Mary Jo Lamberti, PhD

	The development of new therapies is not possible without volunteers to participate in clinical trials. Recruiting study participants is extremely challenging regardless of demographic background. Challenges to potential participants include time away from work and loss of income, travel to a site and reimbursement, and the potential risks of a trial. There are, however, unique barriers for minority and underrepresented populations who participate in clinical trials, including mistrust, inadequate communication, and significant fear of the research process. Some of these barriers are rooted in the ethical failures of the history of clinical trials. Most notably, the Tuskegee Syphilis study conducted between 1932-1972 which promised black male participants free medical care but did not treat them once the cure became available in 1947.

	There is ample evidence in the literature indicating that the primary factor associated with low participation by underserved groups in clinical trials is a lack of trust in research and in the healthcare system.

Unethical practices, and disclosure and transparency failures are two examples of factors that have led to widespread distrust.

Poor access to clinical trials and the low relative availability of experienced minority clinical investigators are also cited as barriers to minority patient participation.

Recently, significant strides have been made to build the trust between minorities and trial investigators by the National Institutes of Health (NIH), FDA, and among industry stakeholders. The 2019 draft guidance released by FDA on enhancing the diversity of clinical trials reflects the perceived importance of having adequate minority representation in clinical trials.

	            Tufts Center for the Study of Drug Development (Tufts CSDD) and Biogen recently conducted a study to inform growing interest in improving diversity of clinical trial participation.  Tufts CSDD conducted ten in-depth interviews with investigative site staff during July and August 2019 and co-moderated two advisory boards with 11 clinical research professionals in Atlanta and Phoenix. The primary aim of the advisory boards was to understand investigative site experiences and barriers that hinder minority participation. The results of this research provide key insights into increasing the community of minority investigators and study staff and presenting greater access to clinical trials among minority study volunteers.

	The advisory boards noted that trust should exist at both the individual level (e.g., physician, healthcare provider) and the institutional level (e.g., healthcare or medical system) with the coordinator and/or investigator acting as a critical liaison.  Advisory board members expressed:

“In dealing with minority populations, the coordinator needs to know how to address the issues of trust and the distrust of the medical system, and distrust in research.”

“You have to know where that fear and distrust comes from, and then you have to know how to address it appropriately.”

“I usually tell them straight out we don’t have enough African Americans in research, and we’re giving you all this information on medications that are not tailored for us. It’s tailored to Caucasians.”

	Prior research supports the concept of establishing trust at the individual and institutional level. Trust in a physician or researcher is typically based on the quality of personal interactions, while trust in the medical research enterprise  is often based on the reputation of an institution.

One strategy to increase trust at the individual level is through strengthening a patient’s relationship with their healthcare provider. 

	Establishing trust between a healthcare provider and patient requires recognition of diverse patients’ needs, which commonly involves awareness of language preferences. Unfortunately, many sponsors and study teams often overlook language inequity as a barrier to recruitment of diverse participants. Individuals who speak English “less than very well” are considered to be of limited English proficiency (LEP) and constitute 8.5% of the total U.S.population or 25 million people over the age of five.

The population of LEP people continues to grow, and research shows this population to be more likely to live in poverty, have poorer health outcomes, and be underrepresented in clinical research.

Limited participation by LEP patients greatly diminishes the social benefits and generalizability of clinical trial outcomes. The advisory boards noted that the development of culturally and linguistically appropriate educational interventions geared toward LEP communities are critically needed to explain the risks, benefits, and practices of clinical research.

	One solution recommended to address language inequities was to recruit bilingual site staff; however, the availability of multi-lingual coordinators is extremely limited and remains an urgent need. To overcome shortages of multi-lingual staff, sites offer cultural competency training and language courses to interested employees. Technology can also be leveraged to translate materials into grammatically correct language. Ad board participants recognized that materials should be inclusive of distinct dialects and languages. Information must be accurately translated to reflect the idiomatic characteristics of the target population. Another common misconception is that someone of Hispanic/Latinx background has the ability to speak one language over another or has the literacy level to understand in their preferred language. Whenever possible, both the English and Spanish versions of materials should be included in one document. Study coordinators related examples of patients who enroll or discontinue studies based on a family member’s advice. Bilingual materials are also beneficial for family members who are involved in the patients’ healthcare and decision-making. As the role of family and tradition are highly valued among diverse populations, including the patient and their family early on in the recruitment process is key to improving participant adherence to the study protocol. 

“The thing is, a patient goes home and explains in a way that’s not going to be the same as what was explained to them during their visit because it’s just–they explain whatever they absorbed, and it might not–to the family, it might sound like an experiment, which is what a lot of patients say, versus someone who is trained to explain it to the family member.”

“A lot of times we’ll have a woman come in, we’ll give her the consent form and talk to her about it, and she’ll say, ‘My husband has to read it,’ or ‘I have to talk to my husband.’ Men will do the same thing, ‘I have to talk to my wife.’ Sometimes they’ll bring their wife or their husband. Then it just makes it a little bit easier, because they’re both there.” 

	Establishing a safe participation environment

	Fear of deportation among undocumented immigrants who become involved as research participants was identified by the Phoenix ad board as a source of concern leading to greater mistrust and fear.  Participant misunderstandings about what they are committing to may occur due to a potentially limited knowledge of the research process. As a result, there is a critical need during the recruitmentprocess to provide and communicate detailed study policies regarding the reporting of undocumented immigrants. Enlisting the aid of community-based groups and clinics that are trusted by migrant communities help guide these conversations. 

“Working with a lot of folks that may have mixed legal status in their family, we had a really difficult discussion around this with our team about our level of comfort of actually having to present that to these families and how much of a deterrent that could be. 

“A lot of our folks are working two jobs, have limited transportation. Then if they’re going to show up and be surprised by: ‘You have to fill out this W-9,’ which basically, if you leave this part blank, is saying something about your status, that absolutely is a: ‘I don’t want to participate.’”

	In addition to ensuring sympathetic translations, partnering with the community may avoid engendering stereotypes or confusion by researchers or sponsors based on potential cultural, socio-economic (e.g. poverty), or linguistic differences. Successful intersections and engagement include investigators and staff from study participants’ own communitiesto increase rapport and build trust.One participant established an group of community leaders to develop targeted and appropriate materials; and ensure consent forms were written at the sixth-grade level. In addition, the group provided on-the-job training and “lay training” for community board members. The “lay training” served as an alternative to the current CITI training that is geared for training researchers and may pose challenges for a non-researcher. The training provided community members with a better understanding of medical research at all stages, including patient recruitment, enrollment, and retention.

	Other strategies that foster community collaboration and facilitate trust are researchers’ active participation in the community,for example, by attending and hosting health fairs, or disseminating the results of prior research studies. A recommendation for sponsor companies is to build lay language results into their patient engagement plans. Contrary to popular belief, churches may no longer be the best form of communication and outreach for minority patients. While churches still play an important role and act as a location for community events, it may have shifted as the main/sole source of communication and outreach as younger generations seek other outlets. Including a variety of community stakeholders from the start to the close of a trial has revealed other recruitment strategies,such as “refer-a-friend,” that may ease the recruitment process of specific subpopulations.

“We’re talking about having that trusted visual in the community. When I go in as a member of a university [in the state of Georgia]. I’m introduced to the community through these entry points, these agents, and the gates are automatically open to me.”

“I’ll notice that more of our Hispanics come from maybe refer-a- friend versus our traditional      methods. We have flyers and they’re not putting ‘flyer,’ they’re putting ‘my sister’ or ’my friend,’            things like that. It’s much more refer-a-friend than anything else.”

	Participants strongly encouraged the use of technology for overcoming not only language and literacy barriers, but also for broadening the reach of diverse trial participants. Remote or virtual trials have become more common and their usage is increasing across the industry.

 These trials use wearables, mobile apps, videoconferencing,or other tools to ease the burden for both the sponsor and study participants. Despite significant progress made in virtual trial technology over the past decade, research sites continue to play a vital role in moving clinical research forward. One site shared use of an app-based digital storytelling intervention to engage minority groups and facilitate the informed consent process. Sites also offer Uber and/or Lyft ride credits to improve access to participation.

“The app sends push notifications [to their cell phones] and asks patients to answer questions. It prompts them to watch the story they’re supposed to be watching. It’s working really well for us. It’s geared towardsHispanic patients, but everything-the story, the video-is in Spanish, and includes subtitles in Spanish, too. We also have them set to English, so that if you have a mixed language family, everybody can understand, hear, or read it.”

	Strategies that consider the culture and diversity of a population are effective among investigators and research staff. The advisory board discussions revealed that sitesdo not feel prepared or equipped to serve underrepresented populations. Providing adequate compensation, resources, and allocation of additional time for investigators (of all backgrounds) to prepare and learn about appropriate strategies for recruitment and retention of diverse participants alleviates “burnout” and improves staff retention to ensure continuity of community interventions.

Tangentially, providing clinical research education early in an individual’s career increases their awareness and opportunity to be a clinical investigator or study coordinator. 

“If you want to design a study, the site should be equipped with all the materials on all the populations of interest (e.g.,Spanish-speaking patients). The sponsor has to be ready to provide that to sites so that they feel prepared for the patients.” 

	The group noted that additional investments and incentives by institutions (e.g., universities, hospitals) and other organizations (e.g., professional associations) could potentially increase the numbers of diverse investigative site staff and improve minority participation. This investment could be used to stimulate hiring, support underrepresented study coordinators and investigators, and create a supportive and comfortable environment for diverse investigators. Participants offered ideas for incentives and strategies to motivate researchers and investigators to participate, including publication opportunities, promotions, awards and recognition for minority-serving institutions, supportive infrastructure (i.e. mentorship), and carving out time for primary investigators (PIs) to conduct research. 

“Need good mentorship (not sure if through the same race or not) and institutional support. The institution must provide a level of security that they can do this work and it won’t all come crashing down if they lose a grant cycle.” 

	It is widely known that marginalized groups must overcome large barriers in the clinical research process and in order to establish a solid foundation for diversifying trials and research teams, there are critical areas that still need to be addressed. Mistrust of clinical research and of the medical establishment, and low ethnic/racial representation of investigators, site staff, and study volunteers are factors that perpetuate fear and lack of participation in clinical trials. Community-based partnerships with trusted representatives serve to increase awareness of clinical trials and provide extensive information about the process. It was apparent that this group of diverse coordinators and investigators have been working to include underrepresented participants in trials and are willing to forge stronger partnerships with sponsors and other organizations to promote sustainability of their diversity and inclusion efforts. 

		Acknowledge that the HCP role is influential in developing trust with a patient and can help to increase a patient’s comfort level with clinical trials; explain the science of clinical research,including the risks and benefits of participation;,and offer support during the process.

		Resolve language equity issues in clinical research both through the elimination of research-specific language and through providing appropriate translations. Hire additional bilingual staff at sites.

		Recognize the role of family and tradition and include a patient’s family early on to support the decision-making process.

		Promote community involvement by local leaders within the community to build trust and promote awareness of clinical research.

		Use technology and mobile apps for translation and for broader reach of patient participation,including use of decentralized trials.

		Invest in minority investigators through funding and grants and provide education/training early on in a student’s career.

	Greater diversity in research participation is needed to promote justice in clinical research and rectify health disparities. Application of these principles in clinical research will provide meaningful results that are free from bias and represent diverse populations who may use these treatments when they become available. 

, Marketing Communications Coordinator;all from Tufts CSDD; 

; Director, Patient Feasibility, Enrollment, and Retention; both from Biogen

We would like to acknowledge all of the participants of the interviews and advisory board discussions; they shared valuable insights on the opportunities and challenges of diverse clinical trial recruitment and retention at the ground-level. 

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Articles

Tufts Center for the Study of Drug Development and Biogen recently conducted a study to inform growing interest in improving diversity of clinical trial participation. The results of this research provide insights into increasing the community of minority investigators and study staff and presenting greater access to clinical trials among minority study volunteers.

Understanding the Complexities of Diversifying Clinical Trials

	Sponsor and contract research organization (CRO) companies conducting global clinical trials face numerous operational and logistical challenges. With more than 3,000 active global clinical trials conducted annually at approximately 40,000 investigative sites dispersed worldwide, companies are looking for more efficient ways to streamline their processes in order to speed up timelines.

 A number of factors impact study cycle times, including protocol amendments and patient recruitment and enrollment challenges. Tufts Center for the Study of Drug Development (CSDD) research found that substantial amendment presence in a protocol significantly increases study cycle times. Protocols with at least one substantial amendment had a study duration of three months on average longer than those protocols lacking substantial amendments.

 In addition, research reveals a high turnover rate among investigators conducting trials, with about 40% each year choosing not to conduct any further trials, citing regulatory compliance burden and a challenging operating environment.

 Recruitment challenges are typical, and findings from a recent study among examining 151 global clinical trials from 12 companies indicated that 11% of sites failed to enroll a single patient.

	Companies are also looking to increase efficiencies as they face more complex study protocols in therapeutic areas such as oncology (with the use of targeted therapies) and neuroscience (diseases such as Parkinson’s and Alzheimer’s). Prior research examining protocol complexity and burden on clinical site staff found that the investigative site work-effort to administer each protocol had increased 64% between 2002 and 2012.

	Activities associated with site selection, study start-up, and site activation also pose challenges and company practices contribute to inefficiencies in these areas. There are hurdles within the regulatory environment, and timelines for site contracting, budget negotiations, and submissions.

 Organizations are continually looking to improve their study start-up cycle times through investments in technology, including data analytics and other software. These processes can potentially be streamlined through electronic cloud-based solutions, online clinical document exchange portals, and shared investigator databases.

	Tufts CSDD research suggests that the early stages of the site initiation process accounted for the majority of cycle time and the highest variance (the pre-study visit to contract execution), while little variation was observed at the end of the process (contract execution to first patient in) across therapeutic area, type of site, and geographic region.

 In examining over 100 global clinical studies by therapeutic area, Tufts CSDD found that oncology and central nervous system therapeutic areas represented the longest cycle times to first patient in, while cardiovascular, infectious disease, and metabolic and endocrine studies had significantly shorter times to first patient in.

 In addition, academic institutions and government-funded sites took longest to first patient in, while physician practices were fastest. In a further analysis by global regions, sites in Latin America took twice as long as sites in North America to enroll the first patient.

	Study start-up is similarly viewed by investigative site staff as an inconsistent and inefficient process. Over 200 clinical research professionals who responded to a survey identified certain key areas that could be improved upon including contract and budget negotiations, regulatory processes, document management and communication between sponsors and sites.

	Based on the previous research on benchmarking clinical trial initiations and the wide variation and inconsistency among organizations, Tufts CSDD conducted a follow-up study examining practices and inefficiencies in site selection, study start and site activation. In-depth interviews were conducted with senior level pharmaceutical and CRO executives to better understand the challenges and overall strategies that organizations are using to improve these activities. The study was funded by goBalto, a technology solutions company.

	A total of 26 interviews were conducted across 21 companies. In some cases, more than one representative from a company was interviewed across functions to gather more complete information and better understand the approaches for activities associated with site selection through site activation. Respondents represented 13 biopharmaceutical companies and eight CROs across 13 large and eight mid-sized and small organizations. Interviewees were experienced and were primarily senior level executives occupying director level roles or above. A few respondents held newly created roles within separate study start up functions.

	Interviews examined the key criteria utilized to qualify and identify investigative sites and how practices vary across organizations. Use of repeat sites, experience level of sites, and therapeutic expertise were factors investigated. In addition, novel practices adopted by companies and any solutions currently being planned and implemented were identified. Use of performance indicators, including historical site data, and perceived or measured impact on cycle times and cost were also explored. Last, respondents reported the greatest challenges to study start up, site selection and activation and resources or investments that have improved these areas.

	The results suggest that sites are primarily identified based on therapeutic expertise, phase of research, and by global region. Respondents reported that the most critical factors are an organization’s previous experience with a site, site experience, performance, and capabilities, including sufficient staff and resources to conduct a study.

	One respondent from a large pharmaceutical company discussed, “If it’s an area we know well, we go to sites we know. We use benchmarking data to help teams and affiliates. We get a download of all investigators in indications (globally) and rank them. We also do a therapeutic area scan and by country. We ask how active investigators are in the trial landscape. We take a list of top 10 investigators in the field.”

	Another respondent from a small biopharmaceutical company noted that “we are a hybrid house. We outsource some of our trials and some we run ourselves. Outside the U.S. we don’t have boots on the ground; we work with a CRO partner.”

	Global expertise becomes important, as there is regional variation in cycle times to first patient in. These data reflect similarities to the findings of an earlier Tufts CSDD study that found sites in Latin America and Eastern Europe had longer cycle times than sites in other regions, and North American sites took the least amount of time to first patient in (See Figure 1).

	Through feasibility studies, organizations are able to discern a site’s ability to execute the proposed study and complexity of the protocol. A detailed on-site assessment was conducted in some cases. Past experience with a site is a strong indicator and is guided by intelligence gathered both internally and externally. Large companies tend to have more consistent and strategic approaches to gathering central and local intelligence on sites, and follow global processes. Sources used included CiteLine or TrialTrove and intelligence gathered by site management organizations (SMOs) or CROs. Smaller companies reported reliance on vendors that provide solutions searchable by indication or outsource all site selection. Respondents mentioned a number of other solutions to support site selection, including their own internal tools, clinical trial management systems (CTMS), and IMS’s Study and Site Optimizer (see Table 1).

	A site’s compliance with good clinical practice (GCP) and the ability to meet protocol-specific requirements were also noted as site selection criteria. Respondents reported that site selection could be improved by gathering more intelligence on site

 performance and leveraging data from past experience as well as program planning early on. One interviewee indicated that “we are using data more effectively to make decisions. We rely on performance; the number of protocol deviations; number of escalated issues for GCP non-compliance. We rely on the upper percentile of sites. To improve site selection, we can arm our teams with more intelligence.”

	Another respondent reported that “site selection can be improved by earlier planning at the program level. Sites and country decisions are key. As you refine the needs for the protocol, you hone in on the investigator.”

	Across 15 companies, on average, the results indicated that the proportion of sites is comprised of 70% familiar and 30% new sites. An overwhelming majority of companies use familiar sites rather than new sites, but usage may vary based on indication and geographic area (global location) of a study.

	On average, site selection was reported to take approximately 3.2 months and could potentially range from two weeks to six months. In all, the process of site identification to activation is a one-year cycle. Factors impacting site selection timelines vary by therapeutic area, indication, geographic area, size, and phase of study. Type of site is also of particular influence since academic site selection 

typically takes longer than community-based sites. Academic sites have several layers of review, including institutional review boards (IRBs) or ethics committees and scientific review committees. Some larger academic sites in the U.S. also have operational review committees, which can delay site activation and impact study start-up.

	In particular, companies conducting oncology trials typically report lengthy timelines as they rely on large academic sites to conduct their trials. These results are comparable to earlier research examining first-patient-in cycle time by type of site and by therapeutic area.

 Academic or government sites have longer cycle times and physician practices have the shortest cycle times to first patient in. In addition, oncology and CNS or neuroscience studies had longer cycle times to first patient in than either metabolic/endocrine or infectious disease studies. In examining cycle times for Phase I compared with Phase II, III, and IV studies, a Phase I study took 6.5 months on average from pre-study visit to first patient in, while Phases II to IV took 10.4 months on average.

	Use of historical site data to guide future site selection activity

	Historical data are gathered at the study, site, and country levels and used to guide future site selection. Metrics collected include protocol approval to first site activated, first country activated, and average number of days to have a site up and running typically measured as time from site selection to final protocol approval to ready to enroll patients. Organizations like KMR Group and CMR provide benchmarks for company comparisons with internal data.

	In addition to the key metrics cited, respondents reported that contracting and budgeting approval and execution cycle times were tracked. In particular, cycle times for a contract and budget sent to a site to contract execution, and contract execution to site initiation, are also measured. Findings from a prior Tufts CSDD study indicate that these early stages of the site initiation process account for the majority of cycle time and explored these results through further analyses. The results revealed that the cycle times associated with activities occurring from the pre-study visit to first patient in revealed more variation than those cycle times associated with site identification and with last patient last visit to database lock (see Table 2). In addition, site initiation 

to first patient in had the largest coefficient of variation, indicating the greatest variability.

	Other metrics cited by company representatives interviewed included: first patient enrolled or first patient first visit (FPFV) and number of patients randomized; IRB and ethics approvals and country submissions; and investigator and site staff performance, including turnover. Timelines around data entry, serious adverse event reporting (SAEs), and query resolution rate (or number of queries) were also part of historical data gathered on a site’s performance. Virtually no qualitative data was reported gathered by individuals interviewed, such as assessments of a working relationship with a site; the quality of the data; or number of queries relative to other sites.

	New practices implemented by organizations

	Of the 21 companies examined in this study, six companies were implementing new practices. Four companies (including pharmaceutical and CROs) have developed a new start-up function or created study start-up roles within their organizations. These organizational changes were designed to streamline all activities occurring from site selection to study start-up. Focusing on study start-up enables a dedicated group to provide needed support on trials and make continuous improvements. Cluster training has also been established at one company where core groups of sites are identified based on IRB approvals prior to the investigator meeting, and training is then provided on a site initiation visit (SIV).

	Another company has eliminated the time between a site being protocol ready and the receipt of site documents. This process involves having all supporting documents sent to a site within 24 to 48 hours of a final protocol. A few companies also had recently implemented master service agreements (MSAs) between sponsors and sites and creating standard language for contracts.

	Investments in technology are enabling novel practices in a number of ways. Some organizations are moving toward more data-driven site selection and are implementing centralized systems, using data visualization software, or other data analytics tools. Quintiles Infosario Site Gateway and further customization of the IMS Study and Site Optimizer were also mentioned as solutions.

	Despite the new practices being instituted among organizations, only about one-third of companies indicated that there has been an impact on their non-enrolling or unproductive sites as well as greater percentages of sites being activated faster relative to internal benchmark data. The remainder did not report impact on cycle times or costs or have not yet assessed the impact of recently implemented practices. One interviewee noted an impact on non-enrolling sites: “Before the implementation of local dedicated study start-up staff, we had about one-third of our sites that were not delivering. We reduced that number to 10%.” This improvement was accomplished by adding dedicated staff and regional therapeutic area experts to manage site selection. This company representative serves as a liaison between the sites and the sponsor company.

	Greatest challenges to site selection, study start-up and site selection

	The results suggest that the most critical challenges are not only increased competition for sites but also fierce competition for other studies at sites in therapeutic areas such as oncology or rare disease. Challenges with site feasibility occur in the ability to obtain quality completions and having sufficient time to complete each part of the set-up process. Enrollment issues add additional pressures to the site selection process. Determining whether or not sites will be able to enroll patients within a tight timeline are continual challenges.

	A major hurdle to study start-up is the contracting and budget negotiation process. Key issues cited by respondents include the lack of standardization on informed consent and site contract language, the absence of master service agreements (MSAs) with sites, and the need for country-specific templates to expedite contracts. Unpredictable timelines by IRBs and ethics committees were also cited as major delays to study start-up and some companies reported more efficiency and speed with the use of central IRBs.

	Organizational resources and process changes

	Expanding use of technology to implement process changes was a key theme across companies. The use of electronic medical records (EMRs), data warehousing, and data mining is used by companies to inform numbers of patients that meet inclusion/exclusion criteria. Some cited the use of the Investigator Databank or TransCelerate Biopharma’s Shared Investigator Platform. Other solutions mentioned were site feasibility software, internal investigator dashboards, and the use of goBalto technology.

	Contracts and budgets functions were also identified as areas where resources were added. Some companies added staff primarily to negotiate and execute contracts and worked to establish MSAs with sites and improve legal agreements. Establishing fair market value for budget negotiations was mentioned as standard practice. Informed consent was also an area being improved upon through the development of more standard, “user-friendly” templates.

	Some respondents indicated that their trial optimization or strategic planning groups contributed to the efficiency of start-up activities. These groups established an increased focus on site selection and start-up or in some cases developed an integrated site activation plan.

	Despite the attempts to streamline and speed study start and improve site selection and activation, these activities are still fraught with challenges and many of the findings from this study are corroborated by an earlier Tufts CSDD analyses on study start-up. The earlier study found that sites conducting oncology trials represented the longest cycle times to first patient in and academic- and government-funded sites took longest to enroll the first patient.

 Companies in our current study also noted the lengthy and cumbersome review process occurring at academic sites. Also, these were typically large academic sites conducting oncology trials with lengthy timelines.

	Additionally, one of the areas with the greatest cycle times in the earlier Tufts CSDD study focused on the pre-study visit to contract execution.

 Similarly, the results of the current study indicate that one of the major challenges to study start-up is the contracting and budget negotiation process-and it is an area where new processes are being implemented across organizations. In addition, the results on cycle time variance suggest that contract execution to site initiation and site initiation to first patient in may potentially be improvement areas for organizations.

	According to the results of our study, despite new practices and process changes being instituted, the impact on improving study start-up cycle times has been fairly small. The investment of new technology and other solutions has made incremental improvements and has provided added intelligence on site performance globally, specifically start-up cycle times and site activation. These solutions have enabled companies to implement more efficient start-up and site selection processes. Adoption of these solutions, however, has been inconsistent as is the ability to integrate data from multiple sources. Some organizations are continuing to strengthen their cycle times and improve efficiencies through a focus on study start and site activation either with adding new functions or additional resources in combination with using data and other solutions more efficiently.

, MBA, is Director of Sponsored Research and Chirman of CISCRP; all with the Tufts Center for the Study of Drug Development

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Assessing practices and inefficiencies with site selection, study start-up, and site activation.

New Benchmarks for Trial Initiation Activities

Global clinical supply professionals are driven by a simple credo: to provide the highest possible quality clinical trial supplies in a fast and efficient manner. Given the scope of global clinical trial activity today, delivering on this credo is a tall order. There are approximately 40,000 unique investigators worldwide conducting at least one FDA-regulated clinical trial.

	There are a number of factors intensifying pressure on global clinical supply professionals. To mention a few key factors: the economics of supply chain management and distribution have grown substantially due to study complexity and increases in shipping costs, labor costs, technology solutions costs and changes in drug therapy properties requiring additional shipping and packaging considerations (e.g., cold chain and temperature sensitive shipping requirements; combination therapies; and companion diagnostics).

 A recent survey of 250 supply chain executives found that two-thirds anticipated significantly increasing spending on clinical trial logistics over the next two years.

	Investigative site workload has increased substantially, making it more difficult to receive operating support from study staff. A Tufts Center for the Study of Drug Development (Tufts CSDD) study examining protocol complexity and burden on clinical trial site staff, for example, found that investigative site work effort to administer each protocol had increased 64% between 2002 and 2012.

Short study start-up lead times, more complex study drug packaging requirements and tight study conduct durations place significant pressure on supply chain managers to provide efficient supply ordering and tracking solutions for investigative sites to use.

	Increasing demands from global regulations are also impacting the supply chain. In 2013, the European Union enacted good distribution practices (GDPs) which are becoming the adopted guidance globally.

 Although the timeline is still under discussion, new regulations for clinical trials conducted in the European Union will occur in October 2018.

 This new law could potentially impact the supply chain, although it is primarily geared to existing good manufacturing practices (GMPs) for products covered by an existing directive. 

	Clinical supply professionals face ongoing risks to the supply chain security, traceability and authentication of a product. There are constant threats of counterfeiting, which can impact patient safety.

 At the same time, clinical supply logistics managers face substantially higher levels of visibility and demand to play a more strategic role within their organizations. 

	Despite the heavy and increasing pressure on clinical supply chain professionals, there is little to no historical data characterizing performance, measuring the impact of new processes and solutions and identifying areas of improvement. In response, Tufts CSDD-in collaboration with a diverse group of pharmaceutical and

 biotech companies, clinical supply logistics providers and suppliers-conducted a global clinical supply logistics study. The study gathered survey data and clinical study performance data from companies in order to examine current management practices and strategies that have been implemented to enhance efficiency and productivity within the clinical supply logistics area. The results of the study suggest that companies are implementing a variety of strategies that, together, are assisting organizations in maintaining high quality and low error rates and identifying contributing factors for waste. All sponsor companies, however, are encountering wide variation in mean shipping times.

	Tufts CSDD convened a roundtable meeting with global clinical supply managers and directors to identify the most critical areas for which benchmark data could be gathered. Later, the group narrowed the list of topics to the focus of the current study. A total of 15 companies participated in the study, including Astellas, AstraZeneca, Biogen, Bristol-Myers Squibb, Eli Lilly, Janssen (a Johnson & Johnson company), Merck Serono, Pfizer, Sunovion, UCB, Catalent Pharma Solutions, Fisher Clinical Services, Clinigen Group, Medidata Solutions, and Endpoint Clinical. This working group collectively developed both a survey and a data collection instrument. The study aims were to gather quantitative metrics and to capture practices and strategies regarding clinical supply logistics. The study focused on warehousing and distribution and did not examine supply sourcing, manufacturing or packaging and labelling. 

	The study examined a number of areas within global supply logistics, including management of distribution strategies among organizations and measures of success of these strategies. Approaches to temperature monitoring and implementation of cost-reduction measures were also investigated. Lastly, use of interactive response technologies (IRT) and other tools used to increase inventory visibility and study supply forecasting were explored as part of the study.

	Tufts CSDD facilitated the working group process and collaborated on the development of the survey and data collection instrument. All data was gathered and analyzed by Tufts CSDD. The study was launched in the fall of 2014 and data was gathered through early 2015. A preliminary results meeting was held in London in June 2015 and a final results meeting was held in Boston in October 2015 with working group companies to discuss the results of the analyses.

	The survey gathered demographic data on respondent’s organization type and size, the top therapeutic areas in which clinical trials are being conducted at their organization, and countries to which their organization is sending drugs and supplies. Data was also gathered on depot locations and regional hubs; distribution networks and strategies; return management; temperature sensitive shipping, use of IRT; inventory and planning systems; and training and communication. The survey was sent via an email invitation to select company contacts as well as to the working group companies. In addition to the working group, there were 97 invitations sent out across the industry, to pharmaceutical companies, contract research organizations (CROs) and service providers, asking potential respondents to complete the survey. A total of 17 respondents completed the survey.

	In addition to the survey component, data on clinical supply logistics were gathered for recent clinical studies conducted by the working group companies. These data examined global studies conducted by companies in the past five years. Organizations were asked to contribute data from at least eight of their studies (two trials per phase) across a broad range of therapeutic areas.

	The data collection instrument gathered clinical study-specific cycle time and performance data from participating companies. Data was gathered on study characteristics, including study phase and status, therapeutic area, disease states, 

global sites and planned enrollment. Data on key metrics included number of shipments, on-time shipments, cycle times, product impact, waste, costs spent on study services and outsourced logistics services. After an interim results meeting, working group participants agreed to provide additional data on product impact, waste and shipping times based on refined definitions. Additional data was contributed by 12 working group companies. These data are included in the current analyses in this article.

	Seventeen companies responded to the logistics survey and 12 companies provided logistics data for 73 clinical studies across a diverse group of therapeutic areas, including oncology, neuroscience and central nervous system (CNS), immunology and respiratory studies. Of the 73 studies gathered, there were 14 (19%) in Phase 1, 19 (26%)  in Phase II, 31 (42%) in Phase III  and nine (12%) in Phase IV. (Some companies contributed less than two studies per phase as additional data were not available). The top therapeutic areas of studies gathered were oncology, CNS and neuroscience, immunology and respiratory (see Figure 1 below). For all study data gathered, companies sent drugs and supplies to 5,682 sites across all global regions. Shipments were distributed across North America, Western and Eastern Europe, Asia-Pacific, Latin American and “Rest of World.”

	The mean planned enrollment time of studies in Phase II and Phase III were 11.8 months and 16.3 months, respectively. Variance in enrollment time across studies from 11 therapeutic areas was small, ranging from 0.1 to 0.9 (see Figure 2 below). The variance in enrollment drives clinical supply logistics strategy and performance. The studies in CNS and neuroscience, oncology and metabolic and endocrine areas had high variances, while hematology and infectious disease had low variances.

	Survey respondents indicated that drugs and supplies were shipped across all regions with the largest proportion of shipments in North America (78%), followed by Western Europe (66%), Eastern Europe (63%), Latin America (29%), Asia-Pacific (22%) and Rest of World (18%). (Percentages represent percent of total shipments and do not add up to 100%). Companies reported that their top regional hubs are in Western Europe (38%), Asia-Pacific (31%) and the Rest of the World (13%). Top local depot locations are in Latin America (49%), North America (41%) and Asia-Pacific (36%) regions. Distribution strategies varied with 31 studies (42%) using a centralized approach, 30 (41%) were managed regionally and 12 (16%) were locally managed. A centralized approach is defined as one depot for a global study distributing to all sites. Regional hubs were defined as the main distribution hub responsible for shipping to each country within a wider region, and local depots were depots with regular shipping only to domestic locations.

	Respondents estimated that nearly 70% of studies were using IRT systems for multiple processes, including drug ordering, randomization and expiry data management. Data was gathered from 12 companies for this question. Other usage of IRT systems were in the areas of drug reconciliation and temperature excursion tracking (see Figure 3 below). The majority used IRT for drug ordering (12 of 12 companies), randomization (10 of 12) and data extension management (eight of 12). IRT is also being used for effective control of blinding and unblinding, as it hosts dosing assignment information, instead of paper-based control. The primary ways that companies envision the use of IRT evolving in their organization were through new functionalities and standardized modular platforms. Staff from clinical supply and clinical operations were identified as primary decision-makers in outsourcing or keeping IRT systems in-house. 

	The results of the survey also suggest that use of IRT and integration are two approaches that have increased inventory visibility within organizations. Being able to integrate multiple systems (for example, an integrated EDC/IRT approach) provides access to all sources of data. Survey respondents indicated that they used multiple systems, ranging from one to six, and the majority of these systems are outsourced. Some of the platforms were integrated with IRT and included EDC, drug accountability and enterprise resource planning (ERP).

	Many companies report IRT improvement initiatives in new systems or processes through standardization of requirements, interfacing with other clinical systems or revising system specification processes or functionalities. Also, cross-functional governance teams are in place at most organizations as part of improvement initiatives that oversee functionality standards and processes internally as well as with vendors. Lastly, IRT improvement initiatives for provider and partner evaluations were also being implemented. Examples of these initiatives included providing formal training and improving IRT standards among sponsors, CROs and IRT providers.

	For the 73 studies evaluated, there were 1,538 shipments, on average, made to investigative sites and 17 bulk shipments to in-country depots in our analyses. An overwhelming majority of shipments-97%-arrived on time to sites and 80% to in-country depots. We also found that in analyzing mean shipping time in days by distribution strategy that there was a wide variation and the longest times were found in centralized approaches (5.8 days in North America to 27.8 days in Rest of World) or one depot for a global study distributing to all sites (see Figure 4 below). Distribution strategies were divided among centralized (27 studies), local (11), and regional (19) approaches.

	The largest proportion of clinical supply logistics costs across all clinical studies analyzed were for courier and depot costs (49%) and storage and distribution costs (40%). Of the total studies, 43 were outsourced and 30 were run internally. A small percentage of total studies (3%) from the company data gathered experienced product impact with the greater number of reports involving errors in shipping and handling, including temperature excursion. Other errors included site mishandling, customs intervention and errors with IRT. Errors with packaging in labelling are among the least (see Figure 5 below).

	Product waste was examined across studies on three measures: the percent of total manufactured product packaged, percent of the total packaged product that was shipped to sites, and the percent of product shipped that was dispensed. The results indicated that 67.8% of the product shipped to sites was dispensed to patients based on 12 companies and 57 studies (see Figure 6 below). 

	Companies varied in their approaches to calculating supply overage. Nine of 12 companies calculated the percentage overage added into each study forecast; two in 12 used percentage added into aggregated study forecast; and one company calculated overage as a percentage of actual used (based on historical use).

	Additional data in Figure 6 revealed more insights into organizations’ attempts to manage waste or overage. As shown, 74% of packaged product was shipped to clinical sites and 90% of manufactured or procured product was packaged. However, with the aforementioned 67.8% of product shipped and dispensed, this reflects challenges and opportunities in the alignment of clinical supply and clinical study operation execution.

	The majority of respondents indicated that strategies did not differ between Europe and the U.S. for sourcing temperature maintenance products (e.g., shipping containers). Temperature monitoring strategies were primarily electronic. From the survey data gathered on temperature excursions occurring in transit were more frequent at customs clearance or at a site. The time taken to perform disposition of a shipment excursion was 57 hours, on average, with a range of six to 114 hours.

	A number of other factors impact distribution, creating additional challenges for clinical supply executives. One challenge is the delay caused by obtaining import licenses-and the top countries listed were Argentina, Russia, China, Colombia and India. 

	Company approaches varied regarding the use of expiry dates. They were split on this issue, with five companies indicating their approach varied and six saying it did not. In addition, 11 companies indicated that they allow different expiry or “use-by” dates at different levels of the distribution chain; four reported they did not. Another area where companies had mixed approaches was regarding consistency in putting expiry dates on the shipping package. Nine organizations indicated they put expiry dates on a shipping package while seven revealed they did not. The primary methods for managing expiry date updates were to perform extension labelling at the site or to return to a depot to conduct it. 

	Challenges in managing returns of drugs and supplies are also evident in a few key areas, including reconciliation and document destruction, complexity of managing returns and regulatory requirements. Managing returns varied across companies and could be destroyed at a site, returned to a local depot by region or country or returned to a central location. 

	Key performance indicators of distribution success were on-time shipments, percent of shipments with temperature excursions, percent minor deviations and on-time release or product released for use at a site (see Figure 7 below). Other indicators used were percent major deviations and on-time receipt of shipments.

	Companies were split on use of pooled supplies, with nine reporting that they used pooled supplies, while seven did not. The top challenge to using pooled supplies is the regulatory variation in acceptance across countries. No companies report using e-labelling, as regulations regarding its usage were expected to be clarified in the middle of this year.

	The results of this study reveal that a great number of supplies are shipped across the globe. Of 73 global clinical studies reaching 5,682 sites, there were, on average 1,538 mean shipments. Companies used a mixed approach of centralized, local and regional strategies for shipments. Shipping times to investigative sites took an average of 3.4 days, with a coefficient of variation of 1.4, indicating disparities among shipping times to global sites (Figure 6).

	Our findings for product impact and overage can help identify areas for continued improvement regarding cost and quality issues within clinical supply. Of the 57 studies further analyzed, there were 19 errors in shipping and handling and nine with site mishandling. This result represented 3% of studies and can be examined in further detail. Within the shipping and handling category, errors with temperature excursion were included. Any clinical supply logistic error rate may translate to potential site stock-out or product quality impact of the treatment that study subjects are waiting for. Companies can potentially look more closely into errors with product impact to see if there are strategies that can be implemented either within organizations or at the site level to reduce such instances. It is also critical for companies to achieve a balance between the risks and costs to optimize the clinical supply chain and increase quality. While cost containment is a priority, reducing inefficiencies in the supply chain is an ongoing challenge.

	The results of this study indicate that two-thirds of all product shipped to sites was actually dispensed to patients. This result is considered typical given anecdotal evidence, with some organizations potentially having higher rates of overage as suggested by published data on this topic.

 Coverage for geographic spread is another factor. It is acknowledged that waste varies by study, but the amount of overage impacts both cost and efficiency of supply. In addition, there is a

 relationship between clinical supply availability and the success of a study. A number of other factors such as cross-collaboration with clinical operations and other functions should be considered, especially those that manage the security of the supply. Companies may need to increase their “safety” stocks to address all the risks and potential scenarios that may occur. 

	Cross-collaboration also plays a role in the distribution strategy that an organization adopts. The studies we analyzed were split among centralized, local and regional strategies. Strategies varied across studies and by organization, perhaps due to the wide fragmentation and varied infrastructure of the global markets involved, but also due to unique company practices, set-up and strategies. It would require further study to examine what the drivers are for implementation of specific strategies and how best to optimize their usage. Nearly 60% of the trials we examined utilized outsourced logistics in managing the clinical supply chain, indicating that coordination among partners and vendors is also an important part of managing costs and efficiencies. 

	Forecasting supply can be linked to use of technology. Being able to forecast supply and the impact of factors such as enrollment, site selection and productivity and country selection is critical. Compared to 10 years ago, IRT plays a larger role in various clinical supply processes, from drug ordering and randomization to data extension management and drug reconciliation. Companies in our study estimated that nearly 70% of their studies are using IRT systems. The use of IRT is also evolving and taking on new functionality and standard platforms, as well as being integrated with other systems. Necessity and dependence of IRT becomes ever more critical to meet today’s clinical study complexity, improve study efficiency and enhance compliance. Many organizations have already implemented cross-functional IRT governance teams to align processes within the organization and with vendors. 

	The results of this study provide a useful set of baseline measures for clinical supply professionals. The major findings also suggest an even greater need for upfront planning, risk mitigation, reducing waste, increasing efficiency and promoting cross-collaboration among those managing or involved with drug supply. In addition, there may be missed opportunities for cost savings by reexamining approaches to overage. There are also potential opportunities to improve the quality of product impact during shipping and handling. Furthermore, the relationship of clinical study efficiency with clinical supply logistics shall be studied by identifying and correlating the key strategy designs and key performance indicators.

, PhD, is Senior Research Fellow, Tufts CSDD, Tufts University, email: 

, is Senior Director, Clinical Trial Materials Management, Sunovion Pharmaceuticals Inc.; 

, PharmD, is Director, Clinical Pharmacy, Astellas US Technologies Inc.; 

,  PhD, MBA, is Global Director, Strategic Development Solutions, Clinical Supply Services, Catalent Pharma Solutions; 

, MBA, is Director of Sponsored Research Programs, Tufts CSDD

To whom all correspondence should be addressed

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Study collects first comprehensive metrics on current supply management and distribution practices.

Assessing Global Clinical Supply Logistics

 In addition, academic institutions and government-funded sites took longest to first patient in, while physician practices were fastest. In a further analysis by global regions, sites in Latin American took twice as long as sites in North American to enroll the first patient.

	A total of 26 interviews were conducted across 21 companies. In some cases, more than one representative from a company was interviewed across functions to gather more complete information and better understand the approaches for activities associated with site selection through site activation. Respondents represented 13 biopharmaceutical companies and eight CROs across 13 large and eight mid-sized and small organizations. Interviewees were experienced and were primarily senior level executives occupying director level roles or above. A few respondents held newly created roles within separate study start up functions (see chart 1).

	Global expertise becomes important, as there is regional variation in cycle times to first patient in. These data reflect similarities to the findings of an earlier Tufts CSDD study that found sites in Latin America and Eastern Europe had longer cycle times than sites in other regions, and North American sites took the least amount of time to first patient in (chart 2).

	Through feasibility studies, organizations are able to discern a site’s ability to execute the proposed study and complexity of the protocol. A detailed on-site assessment was conducted in some cases. Past experience with a site is a strong indicator and is guided by intelligence gathered both internally and externally. Large companies tend to have more consistent and strategic approaches to gathering central and local intelligence on sites, and follow global processes. Sources used included CiteLine or TrialTrove and intelligence gathered by site management organizations (SMOs) or CROs. Smaller companies reported reliance on vendors that provide solutions searchable by indication or outsource all site selection. Respondents mentioned a number of other solutions to support site selection, including their own internal tools, clinical trial management systems (CTMS), and IMS’s Study and Site Optimizer (see chart 3).

	A site’s compliance with good clinical practice (GCP) and the ability to meet protocol-specific requirements were also noted as site selection criteria. Respondents reported that site selection could be improved by gathering more intelligence on site performance and leveraging data from past experience as well as program planning early on. One interviewee indicated that “we are using data more effectively to make decisions. We rely on performance; the number of protocol deviations; number of escalated issues for GCP non-compliance. We rely on the upper percentile of sites. To improve site selection, we can arm our teams with more intelligence.”

	On average, site selection was reported to take approximately 3.2 months and could potentially range from two weeks to six months. In all, the process of site identification to activation is a one-year cycle (chart 4).

	Factors impacting site selection timelines vary by therapeutic area, indication, geographic area, size, and phase of study. Type of site is also of particular influence since academic site selection typically takes longer than community-based sites. Academic sites have several layers of review, including institutions review boards (IRBs) or ethics committees and scientific review committees. Some larger academic sites in the U.S. also have operational review committees, which can delay site activation and impact study start-up. In particular, companies conducting oncology trials typically report lengthy timelines as they rely on large academic sites to conduct their trials. These results are comparable to earlier research examining first-patient-in cycle time by type of site and by therapeutic area.

Study finds that despite the use of new approaches to streamline and accelerate study start and improve site selection and activation, the impact on start-up cycle times has been limited. The reasons why are explored.

Author | Mary Jo Lamberti, PhD