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Claudia Kimie Suemoto,1,2 Sherine Ismail,1,3 Paulo César Rodrigues Pinto Corrêa,1,4,5 Faiza Khawaja,1,6 Teodoro Jerves,1 Laura Pesantez,1 Ana Claudia Camargo Gonçalves Germani,1,7 Fabio Zaina,1,8 Augusto Cesar Soares dos Santos Junior,1,9,10 Ricardo Jorge de Oliveira Ferreira,1,11 Priyamvada Singh,1,12 Judy Vicente Paulo,1,13 Suely Reiko Matsubayashi,1,14 Liliane Pinto Vidor,1,15 Guilherme Andretta,1,16 Rita Tomás,1,17 Ben MW Illigens,1,18 Felipe Fregni1,18,19 1Collaborative Learning in Clinical Research Program, Principles and Practice of Clinical Research (PPCR), Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; 2Discipline of Geriatrics, Department of Internal Medicine, University of São Paulo Medical School, São Paulo, Brazil; 3King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Pharmaceutical Care Department, King Khalid Hospital, NGHA, Jeddah, Saudi Arabia; 4Discipline of Internal Medicine and Medical Semiology, Department of Internal Medicine, Federal University of Ouro Preto (UFOP) Medical School, Ouro Preto, Brazil; 5Discipline of Pneumology, Department of Internal Medicine, Centro Universitário de Belo Horizonte (Uni-BH), Belo Horizonte, Brazil; 6Canadian Centre for Advanced Eye Therapeutics, Mississauga, ON, Canada; 7Department of Preventive Medicine, University of São Paulo Medical School, São Paulo, Brazil; 8Italian Scientific Spine Institute (ISICO), Milan, Italy; 9Hospital Osvaldo Rezende Franco, Betim, Brazil; 10Nucleo de Avaliação de Tecnologia em Saude, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; 11Department of Rheumatology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; 12Department of Internal Medicine, Saint Vincent Hospital, Worcester, MA, USA; 13Portuguese Institute of Oncology, Coimbra, Portugal; 14Acupuncture Center, Orthopedics and Traumatology Institute, University of Sao Paulo Medical School, São Paulo, Brazil; 15Department of Medical Science, Faculty of Medicine, University Federal of Rio Grande do Sul, Porto Alegre, Brazil; 16Quintiles Transnational, São Paulo, Brazil; 17Department of Physical Medicine and Rehabilitation, Hospital de Curry Cabral, Centro Hospitalar de Lisboa Central, EPE, Lisbon, Portugal; 18Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; 19Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Boston, MA, USA Abstract: The exponential increase in clinical research has profoundly changed medical sciences. Evidence that has accumulated in the past three decades from clinical trials has led to the proposal that clinical care should not be based solely on clinical expertise and patient values, and should integrate robust data from systematic research. As a consequence, clinical research has become more complex and methods have become more rigorous, and evidence is usually not easily translated into clinical practice. Therefore, the instruction of clinical research methods for scientists and clinicians must adapt to this new reality. To address this challenge, a global distance-learning clinical research-training program was developed, based on collaborative learning, the pedagogical goal of which was to develop critical thinking skills in clinical research. We describe and analyze the challenges and possible solutions of this course after 5 years of experience (2008–2012) with this program. Through evaluation by students and faculty, we identified and reviewed the following challenges of our program: 1) student engagement and motivation, 2) impact of heterogeneous audience on learning, 3) learning in large groups, 4) enhancing group learning, 5) enhancing social presence, 6) dropouts, 7) quality control, and 8) course management. We discuss these issues and potential alternatives with regard to our research and background. Keywords: education, distance learning, biomedical research, critical thinking, e-learning