Cindy H. Dubin

	Effectively and compliantly managing clinical development programs that evaluate the efficacy, safety, and tolerability of new therapies requires close internal collaboration, including regulatory operations, which like many functional areas, can no longer operate in a silo. Driving this collaboration is the slowly evolving shift from paper to cloud-based regulatory information management systems (RIMS) to address regulatory operations challenges, such as information sharing, changing regulatory requirements, managing a global network and multiple products, track commitments, and streamline submissions and approvals.

	The traditional regulatory technology landscape has not made life easy for regulatory operations to have visibility into the progress of submission development. It is not uncommon for publishers to receive final submission documents at the last minute-or close to the submission due date, leaving little time to publish, validate, and submit the submission to the respective health authority.

	“Disparate systems, trackers, and divergent processes make it difficult for regulatory to allocate resources for known major filings, in addition to routine or maintenance filings, and the planning becomes more complex when you factor in the unknowns (e.g. HA information requests),” says Rachel Belani, director, Vault RIM, Veeva Systems. It’s just in the last three to five years that this is changing, because modern cloud technology allows regulatory to plan more effectively, identify potential risks earlier in the process, and have real-time visibility into the completion status of critical path deliverables.”

	A common scenario in many regulatory operations groups is a disjointed mix of homegrown and legacy systems, email, spreadsheets, and file-hosting services for tracking and sharing regulatory data.

	“There is often a patchwork of systems and processes in place to get the job done, and as a result, regulatory professionals are working with a combination of stand-alone document management systems, spreadsheets for planning and tracking submissions, files shares, and stand-alone archiving systems-making it difficult for regulatory staff to understand what has been submitted, and ultimately accepted by health authorities,” says Belani.

	For a big pharma like Merck Healthcare KGaA, Darmstadt, Germany, its core regulatory information management system was no longer being supported, and updated releases were not meeting needs and expectations, explains Regina Freunscht, vice president, global head of regulatory operations, Merck Healthcare KGaA. Managing large and complex electronic submissions with numerous systems (document management, RIM, publishing tool, and publishing archive, complemented by numerous planning trackers and project management tools) had become an increasing battle, she says. The cloud-based Vault RIM provides Merck Healthcare KGaA a centralized hub for storing and sharing documents, data, and information that drive completion of critical regulatory activities.

	After almost 25 years in the industry, Sonja Justice, director for global regulatory operations, Amicus Therapeutics, says she is witnessing the industry begin the transformation from paper to cloud. As a small biotechnology company, Amicus relied on email correspondence and a network file-sharing share system. But the company is growing from having one product in its pipeline to multiple products and is working in multiple countries. Additionally, Amicus, which is focused on addressing unmet needs for rare and orphan diseases, has more than doubled its employees in the last few years.

	These various factors were the tipping point for finding a way to centralize its product information. Amicus also chose to implement the cloud-based suite of RIM applications from Veeva. Amicus implemented the submission document management and regulatory submissions archive components last year, and is currently implementing the product registration tracking application.

	Amicus has one commercial product on the market and is submitting dossiers for several investigational products. “Having a defined manner of finding documents or submissions related to these products and the ability to look at historical data in the Veeva system is much more efficient than trying to search information in a network file-share system,” says Justice.

	Managing information and a broad product portfolio across a global network can be inefficient if a patchwork of systems is used. “With the complexity of our product portfolio that we manage around the world, we needed a system that eased our work, is globally available, and meets the changing and improving demands from various health agencies,” says Freunscht. “Although our regulatory system landscape was connected, we did not have a harmonized data strategy across our systems. This complicated analytics on our regulatory data and made joint/co-development of our assets with other companies and academic centers difficult. As a result, reuse of dossiers and managing parallel submissions across the globe was a complex and difficult task.”

	To address the myriad of regulatory requirements, IQVIA developed the modular, cloud-based RIM Smart, says Ronan Brown, senior vice president, integrated technology and compliance solutions, IQVIA. Utilizing proprietary artificial intelligence (AI) and machine learning (ML) algorithms, RIM Smart includes an embedded, real-time regulatory intelligence database that covers most of the world’s regulatory requirements. “We scan this information continually and update the database so that users are compliant with requirements,” he says.

	The ever-changing regulatory scenario in the market proves to be one of the important driving factors for adoption of regulatory information management software. Since 2000, FDA has issued thousands of regulation changes with regard to reporting requirements, and pharma struggles to keep pace. According to Coherent Market Insights, the global RIMS market was valued at $797.2 million in 2018 and is projected to exhibit a CAGR of 13.7% over the forecast period (2019–2027), owing to the increasing volume of data to be collected and provided by regulatory bodies.

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The shift from paper to cloud-based regulatory information management systems (RIMS) to address operations challenges.

How Do Regulatory Intelligence and Operations Envision Technology?

As the complexity of medical science continues to accelerate, so does the complexity of clinical trial research. In his State of the Industry presentation at the annual Association of Clinical Research Professionals (ACRP) meeting earlier this year, Ken Getz, director of sponsored research at the Tufts Center for the Study of Drug Development (CSDD) and chairman of CISCRP, hit attendees with some hard facts about how complex protocols are impacting clinical trial outcomes. Among them:

		There has been an 86% increase in total data endpoints per clinical research trial over the past 10 years.

		Nearly 40% of trials begin under enrolled and 11% of sites fail to enroll a single patient, resulting in those sites operating in the red.

		The cost to develop a successful drug has increased from $802 million in 2003 to $2.6 billion today, yet, the average ROI has continued to decline, hovering around 3%.

		The average time it takes to bring a drug through clinical trials has decreased, but the rate of success has gone down by almost half, to 12%.

	Couple all of this with varied site performance, increasing staff workloads, limited access to data analytics, and difficulty finding patients, and the result is a clinical site landscape on the cusp of change. This transformation is most evident in how clinical research sites define their business models to be more flexible, collaborative, customized, and efficient.

	Is 100% reliance on a preferred partner sustainable?

	One common business model is for a sponsor to work with a preferred provider. In this model, there is an established relationship/rapport between companies. The advantage is working with a known team, known quality, and expected performance.

	 “The preferred partnership model provides visibility in the pipeline and may bring forth technology assets and dedicated internal people and resources,” says Jennifer Byrne, CEO of Javara, an integrated research organization (IRO) based in Winston-Salem, NC. “But where these relationships often fall short is that they are not centered on a deep understanding of the provider/partner’s infrastructure. While I have seen that preferred relationships can yield improvement, it’s my strong belief that preferred providers have much greater potential to bring about a long-term and transformational partnership vs. a short-term, transactional collaboration.”

	Joan Chambers, former vice president of marketing and strategy for ClinX affiliated companies, which provides clinical and outsourced business services, agrees. “Preferred providers hold the promise of delivering high levels of performance and efficiencies, but this type of relationship can sometimes come at a high cost,” she says.

	Additionally, there is concern with high turnover within these organizations that results in disruption and impacts the investigative site staff, and potentially the study. Having preferred providers is important, however, Chambers says having a blend of other providers to work with is equally important. Building multiple relationships with stakeholders in different capacities can prove more beneficial than being 100% reliant on a specific company. As an alternative, sponsors are forming partnerships with clinical networks that can offer access to multiple companies, accelerated research, faster patient recruitment, and more viable patients.

	The next generation of preferred providers

	Offering sponsors a group of provider sites in a single network could be the next generation of preferred provider. According to Mark Lacy, CEO of hyperCORE International, the clinical research industry is fraught with inefficiencies due to a disconnected and fragmented system between sponsors/CROs and research sites. hyperCORE is looking to change that by offering a centralized network. Formed in April of this year, hyperCORE is a network of clinical research sites and network companies that provide Phase I-IV clinical trial services at more than 80 sites worldwide. Each member operates as an independent company but integrates common functions to streamline business and clinical operations by sharing best practices.

	“Years ago, the pharma industry didn’t look upon networks very kindly because they were loosely set up,” says Lacy. “Now, pharma companies and CROs are more interested in going to more organized networks.”

	hyperCORE’s bespoke model allows a customer to contract with one or multiple companies within the network. “One contract saves time and money, but that doesn’t mean everyone necessarily wants that kind of partnership,” says Lacy. “So, our model allows clients to customize a model that is best for them. We really offer the best of both worlds: a one-stop-shop with many areas of expertise.”

	“Getting a group of site networks working together to provide a one-stop-shop is an interesting idea,” says Jim Kremidas, executive director of ACRP. “From a business model perspective, the value of a site network is more than the value of each individual site. Achieving standardized processes and business activities would create operational efficiencies and better quality data.”

	Member companies are adept at examining protocols at the point of development to determine what is practical and what is not. As protocols become more difficult, the goal, says Lacy, is to write protocols with fewer endpoints that will require approval. “And that means we can accelerate research, get a drug to market faster, and save money for our clients.”

	Companies in the hyperCORE network go through an initial vetting process and are then assessed annually in an effort to maintain quality. “Companies will be kicked out if their quality falters,” says Lacy. “Metrics are the biggest indication as to whether they are collecting good data and enrolling high quality patients.”

	High quality data and faster patient recruitment are also at the heart of the Javara’s IRO model. It’s a patient-centric approach that ensures clinical trials are readily accessible as part of the care delivered by health organizations and academic medical systems, while improving the clinical trials experience for all stakeholders.

	“Our IRO model is expanding the value proposition of clinical research and brings forth a more efficient and reliable model for pharma and CROs that, together with our health system partners, delivers on patient accrual and data quality,” says Byrne. “At the same time, we are intentional about improving outcomes for patients.”

	The IRO uses data analytics to align clinical trials with the patient population within a healthcare organization to better serve the needs of those patients. While larger populations are a target, Javara and the healthcare organization also pursue any therapeutic/disease category that fits unmet medical needs for smaller populations. By aligning clinical trials-matching patient to trial-with the unmet patient needs, clinical trials can help to decrease costs to healthcare organizations, enhance health outcomes for patients, and increase engagement of patients in their own healthcare management. The IRO embeds so-called clinical trial navigators (CTNs) within the day-to-day workflow of a healthcare organization to work alongside providers and patients (both in-person and remotely) to increase participation in clinical trials.

	“Our greatest value proposition to the healthcare system is that we are bringing the best of the best trials to patients,” says Byrne. “Sometimes we are talking about millions of patients; understanding their unmet medical needs, and looking across the drug development pipeline to match the patients to companies researching cutting-edge treatments.”

	“Sponsors want to get closer to patients and create more high performing sites,” says Kremidas. “Integrating clinical care-working with healthcare institutions-and offering clinical research as a therapy option will bring access to more patients.”

	In the year since its launch, Javara has forged partnerships to offer that access. One is a research relationship with Wake Forest Baptist Medical Center to provide integrated research models within specific sectors of the complex health system, which includes an academic medical center, a health network, community-based physicians, a medical school, and five community hospitals. Additionally, a relationship between Javara and a practice management organization in the Houston metro area has Javara building a research infrastructure in the region to match thousands of potential clinical trial patients to hundreds of providers within one electronic health record (EHR).

	Bringing the right patient to the right trial with the right provider at the right time is the North Star, says Byrne. Slightly more than two million patients participate in clinical trials. While this may seem like more than enough patient volunteers to meet the needs of existing clinical studies, an estimated 58 million patient volunteers are actually needed. “I believe that low trial participation is a public health issue,” says Byrne. “Working with healthcare partners highly committed to clinical trial access for their patient population is success for us.”

	According to Kremidas, one of the biggest bottlenecks, even with good performing sites, is access to patients. “The hyperCORE and Javara models will offer better access to patients, a more streamlined operational business model, and improved efficiency and effectiveness,” he says. “This will produce better quality data and help trials be done more quickly. That, in turn, leads to new therapies for patients, which is the ultimate goal.”

	Turning physician clinics into trial sites

	Helping healthcare practices bring therapies to patients is the goal at Elligo Health Research. This healthcare-enabling research organization provides technology, infrastructure, processes, and study coordinators to specialty physician practices. In turn, physicians can offer clinical trials to patients. “The patients are participating in clinical trials with their trusted physician at a location they are used to visiting,” explains John Potthoff, PhD, CEO of Elligo.

	Elligo creates partnerships with its physician clients, such as Austin Area Obstetrics, Gynecology and Fertility, which was interested in offering an oral alternative to surgery for treating endometriosis. The physicians had tried to conduct clinical studies, but found it challenging to balance their regular patients with the added commitment of leading a study at a standalone research center. Additionally, patients were reluctant to travel consistently to an unfamiliar location.

	Ultimately, Austin Area Obstetrics, Gynecology and Fertility chose to work with Elligo to conduct a Phase II double-blind trial of the oral endometriosis treatment. Elligo study managers joined the full-time physician staff and handled all aspects of clinical trial management. And, using the clinic’s EHRs, the Elligo staff identified patients that would benefit from participating in the endometriosis trial.

	“We embed into their practices so it’s a seamless integration,” says Potthoff. “We follow their processes and procedures and adapt our infrastructure to the way they practice medicine. We do a custom implementation that allows us to work alongside and enable them to provide clinical research as a treatment option for their patients.”

	Eight months after trial commencement, Austin Area Obstetrics, Gynecology and Fertility became the highest screening and enrolling site on this study in the U.S., says Potthoff. Coming off the success of the endometriosis study, the practice added three trials in its office.

	For it and other clinics with whom Elligo partners, Potthoff says the benefit of Elligo is giving its partners more access to resources than any one individual practice may have to do a clinical trial. Elligo brings the research into the clinic, including staffing, technology, basic infrastructure, and supplies, without the physicians needing to invest their own clinic’s dollars into the research program. Potthoff says that is typically the number one deterrent against physicians conducting their own research within their clinics.

	“Many don’t have the capital or bandwidth to put together the infrastructure to participate in clinical trials,” he says. “Partnering with Elligo allows them to be focused on healthcare and clinical delivery of services to patients. It’s a low-risk opportunity for them.”

	A framework for staff and workflow process standardization

	The pharma industry does recognize that the performance quality of sites varies dramatically. Kremidas believes the root cause of this variance is a lack of consistency in how staff-including principal investigators (PIs) and study coordinators-at investigator sites are screened, hired, trained, and validated for their competency.

	“This is a major problem in the industry right now,” he says. “Many of these people are dropped into their positions and are expected to learn on the job. Site performance comes down to people and if the wrong people are in the job, the site will not perform well.” Kremidas says it’s critical that the industry comes together and determines what it wants in terms of staffing, hiring qualifications, training, career development, and validation that site staff is indeed performing well.

	In an effort to establish consensus on these topics, ACRP created a multi-stakeholder Workforce Innovation Steering Committee (WISC), which includes sponsors, CROs, site networks, academic sites, regulatory folks, and technology vendors. Together, they developed a Core Competency Framework (based on the work of the Multi-Regional Clinical Trials Joint Task Force out of Harvard and Bringham Women’s Hospital) that defines every role at investigator sites. The committee has also created hiring guidelines for study coordinators that provide a framework for defining various competency levels for those executing protocols.

	Both Javara and most of hyperCORE’s members are using the ACRP Core Competency Framework. “We utilize the core competencies as part of our performance evaluation process and incorporated some of the key areas of job responsibility related to the clinical trial navigator job description, which we use when assessing and interviewing potential new CTNs,” says Susan Donahue, director of operations for Javara. “The benefits to Javara is a workforce that is being molded and trained with uniformity and aligns with industry-wide competencies and proficiencies.” She adds that the ACRP Core Competency Framework provides a foundation, but Javara has created a highly bespoke training experience specific to its team that focuses on customer service training to elevate the patient, healthcare provider (investigator), and pharma/CRO client experience.  

	Like site networks, academic research institutions have evolved. This has placed demands on the academic clinical research workforce, as people are being asked to take on increasingly diverse and sophisticated tasks. As new responsibilities emerged, existing jobs needed to be redefined. This resulted in a work environment that was frustrating, unfair, and inefficient in the eyes of workers and leadership.

 In response, some academic research sites turned to ACRP’s Core Competency Framework to standardize workflow processes, how they staff clinical research studies, and how they define staff roles.

	One of these institutions is Duke University School of Medicine. Four years ago, Duke set out to modernize its clinical research landscape. Denise Snyder, associate dean for clinical research in the Duke School of Medicine, says Duke used to have 80 job classifications, and job titles were selected based on salary. “I knew we needed uniformity,” she says. “We couldn’t define accountability and responsibility without consistent job classifications.”

	Duke’s Workforce Engagement and Resilience group utilized the work of the Joint Task Force for Clinical Trial Competency (JTFCTC) to create a framework for clinical research jobs at Duke. The competencies are used as the foundation to help managers select titles for new positions, and provide professional development and career advancement opportunities. Duke ultimately reduced its job classifications from 80 to 12 based on competencies. Employees have consistent job classifications and responsibilities, as well as a clear path to advancement. The university is projected to save millions in costs through the ability to retain excelling employees and operate more efficiently.

	“The clinical research profession has been standardized across the institution,” says Snyder. “This reduces organizational turbulence and creates opportunities for staff to grow their careers in a transparent, competency-based system.”

	With its clinical research team’s competencies now established, Snyder says the next step is to help the workforce think about clinical research workflow from beginning to end. This requires identifying the touch points that may slow things down and working closely with its IT partners to streamline the workflow. An OnCore clinical research (trial) management system tracks data and helps establish the workflow.

	“It is important for academic research sites to strategize, plan, and implement standardized workflows for clinical research programs if they are interested in continuing to conduct and manage clinical research programs or to even enter into clinical research,” says Chambers. 

	Vanderbilt also recognizes the importance of workflow standardization to support project managers, research nurses, and research coordinators. Teams use custom software to automate the workflow, internally audit processes, provide suggestions to leadership based on findings, and identify a central point person accountable for all aspects of study setup and ongoing regulatory oversight. Additionally, new software installations support detailed time tracking and effort reporting, dynamic project management, and the ability to design mobile applications, dashboards, and work queues.

	“These new technologies have empowered us to operate more efficiently and gain business insights that would not be possible through an off-the-shelf, standard clinical trial management system,” says Bree Burks, senior director, Vanderbilt Coordinating Center, Vanderbilt Institute for Clinical and Translational Research.

	Standardizing processes has led to an extended career ladder for Vanderbilt’s more experienced research staff. Burks explains that this ladder begins by serving in more of a supportive role where entry level staff are tasked with work from lead research coordinators and nurses based on their current level of knowledge and abilities. When ready, support staff then serve as the independent coordinator for clinical research studies. “We have further identified tiers of studies based on complexity of the work,” she says. “Studies are considered basic if they do not require our coordinators to interface with a patient’s clinical care team, are considered routine if the study requires the coordinator to partner with the clinical team in order to drive clinical care in a way that is not critical to the patient’s treatment plan, and are considered complex if the study requirements are a critical part of the patient’s care plan.” 

	Once research coordinators have independently managed a complex study, they have the option to transition into one of five different career tracks: CRNs; business intelligence and informatics; personnel management; auditing, compliance and education; and investigator- initiated trials. “These career tracks allow us to offer more advancement for our staff, and have increased job satisfaction as employees can spend more time focusing on their individual passions and strengths,” says Burks. 

Kremidas says that Duke and Vanderbilt are among a handful of academic institutions that are leading the charge in workflow process standardization. “We are trying to help them get the word out about how effective this is so other academic research centers can do the same.”

	Hybrid studies bring sites into the virtual world

	Technology company VirTrial, which focuses on facilitating a hybrid approach to clinical trials by combining in-person and remote visits, is partnering with members of ACRP and the Society for Clinical Research Sites to spread the word about the value of telemedicine-and help VirTrial carve out a niche in clinical research.

	“We are collaborating to offer all of their members free training on the VirTrial platform as well as training on telemedicine etiquette,” says Amanda Rangel, vice president of business development, VirTrial. “Participating sites will become certified as a virtual trial-capable site and can market themselves as such. Similarly, participating clinicians and site staff can complete the training and become individually certified as virtual-trial capable. Our hope is that we can introduce this slow-paced industry to telemedicine as their first step into the virtual world and eventually get them to add more complex technologies such as wearables.”

	Rangel acknowledges sponsors have some hesitations adopting telemedicine because there is no standard protocol that would allow patients this flexible option and there is no quantifiable return on investment. “It’s a risk-adverse industry,” she says. “And when you ask the industry to spend money upfront on patient-centric solutions, they want to know their savings on the back end. We can show well-vetted estimations, but can’t show them proven data yet.”

	What she can show them is how the VirTrial platform works. Rangel explains that VirTrial purchased a platform from virtual care company Synzi, which is used currently at 1,700 hospitals, and customized it for clinical research (Full disclosure: VirTrial CEO Mark Hanley sat on the Synzi board and was already familiar with the platform). The platform has a secure environment for sharing videos, bidirectional text messaging, and emails between sites and patients, whereby patients can ask questions and study teams can send automated reminders to patients to take their study medication. The platform can be used on any device, including patients’ personal devices. Best suited for Phase III and IV studies and rare diseases, the goal is to reduce the number of times a patient has to visit a clinic. In fact, VirTrial’s vision is to replace about 25-40% of standard clinical trial visits with virtual visits to create hybrid studies.

	“Our vision is not to replace sites,” says Rangel. “We don’t want 100% virtual trials because we know the intrinsic value of having patients develop a relationship with a study coordinator. VirTrial is a tool that helps sites remain sustainable and competitive in this new virtual world.”

	Clinical research is a competitive business

	Staying competitive is crucial in the virtual and real worlds. “Historically, the site enterprise has been a cottage industry, like healthcare in general,” says Kremidas. “Today, improved efficiencies are required to manage the site business in an effort to offer a full spectrum of offerings.”

	Burks agrees: “Recent changes within the healthcare market have forced academic medical centers to manage their clinical research portfolio like a self-sustaining business. Although discovery has been a long-time part of our mission, only recently have we had to identify the true cost of discovery and proactively plan for and manage it independently.”

	She adds that tighter budgets gave way to consolidation and centralization, with the challenge of continuing to foster unique clinical expertise where necessary. “Not everything is a ‘widget’ that can be easily managed centrally across our medical centers to increase efficiency and drive down costs,” says Burks. “However, many administrative functions (such as financial planning and management, regulatory support, data abstraction, and informatics support) can be effectively standardized.”  

	Currently, Vanderbilt offers an array of options for its clinical research investigators. The Vanderbilt Coordinating Center provides support to investigators for all levels of clinical and translational projects. Its fee-for-service model means investigators only pay for the resources required to support their study. “This provides flexibility in that investigators do not have to pay for full-time staff to support a new study unless full-time effort is required,” says Burks. “This flexible model also allows well-funded investigators the opportunity to build up and manage their own coordinator (or team of research coordinators) that can provide dedicated support for their specialized area.”   

	Overall, Burks believes that the changes made at Vanderbilt have allowed the academic research institution to remain competitive with smaller, private clinical research sites. “This enables patients to be treated in a clinical trial with the support and active involvement of their physician and multidisciplinary healthcare team,” she says. “Although we previously struggled with providing competitive turnaround times and consistency in communication and staff, we are dedicated to the mission of research and innovation. We recognize we have a unique ability to leverage our rare expertise in an effort to continue to provide our patients with unmatched treatment options.”

	Snyder also believes there is always more work to be done. “We’ve come a long way, but we have a long way to go,” she says. “For instance, we still need to think about site quality. We have the right people, the right systems, and better processes but we have to continue to chip away at all these things to improve the quality of the research coming out of Duke’s School of Medicine. We want to attract sponsors. It takes a cultural shift to accomplish quality research. And if we deliver more quality, not quantity, then we will change care because clinical research changes care.”

		Ken Getz, ACRP 2019, The State of the Industry, Nashville, TN, April 12-15, 2019.

		Duke’s sweeping overhaul of clinical research is paying off. Duke Clinical & Translational Science Institute. Published online June 10,  2019, 

https://ctsi.duke.edu/news/dukes-sweeping-overhaul-clinical-research-paying

Exploring how clinical research sites are redefining their business models to be more flexible, collaborative, and customized.   

Cindy H. Dubin

Articles

How Do Regulatory Intelligence and Operations Envision Technology?

The Changing Landscape for Clinical Trial Sites