Observing the many digital applications available nowadays to assist in data generation and collection in the field of clinical research, has made me reflect on how differently we did this in the past. When I started my career in the industry as a clinical research physician in the early 1990s, paper was the norm. Most clinical studies’ data collection took place on paper. Investigators would fill in case report forms (CRF) using triplicate (or sometimes quadruplicate, depending on the appetite of the sponsor), which clinical research assistants would tear, distribute to the various study folders and carry back to the office. Besides the medical information included in the CRF, paper was also the primary tool for most of the patient-reported outcome data.

If you were working in a disease area where one could not rely on any objective measures (eg: glycemia) but rather where the primary outcome measure for your trial was based on symptoms reported by patients on a daily basis, then you had to rely on paper collection.

That is until providers began to develop digital tools that could be programmed to collect specific data, at a specific time, and provide a time stamp for data entry.

Some significant steps took place to introduce digital solutions for pre-clinical studies, data generation and collection in early Phase I studies. It suddenly became possible to generate, capture and organize healthy volunteer data automatically. This was also the time when the first electronic CRFs started to appear. Seen with today’s standards in mind, the early solutions looked a little clunky; instead of using what would now be known as cloud-based solutions, these electronic CRFs were individual computer laptops that usually belonged to the sponsor or the CRO running the study. If an investigational site was running several studies at the same time, this site may have had to store as many computers as studies. Digital solutions were also introduced in other areas, such as centralized patient assessment, image analysis and the creation of centralized reading centers.

The movement to develop and introduce digital solutions in clinical trials sped up, with more sophisticated disease area-specific solutions being developed and piloted into clinical trials. For the first time, these solutions were able to objectivize and quantify biological or physiological changes related to the effect of the intervention on the disease process, and place it into the context of the real patient’s life. For disease areas relying primarily on subjective outcome measures, these solutions prove invaluable. However, many of these remain add-ons to what is otherwise being used or collected in normal practice, which generates additional costs and complexity to deploy.

All is now changing with solutions that can be fully integrated to devices most of us carry with us, like our smart phones. These devices, which follow us almost all the time, provide a goldmine of information pertaining to our functioning as individuals. They are able to observe our daily activities, in a very unbiased fashion. Coupled with disease-specific applications, the combination becomes a powerful tool to assess how we function in healthy and diseased states. This opens the door for increasingly decentralized clinical trials, with the participation of truly empowered patients–for whom clinical trials may represent an important therapeutic alternative.

Over the last 30 years, digitization has fundamentally revolutionized the clinical trials’ process. Data generation, standardization and hypothesis testing capabilities have been hugely enhanced, at the same time the deployment of digital solutions has become easier. Data collection and facilitating patients’ knowledge, information and detection has also been a game changer. By combining real world evidence and disease specific measurement through increasingly powerful data analytics at an affordable cost, digital technologies have completely transformed the clinical trials landscape.

Articles

A Closing Thought

Digitalization has revolutionized an industry once reliant on paper collection.

A Look Back: How Far Clinical Trial Technology Has Come

HG Wells said it best, “adapt or perish, now as ever, it is nature’s inexorable imperative.” In life sciences, change is happening out of necessity to navigate COVID-19 disruptions. The pandemic brought urgency to simplify processes and keep studies going, accelerating transformation across the industry. This is especially true in clinical data management, and CROs have been at the forefront.

By adopting digital strategies and technologies, CROs are embracing new ways of working to meet growing sponsor requirements and patient expectations. The improvements in collaboration and efficiency have proven what is possible, and now there is no going back.

As we get closer to a post-COVID-19 world, sponsors and patients will look for the same levels of speed and agility. CROs are prepared to take on the challenge by using agile study design and artificial intelligence (AI), incorporating data from remote data sources, and enabling connected clinical processes to accelerate trial execution.

COVID-19 stopped or delayed more than 2,000 clinical trials,

 exposing potential points of failure in how trials are conducted. This is true in data management, where it takes approximately 72 days for monitors to conduct onsite source data verification (SDV) for a study.

 But as trials slowed down at the height of the pandemic, new COVID-19 treatment and vaccine studies presented an opportunity for CROs to innovate and complete trials faster than ever before.

With the industry’s success in bringing vaccines to market in much shorter periods, sponsors expect CROs to continue the momentum and deliver faster cycle times throughout the development process. One area with significant opportunity for improvement is study start-up, where EDC study builds take a mean cycle time of 69 days from protocol approval to database go-live.

 To improve the pace, CROs are using modern clinical data management systems (CDMS) that empower teams with agile study designs.

“We found a lot of innovation using agile study design, where we were able to set up COVID-19 trials in just a few weeks,” said Trevor Griffiths, director, clinical data management at Syneos Health. “To do this, we developed standards specifically for COVID-19 trials and worked hand in hand with our partners and
technology providers.”

Unfortunately, protocol changes—which were exceedingly common in COVID-19 trials—are the top cause of build delays. In today’s climate, sponsors expect to see these changes handled quickly and efficiently. Month-long delays, manual processes, and inflexible systems are no longer acceptable, especially for mid-study changes. More CROs are adopting CDMS to eliminate downtime when making amendments, regardless of the visits and rules impacted.

The use of new external data sources in trials increased during the pandemic, presenting numerous challenges for data managers. The industry is already embracing sources like real-world evidence or wearables. With studies shifting from the clinic to patient homes, alternative means of gathering data are rising. This change exacerbates the downstream issues of incorporating diverse data sets, increasing the need for solutions to manage data from disparate sources.

Cleaning remains a challenge since it requires the review of a growing volume of data points. More CROs are looking for scalable, flexible technology to accelerate the process.

“COVID-19 kickstarted the use of AI for data cleaning, especially because we were working on massive vaccine trials with tens of thousands of subjects,” added Griffiths. “We were able to successfully train and program AI, nearly eliminating manual review of medical data.”

Today’s data aggregation tools, analytics solutions, and pre-built integrations are essential to making this a reality. “Externally, a connected approach addresses the issues of multiple sources for data but working with different functions internally requires having a strong workbench,” said YaFang Wu, senior director, Parexel. “By using both, you’re able to manage different information and paths altogether, in one single area.”

Applying data workbench and AI strategies will help data teams perform rapid data cleaning and accelerate lock times.

The increased adoption of decentralized approaches represents a positive development in the industry, and CROs are leading the charge to enable a more patient-centric, digital clinical trial. For example, using applications for eConsent or electronic patient-reported outcomes (ePRO) allows researchers to collect and record patient consent and clinical data digitally, making it easier to review, share, and report information.

“With limited access to research sites, we quickly had to adapt and implement a more patient-centric approach to bring trials to the patient,” said Sam Ryan, director of data management at ICON. “We expect this trend will remain beyond COVID-19 to assure flexibility for patients, meaning an increase in home visits, more technology, and an explosion of data.”

Leveraging decentralized approaches reduce the patient burden of participating in trials and ease the administrative burden on research sites. For CROs, the increase of patient information sources added complexity in managing the data produced during the trial.

“The explosion of data driven by decentralized approaches, like wearables and sensors, presents an opportunity to reimagine the data manager. Making roles more technical and data science-focused can ensure companies have the people to set up, oversee, and manage each interconnection and data source in a trial,” added Ryan.

CROs are evolving their infrastructure for greater oversight and control. With the right systems and people in place, they can ensure accurate data, manage change proactively, and accelerate trials.

As shown in Figure 1 below, CROs are advancing toward unifying their clinical systems for better visibility and oversight (70%), reduced manual processes (69%), and improved study quality (60%). A big part of achieving those improvements is connecting clinical data and trial management systems to automatically exchange new records and updates to existing subjects quickly and easily.

With an integrated approach, shown in Figure 2 below, pharma companies and CROs can streamline processes like remote monitoring, allowing clinical research associates to seamlessly navigate from monitoring visits to subject case books for SDV. Bringing together data and operations increases cross-functional efficiency and visibility, enabling leaders to proactively manage studies and identify issues early on.

A unified approach to clinical automates data transfers, eliminating the need for duplicate data entry and, in turn, reducing transcription errors. With a single log-in, study teams can access real-time patient enrollment and status information to speed study start-up, a critical area that accounts for 61% of total trial cycle times.

Life sciences is especially adept at identifying problems, putting together new formulas, and applying learnings. COVID-19 placed the industry on a steep curve, and the lessons coming out of it have improved clinical trial processes.

Sponsors and CROs have enabled more connected ways of working in studies powered by agile digital solutions. Whether onsite, decentralized, or hybrid, tomorrow’s trials will be conducted in a way that is most convenient to sites and patients and will be executed by teams who have brand new skillsets. The shift is long overdue.

Berlin Institute of Health, Clinical Trials Stopped by COVID-19, 2021

, Risk-Based Monitoring Versus Source Data Verification, 2018

Tufts CSDD, Impact Report, Volume 23, Number 2, March/April 2021

Veeva Systems, Bioforum The Data Masters interview, 2021

Tufts Center for the Study of Drug Development Impact Report, Clinical Site Initiation Process Remains Lengthy and Highly Inefficient, 2018

Senior Director, Strategy, Vault CDMS, Veeva Systems

Feature Articles

Improvements in data management and collaboration forge path to greater efficiency.

Driving Clinical Speed and Agility Post-COVID

An emerging trend for developers looking for ways to increase the likelihood of success and their return on investment is adaptive trial designs. Defined by FDA as a “clinical design that allows for prospectively planned modifications to one or more aspects…based on accumulating data,”

 an adaptive trial can help “de-risk” the arduous process of drug development.

 in 2017, the approach is motivated by “both ethical and resource considerations.” An integral feature of an adaptive trial is the existence of an independent data-monitoring committee (IDMC) or alternatively of a separate dedicated independent adaptation committee, to carry out interim review of accruing outcome data that allow pre-specified adaptations to be made while the trial is ongoing.

There are various types of adaptive trials and of adaptations that can be proposed, each with their risks and benefits. Sample-size re-estimation (SSRE) is a family of designs that allow for increasing the sample size based on blinded or unblinded interim data analysis of randomized trials. This is important because research has shown that underpowered clinical trials, when the sample size is too small to reject the null hypothesis, is one of the common reasons a potentially efficacious drug can fail to demonstrate its worth during a study.

Sample-size calculations performed before the start of a trial require assumptions about the hypothesized treatment effect and the outcomes in each arm. Incorrect assumptions can result in a trial being underpowered or even overpowered. Both situations pose ethical and scientific concerns: either recruiting an insufficient number of patients without being able to fully answer the research question or subjecting more patients than necessary to a potentially inferior treatment when there’s already sufficient evidence to answer the research question.

 Unblinded SSRE methods assess the validity of the assumptions and enable an increase of the sample size based on the observed interim treatment effect, if necessary. Unblinded SSRE methods inherit the group sequential capacity to stop the trial early as soon as the scientific question addressed by the trial is answered.

The promising-zone SSRE method was first described by Mehta and Pocock in 2011, based on earlier work by Chen et al.

 It allows to recalculate the required sample size based on interim data, while minimizing the inevitable risks of bias and type-I error and yet, use a conventional test statistic at all stages of the study.

At the last interim analysis for efficacy, the IDMC will use the observed data and the assumption that future treatment effect will follow the same trend to re-calculate the conditional power. This value will fall into one of three pre-defined zones:

 The observed treatment effect is not sufficient to warrant the increase in sample size needed to maintain study power.

 The observed treatment is effect is lower than expected, but assuming the observed trend exactly reflects the true effect and that the trend continues, the power can be recovered, by increasing the sample size.

 The observed treatment effect is sufficiently favorable, and no sample-size increase is needed to maintain power.

It is a relatively simple approach to SSRE as it allows using a conventional test statistic at the end of the study, and, in some cases, can be very beneficial. However, it is worth noting that the promising-zone approach is not always the most optimal. It can, as all SSRE methods, introduce the risk of operational bias, and it creates additional regulatory hurdles. Moreover, the promising zone is defined on a statistical basis to enable the use a conventional test statistic, and not on clinical basis, and has been criticized for that.

When used appropriately, this approach can confer several benefits, not least of which is the ability to salvage a slightly underpowered trial, by adjusting the sample size when interim results show a treatment effect that is somewhat smaller than anticipated.

Unlike other SSRE methods, it allows the use of a standard test statistic without type-I error inflation. The promising-zone method is particularly useful for small organizations with limited upfront resources. Starting with the smallest sample size and reasonably optimistic assumptions regarding the treatment effect, they can then attract additional investment to expand the study based on promising interim data.

However, it is not a one-size-fits-all solution. At IDDI, we recommend sponsors to compare the risks and benefits of different forms of adaptive designs, including the more classical group-sequential designs, and select the one that best suits their individual circumstances and likely total sample size. In many cases a group-sequential design can be more advantageous than a trial with unblinded sample-size adaptations. Sponsors must also keep in mind that sample size re-estimation will be inefficient if the initial study was largely underpowered.

When unblinded SSRE is the right approach, sponsors and CROs must ensure they consider and respond to some added challenges.

First, the method can increase the risk of operational bias if the announcement of the SSRE conveys the anticipation of an effective treatment. To minimize that risk, it’s important to tell sites to continue recruitment until asked to stop, without announcing the magnitude of the sample-size increase. Moreover, knowledge of that increase can allow “back-calculation” of the treatment effect, which undermines the blinded nature of the interim analysis outside the circle of the IDMC.

The method also comes with increased regulatory hurdles. These are similar for FDA and EMA,

 and we expect similar requirements to be included in the upcoming ICH E20.

demonstrate, through extensive simulations, that they have controlled for type-I error and the chance of erroneous conclusions.

show that the methods used can correct for the potential bias introduced by the adaptation and ensure an unbiased treatment-effect estimation.

complete a pre-specification of the plan that includes the timing of the interim analysis, and stipulates the SSRE method used (i.e., the promising-zone rule), and test statistics.

ensure unplanned changes are not influenced by knowledge of the data, and ensure the homogeneity of effects before and after adaptation.

SSRE is a relatively new concept, but, thanks to its simplicity, SSRE using the promising zone is one that has grown in popularity in recent years. It comes with a host of benefits: it can increase study power, reduce upfront investment, and has the potential to shorten trial duration, for example. But it is important to note that it is not suited to
all situations.

Despite its appeal, the promising-zone method, like other SSRE methods, comes with additional logistical and regulatory hurdles, and organizations must consider how each of these relate to their own individual development program. Ultimately, organizations should choose the design that best suits the needs of their study, because there is no panacea in the world of adaptive clinical trials.

FDA. Adaptive Designs for Clinical Trials of Drugs and Biologics Guidance for Industry. (2019). 

https://www.fda.gov/media/78495/download#:~:text=For%20the%20purposes%20of%20this,from%20subjects%20in%20the%20trial

Fogel, D. Factors associated with clinical trials that fail and opportunities for improving the likelihood of success: A review. (2018). 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092479/

Edwards, J., Walters, S., et al. A systematic review of the “promising zone” design. (2020). 

https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-020-04931-w

Chen YH, DeMets DL, Lan KK. Increasing the sample size when the unblinded interim result is promising. Stat Med. 2004 Apr 15;23(7):1023-38. doi: 10.1002/sim.1688. PMID: 15057876.

https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-methodological-issues-confirmatory-clinical-trials-planned-adaptive-design_en.pdf

https://database.ich.org/sites/default/files/E20_FinalConceptPaper_2019_1107_0.pdf

Consultant, International Drug Development Institute (IDDI)

Using the promising-zone approach can salvage an underpowered trial.

Sample Size Re-Estimation as an Adaptive Design 

Prior to the COVID-19 pandemic, biotech and emerging biopharma companies were increasingly turning to contract research organizations (CROs) to contain costs and secure therapeutic and clinical trial expertise to help meet their individual objectives. COVID-19 has necessitated the industry further modernize clinical trials. In navigating the pandemic’s impact, growing investments in the sector and the related growing market competition, it can be a “make it or break it” time for these companies.

Biotech clinical trial sponsors often seek a CRO partner for strategic guidance, end-to-end services and solutions, and deep expertise for their pipeline with the ultimate outcome to streamline development processes and timelines to meet ambitious goals. These sponsors may find it beneficial to integrate a CRO partner prior to, or part of, the Investigational New Drug (IND) submission process, setting the foundation for a long-term partnership where a versatile CRO can help them identify the right solutions and services to operationalize trials with efficiency from the start and transition further into the development process.

For CROs to earn trust, it is important to enter into a partnership without preconceptions. Listening with intention to the sponsor’s needs is key. Start-up biotech companies may not have the in-house resources to draw upon to develop an asset. A good partner listens, guides and asks the right questions to ensure success. A start-up’s leadership team may have exceptional scientific, business or financial backgrounds with limited clinical trial, regulatory or commercialization experience. CROs are willing to collaborate and provide complementary support in every aspect of their clinical journey. As development goals evolve and business priorities change, communication and directional intent for an asset is critical.

In some cases, as trust grows, a well-balanced partnership may allow sponsor teams to focus their attention on strategic planning for future development. “Having the IQVIA Biotech project team’s collective experience to manage a Phase I/II escalation expansion study for our lead immuno-oncology therapy was a huge lift for our team,” said David Bohr, head of clinical operations at Bicara Therapeutics, a clinical-stage biotech company. “We were able to refocus on our long-term strategy and begin discussions with key thought leaders and advisory boards about what expanded programs may look like based on the team’s planning and guidance.”

Many sponsors in this sector need a reliable partner to take a potential treatment from the bench to the clinic. A strong CRO-sponsor relationship is highly consultative, where sponsors can lean on a CRO’s therapeutic expertise, technology and analytics capabilities, and global reach to overcome barriers to completion. As part of their working relationship, some specific ways biotech sponsors may lean on their CRO are noted below.

–Before a single patient is enrolled into a trial, sponsors should reach out to their CRO to support the development of a comprehensive clinical development plan to create alignment in strategic direction and ensure the probability of success.

For sponsors, integration of a research partner early in the process can help circumvent issues during preclinical and clinical development. Particularly in oncology, a skilled partner can be instrumental in the generation of a comprehensive biomarker strategy together with the ensuing operational execution, including the identification of companion diagnostics. Working in concert with a specialized clinical trial in vitro laboratory can make the process more seamless. A CRO can help by leading discussions on assay validation and regulatory pathways for approval, while keeping feasibility, risks, costs and timelines in mind as well. CROs may also be able to enhance study delivery through predictive or machine-learning approaches and provide direct insight to patient populations and sites of interest to improve trial performance and timelines.

“For Bicara, it is important to work with a team that shares the same voice as us,” said Bohr. “This way, the CRO team is readily available to have discussions around patient safety with site investigators or help pre-select target patients based on clinical and biomarker data insights, which improve efforts on companion diagnostics. It would require a lot of in-house resources for us to successfully oversee all those key activities.”

–With exploratory drug development often focused on multiple indications, a CRO with depth of therapeutic expertise can optimize clinical delivery enhancing quality and reducing timelines. Furthermore, years of therapeutic expertise and interaction with investigational sites ensure site engagement with heightened interest and attention to the target patient population. That long-standing base of knowledge regarding delivery challenges within the therapeutic space allows the CRO to prioritize the work needed for the sponsor while knowing what challenges to anticipate.

–Though a strong CRO partner should have a wide range of end-to-end services to assist biotech companies, capabilities must be scaled to best meet their individual needs.

The pandemic is a prime example, opening up a greater degree of patient-centered approaches by sponsors. Through remote monitoring capabilities, telemedicine, digital tools and other decentralized solutions, sponsors and CROs worked together to pivot strategies and maintain trial continuity. Implementing technology-based solutions that fit today’s needs, and can evolve and meet the sponsor’s future needs, will increase probability of trial success.

Bohr notes, “During the pandemic, we were unsure of how we would continue to collect quality data with overburdened hospitals and no on-site clinical research associates. Working with our CRO partner, the team quickly pivoted to coordinate with site institutions, through their established relationships, to determine needs such as at home study coordinators and telemedicine to continue collecting verified data critical to understanding therapeutic dosage while keeping patient safety top of mind.”

–Understanding that biotech companies are under tremendous pressure to meet business objectives—especially one developing a single asset—a CRO that can pivot on strategy and execution can help in this fast-paced environment. CROs should be ready to support delivery of critical milestones, co-development with a pharmaceutical partner, or commercialization.

The right partnership between a sponsor and CRO can fuel success through optimized clinical trials. With clear communication and growing trust between both groups, CROs can be an aligned collaborator to provide strategic guidance and help address needs at each milestone on the clinical development pathway, which is critical as the development landscape continues to evolve.

Strong collaboration critical as trial development advances.

Building Relationships Key for Smaller Sponsors 

While rebadging is an option that has been around for years, the COVID-19 pandemic spurred more widespread use. As pharmaceutical and biotech companies grappled with the pandemic and needed options to reduce internal headcount while maintaining expertise and business continuity, many turned to the flexibility and value that makes rebadging appealing in both the short and long term.

In a nutshell, rebadging is the process by which a client transfers employees and/or contractors off its payroll and onto the payroll of a functional service partnership (FSP) vendor. The client then re-engages those same staff members, who are now employed by the FSP vendor. While rebadging is disruptive, when done well it offers benefits to all parties involved.

Clients maintain speed and stability as tried-and-true staff members continue in the same roles as before, without negatively impacting ongoing programs. Rebadging also reduces fixed or direct costs for clients, as well as the legal risks associated with using contractors in full-time, long-term engagements.

Employees are assured secure employment, re-assigned back to their original employer (as a vendor contractor) or via new positions within the FSP vendor.

Vendors find rebadging not only an important source of revenue, but also gain broader access to top-level talent, critical for any successful service provider.

In this article, we’ll take a closer look at the benefits and challenges of rebadging for companies that perform clinical trials and other pharmaceutical/biotech services.

Rebadging offers numerous benefits and the risks are manageable, so it’s an effective way for companies to address workforce capacity and labor uncertainty while retaining access to the skilled, experienced personnel on whom they rely. First and foremost, the client maintains continuity across programs. In some cases, rebadging can help to avoid costly severance packages and payouts, as well as the bad press that can be generated for layoffs. It also shows good will to departing employees by helping make the best of an unfortunate scenario.

While FSP models with or without rebadging are ultimately about capacity management, the best vendors deliver wide-ranging value to help the client:

retain access to a dedicated team of full-time equivalent (FTE) staff for a broad range of services (data management, medical writing, program leadership, clinical supplies, regulatory, clinical monitoring, statistics, medical, etc.).

increase flexibility, including on-demand access to time and materials (T&M) or unit-based models that can deliver services with work volume that does not require
dedicated FTEs.

access additional vendor expert staff from across the globe and shift or centralize services to increase efficiency, reduce timelines and save costs.

accelerate and optimize key HR processes, including hiring, onboarding and training.

Working with a vendor may offer reduced risk

Legislative restrictions around co-employment and contingent workers can increase legal and operational risks when “temporary” staff are dedicated to a client in a full-time, long-term capacity. Examples include:

assuming risk when there are employment law violations–companies can be liable for a staff member’s actions when they are
a co-employer.

inadvertently violating wage and hour laws, which are complex and vary by country
or region.

It is important to ensure that co-employment risks are successfully mitigated through a series of contractual and operational designs, and clear delineation between vendor and client responsibilities and oversight for staff.

Ideally, contracts define the specific services and obligations of the vendor and client in respect to the staff. For example, as the legal employer of the staff, the vendor should deploy a management layer with the responsibility of providing day-to-day direction to the staff. These managers should also cover the usual line management responsibilities such as career development, performance management, while the overall functional oversight remains with the client.

For employees affected by a rebadge, the primary benefit is obvious: their continued employment, surrounded by familiar teammates, systems and project work. Rebadging, when done well, should not result in undue financial burden for the employees. For example, in the EU and elsewhere, ARD-type regulations are in place to help ensure employers don’t take advantage of their employees by offshoring their work or forcing them to rebadge with lower salaries and benefits. The FSP vendor must be expert at navigating these regulations to meet the needs of all parties to ensure each employee is “made whole.”

Moreover, joining a successful FSP vendor gives the employees a range of value beyond job security. Over time it allows for easier movement from one client to another via assignment within the vendor, rather than having to quit one client company and take a chance on another.

During any organizational transition, is important to keep employees engaged to keep turnover in check, and rebadging can help. Like many other fields, average voluntary turnover rates in the global CRO industry are increasing–from 15.5% in 2019 to 16.3% in 2020 alone.

The global market for outsourced clinical development services to CROs, including FSP providers, is estimated at approximately US $44.3 billion, and projected to grow to US $57.2 billion by 2024 (CAGR: 6.5%).

 While it is uncertain how much of this comes from rebadged employees, this large market does indicate that the overall appetite for outsourcing is strong.

For vendors, one of the major benefits of the rebadging model is that it gives access to proven professionals who are among the clients’ most valued employees. This in turn helps the vendor understand the client’s needs and perspective to ultimately serve them better. Transferring qualified employees is also much easier and more economical than the typical recruitment and new hire process.

Rebadging is a great way to identify and onboard employees who are highly motivated, self-sufficient, tech-savvy, adaptable and able to learn quickly, make decisions and take action. For FSPs servicing the pharmaceutical and biotech industry, among the functions and key roles that are in high demand are project manager, oversight director, clinical research associate, clinical trial coordinator, medical writer, global clinical supplies manager, biostatistician, medical writer, data manager, safety manager and regulatory expert. For these and many other roles, rebadging is an important means for vendors to identify and retain the top talent that enables them to keep pace with the rigors of clinical development, just as it is an important way for that top talent to remain meaningfully engaged (and steadily employed).

Rebadging can be an attractive win-win proposition, but the implementation is no simple matter. Companies need to have the following capabilities:

–The knowledge to handle all aspects of each staffing transfer properly and compliantly, including ARD and non-ARD staffing models and global best practices.

–Planning for rebadging, change management and business continuity, which is especially vital when transferring staff. The staff transfer process needs to be handled thoughtfully, with a transition manager coordinating interactions with HR, legal, IT, contracting and the affected employees.

–Look for an FSP vendor that is growing and has plentiful business aside from your own work, including through the COVID-19 pandemic or other disruptions. This helps assure they can readily absorb your employees and promote a positive outcome for everyone involved, regardless of the ebbs and flows in work volume.

–It’s critical to have a partner to calibrate your capacity and ramp up quickly across any function or service. Service-level agreements are an important step to ensuring FSPs interview, vet and make offers to candidates within a set timeframe. Transfer varies widely, from as little as 10 business days in the United States to three to six months in countries with ARD legislation and works councils or unions.

While there are numerous reasons why pharmaceutical and biotech companies would want to shift workforce from the traditional headcount to a contract or on-demand model with FSP vendors, clients need to recognize the potential for significant hurdles, including regulatory and legal risks. By navigating the regulatory waters and focusing on maintaining both employee and employer satisfaction, an FSP vendor can help companies engage a steady, agile, full-time workforce while avoiding burgeoning payrolls, direct costs and debt–all while maintaining continuous, high-quality service and speed.

Rebadging is just one option an experienced and trusted FSP can offer to help manage significant volatility in work volume. Successful FSP vendors should help calibrate capacity and ramp up quickly across any function and service, including pharmacovigilance, regulatory, biometrics, on-site and remote monitoring, supporting both clinical trials and post-approval marketed products.

2020 CRO Market Size Projections: 2019-2024 - COVID 19 Update. July 2020. Accessed May 18, 2021.

Capacity management and stability offer value for clients, their employees and FSP vendors.

Rebadging Gains Momentum Amidst COVID

First, what is crystal clear: the spate of mergers, acquisitions, and partnerships involving CROs is ongoing and evolving.

Second, what’s still blurry: how these business transactions will impact the future of the CRO industry, for better or worse. It’s not a couple of factors that propel these pacts. There are many—some permanent, some temporary, with others unknown. And still more have the indelible stamp of
“COVID-caused.”

None is inconsequential: advancing digital technology, globalization of clinical trials, changes in clinical trial design, the inflow of private equity dollars, fewer sponsors lost to mergers and acquisitions, more CROs, the costs of clinical trials, precision medicine, lack of available talent, and—an under the radar trend—the continuing challenges of chronic disease. More people are developing them, but true cures elude pharma. One report says chronic diseases are likely to “support the growth of the global clinical trials market to a significant extent.”

The industry felt the impact of the pandemic, not all of it bad. It forced suspension of trial activity or its abandonment, thereby slashing income, but it also revealed ways to grow, either through an M&A, or how to morph from a jack-of-all-trades to a niche-specific entity.

“The trend toward more patient-friendly trial options is here to stay,” said Peter Benton, CEO, Worldwide Clinical Trials. “The industry is finally acknowledging the need for a toolkit of decentralized research methods and flexibility built around the patient. CROs have a tremendous opportunity to continue guiding sponsors toward solutions that meet them and their patients wherever they are.”

The pandemic also showed industry that it could reduce risk by shifting the weight. Processes that allow remote audits and monitoring, previously considered too risky, are now risk mitigators. “We adopted them, we experienced success with them, and now the ‘risk’ aspect is gone,” Benton said. That risk-sharing is driving continued technological evolution.

COVID forced everybody onto the risk curve, said Christine Dingivan, CEO of global full service CRO, Emmes. “Digital development and technology are just exploding.”

Two interesting maybe-trends: Many people interviewed for this article said that some pharma members, perhaps looking for more control over the management of their trials, let alone cost, are taking CRO functions in-house. One reason they can do this is through a bevy of new vendors, who are devising digital solutions and services to address the chronic migraines of the clinical world: enrollment and site management.

These vendors also have a lot of money from private equity. “It’s incredible,” said Henry McNamara, senior vice president, general manager, Oracle Health Sciences.

Some examples of the private equity cash flow includes Goldman Sachs’ investment of $230 million in 4G Clinical, a developer of randomization and trial supplement management software, two months ago. In May, the investment arms of these household names—Bayer, Hitachi, Samsung, Sony, Unilever—raised more than $200 million for Huma Therapeutics, whose DCT software lets patients trial-in-place; home, hospital, nursing home.

Another tech company that has caught private equity attention is Reify, whose valuation hit the $2.2 billion mark after a recent C round added to the coffers. Reify has two software products—StudyTeam and CareAccess—the former for patient recruitment, the latter for running decentralized trials. The true north of Reify, said co-founder Ralph Passarella, is to predictably enroll trials in three to four months, beating the average time of 1.5 years.

Mike Jagielski, CEO of KCR, an international clinical development solutions provider, said underestimating what these new technologies can do, from a business perspective, is unwise. These products, he said, create incredible organic growth opportunities for companies like his that can scale in a controlled way to “capitalize quickly and efficiently on new platforms, like Veeva.”

Similarly, said McNamara, CROs want Oracle to design agile systems that can respond quickly to change and adopt new service models, per pharma’s new direction.

From a 30,000-foot perch, M&As are a large example of an industry revamping itself. The larger mergers and acquisitions, said Jagielski, have established engaging in M&A as “part of doing business.” A 2020 report called them a “primary factor” in the growth of global CRO services market.

Casey McTigue, an executive director at SRS Acquiom, an M&A services firm, put it this way: “We have seen record setting volumes for M&A.”

In 2019, the life sciences recruiter ProClinical considered the following CROs worthy of close attention from investors and pharma alike: PPD, Medpace, PRA Health Sciences, KCR, ICON, IQVIA, PSI, Parexel.

Of the eight, three still stand alone; the rest have merged or been acquired. Obviously, investors and pharma already were paying attention. ThermoFisher acquired PPD earlier this year; ICON plc now owns PRA Health Services; Parexel is now owned by Goldman Sachs and EQT—the smaller of the group, PSI, Medpace, and KCR, stand alone.

The pandemic crystallized these truths: decentralized trial design has value and the CRO industry is not immutable to financial sledgehammer.

One study, which examined more than 62,000 trials started before and during the pandemic, found that the number of US-initiated studies between February and May 2020 was 57% of what would have been expected had the pandemic not occurred.

A GlobalData survey released in July 2020 found that 322 companies announced their trials had been disrupted; most were in Phase II.

 More than 67% of these trials stopped because enrollment was suspended.

That’s a large monetary hit for the CROs, considering that 72% of all trial sponsors employ some CRO talent, according to a 2015 Research and
Markets report.

For CROs, trials ground to a halt, said McTigue. In turn, trial cessation “impacted our deals with [sponsors] quite a bit. I will say there were a substantial number of disputes” over missed milestones.

Even before the latest M&A moves and the pandemic, CRO specialization was a way CROs could differentiate themselves in an industry dominated by large companies. For the smaller CROs, specialization is a matter of survival. Based in Rockville, Md., Emmes, said Dingivan, has been a “long-standing partner” of the NIH and National Institute of Allergies and Infectious Disease. The company specializes in biostatistics and infectious disease and 20% to 25% of its staff worked on COVID-related studies in 2020. Last year, the company created Emmes Biotech to expand its work with federally-backed trials.

McNamara said specialization “has accelerated because of the science.” Biomolecules, biosystems, combination therapies, orphan drugs, rare diseases…all require deep knowledge, he said, not only for managing therapeutic trials, but also their different phases. CRO regulatory experts are also valuable, he said, such as those working with academic centers or with the federal government.

Another reason to merge or acquire is to literally cover more ground.

That was a good reason for dMed Global, based in Shanghai, and Clinipace, with headquarters in N.C., when the two merged in April. Alira Health, an advisory firm based near Boston, acquired CROS NT, a CRO based in Italy. Dingivan said that when she was looking for a firm for Emmes to acquire, she chose a CRO based in Prague called Neox because of its network throughout Eastern Europe. Another CRO acquisition, Orphan Reach, has allowed Emmes to become well-versed in the rare disease space. Behr-man Capital funded both acquisitions.

The Asia-Pacific area has become attractive to sponsors because it’s cheaper to run costs there and because of its assets, namely larger populations of people, patients and physicians.

Then there are those CROs that wish to complement existing service offerings.

Alimentiv Health Trust, parent of the GI-focused CRO Alimentiv, acquired the CRO McDougall Scientific in March, and a month later launched AcelaBio, a histopathology and precision medicine research lab for global clinical trials.

Think Research, in a venture-backed move, acquired the CRO BioPharma. Think Research, based in Toronto, provides technology products to healthcare facilities, including those that serve seniors. Combined, their network covers 2,800 hospitals, clinics and long-term care facilities, and 200 research and pharmaceutical companies, a press release says.

Since the combined R&D outlay of the top pharma houses now hovers at the $100 billion—and that majority of trials have CRO involvement—even the math challenged can appreciate the CRO industry’s losses, or gains, depending on the road chosen.

But the CRO industry has already proved
its resiliency.

Despite changes in market conditions between 2008 and 2019, SRS Acquiom found that of the 227 private life sciences deals in which it was the shareholder representative, 163 had earnouts, the potential dollar figure more than $37 billion. In its 2019 Life Sciences Deal Terms Study, SRS Acquiom estimated that milestones due by mid-2019 have been achieved on average 33% of the time in biopharma (paying 33% of earnout potential dollars).

Some trial sponsors, said those interviewed, are changing their relationships with CROs by bringing CRO services in-house. One source in pharma said the move in-house is predicated on the success of DCTs and eSource. But the switch isn’t a topic of conversation among her peers, which “raises the perception this is what is happening.”

Said Passarella: ”Our industry is in an interesting state of flux, we are seeing internal shift. Sponsors are getting better support to run studies, but it’s too early to see how everything will shake out.”

Craig Steger, senior vice president, Life Sciences Outcome Capital, LLC, said Outcome did not uncover that trend in a recent report. “The only transaction that we know of where pharma or biotech acquired a CRO, whether in the clinical or pre-clinical space, was when UCB pharma acquired Beryllium Discovery [in 2017].

“I suspect that this may be a talent play,” he wrote in an email.

McNamara concurred...the need for talent is another reason for consolidation. He added that much industry talent is nearing retirement, as well as turnover. Employee turnover in the CRO industry doesn’t seem to be slowing down; before the pandemic, turnover was 24%; in November 2020, it was 21%.

On LinkedIn, CROs are offering sign-on bonuses to fill the roles they need. Charles River offered animal care associates $1,000 to come aboard, while formulation technicians would receive $750. Despite the duplicate ads and the occasional non-CRO job ad, LinkedIn, in early August, showed 40 pages of ads, each with 25 job offerings, for roles that CROs needed to fill. Many of those ads had fewer than six applicants.

Dingivan said she didn’t think the CRO industry was in imminent danger of folding in on itself, due to the new technology firms, mainly because this country’s EMR systems have yet to connect. Trial sponsors need standardization for global-wide trials. The other thing, she said, is that these firms, like Google’s Verily, need a regulated infrastructure to run trials. “You can’t just know how to build a plane, you need the regs, too.”

M&A is always a distraction, as compared to organic development, said KCR’s Jagielski. The extent of the disruption depends on whether it’s your CRO that is acquiring or was acquired. “If it’s the former, it’s less destructive,” said McNamara.

But always count on a talent exodus. “The number one objective is to preserve talent,” said McNamara.

When two companies come together, said Jagielski, the hard part is figuring out what to do with the combined labor force. “In our business you are not buying IP, you are always mostly buying people,” said Jagielski, who has no intention of merging KCR with anyone, unless KCR stops enjoying “double digit growth” year after year.

Said Benton: A merger can force sponsors to reevaluate their relationship with the new CRO, or perhaps look for a new one. If that happens, the integration can lead to turnover, to system-integration irritations and service disruptions. “Integration can take years.”

Businesswire. The Worldwide Clinical Trial Industry is Expected to Reach a Value of $57+ Billion by 2026 - 

Fortune Business Insights. How Contract Research Organization Services Market Will Dominate In Coming Years? Nov. 25, 2020.

https://www.proclinical.com/blogs/2019-5/top-10-contract-research-organisations-cros-to-watch-in-2019

Unger JM, Xiao H. The COVID-19 pandemic and new clinical trial activations. 

GlobalData. 67.3% of clinical trials disrupted by COVID-19 are due to enrollment suspension. July 1, 2020.

Ben Adams. The top 10 pharma R&D budgets in 2020. Fierce Biotech. April 6, 2021.

Andy Studna. Turnover for Clinical Monitoring Remains High. Applied Clinical Trials-04-01-2021, Volume 30, Issue 4

Technology, talent and specialization add up to a plethora of industry M&As.

The Post-Pandemic CRO Landscape

During the pandemic, patient engagement (e.g., participation convenience, safety, research relevance, ease of use) has been a guiding principle in the transition to remote and virtual clinical trial support. Given the high level of customization inherent in decentralized and hybrid clinical trial execution models, a growing number of sponsor companies are now looking in earnest to quantify the impact of patient-centric initiatives. Although the Tufts Center for the Study of Drug Development (CSDD) and others have dedicated considerable time and attention to gathering objective evidence, until recently, very little has been available.

Several years ago, the Drug Information Association (DIA) and Tufts CSDD analyzed 121 distinct case studies to quantify the impact of patient-centric initiatives. In this early study, patient engagement initiatives that offered the highest impact given the investment required were patient advisory boards, professional panels, social media engagement, and patient education programs. These initiatives were relatively simple to implement and inexpensive, yet they reportedly resulted in faster study planning, improvements in recruitment and retention rates, fewer disruptions and delays, and more positive study volunteer feedback. Unfortunately, there was too much variability in definitions, types, and quality of the metrics collected across case examples. As a result, return on patient engagement could not
be generalized.

In another study, Tufts CSDD—in collaboration with the Clinical Trials Transformation Initiative (CTTI)—developed a method for projecting the financial value of patient engagement using standard risk-adjusted financial modeling techniques. The CTTI-CSDD team assessed the impact of patient engagement on the expected net present value (ENPV) for a typical oncology development program entering Phase II or III clinical trials. For a Phase II project, the cumulative impact of a patient engagement activity (e.g., patient advisory board review) that avoided one protocol amendment and improved enrollment, adherence, and retention was an increase in NPV of $62 million, rising to $65 million by Phase III, and an increase in ENPV of $35 million, increasing to $75 million by Phase III. Depending on the scenario, a $100,000 investment in a patient-centric initiative during the design of the study could produce NPV and ENPV 500 times that amount. This ENPV increase is equivalent to accelerating a pre-Phase II product launch by 30 months or 18 months for a pre-Phase III project.

During the past 24 months, Tufts CSDD has undertaken several new studies to gather more objective and practical evidence quantifying the impact of patient engagement. Sponsor focus of late has been particularly high on protocol design given the fundamental role it plays in directing downstream clinical trial activity. Sponsors expect that the ability to incorporate patient preferences and needs during the protocol authoring and finalization period offers a unique and unprecedented opportunity to optimize study design and positively impact clinical trial performance and cost. The results of two CSDD studies underway inform this area.

Patient advisory boards (PABs) usually entail soliciting feedback from a group of patients and their caregivers (e.g., patient advisory boards or input panels) on the feasibility and convenience of near final protocol designs. PABs are typically moderated meetings among six to 10 people. Although they are not enrolled in clinical trials, participants in an advisory board usually share the burden of disease investigated by the protocol permitting them to speak from direct experience. At this time, an estimated two-thirds of the top 50 largest pharmaceutical and biotechnology companies have implemented one or more PABs to obtain specific protocol design feedback.

To assess the impact of PABs, Tufts CSDD has analyzed data from a convenience sample of Phase II and III protocols conducted between 2015 and 2019 across multiple therapeutic areas. Of 153 protocols analyzed, 12 utilized PABs. Given this small sample size and the wide variation in disease conditions represented, these results should be interpreted with caution until a more robust sample has been analyzed.

PAB input resulted in simpler protocols and more targeted designs compared to those that did not receive input. PAB-informed protocols had, on average, fewer endpoints, eligibility criteria, and distinct procedures.

The number of procedures performed per visit and the total volume of data collected per patient was significantly lower for PAB-informed protocols. Protocols informed by PABs had an average of 15 endpoints and 27 eligibility criteria, 30% and 20% less, respectively, than did protocols that were not informed by PABs. Protocols that used a PAB for design input collected 2.2 million data points, 50% fewer than protocols that did not receive PAB input. And PAB-informed protocols had a lower percentage of procedures supporting tertiary and miscellaneous endpoints.

The results also indicated that protocols receiving PAB input had better relative performance and efficiency. Notable differences between protocols informed by PABs and those that were not informed include faster study initiation, shorter clinical trial duration, quicker study close-out, lower-than-planned study budgets, and fewer average number of substantial protocol amendments.

The actual cycle times of protocols that did not use PABs typically exceeded planned timelines by between 20% and 90%. Actual cycle times for PAB-informed protocols came in closer to plan (e.g., study initiation cycle time) or beat the plan time lines by 6% to 17%. And actual PAB-informed protocol budgets came in 28% below planned budgets. Protocols that did not use a PAB tended to have actual budgets 3% above plan. Protocols that used a PAB had on average one fewer substantial amendment than those that did not.

The use of a patient burden assessment score or algorithm has been gaining momentum as valuable input into early-stage protocol authoring. A tool developed by the National Institute of Health several years ago measured patient attitudes and correlated them with patient self-report of the likelihood to participate in, and the intent to drop out of, a clinical trial.

Dassault Systems and IQVIA have been developing and beginning to pilot-test patient burden assessment tools (e.g., the Patient Burden Index and the Patient Friction Coefficient, respectively) among pharmaceutical companies.

In 2019, Tufts CSDD—in collaboration with ZS, a global management consulting firm, developed and tested an initial participant burden algorithm against pharmaceutical and biotechnology company protocols based on the perceptions and preferences of 591 patients living with one of five disease conditions in the US.

Insights from studies on advisory boards and participation burden.

Applied Clinical Trials-09-01-2021

A Look Back: How Far Clinical Trial Technology Has Come

Driving Clinical Speed and Agility Post-COVID

Sample Size Re-Estimation as an Adaptive Design

Building Relationships Key for Smaller Sponsors

Rebadging Gains Momentum Amidst COVID

The Post-Pandemic CRO Landscape

Amplifying Patient Voices in Protocol Design

The State of IRT and RTSM Technologies

Rhetoric and Realism Colliding on EU Discussions of Drug Repurposing

Could Technology Supplant CROs?

Applied Clinical Trials September 2021 Issue (PDF)

Biosimilars Move to Center Stage