Multicenter Collaboration in Observational Research: Improving Generalizability and Efficiency

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1 This is an enhance PDF from The Journal of Bone an Joint Surgery The PDF of the article you requeste follows this cover page. Multicenter Collaboration in Observational Research: Improving Generalizability an Efficiency Sheila Sprague, Joel M. Matta, Mohit Bhanari an on Behalf of the Anterior Total Hip Arthroplasty Collaborative (ATHAC) Investigators J Bone Joint Surg Am. 2009;91: oi: /jbjs.h This information is current as of May 1, 2009 Reprints an Permissions Publisher Information Click here to orer reprints or request permission to use material from this article, or locate the article citation on jbjs.org an click on the [Reprints an Permissions] link. The Journal of Bone an Joint Surgery 20 Pickering Street, Neeham, MA

2 80 COPYRIGHT Ó 2009 BY THE JOURNAL OF BONE AND JOINT SURGERY, INCORPORATED Multicenter Collaboration in Observational Research: Improving Generalizability an Efficiency By Sheila Sprague, MSc, Joel M. Matta, MD, an Mohit Bhanari, MD, MSc, FRCSC, on Behalf of the Anterior Total Hip Arthroplasty Collaborative (ATHAC) Investigators* Utilizing a multicenter approach in observational clinical research allows for improve generalizability of the results, a larger sample size, an, consequently, improve efficiency. This paper highlights important issues with regar to the organization of multicenter observational stuies in orthopaeic research. Specifically, we emphasize the evelopment of trial committees, stress the importance of having a methos center for the purpose of coorinating ay-to-ay stuy activities, an escribe the roles of the participating clinical sites. The successful conuct of multicenter stuies requires careful stuy organization, a eicate an experience methos center, an motivate participating surgeons an stuy staff at the clinical sites. To illustrate the organization of a multicenter initiative, we use the example of a total hip arthroplasty collaborative. Introuction Alarge clinical stuy conucte cooperatively at multiple centers has a number of important avantages over a small stuy performe at a single center or small number of centers. Multicenter stuies have the avantage of increase generalizability of the results 1. Typically, the more surgeons an the more clinical sites participating, the more generalizable to other patient populations the results of the stuy become. Multicenter collaborations also offer the potential of recruiting more patients within a much shorter time frame 1. In other wors, multicenter clinical research is more efficient than single-center research because it allows the accrual of sufficient numbers of iverse participants in a substantially shorter perio of time than coul be effecte at a single center. Reports on large multicenter trials, international trials, an large cohort outcome stuies are generally sparse in the orthopaeic trauma literature 2, whereas single-center observational stuies are frequently reporte. One major limiting factor of single-center initiatives is the ifficulty of enrolling a sufficient number of participants from one clinical site within a reasonable time frame to answer the research question 3.To provie a vali answer to a clinical question, a sufficient number of patients must enter the stuy an then be available for followup at the en of the trial. Despite the volume of observational stuies in the orthopaeic literature, there are few aequately powere observational stuies. Although some conitions of interest to orthopaeic surgeons are common, such as back pain an lower-extremity osteoarthritis, many are relatively rare. For this reason, the participation of multiple investigators at multiple sites is necessary to obtain sufficient numbers of subjects for much of the research that is neee in our fiel 4. Unfortunately, most stuies still inclue one or only a few centers, which results in limite external valiity 2. In other wors, if a stuy is not aequately powere, the results may not be believable, as the outcomes may be ue to chance alone. Consequently, singlecenter an especially single-surgeon stuies may not prouce results that are generalizable across ifferent jurisictions. Observational stuies can be useful in assessing patient profile, objective outcomes, an appropriate clinical en points before beginning a larger clinical trial 2. These observational *ATHAC Investigators: Steering Committee: Joel M. Matta, MD (Chair), Mohit Bhanari, MD, MSc, FRCSC, an Davi Dogin, MD Stuy Concept an Design: Mohit Bhanari, MD, MSc, FRCSC, Joel M. Matta, MD, Stefan Kreuzer, MD, Davi Dogin, MD, an Gary Braley, MD Stuy Coorination: Mohit Bhanari, MD, MSc, FRCSC (Chair), Sheila Sprague, MSc (Project Manager), Natalie Siorkiewicz, BSc (Research Coorinator), an Tashay Mignott, BA (Research Assistant) Writing Committee: Mohit Bhanari, MD, MSc, FRCSC (Chair), Joel M. Matta, MD, Davi Dogin, MD, Charles R. Clark, MD, Phil Kregor, MD, Gary Braley, MD, an Lester Little, MD Participating Surgeons: Gary Braley, MD, Santa Barbara, CA; Jim Grimes, MD, Bakersfiel, CA; John Masonis, MD, Charlotte, NC; Stefan Kreuzer, MD, Houston, TX; Anrew Yun, MD, Inglewoo, CA; Gary Matthys, MD, Fargo, ND; Brian Jewett, MD, Eugene, OR; Michael Bellino, MD, Palo Alto, CA; an Joel M. Matta, MD, Santa Monica, CA Disclosure: In support of their research for or preparation of this work, one or more of the authors receive, in any one year, outsie funing or grants in excess of $10,000 from DePuy. In aition, one or more of the authors or a member of his or her immeiate family receive, in any one year, payments or other benefits in excess of $10,000 or a commitment or agreement to provie such benefits from commercial entities (Stryker, DePuy, Mizuho OSI). J Bone Joint Surg Am. 2009;91 Suppl 3:80-6 oi: /jbjs.h.01623

3 81 stuies can establish a baseline for interventional trials in which an implant or proceure is teste 2. In aition, in many situations, a multicenter observational stuy is the only ethical stuy esign that can aress a research question. One of the barriers to conucting large multicenter observational stuies is their relatively complex organization. However, these stuies can be esigne to reuce complexity by giving careful forethought to the evelopment, implementation, an execution of the stuy from its inception to completion at each participating institution 3. One common metho is for a single investigator to establish the necessary local or national collaborations 5. One of the limitations to this approach is the nee to recruit collaborators anevelop infrastructure for every trial 5. A secon metho has been for groups of surgeons to form collaborative networks supporting one or more trials 5. A very successful example of this approach is the Canaian Orthopaeic Trauma Society, a collaborative of Canaian orthopaeic surgeons who have complete an publishe multiple research stuies together. A potential isavantage of this approach is that a permanent infrastructure may not exist; consequently, the network runs the risk of issolution with gaps in funing or investigator interest 5. Wright an Gebhart also suggeste national leaership from organizations (e.g., the American Acaemy of Orthopaeic Surgeons); however, they conclue that such organizations have broa manates an that their members were not likely to have sufficient share interests to make such organizations successful in facilitating ranomize clinical trials 5. They conclue that the musculoskeletal specialty societies (e.g., the Orthopaeic Trauma Society) woul be the more logical groups to have the potential to facilitate clinical trials, as specialty societies have the necessary share interest to promote the trials 5. Moels for Multicenter Observational Collaborations Several large orthopaeic collaborative groups have been establishe with the goal of conucting large multicenter observational stuies. The Lower Extremity Assessment Project (LEAP) investigators successfully complete a multicenter, prospective, observational stuy to etermine the functional outcomes of 569 patients with severe leg injuries resulting in reconstruction or amputation 6. Eight level-i trauma centers participate in the LEAP stuy, an they enrolle patients from March 1994 to June The LEAP stuy provies an excellent example for the justification of multicenter collaboration, as, prior to the LEAP stuy, the observational stuies that evaluate limb reconstruction were small an retrospective, making the results less than efinitive. In aition, many of the results of those stuies were contraictory 6. Another recently evelope collaborative is the Anterior Total Hip Arthroplasty Collaborative (ATHAC). This is a multicenter research group with an interest in cooperative research aime at improving knowlege about this surgical technique. They have recently complete a retrospective multicenter observational stuy that was conucte at nine clinical centers in the Unite States an that evaluate function an complications associate with the anterior approach to total hip arthroplasty in 1152 patients. The ATHAC stuy was coorinate by an inepenent an experience methos center in Canaa. The purpose of this manuscript is to provie an overview of key elements of a multicenter collaborative an to iscuss some consierations for organizing a successful collaboration an completing an observational stuy. Overview of Key Elements of a Multicenter Collaborative Multicenter trials will only be successful with appropriate infrastructure 4. A high-quality multicenter observational stuy requires as much time in its planning, preparation, an organization as it oes in its execution 7. Every successful clinical stuy requires a motivate, cooperative, an competent research team 7, an multicenter observational research stuies require a much larger an more organize team of professionals than single-center observational stuies o. Typically, this research team shoul have clinical experts (orthopaeic surgeons), biostatisticians, health-research methoologists or epiemiologists, an research staff, incluing a project manager an research coorinators. Ieally, iniviuals with previous experience or expertise in observational research shoul be inclue as part of the stuy team. Figure 1 shows how a multicenter observational stuy can be organize. The steering committee is responsible for the trial oversight. Other important committees inclue the central ajuication committee, the ata safety an monitoring boar, an the writing committee. At the center of the activities is the methos center of the stuy. The methos center is responsible for the overall coorination of the trial an the ay-to-ay activities. The clinical sites are responsible for enrolling patients into the stuy an collecting the ata. Deicate, organize, an efficient clinical sites are essential for the successful completion of any observational stuy. The ATHAC stuy use a moel similar to the one shown in Figure 1. Since their stuy was retrospective, they i not inclue a ata safety an monitoring boar or a central ajuication committee. In aition to the steering committee, they ha a subcommittee that was responsible for the esign an finalization of the stuy protocol. A methos center coorinate the trial committees an the aily activities, incluing the communication with the clinical sites. Nine eicate clinical sites participate in this stuy, submitting ata on more than 1000 patients. The ata were then valiate an analyze at the methos center. A writing committee was establishe to prepare the manuscript for publication. Stuy Committees Steering Committee The complexity of a stuy with multiple participating centers requires key organizing committees to oversee the conuct of the observational stuy 1. A steering committee can be comprise of iniviuals who are irectly involve in the trial or iniviuals who are not active participants of the trial 1. Members often inclue the principal investigator(s), a biostatistician, a research methoologist, multiple clinical experts, an other key iniviuals who are eeme important to the

4 82 Fig. 1 Organization of multicenter trials. This figure provies a moel of how to efficiently organize a multicenter observational stuy. esign an conuct of the stuy 1. The size of the steering committee often epens on the size of the initiative an the complexity of the research question an stuy esign. The steering committee shoul have a sufficient number of experts to aequately oversee the esign an conuct of the trial, but not so many that it becomes inefficient anysfunctional. The steering committee is usually responsible for eveloping an finalizing the stuy protocol an proceures. During the planning an conuct phases of the observational trial, the steering committee communicates frequently with the methos center an the participating clinical sites regaring any issues that arise, such as protocol eviations, recruitment issues, an ata-quality issues. At the completion of the trial, the steering committee maintains responsibility for the ata analysis an is responsible for the organization of the writing committee. The ATHAC steering committee was comprise of the principal investigator an two clinical experts, an these iniviuals were responsible for the overall esign an conuct of the observational trial. Two aitional clinical experts provie a substantial amount of input into the stuy protocol. Data Safety an Monitoring Boar Data safety an monitoring involves reviewing accumulate outcome ata from an ongoing clinical trial to ensure the continuing safety of current participants an those yet to be enrolle. The ata safety an monitoring boar also ensures the continuing valiity an scientific merit of the trial. Most clinical trials, especially ranomize controlle trials that are evaluating a new or existing treatment, require a safety monitoring plan. A ata safety an monitoring plan shoul be tailore to the nature, size, an complexity of the research protocol, the expecte risks of the research, an the type of patient population being stuie. Items to consier are the type of ata or events that are to be capture uner the monitoring plan (such as averse events), who will be responsible for reviewing the safety ata, time frames for reporting averse events or unanticipate problems to the methos center, anefinitions of stuy stopping rules for patient safety. After reviewing an analysis of the stuy s safety ata, it is a funamental responsibility of every ata safety an monitoring boar to make recommenations to the steering committee concerning the continuation of a stuy. The ata safety an monitoring boar may recommen that the stuy continue as esigne, that the stuy be terminate because it is causing harm to the participants, that the stuy continue with major or minor moifications, or that the enrollment an/or stuy intervention be temporarily suspene until some uncertainty is resolve 1. The iniviuals responsible for monitoring patient safety must be completely inepenent from the stuy an the stuy investigators. Many sponsors an funing agencies have set guielines for establishing ata safety an monitoring boars. Data safety an monitoring boars are typically mae up of experts in the clinical fiel being stuie an they often inclue a biostatistician or an epiemiologist. The ATHAC stuy i not have a ata safety an monitoring boar; however, the safety was analyze an inclue in the final report. Central Ajuication Committee The central ajuication committee may review patient eligibility, stuy en points, an protocol eviations to etermine if

5 83 Fig. 2 Organization of the methos center. This figure shows the roles an responsibilities of the key personnel at the methos center. they meet protocol-specific criteria. The central ajuication committee shoul be bline to treatment allocation 1. This ajuication process is an important metho of reucing bias an is necessary when the items of interest are subjective in nature. The central ajuication committee will review raiographs, operative notes, an clinical notes to ensure that the patient was eligible for the stuy, to etermine if any protocol eviations occurre, an to etermine if the patient ha any of the stuy outcomes. The ATHAC stuy i not have a central ajuication committee, which is one of the limitations of this stuy. Writing Committee At the onset of a multicenter observational stuy, the steering committee shoulevelop the writing committee. Often the writing committee inclues the steering committee members an several aitional clinical or methoological experts. The authorship policies shoul be establishe by the steering committee relatively early in the course of the observational stuy, so everyone is aware of how creit for their work will be presente. Options for authorship inclue group authorship (for example, the ATHAC Investigators), representatives of the collaborative who are publishing on behalf of the other investigators (for example, Author A, Author B, an Author C on behalf of the ATHAC Investigators), or iniviual authorship (for example, Author A, Author B, an Author C). Responsibilities of the writing committee inclue the planning, oversight, an interpretation of the ata analysis an the rafting of the manuscript. Depening on the stuy policies, the steering committee an/or all site investigators may be require to review an provie input into the stuy manuscript. If several manuscripts are anticipate to result from a large observational stuy, several writing committees may be forme. This provies many iniviuals with the opportunity to prepare a manuscript an be involve with one of the trial committees. The ATHAC writing committee was comprise of the steering committee an four clinical experts. Methos Center Overall Organization In multicenter observational trials, the methos center is responsible for the ay-to-ay management an coorination of the trial 1. Typically, a number of ifferent staff members are require for the successful coorination an completion of a high-quality observational stuy (Fig. 2). The tasks an iniviuals require at the methos center epen on the scope of the stuy an the phase the stuy is in. The number of personnel require for an efficient methos center epens on the size an the complexity of the observational stuy. In the ATHAC stuy, the stuy staff at the methos center inclue a project manager, a research coorinator, a research assistant, an a statistician. During the start-up phase of an observational stuy, iniviuals at the methos center are responsible for finalizing the stuy protocol, esigning the case report forms, writing the manual of operations, programming the ata-management system, obtaining approval from the ethics boar, an selecting clinical sites. The methos center is also responsible for preparing grant applications to secure funing for the observational stuy. The methos center may also conuct pilot testing or pretesting prior to the initiation of an observational stuy. In the ATHAC stuy, prior to the istribution of the case report forms to all participating centers, the methos center project manager conucte a pilot ata-abstraction site visit to one of the clinical centers. The project manager reviewe an abstracte a ranom sample of 100 patient recors, an, as a result, the pilote case report forms were revise to inclue patients who unerwent bilateral total hip arthroplasty, questions on the case report forms were rearrange to make ata abstraction

6 84 Fig. 3 Organization of the clinical site. This figure shows the roles an responsibilities of the key personnel at the clinical sites. as efficient as possible, an other minor changes were also implemente. The methos center is also responsible for sening the stuy supplies (i.e., protocol, manual of operations, an case report forms) to the clinical sites an ensuring that the personnel at the clinical sites are traine in the stuy methos to ensure high-quality ata collection. Stuy training may be complete by hosting an investigators meeting, holing a teleconference or Internet meeting, or visiting the iniviual clinical sites. In the ATHAC stuy, personnel at the sites receive training through participation in investigators meetings an by means of teleconferences. It is important to review the protocol, stuy proceures, an expectations at the investigators meetings. Proper training is invaluable in conucting high-quality research. During the ata-collection phase, the methos center is responsible for overseeing the collection of the ata at the clinical sites an valiating the ata as it is submitte to the methos center. Data can be submitte via an electronic ata capture system, by facsimile with use of a system such as DataFax (Clinical DataFax Systems, Hamilton, Ontario, Canaa), or by courier, epening on the resources available an the organization of the methos center. It is important that ata be submitte an reviewe in a timely fashion to facilitate quality assurance. Documents summarizing the queries an outstaning ata shoul be sent to the clinical sites frequently to ensure that clean ata are available for the analysis. This approach often helps to avoi missing an inconsistent ata. In aition, the research coorinators at the methos center shoul be available to answer any questions raise at the clinical sites. In the ATHAC stuy, ata abstraction was conucte with use of one of two methos. The majority of the clinical sites retaine all patient information in personal an meical recors. There were a few clinical sites that recore all information into an electronic atabase. The emographic, surgical, an outcome ata for each patient were recore on stuy-specific case report forms that were submitte to the methos center by fax or courier for valiation. The methos center staff was available to answer any questions from the clinical sites regaring ata collection. In aition, the staff at the methos center contacte the clinical sites with questions about any inconsistent or missing ata that were noteuring the valiation process. Three centers require site visits by the research coorinator from the methos center to assist with completion of the case report forms. Once ata collection is complete, the tasks require to complete an observational stuy inclue ata analysis an manuscript preparation. The statistician, uner the guiance of the writing committee, is responsible for the ata analysis. The project manager typically assists with the organization of the writing committee an the manuscript preparation. Clinical Sites The primary responsibilities of the clinical sites in an observational stuy are the ientification of eligible patients an the collection of high-quality ata (Fig. 3). The clinical sites are le by a site principal investigator, usually an orthopaeic surgeon, who assumes the overall responsibility of the stuy at the site. This iniviual shoul be committe to the completion of the stuy an have sufficient time to oversee all aspects of the trial an ensure that patients are enrolle anata are collecte. Most surgeons intereste in clinical research woul like to be intellectual partners, an these surgeons o not want to be presente with someone else s approve project an be invite only for their ability to enroll patients 4. Instea, the success of the project requires that a core research team be evelope early enough to critically assesses the potential of the research question an that the members of the team then work as a group to efine, esign, anrive the project 4. It is imperative to inclue key site principal investigators on trial committees. Aitional orthopaeic surgeons may participate in the stuy at the clinical site as co-investigators. Their role is typically patient enrollment an follow-up. Site investigators shoul not be so overburene that they cannot evote the requisite time to manage the clinical trial 3. If the protocol is complex, it is best to collaborate with a few surgeons who are eicate to the stuy an are willing to learn an follow a complex protocol 3.

7 85 As surgeons o not have sufficient time to monitor the aily activities at each site, eicate personnel are require to conuct ay-to-ay stuy operations 4. The success of the stuy is ultimately epenent on the expertise an commitment of these iniviuals 4. A research coorinator or research nurse, uner the supervision of the site principal investigator, is responsible for the ay-to-ay activities at the clinical site. These responsibilities inclue obtaining ethics approval to conuct the stuy at the clinical site; this approval may be obtaine either through the local institutional review boar or through a central institutional review boar, if this option is permitte by the institution. Opting to obtain approval from a central institutional review boar can reuce the buren of obtaining local ethics approval, as the protocol, informe consent template, an other stuy ocuments are submitte to the central institutional review boar by the methos center an are approve for the stuy as a whole. Iniviual sites can then submit their own site-specific information an informe consent an receive approval quickly an easily rather than having to obtain inepenent approval from their local ethics boar. Other responsibilities inclue obtaining patient consent, ata collection an submission, an communication with the methos center. The research coorinator an the site principal investigator work together to ensure compliance, ata quality, an effective communication with the methos center 1. The research coorinator shoul be well organize anetail oriente an able to inepenently troubleshoot, problem-solve, an maintain communication with all parties involve in the stuy 3. The ATHAC observational stuy inclue nine clinical sites across the Unite States. Each site ha a site principal investigator, some sites ha co-investigators, an most sites ha a research coorinator. If a clinical site i not have a research coorinator, a research coorinator travele to the clinical site to complete the ata collection. This was appropriate ue to the retrospective nature of this observational stuy; however, this approach will not work very well in large prospective stuies because of the costs involve. International Collaboration International collaboration in multicenter observational research is relatively uncommon in orthopaeics. Avantages to international collaboration inclue an increase generalizability of the stuy results an the opportunity to enroll more patients in a shorter time frame. Countries such as Inia 8 provie an excellent opportunity for multicenter collaboration outsie of North America. Accelerate urbanization an inustrialization in Inia, with its population of 1.2 billion people, has resulte in an alarming increase in traumatic injuries an, consequently, orthopaeic proceures. In aition to high patient volume, research output from Inia is currently insufficient an unfocuse, which provies an excellent opportunity for eveloping research initiatives 8. During the last ecae, the number of clinical trials that are being conucte in Inia has increase rapily 8. It is estimate that nearly 20% of all global research stuies will inclue clinical sites in Inia by Inia is well on its way to attracting high-quality researchers TABLE I Consierations for Organizing a Successful Collaboration an Completing an Observational Stuy Collaborative-Specific Consierations Have committe leaership at the steering committee level an site level Develop a cohesive stuy team Establish a communication anecision-making process Obtain aequate funing Foster a cohesive spirit Establish a eicate methos center Set realistic goals an timelines (an stick to them) Stuy-Specific Consierations Develop a feasible protocol Conuct pilot tests to ensure feasibility an efficiency Ensure protocol aherence Ensure ata quality Monitor site performance Ahere to the analysis plan Ahere to goo clinical practice an establishing itself as having a global capacity for research stuies 8. Potential challenges of international collaborations inclue an increase complexity of the stuy, challenges in the stanarization of the stuy protocol an proceures ue to variations in practice patterns, a potential for increase costs, anifficulties communicating if language barriers exist. Consierations for Organizing a Successful Collaboration an Completing an Observational Stuy Anumber of components are essential for successful collaboration an the completion of a high-quality observational stuy (Table I). The success of any multicenter clinical trial epens on the collaborative efforts of a highly functional an cohesive team, an this team requires strong leaership to provie motivation, to keep tasks progressing, an to ensure that a high-quality project is complete in a timely fashion 3. Other items to consier are the establishment of a etaile communication anecision-making process, methos of obtaining aequate funing to support the initiative, the establishment of a eicate an qualifie methos center, an the setting of realistic stuy goals an timelines. Developing a feasible an realistic protocol is essential to the successful completion of an observational stuy. If a stuy is not feasible, the stuy will not be complete, regarless of any other factors. It is important to conuct pilot tests to ensure the feasibility an efficiency of the stuy protocol an proceures. Although this may seem like an aitional step an may elay the start of a larger stuy, proving feasibility is vital. Another factor to consier is aherence to the stuy protocol. During the pilot phase, all protocol eviations shoul be recore. The methos center shoul monitor ata quality an site performance throughout the stuy. If a clinical site is not enrolling a sufficient number of patients or if ata quality is poor, the problems nee to be aresse at the site immeiately. Finally,

8 86 when the stuy is complete an all ata are valiate, ata analysis shoul begin. It is extremely important to ahere to the ata analysis plan an ensure that the ata are not rege for aitional finings. A final point is to ensure that all clinical sites ahere to goo clinical practice to ensure that the rights an the safety of all stuy participants are protecte. Summary Multicenter observationalstuies require vigilance to etail, comprehensive planning, an collaboration with colleagues. While challenging, such stuies offer great potential for builing a scientific base for the practice of orthopaeic surgery. Several large observational stuies have been conucte in the fiel of orthopaeic surgery. Future collaboratives shoul inclue international sites in aition to North American sites for the purpose of improving external valiity an efficiency. n Sheila Sprague, MSc Mohit Bhanari, MD, MSc, FRCSC, Departments of Clinical Epiemiology an Biostatistics (S.S. an M.B.) an Surgery (M.B.), McMaster University, 293 Wellington Street North, Suite 110, Hamilton, ON L8L 8E7, Canaa. aress for M. Bhanari: bhanam@mcmaster.ca Joel M. Matta, MD Hip an Pelvis Institute, Saint John s Health Center, Orthopeic Center, 2001 Santa Monica Boulevar #1090, Santa Monica, CA References 1. Bhanari M, Schemitsch EH. Beyon the basics: the organization an coorination of multicenter trials. Tech Orthop. 2004;19: Csimma C, Swiontkowski MF. Large clinical trials in musculoskeletal trauma: are they possible? Lessons learne from the international stuy of the use of rhbmp-2 in open tibial fractures. J Bone Joint Surg Am. 2005;87: Irving SY, Curley MA. Challenges to conucting multicenter clinical research: ten points to consier. AACN Av Crit Care. 2008;19: Trippel SB, Bosse MJ, Heck DA, Wright JG. Symposium. How to participate in orthopaeic ranomize clinical trials. J Bone Joint Surg Am. 2007;89: Wright JG, Gebhart MC. Multicenter clinical trials in orthopaeics: time for musculoskeletal specialty societies to take action. J Bone Joint Surg Am. 2005;87: Bosse MJ, MacKenzie EJ, Kellam JF, Burgess AR, Webb LX, Swiontkowski MF, Saners RW, Jones AL, McAnrew MP, Patterson BM, McCarthy ML, Travison TG, Castillo RC. An analysis of outcomes of reconstruction or amputation after legthreatening injuries. N Engl J Me. 2002;347: Bhanari M, Schemitsch EH. Planning a ranomize clinical trial: an overview. Tech Orthop. 2004;19: Mathew G, Sancheti P, Jain A, Bhanari M. Multicenter collaborative for orthopaeic research in Inia: an opportunity for global leaership. Inian J Orthop. 2008;42:165-8.