierViewall">Many of the problems that arise in a multicentre study are caused by inadequate communication between the principal investigator and the co-investigators from the different sites&#46; Therefore&#44; fluid communication among the investigators plays a fundamental role in the success of collaborative research&#44; especially when&#44; as is often the case&#44; the sites are geographically far apart&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> Effective and constant communication is essential for several reasons&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> First of all&#44; it establishes a solid foundation for understanding the objectives&#44; protocol and expectations of the study at all participating sites&#59; this ensures uniform and consistent implementation of procedures&#44; reducing variability in data collection and improving comparability of results&#46; Secondly&#44; constant communication allows challenges and potential obstacles to be identified as they arise&#44; which facilitates early resolution of problems&#44; minimising delays&#46; Thirdly&#44; regular interaction with investigators promotes a sense of community and collaboration between the different sites&#46; In addition&#44; feedback and the exchange of experiences allow shared learning and joint adaptation to changes during the course of the study&#46; Last but not least&#44; effective communication keeps investigators informed about targets achieved&#44; interim results and pending objectives&#46; Communication is the basis of fidelity in research studies<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a>&#59; we can hardly demand that the participants in our study act quickly and effectively if we do not show our interest and keep them periodically informed&#46; All of this stimulates the collaboration&#44; commitment and motivation of investigators&#44; who feel valued and in tune with the objectives of the research project&#59; communication between investigators becomes the &#8220;glue&#8221; that effectively bonds the various components of a successful multicentre study&#46;</p><p id="par0320" class="elsevierStylePara elsevierViewall">There are many different and complementary means of communicating with investigators&#44; mainly involving telephone calls&#44; emails and newsletters&#46; It may also sometimes be a good idea&#44; or even necessary&#44; to organise face-to-face meetings<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a>&#59; to do this&#44; we could take advantage of the scientific events that many of these professionals attend&#46; Remote meetings&#44; by videoconference&#44; can be sufficient in most cases&#44; and are also much more convenient and economical &#40;especially in multinational studies&#41;&#44; although the communicative effectiveness of face-to-face meetings is undeniable&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> In addition to group meetings&#44; it is often necessary to hold other personal meetings with the investigator from a specific site&#44; for example&#44; when a problem at that site is identified&#46; In meetings with investigators&#44; whether in-person or remote&#44; open communication should be encouraged&#44; where they can ask questions&#44; express concerns and offer suggestions&#46; For example&#44; a site that is particularly effective in recruiting patients could share its experience and so help inclusion by other investigators&#46;</p><p id="par0325" class="elsevierStylePara elsevierViewall">Newsletters enable periodic &#40;for example&#44; monthly&#41; updates on study status&#44; progress&#44; milestones reached and next steps&#46; It is recommended that they be brief&#44; concise&#44; specific and also intuitive&#44; with a predominance of figures and graphs over written information&#46; These iconographic bulletins are especially useful for providing updates on the sites&#39; progress in patient recruitment&#59; publicly sharing this information can have an incentive effect stimulated by healthy competition&#46; Public recognition and appreciation of investigators&#39; contributions as the study progresses can also be encouraging&#46;</p><p id="par0330" class="elsevierStylePara elsevierViewall">An essential aspect of an effective communication strategy is the dissemination of study results and the celebration of various achievements&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> Sharing results with investigators in a multicentre study is of utmost importance&#44; as it strengthens transparency&#44; promotes collaboration and maximises the impact of the research&#46; Dissemination of results can lead to new discoveries&#44; innovative approaches and additional scientific advances&#44; amplifying the value of the investment made in the initial multicentre study&#46; Dissemination also reinforces the prestige of the participating sites and the reputation of their investigators in particular&#46; In light of the above&#44; it is essential to design a good communication plan to share the results of the study both within the scientific community and with the general public&#46;</p><p id="par0335" class="elsevierStylePara elsevierViewall">In relation to the dissemination of the study results in scientific forums&#44; the preparation of abstracts and their presentation at conferences is essential&#46; This allows the early dissemination of the study&#44; well before the complete article that will eventually be published in a scientific journal can be finalised&#44; especially when it comes to preliminary results or interim analyses&#46; Although this involves additional work for the principal investigator&#44; it is worthwhile as&#44; for the co- investigators&#44; this is obvious confirmation that the study is on the right track or that it has even come to a successful conclusion&#46; The preparation and publication of the full article in a scientific journal will be discussed in the next section&#46;</p><p id="par0340" class="elsevierStylePara elsevierViewall">Finally&#44; celebrating the achievements of a multicentre study has a very positive influence on the motivation and cohesion of investigators&#46; Recognising and commemorating milestones achieved is not only personally rewarding&#44; but also has a positive impact on the quality and success of the project&#46; The celebration of achievements recognises the hard work&#44; dedication and commitment of all the investigators involved at the different sites&#46; This creates a positive environment&#44; fosters a sense of belonging to the group and strengthens team morale&#44; which in turn increases motivation and job satisfaction&#46; Anyone who has even minimal responsibility in managing or coordinating human teams knows perfectly well that a motivated team tends to be more productive and more willing to face up to challenges with determination&#46;</p><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Clear &#40;and generous&#41; authorship policy and commitment to publish</span><p id="par0345" class="elsevierStylePara elsevierViewall">Multicentre studies increase the complexity of determining authorship of the resulting publications&#44; which can pose unique practical and ethical challenges&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> Authorship in multicentre studies therefore requires careful planning to meet ethical standards&#44; promote a fair distribution of credit and avoid potential conflict&#46; It is essential to clearly establish <span class="elsevierStyleItalic">a priori</span> the rules of authorship and publication&#44; in order to guarantee transparency&#44; equity and credibility in the dissemination of the results&#46; The criteria on which the selection of authors will be based must be made clear from the beginning &#40;for example&#44; defining a minimum number of patients recruited&#41;&#46; Naturally&#44; this order can only be specified at the end of the study&#44; when the relative contributions can be accurately assessed&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> In any case&#44; the final order of authorship should be clearly determined before starting to write the first draft of the manuscript&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">61&#44;62</span></a></p><p id="par0350" class="elsevierStylePara elsevierViewall">To start with&#44; the concept of authorship must be clearly established&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">61&#8211;63</span></a> The International Committee of Medical Journal Editors &#40;ICMJE&#41; states that authors must be active contributors to the study&#44; participate in the preparation of the manuscript&#44; approve the final content and accept responsibility for its publication&#46; That said&#44; our philosophy is to try to provide the maximum possible representation&#44; being generous &#40;as well as fair&#41; with the investigators&#44; who are fully deserving of it&#46; We try&#44; as far as possible&#44; to include the maximum number of authors who have made a significant contribution to the study and that the journal allows&#46; When there is a large number of authors and they cannot all be included on the front page of the manuscript&#44; the rest of the investigators &#40;usually called collaborators&#41; should be included in a list as an addendum&#44; linked by an asterisk located after the name of the research group at the end of the list of main authors&#46; In this case&#44; it is important to confirm with the editor of the journal in which the article is to be published that all authors included in this appendix will be linked to the manuscript&#39;s PubMed reference&#44; so they are identified as co-authors when searching for this manuscript in that search engine&#59; this is the only way these authors will have a contribution equivalent to being a signatory of the article in terms of including it on their curriculum vitae&#46;</p><p id="par0355" class="elsevierStylePara elsevierViewall">Journal embargo and copyright rules often prevent dissemination of results before manuscript publication&#46; Therefore&#44; the research team needs to carefully plan the best strategy to disseminate these results through traditional media &#40;for example&#44; television or newspapers&#41;&#44; social networks&#44; webinars&#44; podcasts or blogs once they have been published&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0360" class="elsevierStylePara elsevierViewall">Last of all&#44; it is essential to comply with reasonable publication deadlines&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Our role as coordinators must be to guide the project to a successful conclusion&#44; and this means not only the successful completion of the study&#44; but also the prompt and appropriate publication of the results&#46; Unfortunately&#44; this is not always achieved&#46; An analysis of 244 randomised clinical trials funded by a research agency showed that only 57&#37; of the results of these studies were published within 30 months after the trial ended&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a> Furthermore&#44; for many of these funded projects&#44; no publication deriving from their results was ever generated&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a> The following is a series of tips we want to share with the reader&#44; which&#44; in our experience&#44; can be useful for guaranteeing appropriate and timely publication of the results of a multicentre study&#46;<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0140"><span class="elsevierStyleLabel">a&#41;</span><p id="par0365" class="elsevierStylePara elsevierViewall">First of all&#44; we should plan at an early stage when the article &#40;or more frequently articles&#41; deriving from the study will be published&#46;</p></li><li class="elsevierStyleListItem" id="lsti0145"><span class="elsevierStyleLabel">b&#41;</span><p id="par0370" class="elsevierStylePara elsevierViewall">Initially&#44; it is practical to publish the study protocol&#44; particularly the methodology aspects&#44; as this can have several benefits&#58; it is usually quick to write &#40;as much of the information should already be in the initial study protocol&#41;&#59; it facilitates subsequent publication of the full article &#40;among other things because it will save space&#44; if necessary&#44; as different aspects of methodology can be referenced&#41;&#59; and it serves as encouragement for the investigators&#44; who can see how their hard work is beginning to bear fruit&#46;</p></li><li class="elsevierStyleListItem" id="lsti0150"><span class="elsevierStyleLabel">c&#41;</span><p id="par0375" class="elsevierStylePara elsevierViewall">We can begin writing the introduction section of the manuscript even before the study is completed and the results have been analysed&#46; We have already seen that the methods section will be all but finalised after the publication of the protocol&#46; The literature review should have already been carried out in the initial stages of the study&#44; so it should be quick and easy to organise the articles to be included using a bibliographic reference manager&#46;</p></li><li class="elsevierStyleListItem" id="lsti0155"><span class="elsevierStyleLabel">d&#41;</span><p id="par0380" class="elsevierStylePara elsevierViewall">Once we have written the draft of the manuscript&#44; we should circulate it amongst the rest of the investigators&#44; giving the co-authors a reasonable&#44; but relatively short&#44; period of time to review it and make their suggestions&#46; In our experience&#44; if we do not hear back from an investigator within a couple of weeks&#44; we are probably not going to&#44; so we think that time frame may be sensible&#46;</p></li><li class="elsevierStyleListItem" id="lsti0160"><span class="elsevierStyleLabel">e&#41;</span><p id="par0385" class="elsevierStylePara elsevierViewall">If the article is rejected by one journal&#44; we should submit it to another as soon as possible&#44; getting over the disappointment quickly to avoid unnecessary delays&#46; In most cases&#44; the article can be resubmitted as it is to another journal&#44; since the &#34;major&#34; items of criticism received by the first would be difficult to correct&#44; given they were the reason for the unconditional rejection&#46; Only if there are indisputable comments from reviewers that can be feasibly and realistically implemented is it worth including them&#46; We should remember that it is not uncommon for the suggestions of the first journal&#39;s reviewer to be completely different from those of a second journal&#39;s reviewer&#44; so it is probably not worth wasting time making changes that may be unnecessary&#46;</p></li><li class="elsevierStyleListItem" id="lsti0165"><span class="elsevierStyleLabel">f&#41;</span><p id="par0390" class="elsevierStylePara elsevierViewall">Lastly&#44; if the article is potentially accepted &#40;typically&#44; when we are asked for &#34;major changes&#34;&#41;&#44; we should strive to submit the revised version as soon as possible&#44; ideally within a few weeks &#40;not months&#41;&#44; unless new analyses of the data or substantial modifications are required&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a> We should not allow ourselves to procrastinate&#44; but tackle the often arduous task of responding to the reviewers as soon as possible and so make sure that the article is finally accepted&#46;</p></li></ul></p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Conclusions</span><p id="par0395" class="elsevierStylePara elsevierViewall">Multicentre studies generate quality&#44; generalisable medical data that can change clinical practice&#44; which is why they are considered the backbone of evidence-based medical care&#46; There is no doubt that there are many benefits associated with these studies&#44; but to conduct them&#44; solid leadership&#44; detailed planning&#44; constant and meticulous coordination&#44; multidisciplinary collaboration and an effective communication strategy are required&#59; and&#44; above all&#44; a strong commitment from the entire research team&#46; In this manuscript we have shared with the reader a series of recommendations that we consider important to successfully conduct a multicentre study&#44; which are summarised in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46; We hope that these suggestions will encourage some investigators to carry out such studies and&#44; in doing so&#44; we can all improve the quality of research and its application to clinical practice&#46; Finally&#44; we would like to conclude this article by sincerely thanking all the investigators who have collaborated with generosity and commitment to the various multicentre studies that we have had the privilege of coordinating&#44; as well as the staff of our local research team for their outstanding competence and dedication&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conflicts of interest</span><p id="par0400" class="elsevierStylePara elsevierViewall">J&#46;P&#46; Gisbert has provided scientific advice and support for research and&#47;or training activities for MSD&#44; Abbvie&#44; Pfizer&#44; Kern Pharma&#44; Biogen&#44; Mylan&#44; Takeda&#44; Janssen&#44; Roche&#44; Sandoz&#44; Celgene&#47;Bristol Myers&#44; Gilead&#47;Galapagos&#44; Lilly&#44; Ferring&#44; Faes Farma&#44; Shire Pharmaceuticals&#44; Dr&#46; Falk Pharma&#44; Tillotts Pharma&#44; Chiesi&#44; Casen Fleet&#44; Gebro Pharma&#44; Otsuka Pharmaceutical&#44; Norgine&#44; Vifor Pharma&#44; Mayoly&#44; Allergan&#44; Diasorin&#44; Gebro Pharma and Richen&#46;</p><p id="par0405" class="elsevierStylePara elsevierViewall">M&#46; Chaparro has provided scientific advice and support for research and&#47;or training activities for&#58; MSD&#44; Abbvie&#44; Hospira&#44; Pfizer&#44; Takeda&#44; Janssen&#44; Ferring&#44; Shire Pharmaceuticals&#44; Dr&#46; Falk Pharma&#44; Tillotts Pharma and Lilly&#46;</p></span></span>"
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