International Journal of Academic Medicine

: 2016  |  Volume : 2  |  Issue : 2  |  Page : 203--216

Keys to success in clinical trials: A practical review

Tracy Butryn1, Kristine Cornejo1, Thomas R Wojda1, Thomas J Papadimos2, Anthony T Gerlach3, Lena Deb4, Anshuman Sethi5, Cody Kramer6, Stanislaw P Stawicki1,  
1 Department of Research and Innovation, St. Luke's University Health Network, Bethlehem, Pennsylvania, USA
2 Department of Anesthesiology, University of Toledo School of Medicine and Life Sciences, Toledo, USA
3 Department of Pharmacy, The Ohio State University Medical Center, Columbus, Ohio, USA
4 Georgetown University, Washington, D.C, USA
5 School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
6 New Jersey Institute of Technology, Newark, New Jersey, USA

Correspondence Address:
Stanislaw P Stawicki
Department of Research and Innovation, St. Luke's University Health Network, 801 Ostrum Street, Bethlehem, Pennsylvania


Clinical research is a highly specialized and rapidly evolving field of expertise. Clinical trial (CT) sites face a continually changing legal and regulatory landscape, making research conduct and program operations challenging. Despite the high number of CTs being conducted, few sources provide a comprehensive summary of key elements essential to the success of clinical trials units (CTUs). Consequently, we set out to provide a practical review on this topic based on collective experience of CT professionals from major academic medical centers. The ultimate result of our group's work is the list of “top 11” essential components of a successful academic CTU implementation. Specific topics discussed in this manuscript include financial and organizational management, new trial feasibility assessment, standardization of procedures, centralization of resources, compliance and safety monitoring, pharmacy support, patient recruitment, effective marketing, institutional support, building (and working with) diverse teams, encouraging clinician engagement, and the importance of continuing professional education. Academic CTUs able to successfully implement key components of the above 11-point program are more likely to perform better in the high-intensity, complex, extensively regulated, and competitive CT environment of today. The following core competencies are addressed in this article: Interpersonal and communication skills, medical knowledge, practice-based learning and improvement, professionalism, systems-based practice.

How to cite this article:
Butryn T, Cornejo K, Wojda TR, Papadimos TJ, Gerlach AT, Deb L, Sethi A, Kramer C, Stawicki SP. Keys to success in clinical trials: A practical review.Int J Acad Med 2016;2:203-216

How to cite this URL:
Butryn T, Cornejo K, Wojda TR, Papadimos TJ, Gerlach AT, Deb L, Sethi A, Kramer C, Stawicki SP. Keys to success in clinical trials: A practical review. Int J Acad Med [serial online] 2016 [cited 2022 Nov 29 ];2:203-216
Available from:

Full Text


Before the 1950s, relatively few large randomized clinical trials were sponsored or conducted by private industry, with the traditionally defined Academic Health Centers (AHCs) being the champions of clinical research.[1] Because of the continued acceleration in the medical scientific and technological progress, and the shortening of the discovery cycle, the need for clinical trials (CTs) involving new devices and drugs increased markedly.[1],[2] These parallel developments, combined with the evolution of modern research methodologies and the emergence of healthcare economies of scale, prompted the industry, the contract research organizations (CROs), and the AHCs to form partnerships that made large-scale randomized clinical trials (RCTs) the reality of today.[1],[3],[4] Additionally, due to the significant human and financial resources involved in the development and approval of new drugs and medical devices, the potential for ethical misconduct and unchecked conflicts of interest led to increased regulatory oversight of CTs involving human subjects.[1],[5],[6],[7]

Modern CTs constitute a highly specialized professional niche that is ever-changing and evolving. Clinical trials units (CTUs) constantly face diverse challenges and competing priorities, including patient enrollment activities, high staff turnover, maintaining compliance with updated regulations and guidance documents, as well as ensuring that new standards of care and best practices are being implemented and followed.[8],[9],[10] To say that clinical research is complex is an understatement because CTU activities often involve more “moving parts” than other areas of healthcare, simultaneously addressing both short- and long-term objectives.

While the conduct of research and operating a comprehensive CTU can be challenging, it is also very rewarding. The complexity of CTs has been increasing over the recent decades, with trials being conducted in a highly structured and closely coordinated fashion.[11] Key components must be in place for a successful CTU to run efficiently. This article outlines the “top 11” essential strategies for operating a successful CTU. The list is based on collected expert opinions from three high-performing clinical sites. Because each of the components discussed is instrumental to successful functioning of a CTU, topics are not listed by absolute importance but rather according to their relationship to the other points of discussion.

 Creation of Specialized Clinical Trials Teams

The complexity of the task of taking a new drug or device from inception to regulatory approval has increased exponentially over the last few decades.[12] An integral component of this process, CTs constitute an intricate and highly specialized area, with a plethora of complicated rules and guidance documents originating from diverse governing bodies and covering virtually all aspects pertaining to the microcosm of “clinical research.”[13],[14] Successful application of all these laws and guidelines into practice can be overwhelming. Needless to say, the presence of a highly skilled and knowledgeable implementation team is critical.[13],[15]

The multifaceted nature of CTs requires specialized skills in the areas of the clinical conduct of studies, regulatory compliance, data management, financial/billing regulations, human subjects protection, and project management.[16],[17],[18] Therefore, having a well-coordinated, structured unit composed of clinical research experts, with an enthusiastic and knowledgeable leadership, should constitute the core of a successful CT program.[18],[19] The importance of skills-based team stratification is critical. For example, a licensed nurse is best utilized to enroll patients and coordinate clinical aspects of the study, rather than spending time completing documentation required by the Institutional Review Board (IRB) or tending to other regulatory matters. In turn, the latter should be handled by a trained regulatory or compliance expert. Finally, personnel trained in research billing and financial aspects of CTs should be handling budgeting, invoicing, billing, and financial reporting (as well as other quantitative analyses). This type of specialization, taking full advantage of synergies inherent to the “economies of scale,” not only allows individuals to become experts in specific areas but also facilitates the environment of accountability and task ownership where easily identifiable points of communication and contact (both internally and externally) can be established. This general approach may also help prevent staff burnout as each team member is not “pulled in multiple directions” – an aspect that is especially important given the traditionally high CT personnel turnover. The latter point must be emphasized because finding adequately trained and sufficiently experienced replacements is both difficult and expensive, and training new staff can be equally costly and time consuming.[10],[20]

Among other important considerations related to the design and implementation of complex, multispecialty teams are factors such as effective management, teamwork strategies, and standardized group communication to facilitate optimized workflow.[21],[22] Preferred methods for communication among team members include electronic CT management systems (CTMS), regular standing meetings, effective feedback processes as well as tools specifically designed for team coordination and project management.[23],[24]

 Clinical Study Feasibility Assessment Process

In addition to the above-mentioned team and infrastructure considerations, it is critically important to have an optimized portfolio of CTs. Team leaders should remember that the CTU's success depends on the identification and opening of the “right” trials as opposed to simply maintaining a large number of “open studies“. This strategy helps ensure optimal resource allocation, operational efficiency, financial viability, and enrollment success.[18],[25],[26] These four considerations are at the center of the protocol feasibility review.

The feasibility review process should involve all key stakeholders, including the principal investigator (PI), the research team, information technology (IT) specialists, ancillary departments (e.g., clinical laboratory, radiology, and pharmacy), and research administration [Figure 1].[18],[25],[26],[27],[28] The success of any particular CT is heavily dependent on close harmonization of these elements. Lack of adequate infrastructure or resources to conduct the trial will result in poor performance, lack of enrollment, or an unacceptable number of protocol deviations/violations. If the practicality of the trial is beyond the operational limits of a research team or organization, disproportionately high resource consumption and inefficiencies will prevent successful implementation and conduct of a protocol. For CTs that are inadequately funded, the CTU will incur more expense than what is covered by the revenues, leading to loss of quality, protocol violations, or lack of enrollment. In extreme cases, the entire CT program may fail if budgeting mismatches are persistent, especially if this trend is not identified and corrected promptly. Finally, if the desired patient population is not available, either due to low patient volumes or restrictive study-specific inclusion/exclusion criteria, the trial will not enroll participants and will fail to generate sustainable revenues.[29],[30]{Figure 1}

Proper feasibility review during the CT “start-up” process can help avoid misallocations of both time and personnel resources. Such initial investment of effort should focus on screening candidate protocols for compatibility with the institution's ability to deliver results. Downstream benefits include substantial reductions in nonperforming CTs, leading to improved personnel morale, greater buy-in from clinical departments, and enhanced investigator engagement. A careful and proactive protocol assessment by sites is also beneficial for the sponsors and CROs who invest significant resources to get each individual site up and running.[26],[31] Finally, both sponsors and CROs tend to avoid sites that repeatedly underperform. Thus, reliable and consistent site performance is critical to generating future interest from sponsors and long-term success of a program.[28],[32],[33],[34]

 Effective Budgeting and Financial Management

As costs associated with conducting CTs continue to escalate, the importance of effective budgeting and financial management increases.[35] CTUs must therefore consider business aspects of their operations in addition to the scientific merit of research protocols. Industry sponsors understand these realities very well, with the average cost of developing a single new drug being as high as $2.6 billion (most of which is spent on CT-related activities). Consequently, significant efforts are devoted to effective management and cost containment.[5],[36] The sustainability of a research program ultimately lies with its financial stability, which in turn is dependent on the ability to create and maintain diverse revenue streams (e.g., industry funding, grants, endowments, and institutional support).[37],[38],[39]

Financial management of CTs is a complex process that begins with having the appropriate infrastructure in place (as outlined above) and continues through the entire protocol lifecycle from initial feasibility assessment (see the previous section) to the study closeout phase. Detailed cost analysis should be performed at the time a new protocol is being considered. This should be done regardless of the presence or absence of funding (e.g., the use of available slack financial resources may be justifiable if a particular study has high scientific merit) or type of trial. The overall process starts with the development of a coverage analysis for interventional trials to determine what items/services are billable to insurance. For observational trials, a simplified assessment of estimated “time and effort” involved is created [Figure 2].{Figure 2}

A budget proposal (for externally funded trials) or an accounting of resources required and how costs will be covered (for nonfunded studies) should be developed based on the initial coverage/cost analysis. Based on the above procedures, an objective determination should be made whether to move forward with the study. If the CT is funded by an external sponsor, the clinical site should insist that all study costs are covered during budget negotiations with the sponsor or the CRO. This process is very methodical, tedious, and takes time to master. Any negotiation becomes much easier if detailed backup documentation of institutional fees is available for full transparency (a top concern for industry sponsors who are held to regulations surrounding fair-market value and Stark/“Anti-kickback” laws).[40],[41] Of importance, budgets that are set too low usually result in the inability to properly implement the trial, and budgets that are inappropriately high may result in regulatory scrutiny and potential audits. Consequently, the research feasibility assessment team must focus on the accuracy of the study cost estimates as the primary objective.[40],[42],[43],[44]

Once a study budget is finalized and executed, diligent financial oversight must be maintained throughout the entire protocol lifecycle. This includes tracking patient visits and the associated costs, timely invoicing, and effective follow-up to ensure real-time cost reconciliation.[45] This is an intricate and potentially complicated process and again points back to the importance of effective communication and transparent procedures within the CTU.

To promote long-term sustainability, team and individual productivity tracking need to be implemented, utilizing an objective combination of patient enrollment, screening activity, completed study visits, and research revenues.[45] Once standardized and finalized, such performance measures need to be regularly reviewed and updated. To ensure objectivity, it is also important for any criteria to be specific to particular trial types and CT portfolios. The overall institutional “assortment of trials” should be evaluated on an ongoing basis, and nonperforming trial closure should be considered based on the overall use of available resources, especially in the context of potential new trials and other well-performing studies.

Regardless of how thorough the feasibility assessment is before opening a new study, there are some trials that still end up underperforming for a number of reasons (both intrinsic and extrinsic to the institution). Thus, the ongoing assessment of how the current “trials portfolio” is performing is critical to ensuring optimal resource allocation and ultimately financial sustainability of the institution's research infrastructure. Finally, if any new or previously unanticipated costs are identified following the formal activation of a CT, the leadership of the research team should reach out to the sponsor and/or the CRO to renegotiate pertinent aspects of the budget. When indicated, sponsors are usually willing to amend the budget to maintain a high-quality, high-performing site than risk the potential of the site closing the study.

 Dedicated and Knowledgeable Clinical Trials Unit Management: Focus on Understanding Global Needs and Creating Synergies

Demographic changes around the globe drive the need to address a broad range of pressing health issues related to aging and frailty, including cancer, cardiovascular disease, functional and cognitive decline, multimorbidity, and polypharmacy.[46],[47],[48] As our collective scientific understanding of these diverse topics evolves, so does the realization of the true extent of the “unknowns.” Due to the overall degree of complexities involved, increasing amount of work is being done to incorporate multiple, often parallel interventions into either RCTs [49] or comparative effectiveness research (CER) initiatives.[50]

In general, new therapeutic research seeks to establish evidence regarding specific clinical interventions. Ultimately the goal is for innovative, new ideas to benefit patients (e.g., primary stakeholders), inventors (e.g., royalties), and producers (e.g., ability to introduce new scientific and technological advances).[51] The above goals and objectives must be achieved within a framework of highest ethical and scientific standards.[6] Successful conduct of RCTs requires the presence of a collaborative, interdisciplinary team.[52] Differences between disciplinary and interdisciplinary research collaboration must be understood by project leaders.[53] Of note, an interdisciplinary environment is more likely to be fostered by women researchers, more experienced investigators, joint ventures between private companies and the government, and endeavors involving practical implementation of research.[53] Disciplinary work tends to be confined to a particular topic or field (with the investigators being experts in that specific area), and is more commonly seen in disciplines with more theoretical or narrow foci [Figure 3].[53]{Figure 3}

Given the complexity of modern clinical research, it is evident that a single individual is unlikely to have the cumulative skill set or the knowledge required to execute a typical CT project. Effective interdisciplinary collaboration is therefore required.[54] In this context, seven specific attributes are helpful to the success of interdisciplinary teams,[55] including leadership, team purpose, goals, communication, cohesion, mutual respect, and mechanisms for feedback/reflection. In regard to leadership, constructive feedback and coaching are very important. Leaders must be attentive to the needs and concerns of the CTU team, and should pay special attention to any potential “blind spots“. Team purpose is reinforced by its diversity, maturity, mutual respect, acceptance, and goal setting. The group's aims and objectives must be well delineated and clearly understood by all team members. Well-defined goals help galvanize the group and augment team commitment.[56] Effective communication builds trust and encourages sharing of collective knowledge.[57] Team cohesion fosters positive interactions among CTU members and facilitates better coordination of team efforts.[58] Mutual respect is mandatory, with clear understanding that team members must be accepting of each other and embrace the fact that “everyone brings something unique to the table.”[59] Reflection is necessary not only in the context of quality and performance improvement but also from the perspective of group dynamics and team interactions.[60] While all of the above attributes are of great importance to group effectiveness, leadership skills needed to adequately manage diverse areas of team expertise, internal and external group interactions (including conflict resolution) are equally critical [Figure 4].[61],[62],[63] Finally, proper handling of any potential conflict of interest takes special importance from the standpoint of the increasingly complex regulatory environment of clinical research.[7]{Figure 4}

In terms of specialization and expertise, the successful research team is inherently diverse, with physicians, nurses, pharmacists, and other allied health professionals – all working toward the common goal.[30] The CTU leader must select and coordinate members from pertinent disciplines so that the collective “group expertise” helps facilitate project completion. Fostering emotional and social intelligence, both at the individual and team levels, helps optimize group effectiveness, minimize conflicts, and maximize productivity.[59],[64],[65] All team members must interact respectfully, regardless of their academic degrees, educational level, specialty areas, demographics, personalities, levels of commitment, or potential conflicts of interest.[66],[67] After the research team is assembled, project implementation and management questions are addressed, including the establishment of appropriate expectations and performance metrics.

 Standardization and Centralization of Research Processes, Workflows, and Procedures

CTU is an umbrella term for biomedical research departments involved in the development, design, implementation, and coordination of CTs and other types of studies.[68],[69] The development of CTUs at AHCs has been shown to be a cost-effective method of sharing knowledge, resources, and specialty skills.[69],[70],[71] According to Croghan et al.,[69] advantages of creating a CTU include a fee-for-service funding model, centralized access to highly qualified research professionals, streamlined operations without the need for ad hoc backup support, as well as high-quality administrative and regulatory oversight.[69] Building and maintaining a “research team” composed of well-trained, highly professional, experienced, knowledgeable, and flexible employees is one of the most effective ways to ensure clinical research sustainability at an AHC.[69] Services offered by CTUs include training and mentorship for PIs, research team supervision, the development and maintenance of standardized operating procedures (SOPs), assistance in protocol development, regulatory compliance, study coordination, data logistics, financial management, and study feasibility assessment.[69],[70],[72]

Many CTs have to be extended by weeks or months due to the inability to enroll a sufficient number of patients within the allotted timeframe.[71] Study feasibility, discussed earlier in this article, is a very important topic that is often underappreciated or even neglected by clinical investigators.[73] Thew et al.[73] developed a study feasibility tool called Feasibility Assessment and Recruitment System for Improving Trial Efficiency (FARSITE). This approach helps reduce inefficient resource utilization by prospectively identifying under-enrolling (e.g., nonperforming) studies.[73] The widespread utilization of electronic health records (EHRs) has improved efficiency within CTU operations by enhancing the protocol feasibility assessment process, facilitating better identification of potential study patients, allowing streamlined clinical study execution and adverse event reporting, as well as optimizing the management of clinical data.[74] In addition, EHRs may improve financial reimbursement and reduce costs for CTUs.[74]

According to the International Conference on Harmonization (ICH) of Good Clinical Practice (GCP), systems and procedures that assure the quality of each aspect of a CT should be established.[75],[76],[77] To facilitate GCP adherence, institutions should enforce existing SOPs (e.g., detailed instructions developed by members of the CTU or funding/sponsoring organizations) to attain consistency and ensure the provision of high quality services.[20] Institutional SOPs provide a framework that guides the research team through the complicated processes involved in CT conduct (e.g., what, when, who, how, and why).[78],[79] Consequently, SOPs may enhance the efficiency, quality, and safety of research services.[78],[79] This, in turn, may help improve subject recruitment and enhance the overall patient experience related to CT participation.[75],[80] Major benefits of GCP-compliant SOPs are listed in [Table 1].{Table 1}

 Monitoring and Audits: Compliance, Ethics, and Quality

The CT arena is understandably very risk-averse, both due to patient safety concerns [81] and a plentiful history of ethical violations.[82] However, there are few proven methods to assist CTUs and sponsors in pinpointing, analyzing, and mitigating various risks associated with CT conduct.[83] The methodology proposed by Fay et al.[83] consists of risk identification, analysis, evaluation, control, study health tracking, and risk management tools. The implementation of such program should be carried out by CTUs with a cross-functional team that is well versed in quality and risk management principles pertaining to CT conduct, and the ability to identify key risk indicators and essential CT performance benchmarks.[83] Important considerations [Table 2] have to be taken into account when developing an efficient centralized oversight program,[84] including the frequency and extent of monitoring activities, formalized templates for reporting findings, detailed documentation of team members (including their roles and responsibilities), open communication between all stakeholders for problem escalation and resolution, and specified training requirements for monitors and study team members.[84],[85]{Table 2}

 Pharmacy Support in Clinical Trials

Pharmacy professionals play an important role in the conduct of CTs,[86] ensuring that investigational drug services are both prompt and reliable. In this role, pharmacists enforce the integrity of the study and oversee the storage, compounding, and distribution of investigational agents. In addition, pharmacists help facilitate patient safety, regulatory compliance, as well as various other aspects of research monitoring and implementation.[87]

More recently, the role of pharmacy professionals has expanded further to incorporate dedicated oversight over investigational drug services.[86],[88] Many pharmacists have transitioned, either partially or fully, into the area of clinical research. In fact, those with daily rounding responsibilities can play a vital role in both study design and subsequent implementation, including the screening and identification of potential study candidates.[89] Pharmacists are in a unique position of understanding the entire spectrum of pharmacotherapy – from drug prescribing to dispensing and bedside administration. The inclusion of clinical pharmacists in the research process reinforces the multidisciplinary character of CTs as outlined earlier in this manuscript [Figure 5].[90] Finally, many pharmacists are also accomplished researchers in their own right.[86] Consequently, they can serve as research mentors, and provide guidance and insight that spans the entire spectrum of scholarly activities, from grant funding applications to manuscript submission.{Figure 5}

 Identification and Recruitment of Patients

The very concept of CTs is predicated on the ability to recruit study subjects. Regardless of available resources, a perfectly designed study will be unsuccessful if it fails to accrue patients. Declining patient enrollment has become a major issue facing CTUs in the United States.[91] In one report on industry-sponsored CTs, out of 2.8 million individuals, only about 1 in 5 responded to recruitment promotions, 7% enrolled in studies, and only 5% actually completed their participation in trials.[43],[92] Moreover, a significant proportion of potential study candidates are unaware of the amount of effort required on their part to complete study participation, thus contributing to subject attrition.[92],[93]

Effective enrollment strategies are critical to success and timely completion of CTs. Trials should be tailored to the study design, with emphasis on ethical conduct of research, suitability of the study population, and patient recruitment that facilitates data acquisition without introducing undue biases.[94] Reaching the desired subject enrollment within the specified time window is important. The fact that approximately 75% of CTs face completion delays because of recruitment-related issues highlights the need for better trial planning and implementation.[91],[95] Whenever evaluating a new study, clinical sites should consider the protocol from the standpoints of study participants, the sponsoring organization, and the CTU.[91] A study must also meet the needs of a specific population. A thorough justification of the necessity, advantages/disadvantages, and significance of participation provides a foundation for the subsequent informed consent. A technology-driven, patient-centered, professional approach to guiding enrollees through the entire experience of CT participation should include personalized patient visits, timely and courteous study reminders, and reasonable financial compensation for efforts required to complete all study activities (e.g., funds sufficient to pay for time, effort, and cost of travel).[96],[97],[98] Continued patient education and support is central to CT success, including informational brochures, encouragement of family involvement in the decision-making process, and the provision of tools to overcome language barriers [Figure 6].[91]{Figure 6}

Investigators may sometimes overestimate the number of patients who might meet study-specific inclusion or exclusion criteria, resulting in commitment to trials that ultimately under-enroll or fail to enroll subjects.[99] Electronic medical record-based recruitment screening may help improve both critical study feasibility decisions and subsequent patient enrollment.[91] Research staff engagement to help clarify protocols, address operational concerns, and other aspects of CTs may also be beneficial.[100] The physician-patient relationship is of utmost importance in trial conduct and any serious adverse events have the potential to cause harm to this dynamic. This, in turn, may dissuade both physicians and patients from engagement in research. Physician education regarding CT conduct may alleviate any potential misconceptions and encourage greater participation.[101] Same applies to clinical support staff. An appraisal of economic feasibility may ease any concerns over financial considerations. Specialty research conferences that address CT topics may also improve patient enrollment through directed didactics, practical sessions, and sharing of experiences.

Study sponsors are responsible for ensuring safe, ethical, and adequate study design - including patient enrollment considerations. As stated earlier, many CTs face recruitment challenges, not infrequently resulting in study suspension, unplanned increase in the number of study sites, and/or protocol redesign.[95] Performed by the sponsor and the core study team, statistical estimations of the required sample size, including the expected patient recruitment rates, are critically important before opening a trial.[99] Each facet of a protocol should be supported by an exact outcome because any unnecessary laboratory assessments, imaging tests, office or hospital visits are likely to increase the burden on study participants without providing any clear benefits or actionable answers. To increase study participant recruitment, the use of various media platforms can also be helpful.[91],[99] However, such tools need to be cost-effective and must receive IRB approval.[102] A well-designed advertisement should list study inclusion/exclusion criteria, the intended number of patients involved, potential benefits, study contact information, and should peak interest without deception. Other effective methods of accruing patients and increasing clinical site visibility include newsletters, the development of an interactive, up-to-date CTU website, and endorsements from patient-advocacy groups [Figure 7].[103]{Figure 7}

 Clinical Trials Marketing

To attain long-term brand recognition with both sponsors and patients, a CTU must actively market its services.[103] It is imperative for CTUs to build strong relationships with sponsors and CROs. Initially, this can be accomplished through marketing the CTU and its respective institution. Developing an Internet site profile that markets the institution's facilities, staff, and expertise can attract sponsors that may be interested in expanding to new clinical locations.[104] Actively seeking communication with sponsors and CROs can also be a successful marketing technique. If a site can build close relationships with various sponsors and CROs by offering high quality personalized service, transparency, and timely communication, they will be more likely to be selected for future trials. Once a site has developed a track record with a sponsor by successfully completing well-enrolling CTs, the site may then be approached with additional opportunities.[104]

Maintaining excellent rapport with potential CT participants is just as important as building strong relationships with sponsors and CROs. CTU operations are dependent on the enrollment of patients to generate revenue, thus adequate site visibility must be ensured via appropriate marketing efforts. A formal plan should be developed that clearly defines the target audience and each trial's unique characteristics, ensuring that any promotional materials meet established research standards and norms.[105] Potential marketing outlets for advertising CTs to prospective enrollees include the use of newspapers, public transportation ads, radio, television, educational magazines, and the Internet.[106] Again, it is important to remember that any patient recruitment materials have to be approved by the site's IRB.[106]

 Institutional Support and Provider Involvement

Institutional support for CTs is pivotal to establishing and maintaining a successful clinical research department. Without sufficient administrative and financial backing, a CTU may not be able to meet the institution's revenue goals or provide investigators with sufficient opportunities to advance their research efforts.[107] Comprehensive support should begin with research becoming a part of the institutional mission, which usually translates into various forms of intramural innovation, active pursuit of new patient care delivery approaches, and the emergence of “non-price” competitive advantage. It is not surprising that many patients preferentially opt to receive care at facilities that actively promote and conduct CTs.[108],[109] Institutional support for research should also include the understanding that faculty members are empowered to choose alternative methods of contributing to the academic mission, in lieu of the traditional clinical relative value unit (RVU) generation.[110] Details regarding the value of substitutive contributions are beyond the scope of this manuscript, but it is important to understand that the embrace of such innovative approaches will ultimately benefit both the researchers and the institution because substantial revenue streams can be generated from industry sponsors.[110],[111]

Along with providing support to researchers and creating an institutional embrace of CTs, management must also construct an efficient CT infrastructure that can optimize the simultaneous conduct of multiple trials.[112] In a research environment characterized by constantly evolving regulatory and legal requirements, a dedicated CTU is a necessity.[113] The most successful AHCs dedicate significant resources into developing CTUs that are uniquely tailored to the institution's needs. These centers also tend to be at the forefront of organizational innovation when it comes to the makeup of their CTUs. One example is the Duke Office of Clinical Research, which recently instituted systemic changes resulting in improved efficiency of research processes (e.g., decreased IRB approval times, increased subject enrollment).[113] The Mayo Clinic Department of Medicine instituted a number of innovative changes in their Clinical Research Office, resulting in increased publication rates of first-authored manuscripts, decreased study start-up times, and lower overall costs.[69] These two examples show how maintaining a successful CT program requires strong institutional support and the willingness to innovate.

Practitioner engagement in CTs can be significantly increased in the presence of adequate institutional support for research.[111] Many physicians avoid research due to the combined demands of their clinical practice and/or administrative duties.[111] By providing administrative resources, adequate infrastructure, and logistical support institutions may be able to allow physicians devote more time and effort to research. In turn, practitioners can then actively engage in procuring grants, conducting CTs, presenting and publishing research results. Providers should also be given the opportunity to expand their knowledge of clinical research, with suggested didactics in the fundamentals of research design, methodology, and clinical implementation of protocols.[111]

 Study Monitoring and Audits

Principal investigators are responsible for guiding their research teams through all aspects of study conduct, including the assurance of “audit readiness” and regulatory compliance.[114] To ensure that this level of CT performance is indeed taking place, both sponsors and CROs utilize highly trained personnel who regularly audit various aspects of study conduct and actively verify data accuracy. The most common framework for such activities is the so-called “study monitoring visit.”[115] During site visits, CRO monitors (and other “auditors”) are tasked with verifying that study coordinators at the local CTU carry out appropriate case reporting, accurate data collection, and that source documentation procedures are strictly followed.[116] Perhaps the most important aspect of a monitoring visit is the verification of adequate clinical record keeping. “If it was not documented, it did not happen” is the philosophy that best describes this critical verification process.[117] Effective communication is critical during the monitoring process. If the PI, monitor (or auditor), study coordinator, and research staff can work together effectively and address any ongoing concerns in a constructive and efficient manner, study activities will be able to continue without interruptions.

 Continuing Education

Clinical research professionals should ensure continuous maintenance of their research skills and knowledge given the ever-evolving regulatory framework of CTs. Expanding the staff's knowledge can be done through research conferences, grand rounds, or dedicated classroom and web seminars – all designed to create a more versatile team. By fostering continuing professional education (CPE) and specialty certification maintenance among clinical research professionals, a CTU can actively support opportunities for professional growth and optimize staff satisfaction.[113] Education of CTU personnel is also necessary to keep all team members updated regarding the constantly changing regulatory landscape. For this reason, institutions should actively invest in their existing employees though CPE, specialty journal subscriptions, and opportunities for recertification through various professional organizations.[118] Fundamental CPE coursework should incorporate topics such as human subjects protections, the consent process, study documentation requirements, and data security.[113] Supporting team growth through such educational efforts can also help reduce the chances of staff burnout and increase staff engagement.


This review highlights the “top 11” characteristics of a successful research program. Topics presented include financial and organizational management, new trial feasibility assessment, standardization of procedures, centralization of resources, compliance and safety monitoring, pharmacy support, patient recruitment, effective marketing, institutional support, building (and working with) large teams, physician engagement, and continuing education. Methods outlined in this practical review aim to streamline the clinical research process and to optimize institutional research operations. Practical implementation of these components may help expand existing research programs and provide an important foundation when establishing new CTUs. The more efficient the process of clinical research becomes, the more benefits can be realized – both for patients and institutions. The authors believe that AHCs able to successfully implement key components of the 11-point list will gain an important competitive advantage in the high-intensity, extensively regulated, and increasingly complex CT environment of today.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


1DeMets DL, Califf RM. A historical perspective on clinical trials innovation and leadership: Where have the academics gone? JAMA 2011;305:713-4.
2Gelijns AC, Gelijns A. Comparing the development of drugs, devices and clinical procedures. In: Gelijns AC, editor. Institute of Medicine, Medical Innovation at the Crossroads: Modern Methods of Clinical Investigation. Washington, DC: National Academy Press; 1990. p. 147-201.
3Psaty BM, Rennie D. Stopping medical research to save money: A broken pact with researchers and patients. JAMA 2003;289:2128-31.
4Glickman SW, McHutchison JG, Peterson ED, Cairns CB, Harrington RA, Califf RM, et al. Ethical and scientific implications of the globalization of clinical research. N Engl J Med 2009;360:816-23.
5DiMasi JA, Hansen RW, Grabowski HG. The price of innovation: New estimates of drug development costs. J Health Econ 2003;22:151-85.
6Angell M. Industry-sponsored clinical research: A broken system. JAMA 2008;300:1069-71.
7Morin K, Rakatansky H, Riddick FA Jr., Morse LJ, O'Bannon JM 3rd, Goldrich MS, et al. Managing conflicts of interest in the conduct of clinical trials. JAMA 2002;287:78-84.
8Ireland DC, Hine D. Harmonizing science and business agendas for growth in new biotechnology firms: Case comparisons from five countries. Technovation 2007;27:676-92.
9Rochon PA, Berger PB, Gordon M. The evolution of clinical trials: Inclusion and representation. CMAJ 1998;159:1373-4.
10Jackson M, Berman N, Huber M, Snetselaar L, Granek I, Boe K, et al. Research staff turnover and participant adherence in the Women's Health Initiative. Control Clin Trials 2003;24:422-35.
11Bleyer WA. Cancer in older adolescents and young adults: Epidemiology, diagnosis, treatment, survival, and importance of clinical trials. Med Pediatr Oncol 2002;38:1-10.
12Dickson M, Gagnon JP. The cost of new drug discovery and development. Discov Med 2004;4:172-9.
13Fleming TR, DeMets DL. Monitoring of clinical trials: Issues and recommendations. Control Clin Trials 1993;14:183-97.
14Ellenberg SS, Fleming TR, DeMets DL. Data Monitoring Committees in Clinical Trials: A Practical Perspective. West Sussex, England: John Wiley & Sons; 2003.
15Schott M. Medical research on humans: Regulation in Switzerland, the European Union, and the United States. Food Drug Law J 2005;60:45-77.
16Teo AR. The development of clinical research training: Past history and current trends in the United States. Acad Med 2009;84:433-8.
17Friedman LM, Furberg CD, DeMets DL. Fundamentals of Clinical Trials. Vol. 4. New York: Springer; 2010.
18Pocock SJ. Clinical Trials: A Practical Approach. Hoboken, NJ: John Wiley & Sons; 2013.
19Lee-Kelley L. Situational leadership: Managing the virtual project team. J Manage Dev 2002;21:461-76.
20Califf RM, Morse MA, Wittes J, Goodman SN, Nelson DK, DeMets DL, et al. Toward protecting the safety of participants in clinical trials. Control Clin Trials 2003;24:256-71.
21Ferrante S, Bonacina S, Pozzi G, Pinciroli F, Marceglia S. A design methodology for medical processes. Appl Clin Inform 2016;7:191-210.
22de Carvalho EC, Jayanti MK, Batilana AP, Kozan AM, Rodrigues MJ, Shah J, et al. Standardizing clinical trials workflow representation in UML for international site comparison. PLoS One 2010;5:e13893.
23Zarin DA, Tse T. Medicine. Moving toward transparency of clinical trials. Science 2008;319:1340-2.
24Farrell B, Kenyon S, Shakur H. Managing clinical trials. Trials 2010;11:1.
25Gaydos B, Anderson KM, Berry D, Burnham N, Chuang-Stein C, Dudinak J, et al. Good practices for adaptive clinical trials in pharmaceutical product development. Drug Inf J 2009;43:539-56.
26Rettig RA. The industrialization of clinical research. Health Aff (Millwood) 2000;19:129-46.
27DeMets DL, Friedman LM, Furberg CD. Data Monitoring in Clinical Trials. New York: Springer; 2006.
28Pelke S, Easa D. The role of the clinical research coordinator in multicenter clinical trials. J Obstet Gynecol Neonatal Nurs 1997;26:279-85.
29English RA, Lebovitz Y, Giffin RB. Transforming Clinical Research in the United States: Challenges and Opportunities: Workshop Summary. Washington, D.C.: National Academies Press; 2010. p. xvii, 131.
30Pruitt RH, Privette AB. Planning strategies for the avoidance of pitfalls in intervention research. J Adv Nurs 2001;35:514-20.
31Petryna A. When Experiments Travel: Clinical Trials and the Global Search for Human Subjects. Princeton, New Jersey: Princeton University Press; 2009.
32Chin R, Bairu M. Global Clinical Trials: Effective Implementation and Management. Waltham, MA: Academic Press; 2011.
33McCormack S. 3rd international clinical trials methodology conference. Trials 2014; 16(Suppl 2):I1.
34Ehrenberger HE, Lillington L. Development of a measure to delineate the clinical trials nursing role. Oncol Nurs Forum. 2004 May 12;31(3):E64-8.
35Dickson M, Gagnon JP. Key factors in the rising cost of new drug discovery and development. Nat Rev Drug Discov 2004;3:417-29.
36Mullard A. New drugs cost US [dollar] 2.6 billion to develop. Nat Rev Drug Discov 2014;13:877.
37Bell J, Masaoka J, Zimmerman S. Nonprofit Sustainability: Making Strategic Decisions for Financial Viability. San Francisco, CA: John Wiley & Sons; 2010.
38Zerhouni EA. Clinical research at a crossroads: The NIH roadmap. J Investig Med 2006;54:171-3.
39Shane S, Stuart T. Organizational endowments and the performance of university start-ups. Manage Sci 2002;48:154-70.
40Tunis SR, Stryer DB, Clancy CM. Practical clinical trials: Increasing the value of clinical research for decision making in clinical and health policy. JAMA 2003;290:1624-32.
41Reiss JB. Commentary on payment and reimbursement issues affecting the marketing of drugs, medical devices, and biologics, with emphasis on the anti-kickback statute and Stark II. Food Drug Law J 1997;52:99-108.
42Ferris LE, Naylor CD. Physician remuneration in industry-sponsored clinical trials: The case for standardized clinical trial budgets. CMAJ 2004;171:883-6.
43Sung NS, Crowley WF Jr., Genel M, Salber P, Sandy L, Sherwood LM, et al. Central challenges facing the national clinical research enterprise. JAMA 2003;289:1278-87.
44Foster RS Jr. Threats to the scientific integrity of clinical trials. Arch Surg 1994;129:571-3.
45Schroedter LL. Clinical trial management analysis and integration of new policies and procedures into a research department. Fort Worth, Tx: University of North Texas Health Science Center; 2013.
46Stawicki SP, Kalra S, Jones C, Justiniano CF, Papadimos TJ, Galwankar SC, et al. Comorbidity polypharmacy score and its clinical utility: A pragmatic practitioner's perspective. J Emerg Trauma Shock 2015;8:224-31.
47Birriel TJ, Uchino R, Barry N, Butryn T, Sabol DM, Valenza PL, et al. Adverse drug reactions in the era of multi-morbidity and polypharmacy. J Basic Clin Pharm 2015;6:122-3.
48Cohen MS, Paul E, Nuschke JD, Tolentino J, Castellanos A, Mira AA, et al. Patient frailty: Key considerations, definitions, and practical implications. Rijeka, Croatia: Intech; 2016.
49Whicher DM, Miller JE, Dunham KM, Joffe S. Gatekeepers for pragmatic clinical trials. Clin Trials 2015;12:442-8.
50Concato J, Peduzzi P, Huang GD, O'Leary TJ, Kupersmith J. Comparative effectiveness research: What kind of studies do we need? J Investig Med 2010;58:764-9.
51Ioannidis JP. Materializing research promises: Opportunities, priorities and conflicts in translational medicine. J Transl Med 2004;2:5.
52Farrell B, Kenyon S, Shakur H. Managing clinical trials. Trials 2010;11:78.
53Van Rijnsoever FJ, Hessels LK. Factors associated with disciplinary and interdisciplinary research collaboration. Res Policy 2011;40:463-72.
54Gladstein DL. Groups in context: A model of task group effectiveness. Administrative Science Quarterly. 1984;29(4):499-518.
55Lakhani J, Benzies K, Hayden KA. Attributes of interdisciplinary research teams: A comprehensive review of the literature. Clin Invest Med 2012;35:260-5.
56Bell BS, Kozlowski SW. A typology of virtual teams implications for effective leadership. Group Organ Manage 2002;27:14-49.
57Cabrera EF, Cabrera A. Fostering knowledge sharing through people management practices. Int J Hum Resour Manage 2005;16:720-35.
58Podsakoff PM, Ahearne M, MacKenzie SB. Organizational citizenship behavior and the quantity and quality of work group performance. J Appl Psychol 1997;82:262-70.
59Druskat VU, Wolff SB. Building the emotional intelligence of groups. Harv Bus Rev 2001;79:80-91.
60Guzzo RA. Shea GP. Group performance and intergroup relations in organizations. Handbook of Industrial and Organizational Psychology. 1992;3:269-313.
61Stahl GK, Maznevski ML, Voigt A, Jonsen K. Unraveling the effects of cultural diversity in teams: A meta-analysis of research on multicultural work groups. J Int Bus Stud 2010;41:690-709.
62Mathieu J, Maynard MT, Rapp T, Gilson L. Team effectiveness 1997-2007: A review of recent advancements and a glimpse into the future. J Manage 2008;34:410-76.
63Weems-Landingham VL. The Role of Project Manager and Team Member Knowledge, Skills and Abilities (KSAs) in Distinguishing Virtual Project Team Performance Outcomes. Case Western Reserve University; 2004.
64Uchino R, Yanagawa F, Weigand B, Orlando JP, Tachovsky TJ, Dave KA. Focus on emotional intelligence in medical education: From problem awareness to system-based solutions. Int J Acad Med 2015;1:9.
65Papadimos TJ, Sipes AC, Lyaker MR, Murphy CV, Tsavoussis A, Pappada SM. The importance of emotional intelligence to leadership in an Academic Health Center. Int J Acad Med 2016;2:57.
66Buchbinder SB, Buchbinder D. Managing healthcare professionals. Introduction to Health Care Management. Burlington, MA: Jones & Bartlett Learning; 2007. p. 231-64.
67West MA. Effective Teamwork: Practical Lessons from Organizational Research. Malden, MA: John Wiley & Sons; 2012.
68McFadden E, Bashir S, Canham S, Darbyshire J, Davidson P, Day S, et al. The impact of registration of clinical trials units: The UK experience. Clin Trials 2015;12:166-73.
69Croghan IT, Viker SD, Limper AH, Evans TK, Cornell AR, Ebbert JO, et al. Developing a clinical trial unit to advance research in an academic institution. Contemp Clin Trials 2015;45:270-6.
70Rubin E, Lazar D. Clinical Trials Offices: What's New in Research Administration? Washington, DC: Associaton of Academic Health Centers; 2009.
71Ledford H. Translational research: 4 ways to fix the clinical trial. Nature 2011;477:526-8.
72Rapport F, Storey M, Porter A, Snooks H, Jones K, Peconi J, et al. Qualitative research within trials: Developing a standard operating procedure for a clinical trials unit. Trials 2013;14:54.
73Thew S, Leeming G, Ainsworth J, Gibson M, Buchan I. FARSITE: Evaluation of an automated trial feasibility assessment and recruitment tool. Trials 2011;12 Suppl 1:A113.
74Beresniak A, Schmidt A, Proeve J, Bolanos E, Patel N, Ammour N, et al. Cost-benefit assessment of using electronic health records data for clinical research versus current practices: Contribution of the Electronic Health Records for Clinical Research (EHR4CR) European Project. Contemp Clin Trials 2016;46:85-91.
75Manghani K. Quality assurance: Importance of systems and standard operating procedures. Perspect Clin Res 2011;2:34.
76Dixon JR Jr. The international conference on harmonization good clinical practice guideline. Qual Assur 1998;6:65-74.
77Mi Z, Lu X, Bingham S, Collins J. Duplicate identification using non-sensitive information. Clin Trials 2011;8:445-548.
78Kortgen A, Niederprüm P, Bauer M. Implementation of an evidence-based “standard operating procedure” and outcome in septic shock. Crit Care Med 2006;34:943-9.
79Kern H, Kox WJ. Impact of standard procedures and clinical standards on cost-effectiveness and intensive care unit performance in adult patients after cardiac surgery. Intensive Care Med 1999;25:1367-73.
80Portney LG, Watkins MP. Foundations of Clinical Research: Applications to Practice. Philadelphia, PA: FA Davis; 2015.
81Chin WW. Broader transparency on risk-benefit assessment of the bial trial in France. British Journal of Medicine & Medical Research. 2016;15(7): 1-7.
82Cavusgil E. Merck and vioxx: An examination of an ethical decision-making model. J Bus Ethics 2007;76:451-61.
83Fay MF, Eberhart C, Hinkley T, Blanchford M, Stevens E. A Structured Approach to Implementing a Risk-Based Monitoring Model for Trial Conduct; 2014. Available from: model-trial-conduct. [Last accessed on 2015 Dec 29].
84Ghone A. Centralized Monitoring – A Smart, Reliable Approach; 2015. Available from: [Last accessed on 2015 Dec 29].
85Evans S, Ting N. Fundamental Concepts for New Clinical Trialists. Vol. 77. Boca Raton, FL: CRC Press; 2015.
86American College of Clinical Pharmacy Research Affairs Committee, Fagan SC, Touchette D, Smith JA, Sowinski KM, Dolovich L, et al. The state of science and research in clinical pharmacy. Pharmacotherapy 2006;26:1027-40.
87Goldspiel B, Hoffman JM, Griffith NL, Goodin S, DeChristoforo R, Montello CM, et al. ASHP guidelines on preventing medication errors with chemotherapy and biotherapy. Am J Health Syst Pharm 2015;72:e6-e35.
88Hammond RW, Schwartz AH, Campbell MJ, Remington TL, Chuck S, Blair MM, et al. Collaborative drug therapy management by pharmacists-2003. Pharmacotherapy 2003;23:1210-25.
89Lipowski EE. Pharmacy practice-based research networks: Why, what, who, and how. J Am Pharm Assoc 2008;48:142-52.
90Anderson S, Allen P, Peckham S, Goodwin N. Asking the right questions: Scoping studies in the commissioning of research on the organisation and delivery of health services. Health Res Policy Syst 2008;6:7.
91Shewale S, Parekh S. Reinventing patient recruitment in clinical studies. Monitor 2011 Oct; 24:38-43
92Kroll J. An Industry in Evolution. Boston, MA: CenterWatch; 2001.
93Lovato LC, Hill K, Hertert S, Hunninghake DB, Probstfield JL. Recruitment for controlled clinical trials: Literature summary and annotated bibliography. Control Clin Trials 1997;18:328-52.
94Hickson M. Research Handbook for Health Care Professionals. Hoboken, NJ: John Wiley & Sons; 2013.
95Albanese J. Subject recruitment: What can a sponsor do? SOCRA Source 2011;70:65-70.
96Meric-Bernstam F, Farhangfar C, Mendelsohn J, Mills GB. Building a personalized medicine infrastructure at a major cancer center. J Clin Oncol 2013;31:1849-57.
97Shimm DS, Spece RG Jr. Industry reimbursement for entering patients into clinical trials: Legal and ethical issues. Ann Intern Med 1991;115:148-51.
98Grady C. Payment of clinical research subjects. J Clin Invest 2005;115:1681-7.
99Thoma A, Farrokhyar F, McKnight L, Bhandari M. Practical tips for surgical research: How to optimize patient recruitment. Can J Surg 2010;53:205-10.
100Spruill I, Davis BL. Cultural competence: Myth or mandate. Online J Health Ethics 2005;2:3.
101Miller FH. Trusting doctors: Tricky business when it comes to clinical research. Boston Univ Law Rev 2001;81:423.
102Chin Feman SP, Nguyen LT, Quilty MT, Kerr CE, Nam BH, Conboy LA, et al. Effectiveness of recruitment in clinical trials: An analysis of methods used in a trial for irritable bowel syndrome patients. Contemp Clin Trials 2008;29:241-51.
103McDonald AM, Treweek S, Shakur H, Free C, Knight R, Speed C, et al. Using a business model approach and marketing techniques for recruitment to clinical trials. Trials 2011 11;12:74.
104Duke_Clinical_Research_Institute. Keys to Building a Successful Research Site; 2014. Available from: [Last cited on 2016 Aug 25].
105Francis D, Roberts I, Elbourne DR, Shakur H, Knight RC, Garcia J, et al. Marketing and clinical trials: A case study. Trials 2007;8:1.
106Avitable D. Marketing strategies for clinical trial recruitment and patient retention. Product management today; December, 2006. p. 38-40. Available from:
107Iber FL, Riley WA, Murray PJ. Conducting Clinical Trials. New York: Springer Science & Business Media; 2012.
108Brown RF, Butow PN, Ellis P, Boyle F, Tattersall MH. Seeking informed consent to cancer clinical trials: Describing current practice. Soc Sci Med 2004;58:2445-57.
109Llewellyn-Thomas HA, McGreal MJ, Thiel EC, Fine S, Erlichman C. Patients' willingness to enter clinical trials: Measuring the association with perceived benefit and preference for decision participation. Soc Sci Med 1991;32:35-42.
110Nguyen MC, Moffatt-Bruce SD. Relative value unit transformation: Our new reality of worth. Int J Acad Med 2016;2:52.
111Rahman S, Majumder MA, Shaban SF, Rahman N, Ahmed M, Abdulrahman KB, et al. Physician participation in clinical research and trials: Issues and approaches. Adv Med Educ Pract 2011;2:85-93.
112Piantadosi S. Clinical Trials: A Methodologic Perspective. Hoboken, NJ: John Wiley & Sons; 2013.
113Snyder DC, Brouwer RN, Ennis CL, Spangler LL, Ainsworth TL, Budinger S, et al. Retooling institutional support infrastructure for clinical research. Contemp Clin Trials 2016;48:139-45.
114Polit DF, Beck CT. Nursing Research: Principles and Methods. Philadelphia, PA: Lippincott Williams & Wilkins; 2004.
115Sama R, Vijaya Lakshmi N, Sathish M. Audit of an investigator site – A crucial task in clinical research to ensure a reliable clinical trial: Review of planning, methodology and techniques. International Journal of Research and Development in Pharmacy and Life Sciences. 2016;5:13-29.
116Kamp CL, Germain JM. Clinical trial implementation, analysis, and reporting: An academic and industry. Clinical Trials in Neurology: Design, Conduct, Analysis. New York: Cambridge University Press; 2012. p. 338.
117Weeks-Rowe EB. Clinical Research Trials & Triumphs: A heart warming novel following a nurse's journey into clinic. California, USA: Elizabeth Weeks-Rowe; 2014.
118Stanley J, Kinney J, Gwozdek A. Assessment of the skills and education necessary for a baccalaureate-prepared dental hygienist to pursue an entry-level role in clinical research. Am Dent Hyg Assoc 2011;85:114-21.