Precaution continues to dominate EU thinking on science and technology–with politics intervening to offer some intriguing impacts on human health. Amid the heated COVID-driven controversies over vaccination that are ruffling Europe, a specialized European advisory group on ethics has just issued a cautious opinion on the use of gene editing–including a call for a global guarantee that heritable human genome editing is not prematurely clinically applied. In addition to the intrinsic interest of the subject and of the opinion the group presents, the views it expresses offer an interesting comparison to–or contrast with–the apparently haphazard decisions by EU countries over recent weeks in respect of the AstraZeneca vaccine against COVID.

The European Group on Ethics in Science and New Technologies (EGE) is tasked with advising the European Commission with “high quality, independent advice on all aspects of EU legislation and policies, where ethical, societal and fundamental rights issues intersect with the development of science and new technologies.” In a 

new and broad-ranging opinion on genome editing

, the group urges a degree of caution–notably that this technology should not be applied “for purposes other than against serious diseases that cannot be prevented or treated otherwise.” And it stresses the need for safeguards against enhancement or de-enhancement of traits, and to ensure that investments in research on germline genome editing have the purpose of protecting health. But at the same time, the opinion acknowledges that somatic genome editing has the potential to alleviate suffering from diseases that could not be treated effectively before, and recommends pursuing its use, along with providing access to clinical studies and clinical application in healthcare.

Particularly striking is the treatment of expertise in the opinion. This, it says, is vital to “ensure adequate competencies in expert bodies.” As it observes, genome editing technologies are evolving quickly and expertise to assess research and application has to keep pace with new developments, so it is important to widen the basis of expertise and broaden what counts as relevant knowledge at the level of expert committees, fora and other bodies established to examine and set guidelines and standards for research and application of genome editing technologies. It extends the advice to providing due guidance for ethics committees charged with approving and supervising clinical trials involving genome editing, covering safety assessments and risk/benefit determinations of clinical trials are developed, along with training modules for research ethics committees and other involved bodies “to ensure high-standing and consistent application of ethical standards.”

With a view to promoting broad alignment, the group has asked the European Commission to engage in global discussions on regulation of this emerging field with the World Health Organization and the World Medical Association, covering universal adoption of standards on the ethical use of genome editing in human beings. And within Europe it wants to see the creation of a specifically European platform to exchange information and promote “a broad and open public debate” on the ethical and social implications of germline genome editing in human beings. It stresses that this will require a “basis of sound and evidence-based information,” and a heightened awareness of the implications of widely used terminologies and distinctions such as somatic and germline editing, or prevention, therapy and enhancement.

What might the group have said if it had been asked to give an opinion on the EU’s recent performance in the use of vaccines–and specifically, the AstraZeneca vaccine? Not the squabbles between the UK and the EU (and even within the EU!) on delivery, which are almost too unseemly to merit attention here, but on the more sensitive area of efficacy and safety judgments concerning innovations. From the outset, there was disunity among the member states about whether, in the absence of trial data from the elderly, the vaccine should be given to older people–with France, notably, withholding it from those over 75 years of age. But then anecdotal reports of blood abnormalities among a handful of recipients sent national authorities in the EU into paroxysms of incoherent indecision, destroying any semblance of EU alignment on evidence-based decision-making, as some countries suspended use of the product pending the outcome of a European Medicines Agency (EMA) review of the case reports, others imposed some limitations relating to age, and others carried on with administration regardless. And when EMA delivered an interim clearance of the product, many countries still refused to use it.

The picture was of politics replacing evidence-based decision-making, as governments responded to public (and often ill-informed) anxiety rather than to scientific evaluation. The summit of incoherence was reached when member states subsequently reverted to following expert advice: governments that had ignored the advice of the EMA and suspended the use of the AstraZeneca vaccine then reinstated its use–in line with the advice from the same institution. It was another example of action driven by a European tendency to bow to uninformed public opinion, playing safe politically rather than scientifically. It epitomized a question that has assumed growing importance over the last 50 years: how to take account of public sentiment while science itself evolves. The exploitation of gene technology in food and agriculture from the 1980s has manifestly been impaired in Europe by public concerns, not always on the basis of a good understanding of the subject. A similar cloud already hangs over the development of nanotechnology. The debates have often not been edifying, since they have frequently relied on acute emotion rather than on accurate information. And the risks from widespread misinformation and even from conspiracy-driven dis-information are currently crystallizing conspicuously in vaccine hesitancy and frank anti-vaccination movements, frequently linked to the relative novelty of
mRNA vaccines.

The disarray among national governments in Europe will have done nothing to inspire confidence either in science in general, or in Europe’s regulatory institutions–and least of all, confidence in vaccines. Governments’ knee-jerk responses to lurid headlines, with the principal aim of avoiding blame if things go wrong, do not constitute a noble strategy in times of crisis. Defensive appeals to that “precautionary principle” beloved of many European policymakers are not necessarily the right approach to public debate on the relative risks and benefits of alternative courses of action. The advice of the EGE about ensuring “a broad and open public debate” on the “basis of sound and evidence-based information” might be a better guide. And above all, for those utterly obsessed with the precautionary principle, it should have been evident that seeking to protect the public from a minimal risk of vaccine side effects would in any case expose people to an even greater risk–of contracting a serious disease that has already killed hundreds of thousands across Europe.

 is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium

Articles

View from Brussels

European Group on Ethics in Science and New Technologies issues cautious opinion on the use of gene editing amidst COVID vaccination controversy.

Europe's Eternal Struggle with Safety and Innovation

, “Technological Impact on Accelerating Vaccine Trials, Development and Delivery.” With panel members from the leading vaccine manufacturers, it offered interesting behind-the-scenes insights into how these vaccines went through the development process with flying colors.

Marie-Perre Hellio Le Graverand, SVP, head of clinical development and operations from Pfizer, brought the numbers—266 days from the announcement of the pandemic to first EUA; 44,000 enrolled participants; four months to enroll; and 150 sites in six countries; with over 50 million electronic diaries; 7.5 million data management records and 34 million total data points.

To paraphrase Hellio Le Graverand, this was only possible because of digital technologies. The volume and speed of data they managed in real time, all the while maintaining quality, was totally unprecedented.

Similarly, Janssen’s trial included 45,000 participants. Terry Murphy, the company’s COVID-19 clinical development relaunch leader, said they recruited 3,000 patients in one day alone.

Again, unprecedented. But not unpredictable. The two core technologies that pharma and CROs used were predictive analytics and dashboards.

Rachel Berria, VP and medical head of AstraZeneca (US), said that predictive analytics and data from a variety of sources to heat-map where COVID was going, to open up sites in those areas and enroll patients accordingly, was key to the speed.

All of the participants noted that the immediacy and transparency of the dashboards coming from internal and external data sources, allowed for quick decisions, fostering improved trial conduct and data quality. These examples included: applying new strategies to enrollment; shifting focus for diverse populations; and providing site support.

Tal Zaks, chief medical officer for Moderna, concedes that while the company is built from the ground with a digital infrastructure, the tools for collaboration that exist today would have been challenging five to 10 years ago. “As a small biotechnology company that is highly leveraging CRO partners, that was really a key enabler. Where we lack the infrastructure, technology has enabled us to tap into the infrastructure of our CROs partners to achieve what we have.”

But outside of technology, the one factor that helped the unprecedented speed is what Berria pointed to, the rolling regulatory review process...which wouldn’t have been possible without data provided to regulators on an ongoing basis. Technology and science for the win.

 is Editor-in-Chief of Applied Clinical Trials. She can be reached at 

From the Editor

Behind-the-scenes look at vaccine development.

How Did Clinical Trials Move at the Speed of COVID?

Issue PDF

Click the title above for a link to open the Applied Clinical Trials April 2021 issue in an interactive PDF format.

Applied Clinical Trials April 2021 Issue (PDF)

The challenges of finding a large, representative patient sample for a study remain the biggest in drug and vaccine development. Identifying patient candidates via electronic health records (EHRs) has become increasingly powerful. However, complex study protocols, strict patient definitions, along with the mandatory sample size often require investigators to look for patients outside of the healthcare provider system to complete the study on time. A combination of real-world data (RWD) sources can be used to identify proxy measures enabling outreach for a study without jeopardizing privacy rules or directly targeting individuals.

The growing availability of RWD, including EHR, claims, disease registries, and device-collected health data, alongside new data science techniques to combine, protect, and share health data, have led to multiple applications in the new drug development process and in the management of a drug’s lifecycle. For example, in clinical research and operations, RWD is used to validate hypothesis, write clinical development plans, support study design, validate study protocols, and obtain information on study feasibility. This synopsis is focused on applying RWD on patient recruitment for a clinical study.

EHR adoption in clinical care has become more prevalent globally. EHR systems are also an integral part of clinical research. Systematic enhancements enable investigators to search for patients matching the study criteria. The federated EHR (FEHR) research model, developed within the European Innovative Medicine Initiative (IMI; EHR4CR project 2011-2016), provides trustworthy, real-time services via de-identified, aggregated EHR data from a growing network of healthcare organizations (HCO). The FEHR model provides a new level of HCO engagement since the data remains where it was created and in full control by the individual HCOs in the network.

Investigators using the FEHR model can mine the data and identify patients beyond their own clinic to others within the network. To help investigators go beyond the source of patients already known by HCOs, one complementary option is RWD-driven digital advertising to reach suitable study candidates. Whereas traditional digital advertising often results in burdensome screening activities for sites, RWD-driven digital outreach allows for enhanced targeting of suitable and motivated leads that can be referred to sites. This combination of FEHR technology and RWD-driven advertising offers synergies to boost the capability of finding and recruiting patients.

Accessing a growing RWD ecosystem, including consumer and behavioral data, and applying new data science techniques to protect, connect, and securely exchange matching data records, provides sponsors and researchers innovative ways of depicting a holistic patient view beyond clinical profiles found in an EHR system. Researchers can now isolate representative clinical cohorts using EHRs followed by a smart modeling technique matching the clinical cohort with predictable consumer markers, resulting in an expanded “look-a-like” pool of potential trial participants. The enlarged audience can be transitioned through a multiple-step matching approach using self-assessment questionnaires, healthcare professional interviews, and structured data matching against a patient’s medical record retrieved digitally.

The ability to model a suitable cohort using RWD and safely connect, qualify, and scale with measurable outcomes is a critical step forward in further improving the precision of isolating the right audience for a trial. Access to a large number of patients combined with smart-matching techniques are means for researchers to ensure a diverse study population and allow for a more strategic approach to clinical study management. Additionally, it represents a new way of connecting the general public with opportunities to learn and engage in clinical research as one option of care. This approach is particularly attractive for sponsors and CROs using virtual sites and conducting decentralized studies since it requires global reach of prospective subjects without borders.

Director, Health Informatics, Data Science & Artificial Intelligence, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden, 

Assoc. Prof., Carlanderska Hospital, Gothenburg, Sweden, 

Assoc. Prof., Chief Strategy Officer, Trialbee AB, Malmö, Sweden

A Closing Thought

Growing availability of RWD leads new drug development process.

Using Real-World Data in Patient Recruitment

The COVID-19 pandemic has been credited with exposing longstanding challenges in clinical trials,

 including the perpetually inefficient site feasibility process. Finally, this critical step is receiving the attention it deserves, maybe even an overhaul, as the wave of clinical trial decentralization surges on. This effort involves re-thinking the kinds of questions to ask in feasibility questionnaires, now that sites have reopened, and are coping with unprecedented numbers of remote study visits, and increased reliance on digital tools.

Determining a site’s digital readiness is essential, as the pandemic seems to have created the opportunity for access to a broader range of patients, beyond those who live near a site, to include those in rural or in lower income areas, allowing sponsors to meet diversity and geographic targets. Complementing this trend is the growing use of investigator digital platforms designed to eliminate the repetitive nature and drudgery associated with site feasibility.But according to Jeffrey Kingsley, founder and CEO of IACT Health in Columbus, Georgia, there is still a long way to go. “So far, few sponsors and contract research organizations (CROs) are leveraging their databases to eliminate a lot of the questions we get all the time. For example, we are still constantly asked, ‘Do you have a freezer?’ We get this question even from companies we’ve done many clinical trials for. Fortunately, since COVID, this is slowly starting to change,” he explains.

To explore the changes happening to the site feasibility process, 

 interviewed several experts in this field, representing a site, investigator platforms, and vendors. They offer decades of experience and insight into pre- and current COVID efforts to revamp this pivotal first step in increasing the likelihood of a successful trial.

Site feasibility starts by understanding the responsibilities of sponsors and investigators as defined in the International Conference of Harmonisation-Good Clinical Practice (ICH-GCP) Guidelines,

 Notably, these guidelines explain what a qualified investigator is, and the requirement of sponsors to select those investigators to carry out a clinical trial in accordance with a protocol. With this regulatory foundation, the site feasibility process involves choosing sites that not only conform to these requirements, but can also offer the best fit for specific studies, based on past performance, access to a database of appropriate patients, and the bandwidth to perform the study at hand. And with the shift toward decentralized clinical trials (DCTs) or hybrid versions, assessing a site’s familiarity with technology is being added to the process.

It all sounds so simple, but in practice, site feasibility has long been awkward and slow, and often more about checking boxes than turning to sophisticated databases and cloud-based solutions that could eliminate much of the redundancy.

 Today’s thinking suggests that if less time were devoted to repeatedly asking the same questions, more time would be freed up to build relationships and improve communication with sites that have a proven track record in various therapeutic areas.

A recent article by Kurbegov et al. of the American Society of Cancer Oncology (ASCO) describes a Task Force that was convened to evaluate the burdens and challenges of site feasibility, which often lead to delayed study start-up and act as a barrier to site participation.

 With input from sites, sponsors, and CROs in the form of surveys and in-person meetings, the Task Force developed three recommendations for improvement, with a goal of speeding patient access to clinical trial participation, and ultimately, much needed new treatments, as shown in Table 1 below. The third recommendation—leveraging technology to centralize the feasibility assessment—is a nod to performing as much of this process as possible by teleconference due to the pandemic.

The site survey found that the 103 site respondents spent a median of 264 hours annually completing feasibility assessments, with all sites spending a combined 27,192 hours, at a conservatively estimated cost exceeding $1 million for input from the study coordinators alone. Importantly, the stakeholders agreed that standardization will reduce burdens associated with site feasibility, and most thought that sponsors and CROs should use the same set of standardized questions for this process, except for those linked to specific protocols.

These findings align with work from Alliance for Clinical Research Excellence and Safety (ACRES). The organization launched a Site Accreditation & Standards Initiative in 2013, with a goal of addressing the inefficiencies in the clinical trials process, and the lack of uniform standards.

 ACRES promoted the idea that without an accepted, consistent set of standards and accompanying metrics, it is impossible to compare performance across sites, a factor that is critical to site selection. In 2018, ACRES, in collaboration with the British Standards Institution, published its principles for developing standards in 

 with an eye toward site accreditation, and the importance of viewing high performing sites as a critical resource.

At first glance, the changes spawned by the pandemic seem mostly focused on adding questions to the feasibility questionnaire about the status of technology adoption, and whether potential patients are able to participate in televisits, or use apps for patient reported outcomes (ePRO) or eConsent. A closer look, however, reveals those questions as a first step toward using the site feasibility process to expand the geographic area of patients available for study participation.

Mary Costello, head of Site Investigator Network at Medable, a provider of a DCT platform, describes the kinds of pre-qualifying technology questions to be asked for achieving this goal. “These questions might include asking if they have a patient database that tracks details, such as whether patients have smartphones. Do the patients have reliable high-speed internet? If they aren’t comfortable with technology, do they live with someone who can help them log on? We’re in a new era, and you don’t want to leave this information to chance. Successful feasibility is becoming more about anticipating and planning. Anyone who is getting ahead of these questions has a competitive advantage,”
Costello mentions.

She adds further that the pandemic has provided sites with a unique opportunity to expand their outreach beyond patients who live close to a site. “This is a turning point for the industry. Sites have existed on single digit margins for years, and have been limited to a drivable catchment area. Now, a patient might do a one to two-hour drive to an appointment if the rest of the visits can mostly be done remotely. I would suggest enhancing marketing efforts to broader, more diverse communities, as DCT imagines that we can bring in a whole new crop of clinical trial participants,” explains Costello.

Similarly, Diane Carozza, VP, clinical strategic solutions, study planning & site optimization at WCG, comments on how for the first time, site feasibility strategies are having to consider ethnic diversity and inclusiveness for patient recruitment. “We’re on the cusp of a big shift in diversity inclusion that the pandemic is fueling. It’s turning into something that isn’t just a ‘nice to have’. The FDA is calling out sponsors who are submitting applications for indications that have proven epidemiological prevalence data that certain ethnicities have a higher prevalence than others. Carozza explains they are asking, “What are you doing from the beginning to ensure that you include those groups in your trial?”

Attempts to improve site feasibility efficiency have been underway for several years among a handful of organizations, as shown in Table 2 below. Generally, uptake of these efforts was slow,

One of the most visible initiatives is the Shared Investigator Platform (SIP), which was created by TransCelerate BioPharma as an industry-wide solution to the problem of sites having to learn, access, and maintain excessive numbers of portals. SIP was designed with and for sites so they would have a centralized platform for providing information that would be available to multiple sponsors, and would eliminate the burden of repeated duplication of responses. In 2019, TransCelerate considered their SIP project to have met its initial objective, and as originally agreed, ownership of the platform and the intellectual property transitioned to Cognizant. Since then, the company has made significant progress towards establishing SIP as a core platform for clinical operations teams.

Larissa Comis, product owner of the SIP at Cognizant, explains that with the permanent changes to clinical trials brought on by the pandemic, sponsors are keenly interested in sites’ technological abilities to enable virtual collaboration and communication through SIP. As evidence, platform use has grown substantially in the past year, as shown in Chart 1 below. According to Comis, “We now have 146,000 users of SIP, which represents 125,000 site researchers. The rest are sponsors, including 21,000 study teams. SIP is used in 98 countries, in about 25,500 different locations.”

Comis explains that Cognizant was already seeing an uptick in adoption before the pandemic that extended into the early months of 2020. “What was interesting was that other than the first few weeks of the lockdown in March 2020, we did not see a huge fallout of adoption, which amazed us. We were expecting the activity to significantly drop, but it picked right back up really quickly. Now, we see 2021 as totally taking off on the site side and on the sponsor side. We attribute this to the growing use of decentralized clinical trials,” she says.

Jeffrey Kingsley explains that IACT Health is part of an investigator platform through hyperCORE International, a legal partnership of 10 high performing companies. IACT is a founding partner of hyperCORE, which started in 2019, and has evolved into a large, global clinical research site organization with more than 90 sites. To improve efficiency in site feasibility, all of the companies are mandated to use Devana Solutions, a site feasibility technology built on the Salesforce platform. Devana can instantly display and report trial performance metrics on all historic and currently running studies captured in the system. Kingsley remarks, “Within that software, we know everyone’s performance on specific types of trials, and with that transparency of the data, sponsors and CROs can easily see the best sites for their studies.”

Looking forward, Kingsley comments, “It’s about data, data, data.My wish for the industry is that we use data to eliminate all of the waste in the feasibility process. Stop wasting our time asking if we have a freezer. Let’s take steps to address all of the barriers from the site side, such as listening to our input as to how protocol design will impact recruitment and enrollment.”

To secure overall improvement to site feasibility in the long term, stakeholders are focusing on asking the right questions once, rather than repeatedly, all in an effort to speed the finding of the right sites with the right patients and digital readiness for DCTs. Technologies such as electronic health records, internal databases, and investigator platforms will be key as sites use this opportunity to meet enrollment goals by expanding their outreach to patients in underserved and more distant communities.

Henderson L. COVID Exposes the Cracks in Trial Problems. 

https://www.appliedclinicaltrialsonline.com/view/covid-exposes-the-cracks-in-trial-problems

Cotliar J. How a Pandemic Accelerated the Adoption of Virtual Trials. 

https://globalforum.diaglobal.org/issue/may-2020/how-a-pandemic-accelerated-the-adoption-of-virtual-trials/

ICH Harmonised Guideline: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice ICH E6(R2). International Conference on Harmonisation. Available at: 

https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf

Code of Federal Regulations. Subpart D—

Responsibilities of Sponsors and Investigators Electronic Code of Federal Regulations

. Section 312. March 2021. Available at: 

https://ecfr.federalregister.gov/current/title-21/chapter-I/subchapter-D/part-312

Barrett J. Choosing The Right Solution: Improving the Clinical Trial Site Feasibility Process. 

https://www.pharmavoice.com/wp-content/uploads/wp-WCG-03122019.pdf?tracker

Kurbegov D, Hurley P, Waterhouse D, et al. Recommendations to Streamline and Standardize Clinical Trial Site Feasibility Assessments: An ASCO Research Statement.

https://ascopubs.org/doi/full/10.1200/OP.20.00821

Site Accreditation & Standards Initiative (SASI). 

Alliance for Clinical Research Excellence and Safety (ACRES)

http://www.acresglobal.net/about-us/initiatives/site-accreditation-and-standards-initiative-sasi/

Koski G, Kennedy L, Tobin MF, et al. Accreditation of Clinical Research Sites—Moving Forward. 

MBA, President, Medical deScriptions, LLC

Feature Articles

How asking better questions and leveraging site databases can expand access to more patients.

Revamping Site Feasibility as Trials Become Decentralized

The remarkable speed in which sponsors have developed and delivered COVID-19 vaccines and treatments has intensified an already high interest among sponsor companies in compressing drug development cycle times. And there are numerous targeted opportunities in their sights—from protocol design and vendor and site identification to study start-up and patient enrollment; from clinical data management and study closeout through statistical analyses and dossier preparation.

Until recently, however, efforts to target and achieve speed and efficiency have focused on tasks and timelines within clinical phases. Now, more attention is being devoted to the breakdowns that occur between phases when clinical data and operations transition from one research phase to the next. These transitions—also referred to as “white space”—may be ideal targets for information technology, open collaboration, augmented analytics, and machine learning to accelerate program durations, improve performance, and lower costs.

Over the years many sponsor companies—some with assistance from consulting firms and contract research organization (CRO) partners—have measured the white space between their programs’ clinical phases. Regrettably, the results of, and insights from, these exercises have neither been shared publicly nor published.

Recently, my group at the Tufts Center for the Study of Drug Development (Tufts CSDD) was able to conduct a robust analysis based on all drugs and biologics approved between 2008 and 2018 (n=377). Although the transition time between Phase I and II could not be reliably measured due to wide variation in early-stage activity supporting development programs, we were able to measure transition times between the completion of Phase II and the start of Phase III pivotal trials. In our analysis, Tufts CSDD only looked at non-expedited review programs to remove the effects of an accelerated regulatory process.

Tufts CSDD found that for all non-expedited development programs approved between 2008 and 2018, 82% had between-phase transitions (white space) of 17 months on average; 18% had no white space as Phase II completion and Phase III pivotal trial timelines overlapped. Our study also found that white space durations have increased during the past decade. During 2008 to 2013, the mean white space duration was 12 months; between 2014 and 2018, the mean white space duration between Phase II and III pivotal trials nearly doubled to 21.6 months.

To supplement our data analysis, Tufts CSDD interviewed clinical operations, regulatory, and data management executives. The sponsors interviewed widely agree that white space inefficiencies have represented a persistent challenge for decades and that attempts to compress phase transition time have been elusive.

They point to four primary causes of between-phase inefficiencies:

The time-consuming back and forth with regulators and health authorities.

Mistakes sponsors make in gathering inappropriate and incomplete inputs into decision-making late in the process.

The failure to anticipate downstream needs (e.g., manufacturing of clinical trial supplies).

The inability to build the appropriate level of internal consensus and alignment around key decisions.

Most companies acknowledge that they expend substantial resources and time in administrative activity preparing, submitting, and sharing results with regulatory authorities. They also note the inefficient and time-intensive internal process, and post-regulatory meeting, of finalizing the Phase III pivotal trial protocol. One sponsor estimated that they spend on average four to five months of time on this back-and-forth alone.

White space durations are extended during protocol planning when external inputs—from scientific leaders, regulatory agencies, and health authorities—are insufficient, incomplete, and require second-guessing. Misunderstanding of global regulatory environments and the uncertainty around reconciling multiple and diverse scientific and regulatory inputs contribute significant time inefficiencies and delays.

Several executives interviewed believe that to mitigate risk, sponsor companies seek more-than-necessary input from, and spend too much time on relationships with, regulatory agencies during phase transitions.

Sponsor companies also suggest that whereas they generally know their program’s objectives extremely well, they fail to obtain the necessary inputs and insights from Phase II data to optimize critical Phase III decisions. Several sponsors note, for example, the critical and often inadequate role that Phase II data plays in informing primary Phase III endpoint(s), dose-finding, and dose-selection decisions. One executive observed that the failure to properly interrogate and leverage Phase II data is a common problem that ultimately forces sponsors to amend and expand later-stage clinical trial activity to make up for these shortcomings. She suggested that more flexible and adaptive designs may play an important role here.

Many of the executives interviewed suggest that despite the high volume of data collected during Phase II clinical trials, white space inefficiencies are partially caused by collecting the wrong—or an insufficient amount of the right—Phase II data.

Most sponsors note the opportunity to shorten white space by anticipating where problems will occur, developing contingency plans, and responding proactively. Doing so permits companies to make faster decisions and cues up organizational resources to handle situations as they unfold.

Several interviewees, for example, mention the importance of anticipating and coordinating ethics committees and boards of health dispersed widely around the globe. Some acknowledge the importance of planning the commercial formulation of the investigational drug or biologics before initiating later-stage pivotal trials. As one sponsor explained:

“It’s essential that large, treatment-testing studies utilize a commercial formulation of a drug so there’s no question about bioequivalence. But manufacturing that formulation—especially like the complex ones that are becoming more commonplace—can take months or even years to scale up.”

Given high growth in the volume of Phase II data collected, there is wide consensus among sponsor companies that data and analytics—enhanced by artificial intelligence (AI) and open collaboration models—can play a key role in accelerating white space timelines. Another recent Tufts CSDD study found that the typical Phase II protocol generates 2.2 million data points today, up from 378,000 data points 10 years ago. This is nearly a 500% increase and the highest area of growth in data volume per protocol per phase.

Several sponsors go even further and argue that machine learning and other AI-enhanced analytics, combined with information hubs and collaboration solutions, represent a clear and essential approach to best leverage protocol data volume and limited human capacity and competency. In this vein, several months ago, 10 major pharmaceutical companies announced that they had formed a new corporation—Accumulus Synergy—to support collaboration between industry and health authorities. The new non-profit entity will utilize a cloud-based platform to compress the white space caused by the back-and-forth between sponsors and regulatory agencies. The founding companies anticipate substantial acceleration through real-time collaboration, cross-agency harmonization, data exchange, and submission.

In the transition between development phases, there is no defined timeline in which key decisions have to be made. White space inefficiencies represent a unique opportunity for sponsors to accelerate development timelines because they are a function of administrative, project management, information processing and exchange. The efficiencies between phases may be easier to achieve as they rely far more heavily on internal team expertise, collaborative effectiveness, and their interaction and exchange with regulatory authorities. Within-phase efficiency gains rely heavily on improvements in relationships with a large and growing number of external service providers—a more complex, fragmented and difficult area from which to consistently glean speed improvements.

As we imagine opportunities and solutions that are now available to accelerate drug development timelines, the possibility of compressing white space may finally be within our grasp.

Clinical Trial Insights

Compression between phases to accelerate cycle time.

Characterizing White Space in the Quest to Drive Development Speed

 for 2020/2021. Featuring statistics from the organization’s 2020 CRO Industry Global Compensation & Turnover Survey, the report provides clinical research outsourcing companies around the world with data on compensation levels and employee turnover.

For this most recent edition of the report, the main headline continues to be a high rate of employee turnover within CROs, particularly for the CRA role. As shown in Figure 1 below, the average turnover in the US for clinical monitoring from 2015 to 2019 has been consistently high. Judy Canavan, Managing Director, Global Employer Services of BDO said, “The sense that [CRAs] can own their career is important, and organizations are really not enabling employees to do that.”

One influencer of CRA turnover in the US has been compensation levels. BDO found that companies’ approaches to compensation levels have remained mostly the same the last 10 years. The salary increase budgets of CROs in the US have only been around 3% or less. “The market rates of pay have been moving more slowly than one would expect given the demand for talent,” said Canavan. “This is a problem because there’s this huge demand for talent, but on average, the pay for a CRA-level one is only going up a little bit each year.”

Unsurprisingly, CRAs view switching companies as their best career choice. “Their (CRAs) value goes up faster than their salary value if they just stay within the firm,” said Canavan.

At the same time, CROs are finding ways to combat turnover. Canavan explained that companies are creating a wide variety of retention programs which can include compensation plans and merit-based rewards. She mentioned one organization in particular created competency-based career ladders. “This gave the employees a clear, defined path upward,” she said. “The employees actually felt like they owned their careers, and they (the organization) really did document a significant drop in turnover.”

In terms of how COVID-19 has affected CRA turnover, Canavan said it is a growing concern. She explained that things settled down mid-2020, but shortly after, companies were calling her with concerns about employees suddenly leaving for higher salaries. From a BDO-sponsored poll of 15 CROs year-to-date, US turnover was over 21% as of early November 2020.

The CRA role in of itself has also been changed by the pandemic. Kimberly Ray, consultant and working group leader, ACRP, said travel bans forced the role to become more virtual; field CRAs needed to learn how to use new technologies for analyzing data electronically as well as advising site staff to ensure trial operations continued.

While turnover remains high and decentralized trials (DCTs) continue to evolve, CRAs can be confident in their own job security during the pandemic. “Whether a DCT or not, more and more technology is being leveraged in clinical research. Therefore, the CRA role will continue to be needed but it will evolve,” said Ray.

The ACRP Working Group sees the field and in-house CRA roles merging to create a position that works with sites on different levels. “CRAs will be key in helping sites embrace change and navigating this new environment,” said Ray. “They will also likely be the first call when there are technology questions or issues.”

It’s not only at the site that Ray says CRAs’ roles will change in the age of DCTs. One new role needed for DCTs is a “virtual patient guide.” The CRA in this position will be responsible for guiding the patient through a trial via a virtual platform; they are the primary point of contact for the patient.

Looking forward, while CRA turnover continues to be affected by the pandemic, there is hope that the emergence of DCTs can curb some of the contributing factors.

is an Assistant Editor for Applied Clinical Trials. He can be reached at

News

New BDO CRO Insights Report reveals high rate of CRA turnover and what organizations are doing to combat it.

Turnover for Clinical Monitoring Remains High

ACT: Why did you set-up the ACROSS Global Alliance?

 The full name is the ACROSS Global Alliance (of Contract Research Organizations (CROs) and Specialist Service Providers (SSPs)), and it was inspired by my earlier success in establishing a CRO alliance in the Asia-Pacific region in 2009. ACROSS Global was established to address what I believe is a significant gap in the pharmaceutical service provider market. There are many organizations across the globe that simply do not have the budgets to contract with the larger, global CROs. Such organizations may include small and medium size pharma, biopharma and medical device companies, as well as supra-governmental, governmental, and non-profit/private funded institutes.

These organizations may not only have limited budgets, but typically they also lack sufficient internal resources to manage multiple country or regional level service providers to deliver a single global study. ACROSS Global provides the opportunity for smaller and medium sized CROs to combine resources and contract with clients (i.e., clinical trial sponsors) to deliver regional and global projects which they would otherwise be unlikely to secure for themselves if they remained as single entities.

ACT: Is the ACROSS Global Alliance model unique?

 No. The model is based primarily on that by many of the airline industry alliances. You will no doubt be familiar with alliances such as “Star Alliance”, “One World”, and “Sky Team”, to name three of the largest. Taking Star Alliance as an example, it has more than 20 members with over 400,000 employees within its member companies. The headquarters of Star Alliance is in Frankfurt, Germany and includes only 100 employees. The goal of the Star Alliance is to facilitate travel for passengers across the globe by linking its members together to provide what may be described as a seamless global solution for both personal and business travel passengers.

ACROSS Global adopted this concept. We are not a CRO or SSP itself, but an organization that links its Partners and Qualified Vendors to provides clients with a seamless solution for global clinical trials.

ACT: Why did ACROSS Global establish Singapore as its legal entity/registered office?

 Situated in Southeast Asia, Singapore is recognized as a stabilizing force within the Asia-Pacific region and is widely regarded as being a geo-politically neutral country. Singapore is recognized as being a first world country with excellent infrastructure, sound legal system, stable government, a strong financial sector as well as having a clear focus on cutting edge technology and a burgeoning life science industry. English language is the main language of communication within the government as well as in the business sector. From the mid-1990’s Singapore’s Economic Development Board (EDB) set its goal of attracting some of the biggest pharmaceutical and service sector companies to establish their Asia-Pacific regional offices in Singapore. Furthermore, EDB’s goal included the development of a strong pharmaceutical manufacturing base. The growth of the life-sciences sector over the past 25 years means that Singapore now has one of the finest educated, well trained, and experienced workforces in Asia Pacific not to mention the world. Singapore has successfully delivered on its objectives and the life science sector is today one of the major pillars of the Singapore economy.

ACT: What is the difference between an ACROSS Global Partner and a

 As mentioned, ACROSS Global differentiates the two categories of the alliance between Partners (CROs) and Qualified Vendors (SSPs). In general, Partners are CROs, whose primary focus is the delivery of clinical operations in the geographies for which they are assigned. Each Partner has a pre-defined geography so that there is no internal competition between Partners when completing a Request for Proposal for a client. In some countries, ACROSS Global has appointed back-up Partners that can provide additional support as and when required. The Partners are therefore the core of the ACROSS Global organization. However, it is recognized that from study-to-study an array of different SSPs may be required in order to successfully deliver a specific clinical trial. For example, medical imaging, medical equipment rental, pharmacovigilance services, etc., are just a few of the specialist services that may be required in support of specific projects. For this reason, ACROSS Global has qualified a broad range of SSPs and have categorized these companies as Qualified Vendors. Together, the ACROSS Partners and Qualified Vendors can provide a broad range of services to sponsor organizations at short notice, and pre-qualification of both parties avoids unnecessary delays to study starts.

ACT: How does ACROSS Global select and qualify its Partners and Qualified Vendors?

 ACROSS Global has more than 90 countries covering 88% of the world’s population and we have a well-defined process for the on-boarding of Partners and Qualified Vendors, defined in our ACROSS Global Standards and Rules document, which is a component part of the ACROSS Global Partner Agreement or ACROSS Global
Vendor Agreement.

The process involves the completion of a detailed qualification for, similar in concept to a Request for Information form; the due diligence process performed on each applicant organization as well as on the CEO/equivalent of the applicant; and presented and discussed in Partner/Qualified Vendor Application Review Meeting conducted by the ACROSS Board
of Directors.

During this qualification meeting the ACROSS Board of Directors not only the documents and due diligence, but also discuss the potential fit of the applicant within ACROSS Global. To maintain the integrity and professionalism of ACROSS Global, as well as its existing Partners and Qualified Vendors, not all applicants are successful. To date, several applicants have been rejected.

ACT: What are some of the key features that clients should expect from working with ACROSS Global?

 ACROSS Global has one of the largest geographical footprints in the industry. We are a highly sponsor-focused organization that truly puts customer service at the forefront of all its activities. Relationships and transparency are key, both between ACROSS Global and its Partners/Qualified Vendors as well as between ACROSS Global and its clients. We contract with clients irrespective of size, as well as the size of the budget. We provide flexibility and transparency in adjusting to clients’ needs to secure mutually acceptable solutions. Operating on the successful airline industry models, overheads are kept to an absolute minimum meaning that our service fee rates are significantly less than comparable competitors offering similar global reach, whilst not compromising quality and other key deliverables.

For more information on the ACROSS Global Alliance, visit: 

Steven Bukvic, CEO of the ACROSS Global Alliance, speaks to Applied Clinical Trials about how it works to improve the clinical trial experience for smaller- and medium-sized sponsors.

Providing Greater Opportunity for Undersized CROs

Is FDA approving too many new drugs and added indications too quickly based on surrogate endpoints that fail to pan out? While patient advocates and the research community have been strong advocates of early access to treatments that demonstrate potential effectiveness for serious and life-threatening conditions that lack effective treatment, some consumer advocates and research experts believe that FDA has been lax in approving medicines with insufficient supporting data.

Now the agency is reviewing the record of its accelerated approval (AA) program following the recent withdrawals of certain key indications for several leading cancer therapies based on the failure of post-approval studies to document extended benefits of treatment. That development has raised questions about the broader FDA policy, including frequent difficulties in conducting post-approval clinical trails and the relatively few therapies that have had approvals withdrawn by the agency.

These issues will be reviewed by FDA’s Oncologic Drugs Advisory Committee at a three-day meeting on April 27-29, 2021, a notably long session to discuss several supplemental biologics license applications (sBLAs) where confirmatory trials failed to verify clinical benefit (Meeting of the Oncologic Drugs Advisory Committee Meeting Announcement, April 27–29, 2021

). The experts will assess advanced cancer indications for Roche/Genentech’s TECENTRIQ (atezolizumab), Merck’s KEYTRUDA (pembrolizumab), and Bristol-Myers Squibb’s OPDIVO (nivolumab). Since last December, these sponsors voluntarily withdraw these immunotherapies for certain indications based on failure to meet primary endpoints in confirmatory trials, as did Astra Zeneca for use of IMFINZI (durvalumab) to treat advanced bladder cancer.

These monoclonal antibodies target PD-1/PD-L1 proteins to boost immune response against cancer, raising questions about the broader efficacy of such treatment. The confirmatory studies aimed to document overall improved survival compared to standard-of-care chemotherapy, after gaining accelerated approval based on tumor response in early studies. The ODAC meeting will examine the status of efforts by Genentech, Merck and BMS to confirm additional indications for their therapies, and, in the process, will scrutinize the AA program more publicly for a range of cancer types.

The meeting is part of a broad, ongoing effort by FDA’s Oncology Center of Excellence (OCE) to review AA policies and the role of surrogate endpoints in evaluating new therapies. Sponsors are anxious to know whether the agency is focusing on this small subset of treatments or on the use of surrogate endpoints and other accelerated research strategies more broadly. Over its 30-year history, FDA’s AA program has led to speedy approvals of dozens of products, primarily for oncology and hematology in recent years. Although FDA may withdraw an accelerated approval for a product, the manufacturers did so voluntarily in the above cases, and for some dozen other therapies in previous years. There are only two cases where the agency initiated a withdrawal, following a complex and time-consuming process.

OCE’s review is expected to tap a white paper issued by the Friends of Cancer Research (FOCR) at its annual meeting last November 2020 that outlines ways to update the AA policy to provide FDA with greater flexibility in both approving and in withdrawing approvals of innovative drugs.

 Prepared by a multi-stakeholder working group, the report emphasizes the importance to patients of early access to new treatments, the benefits and risks of utilizing surrogate endpoints to streamline research, and challenges in conducting post-approval studies to confirm early evidence. There is discussion of differences and similarities between FDA’s policy and the European Medicines Agency’s conditional marketing authorization policy, particularly related to market withdrawal actions. The panel recommends added flexibility in policies governing AA approval decisions, including the role and design of confirmatory trials and expanded use of real-world evidence to better confirm benefits and risks with broader use of a medicine. Such approaches aim to assist FDA in understanding factors that contribute to failed confirmatory studies and the need for a more efficient process for making withdrawal decisions.

The ODAC meeting will provide an opportunity for sponsors to provide updates on ongoing studies for their therapies and to examine whether further testing could revise the withdrawal actions. A long-debated issue is industry’s poor record in conducting and reporting results from post-approval studies, and FDA appears to be taking a harder line on requiring confirmatory trials to support clinical benefit.

https://www.fda.gov/advisory-committees/advisory-committee-calendar/april-27-29-2021-meeting-oncologic-drugs-advisory-committee-meeting-announcement-04272021-04292021

https://friendsofcancerresearch.org/sites/default/files/2020-11/Optimizing_the_Use_of_Accelerated_Approval-2020.pdf

View from Washington

FDA is reviewing the record of its accelerated approval program following recent withdrawals of certain key indications for several leading cancer therapies, based on the failure of post-approval studies to document extended benefits of treatment.

FDA Reviews Gains, Risks of Accelerated Approval Process

In 2013, the FDA and EMA released final guidance to enhance monitoring by focusing monitoring on the highest risk areas of a trial–a risk-based approach. They recommended use of a risk assessment approach to identify those areas of highest risk. The guidance was finalized by the ICH and adopted by the EMA in 2017, and the FDA in 2018.

MANA RBM is a clinical trials institute and research laboratory. We design, test, and publish methods for conducting remote trial management for traditional site-based trials or decentralized trials. MANA RBM uses an approach called Science Driven Oversight, which is based on using protocol-specific analytics that enable cross-database, automated identification of “errors that matter” and systematic errors which are not readily detected by standard review or SDV.

In 2019, at the start of a large, complex oncology trial, MANA RBM conducted an assessment to determine the areas of highest risk for the trial. Our risk assessment is focused on the “Significant Six” or the six areas of trial conduct that absolutely have to be right:

Informed Consent collection and processes

Primary Efficacy data collection and processes

Safety: identification of critical safety issues and recognizing safety signals

Critical Document collection, including subject source documents.

After identifying the most significant risks as protocol-specific “Errors that Matter”, data and document collection systems were designed and built that enabled us to gather the relevant information to identify errors with the highest risk scores.

Protocol-specific analytics were developed to better identify whether these significant risks occurred. Our goal was to not only identify whether the Errors that Matter occurred, but to proactively prevent the errors using our automated analytic tool, REACHER.

For this trial, four of the largest areas of risk for the trial were as follows:

Subjects may be enrolled in the study that do not meet the complex Inclusion/Exclusion Criteria.

Processes for primary and key secondary endpoints must be correct

Subjects may experience a SUSAR (Suspected, Unexpected, Serious Adverse event) that we would not recognize, resulting in missed reporting requirements

Unblinded IP processes may result in errors affecting the integrity of the trial

Following our initial assessment, major changes were made in the protocol. After finalizing the protocol and re-evaluating the risk assessments, including taking into account the automated protocol- specific analytics, we were able to significantly decrease the most critical risks. The large decreases in the risk scores were due, primarily, to the increased ability to detect the errors.

For new risks not identified in the original risk assessment, the total risk score was lower than would have been the case had we not had a high ability to detect the errors. In one instance the risk could not be decreased because of constraints imposed by the reporting tools available from the IP vendors. Their reporting limitations decreased the ability of the analytics and our team to detect when an error occurred.

Table 1 below illustrates a subset of the risks identified during the Risk Assessment done in 2019 and 2020. Note that a low ability to detect increased the risk score by a factor of five compared to a high ability to detect.

This exercise illustrates several important aspects of our risk-based monitoring approach.

First, the risk score can be positively impacted (reduced) by proactively developing protocol-specific analytics to identify whether errors occur in the areas of highest risk. This is illustrated in our example of the analytics surrounding subject eligibility for randomization. By designing an analytic report to assess all of the available underlying data prior to randomization, the potential risk of incorrectly randomizing an ineligible subject can be identified quickly. In fact, this error can be eliminated entirely and one of the most critical risks to subject safety can be prevented.

Second, the risk assessment should be conducted at multiple times during a trial to assure that any process changes are captured . High risk items should have specific data collection design and an associated report or analytic tool to assure that oversight is focused on the most critical aspects of the trial.

Third, in conducting oversight, the challenge is often getting the sites to enter the data promptly for rapid assessment of errors that matter. This is a major change in standard working practices, where there is often a separate person that completes data entry. That is why the FDA included an eSource guidance document finalized in 2013. Incorporating the prompt data entry requirement into contracts, repeated reinforcement, and demonstrating to the site the value of proactive data analysis and rapid feedback will all help to change this engrained site process.

Finally, this paper also illustrates that pre-existing company limitations related to critical data exports, as we encountered here with IP management systems, can have deleterious effects on the ability to detect some of the most important errors associated with a trial. Companies that provide IP services should have robust reporting and notification tools that provide data across all research sites available to help assure that errors can be eliminated (or caught before they impact a subject’s treatment). Older, “established” companies may not have kept up with the evolving area of data exports, which can have a negative impact on risk-based oversight strategies. Evaluation of vendors should include examination of this critical capability to prevent unwelcome oversight surprises and the inability to mitigate risk.

Risk assessments focused on the significant six areas of highest study and subject risk are a valuable tool to develop protocol specific analytics and review processes for oversight. By focusing risk assessment in these six areas and tying the highest risk areas with reports that are routinely reviewed can significantly decrease the risks for a trial. Using near real time analytic tools offers a proactive solution to prevent errors before they occur and deleteriously affect subject safety or trial data integrity.

Identifying the ‘significant six’ areas of clinical study conduct to mitigate risk.

De-Risking Trials with Science-Driven Oversight

A European Partnership on Personalized Medicine is about to be born—to add to the list of European-flavored but often unproductive and ill-digested initiatives in this contentious field. The new partnership, to be known as EP PerMed, aims to bring public and private sector interests together to set priorities for research funding, align the current diversity of personalized medicine strategies, develop educational and literacy strategies, and support policy development.

It is the latest stage in Europe's long and occasionally meandering exploration of personalized medicine that has left it still trying to chart a clear route. The EU organized a series of desultory conferences a decade ago, then ventured into framing a plan in a 2013 working document entitled "Use of '-omics' technologies in the development of personalized medicine". This boldly concluded that EU pharmaceutical legislation "is flexible enough to address current needs and to authorize personalized medicines in a timely manner," and confidently predicted that "the revision of the Clinical Trials Directive is expected to simplify the conduct of clinical trials and consequently facilitate the authorization of research in therapies using personalized medicine." With that update of the clinical trials rules still not in force today, and with a proposal for updating EU pharmaceutical legislation only freshly landed on the table—in which one of the "flagship initiatives" is to adapt to personalized medicine—the complacency and glibness of that early document is all too clearly revealed.

A trail of good intentions litter the European landscape. During its EU presidency in 2015, Luxembourg valiantly persuaded EU health ministers offer formal support for personalized medicine—but the conclusions they adopted stopped short of any meaningful discussion of mechanisms. The International Consortium on Personalized Medicine, which the EU launched at a major conference in Brussels in 2016, was scheduled to produce a roadmap of its future actions by the end of that year but failed to do so, and although it still exists under the guise of ICPermed, it still struggles to deliver. Estonia spent much of its 2017 presidency trying to build a coalition around the concept, to disappointingly little effect. In 2018, Andrzej Rys, a Commission director for health, was still urging the need to engage scientists, health systems, healthcare professionals and patients to "take this innovation into the regulatory framework".

Now personalized medicine is on the point of winning the status of a European partnership under the EU's Horizon Europe research program for the next seven years, which is in the final stages of agreement. ICPermed, which is enthusiastic about the project, says EP PerMed "will have a major impact on enabling personalized medicine implementation for citizens, ensuring that Europe is at the forefront of personalized medicine research and innovation, hand in hand with international partners." And tellingly, ICPermed looks forward to it allowing "the defragmentation of the personalized medicine field."

According to a joint concept paper from ICPerMed and ERA PerMed (yet another EU initiative in the field), the new partnership "will be a prime driver for developing and implementing personalized medicine." "A lot has been achieved in the field of personalized medicine by a large number of international, pan-European, national as well as regional activities and initiatives," they say, but "there is a need of an even closer collaboration and effort which could be achieved by a European Partnership for Personalized Medicine." The two organizations are now jointly preparing guidelines to support "national and regional authorities, ministries, funding organizations and policy makers as well as the stakeholder community in preparation," on which they will also collaborate with (another!) EU initiative, Regions4PerMed. Meanwhile, a new ICPerMed Stakeholder Forum was launched in February, also aimed at sharing of ideas, identifying research fields, setting up new communication channels and "fostering new partnerships & networks."

With so much partnering and communicating and sharing ideas going on—and for such a long time now—with so few evident results other than further partnerships and communication and sharing of ideas, it might tempt skeptics into wondering if personalized medicine was more of a talk shop than a workshop.

A new partnership, to be known as EP PerMed, aims to bring public and private sector interests together. 

Applied Clinical Trials-04-01-2021