Mary Jo Lamberti, PhD

The COVID-19 pandemic caused major disruptions to clinical trial execution in the U.S., impacting key stakeholders across the industry. Investigative site capabilities experienced upheaval, driven by staff furloughs, social-distancing protocols, financial losses, and concerns over patient safety. Sponsors, CROs and other organizations that support drug development shifted to remote working environments. An estimated 80% of non-COVID-19 trials were stopped or interrupted as a result of the COVID-19 pandemic.

An April 2020 study suggests investigative sites demonstrated flexibility and ingenuity in adopting new approaches in order to cope with challenges presented by COVID, with over half of investigative sites transitioning to virtual approaches to interact with patients. More recently, follow-up studies performed in August 2020 have identified persistent impact of COVID, with over 60% reporting an “average” or greater level of impact on ongoing trials and initiation of new trials. Respondents specifically highlighted challenges in patient enrollment and recruitment.

Recent FDA guidance (March 2020 and updated July 2020)

acknowledged that the impact of COVID-19 may require companies conducting clinical trials to consider virtual patient visits or put new processes in place regarding their current protocols. Therefore, there are now more opportunities for using remote healthcare including conducting virtual or decentralized trials, site-less clinical trials and use of other non-traditional approaches that do not involve in-person visits. This shift, driven by the effects of the pandemic, prompted the team at the Tufts Center for the Study of Drug Development to conduct a qualitative study researching the impact of COVID-19 on clinical trial execution. 

The study examined the effects of COVID-19 on clinical trials by gathering insights and perceptions from clinical operations professionals at pharmaceutical companies in the United States. The goal was to understand the modifications that organizations have made in response to the pandemic, especially with regard to remote or virtual approaches. In addition, the study explored how companies have approached planning and implementing remote and virtual approaches to trials, as well as their experience and lessons learned. Last, Tufts researchers sought to understand initial perspectives on how COVID-19 will impact trial execution in the long-term.

A total of 25 interviews with pharmaceutical and biotechnology executives within the clinical operations department from unique companies were conducted using Zoom. All executives worked in the United States and played a role in U.S. clinical operations. Participants were selected from Tufts CSDD proprietary lists of contacts who work in clinical roles and through other collaborations on prior studies or from professional conferences and meetings. Participants were recruited via email from June to early August and have extensive experience conducting clinical trials across diverse therapeutic areas. Interviews were 30 minutes in duration and were conducted by Tufts CSDD researchers using a comprehensive discussion guide encompassing the following areas: (1) COVID-19 Impact on Ongoing Trials, (2) Organizational Preparedness, (3) Trial Amendments and Remote Technologies, (4) Role of Regulatory Agencies (5) Role of Third-Parties, (6) Long-term Impact of COVID-19.

Interviews were conducted with U.S.-based staff at 25 organizations comprised of pharmaceutical, biotechnology, and non-profit research institutions. There were 15 large organizations represented and 8 mid-sized or small companies based on R&D spending.* Two were non-profit organizations. These were included given they often sponsor government-funded clinical research.

Eleven organizations halted ongoing trials and enrollment for at least one month. Shutdowns were most frequently driven by concerns that patients would not be able to safely travel to and receive care at research centers. These concerns were especially poignant in indications that were considered “high-risk” for COVID infection (e.g., cardiology, pulmonology, immunology) or indications where patients had difficulty traveling or for example, had neuromuscular and/or neurodegenerative conditions. In these cases, studies often resumed only once patient safety was assured and R&D organizations had amended protocols to include suitable pandemic contingency plans. An interviewee discussed the impact of COVID on their ongoing trials:

“We put our entire portfolio on hold for two months—it became clear we were not ready to move to a virtual situation.”

Another 12 organizations reported moderate impacts on ongoing trials, most frequently citing delayed enrollment as the primary challenge related to COVID. Several factors may have reduced impact on ongoing trials. Trials in indications such as dermatology and psychiatry may have faced less severe disruption, given more frequent use of telehealth in clinical practice prior to COVID or relative ease of transitioning collection of outcome measures to remote methods (e.g., measuring skin lesion size over telehealth). Additionally, organizations that demonstrated a higher level of pre-COVID preparedness or greater organizational agility tended to report lower impact. Finally, organizations with modest impact often reported partial, geographically isolated closures or understaffing at select sites, rather than full shutdowns reported by those experiencing greater impact. The impact on an organization’s investigative sites is described by a respondent: 

“Many of our sites were partially closed, and we had to incur additional cost to sustain our study. We are maybe approximately 25% behind on enrollment as a result.”

Most R&D organizations that reported some level of COVID impact suggested that the ability of sites to respond to the pandemic was a key indicator of the level of impact. Given COVID-19 outbreaks occurred regionally in the U.S., differences in site response emerged based on location and time period. Respondents identified four key factors that tended to influence sites’ abilities to respond to the pandemic. First, staffing furloughs were often site-dependent, and often resulted in delays in data processing, as well as scheduling and execution of patient visits. Additionally, many patients felt hesitant to visit research centers, especially in harder-hit regions, with select organizations citing higher rates of patient withdrawal from studies. Sites with poor or non-compliant IT faced significant challenges pivoting to telehealth visits, providing access to EMR to investigators, or completing CRA site visits virtually. Finally, sites set different restrictions based on hospital- and state-imposed protocols (e.g., no lab-only visits, additional PPE needed, etc.) that resulted in potential deviations from protocol or delays.

Figure 1. 23 of 25 organizations reported some level of impact on ongoing trials due to COVID-19.

A couple of organizations (n = 2) reported experiencing small or no disruptions. These organizations were often running early stage trials (e.g., Phase I) where clinical follow-ups to identify adverse events could easily be performed over telehealth. An interviewee conducting studies in early phases noted that “there is a fairly large dichotomy between early phase and late phase—the impact for Phase I and Phase II is a little less.” Organizations with less disruptions also were often running trials in disease areas where patients required urgent treatment and/or had few options for treatment (e.g., oncology, rare disease).

Organization response: successes and failures

R&D organizations reported a spectrum of success in responding to the challenges presented by COVID. R&D organizations that self-reported “successful” responses to COVID-19 often demonstrated at least one of four key success factors: organizational agility, prior investment in remote technologies, development of COVID-19 task forces, and/or strong R&D capabilities in Asia-Pacific (APAC) regions.

Five organizations cited organizational agility as a key factor in the success of their COVID response. Smaller, flatter organizations were less hindered by bureaucracy, and were able to rapidly implement changes to studies.Decisions were made at a study-team level and upper management were informed of decision-making. In these cases, it was critical that leadership trusted their employees to execute trial changes without significant oversight.

Another 5 companies were piloting remote technologies and services prior to COVID and reported transitioning more easily to “virtual” trials.Several organizations were piloting telehealth, remote data monitoring, home health, and other virtual approaches in ongoing studies. Comfort with existing remote infrastructure allowed for rapid expansion into indications that did not initially leverage but could benefit from virtual approaches (e.g., measurement of skin lesions over telehealth in dermatology trials). The trend of shifting to a more remote model was explained by an interviewee:

“We were already in the process of things becoming more virtual anyway. This has definitely accelerated the process because we’ve had to adapt.

We are thinking more about how we collect data, verify data from a remote perspective.”

Establishment of a task force was instrumental for larger companies to prepare and rapidly amend trial designs to include remote modalities, with 5 of interviewed organizations reporting implementing such task forces. For larger organizations, the creation of response teams was critical to preparing for COVID’s impact. Organizations that successfully adapted trials to COVID-19 typically had upper leadership that trusted their task force to execute without significant oversight. In select cases, leadership indicated desire to press forward with additional changes to future trials, in order to continue building upon the trend toward virtual trials. The COVID-19 task force typically encompassed representatives from all key trial functions. Experienced team members with backgrounds in operations, regulatory, and data management were all required for implementation of novel remote technologies. Following general guidelines from the COVID-19 task force, study leads often were responsible for managing direct COVID-19 impact. Study leads needed to consider each investigative site separately, given variable COVID-19 activity across regions in the U.S. Task forces that took a study-by-study and site-by-site approach reported greater success than those that attempted a “uniform” approach. The importance of a relatively independent task force that could communicate with study teams and leadership was explained by two interviewees:

“There wasn’t a one-size-fits-all approach to our trials, given they were in different therapeutic areas and geographic regions. Thus, it was important to allow study teams to make recommendations that we could then adopt.”

“Communication with leadership was important to keep them informed of changes to our trials. They really just let us run with it. Now that we have a plan, leadership is pushing to make ‘the next step’ and make sure we COVID-proof our trials going forward. This includes leveraging more virtual approaches.”

A minority of organizations (~2) reported leveraging their organizations’ R&D capabilities in China and Japan, who had early COVID experience, to prepare ongoing studies in the U.S. Select global R&D programs indicated that their colleagues in China and Japan warned them about the impact COVID may have on trial execution, which allowed them to prepare for COVID and begin to develop protocols in case sites were shut down. Of note, this was a benefit that was not reported consistently by global R&D organizations and may be dependent on specific colleague-colleague relationships.

Adoption of remote monitoring technologies and decentralized approaches

Interviewed stakeholders implemented a wide range of novel remote monitoring technologies and decentralized approaches to make trials more patient-centric in the COVID era.

Figure 2. Telemedicine and eConsent were the most frequently utilized remote technologies, while home health was the most frequently utilized remote service.

Telemedicine and eConsent were the most frequently mentioned technologies adopted during COVID-19. Telemedicine was implemented by the majority of respondents, with 19 interviewed organizations reporting use of telehealth in ongoing trials. Telemedicine was most frequently used for routine follow-ups to identify adverse events, especially in Phase I studies. Telehealth was also used to measure select objective outcome measures (e.g., lesion size in dermatology or plaque psoriasis). Though investigators recognized the potential to collect other measures via telehealth (e.g., depression scales), they expressed concern that the method is not validated and requires proof of concept before regulators would accept data generated through telehealth. eConsent was used by 10 companies and was perceived to be one of the simplest innovations to implement. Respondents highlighted the potential for eConsent to facilitate communication with patients, by leveraging novel modalities such as video explanations, quizzes to assess understanding, etc. Interviewees offered their insights on remote technologies:

“I expect eConsent and telemedicine will become routine and integral parts of clinical trials. They are pretty straightforward steps towards a more patient-centric trial, and could easily be adopted in most, if not all, protocols.”

“We had piloted eConsent on a couple of studies and it (COVID) moved us out of the pilot very quickly. We’re trying telemedicine even more. How do we ‘hybridize’ a trial even outside of COVID to reduce patient burden?

Broader use of telemedicine may encourage enrollment and make trials more patient-centric.”

ePRO was the next most frequently utilized technology, with eight companies citing use. Notably, ePRO was already used in ongoing trials prior to COVID. However, in an effort to further reduce patient burden, research organizations opted to allow patients to use their own devices.

Use of data integration was perceived to be highly useful to R&D organizations, given R&D organizations could access trial data in real-time. Additionally, utilization of EMR provided opportunities for R&D organizations to supplement clinical research data, as potential alternatives to monitor adverse event and clinical care patterns. However, only select companies (n = 4) actually leveraged real-time integration of trial data or EMR during COVID. Several respondents cited challenges with implementation of integrated EMR, given poor investigative site IT infrastructure, investigative site preferences, or challenges with CRO staffing or capability to visit sites. Privacy restrictions, interoperability and compatibility challenges represent additional key barriers to utilization of these technologies. One interviewee discussed the barriers that have emerged in monitoring due to COVID:

“Monitoring is our biggest challenge right now and we’re trying to get back out to sites. Across the board we have major Phase III database locks and we cannot get to some of the final sites that have data. If we don’t have access to their EMR is there another way? We are discussing remote approaches and technologies that can be implemented.”

A number of respondents expressed interest in the future use of integrated EMR, and suggested they were actively seeking CRO partners to implement the technology once sites reopened. In addition to novel technologies, respondents adopted a range of approaches to decentralize trials and minimize patient exposure to investigative sites in the face of COVID-19. Overall, nearly half of respondents implemented at least one approach to decentralize ongoing trials.

Approximately seven organizations implemented some method of home health in their ongoing trials to ensure patients that were unable or unwilling to travel received IV medications and were able to provide blood samples. Rare disease trials reported greater use of home health, given the long distances patients may have to travel to access the investigative site and the need for frequent IV infusions. However, investigators also noted that home health was “hit-or-miss,” given some patients resided in locations inaccessible to home health while others refused to allow nurses in their home due to concerns with the spread of COVID-19. “Home care and direct-to-patient drug delivery are steps to move towards a more patient-centric trial design,” commented one interviewee. Direct-to-patient drug delivery was implemented by five companies and perceived to be a relatively low-risk method to transition trials to be more patient-centric, especially for oral agents with safer expected toxicity profiles.

Decentralized lab work was utilized by five organizations. Many sites did not allow “lab-only” visits during COVID-19, presenting challenges to collecting biomarker-related outcomes in oncology, cardiology, diabetes, etc. Investigators allowed participants to have blood work done at local labs, and in select cases provided co-pay cards to cover the cost of lab work (e.g., via Scout). Decentralized lab/blood work was perceived to be highly effective for oncology and rare disease patients, especially for those that had to travel longer distances to investigative sites.

Overall, remote technology adoption was more extensive than adoption of remote services. One might speculate that remote technology adoption has been more extensive not only because companies had prior experience with these technologies (e.g., piloting) but also because remote personnel and drug delivery require more lead time to set up, more extensive logistics and certification planning.

More than half of organizations interviewed (13 companies) cited leveraging FDA guidance at the start of COVID-19 to adapt and amend clinical trials. Interviewees cited published guidance on home-dosing and telemedicine as being especially helpful at the start of COVID. Interviewees also perceived the FDA to be responsive and accepting of the need for flexibility, so long as the integrity of trial data was preserved, and patient safety was ensured. Several interviewees spoke directly with the FDA and rated the experience as positive and informative.

However, interviewees also noted that regulators’ stances on how or if they would accept data that had been gathered in amended trials was unclear, and how the utilizations of remote technologies would impact filing. Specifically, several interviewees expressed concerns that select outcome measures may not be accepted without proof of concept (POC) demonstrating that collection via remote technology was the same as in a physician practice, given current FDA standards on how data should be measured.

Perspectives on long-term impact of COVID

Ultimately, 20 of the 25 interviewees believed that COVID-19 would permanently accelerate use of remote technologies in clinical trials. Most interviewees perceived increased use of remote technologies as a “silver lining” to COVID-19. Respondents often cited telehealth, e-consent, and EMR/data integration as the approaches that would most likely continue to persist past COVID. Additionally, respondents mentioned that they would aim to streamline the data collected from trial protocols, seeking to provide greater flexibility to investigators while removing “nice-to-have” outcome measures from protocols. Meanwhile, high upfront investment cost and unclear regulatory stance drove several interviewees to predict that trials would return to “normal” post-COVID-19. This perspective was especially clear for oncology and rare disease, where stakeholders believed in-person care was critical. Ultimately, most interviewees acknowledged that while use of remote technologies had been accelerated by COVID, use would not persist without concerted effort from industry and regulators to continue momentum. Change would focus on convenience for the patient as highlighted during an interview:

"We were forced to dip our toes in the water; we will not return to status quo. Patients are likely to expect some of these technologies now to make their lives easier.”

Challenges to adoption of remote technologies

Interviewed stakeholders identified several barriers to the adoption of remote technologies and services. Several interviewees (n = 5) suggested that preference for care at investigative sites would delay implementation of remote technologies. Patients, especially in rare diseases, may prefer to receive care at investigative sites from an in-person key opinion leader (KOL) rather than via telehealth. Others (n = 4) suggested site-specific protocols would hinder adoption. Select sites demonstrated resistance to adoption of new technologies or had specific IT protocols that were barriers to adoption of novel approaches (e.g., poor security delayed remote EMR access). Finally, 8 companies perceived regulators to pose a significant barrier to adoption. Interviewees believe there is low incentive to adopt new technology, given high early investment cost and unclear guidance from the FDA on how they will interpret these technologies during filing. Thus, a firm stance is needed from the FDA to promote utilization of remote technologies post-COVID.

Steps to continuing progression to “patient-centric” trials

Industry, regulators, and investigative sites will need to take several steps to cement the role of virtual approaches and promote patient-centricity in future clinical trials. A strong regulator stance on the use of virtual and remote technologies in clinical trials is necessary to promote adoption by industry. Currently, lack of clarity from regulators on how remotely-generated data will be accepted leads to hesitancy to adopt novel technologies. Published FDA guidance expressing standards for e-Consent, telehealth, and other tools or decentralized approaches may be necessary for organizations to invest in remote technologies. Conversely, POC may be required for regulators to publish such guidance, resulting in a dilemma for companies. 

Additionally, it is critical that all stakeholders including patient advocacy groups and investigative sites be on board in order to move decentralized models forward. Several interviewees perceived that select patients enroll in trials to get “better” care at academic centers. Patient perspectives must be incorporated into trial design in order to balance the patient-centric and cost-related benefits of remote technology with the preferences of patients. Additionally, investigative sites may not have the budget nor the expertise to implement novel remote technologies (e.g., EMR integration, telehealth, e-consent). Industry may need to support sites by investing in technologies and trainings to ensure standardization across investigative sites.

, Research Anlayst; all from Tufts CSDD; 

, MBA, is Deputy Director and Research Professor, 

, both based in Boston, MA. Email: kenneth.getz@tufts.edu 

Dorn, A. V. (2020). COVID-19 and readjusting clinical trials. 

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Medidata. (2020, August 18). COVID-19 and Clinical Trials: The Medidata Perspective. Retrieved from 

https://www.medidata.com/wp-content/uploads/2020/08/COVID19-Response8.0_Clinical-Trials_2020824_v1.pdf

United States of America, Food & Drug Administration. (2020). 

FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency

*Categories of R&D spending based on large companies (R&D >$1Billion); mid-sized (R&D $100 Million - $1 Billion); and small (R&D < $100 Million)

Articles

Findings from a Tufts study examining the effects of COVID-19 on clinical trials.

COVID-19 and Its Impact on the Future of Clinical Trial Execution

	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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https://pdfs.semanticscholar.org/0399/4a30b883e38c05decb9f1f62f439c89e5ae8.pdf

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/enhancing-diversity-clinical-trial-populations-eligibility-criteria-enrollment-practices-and-trial

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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.

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

Mary Jo Lamberti, PhD

Articles

COVID-19 and Its Impact on the Future of Clinical Trial Execution

Understanding the Complexities of Diversifying Clinical Trials

New Benchmarks for Trial Initiation Activities

Assessing Global Clinical Supply Logistics