From e-health records (EHR) to digital twins, technology continues to evolve in an increasingly complex landscape that starts with study approval and planning and extends to long-term sample storage. Understanding best practices for tech integration can help partners across the clinical trial workflow, like CROs, sponsors and suppliers, create reliable, patient-centric, and compliant trials that get critical treatments to market faster.

The scope of technology that supports clinical trials extends across the full clinical trial workflow. As you design the trial, consider the full range of tools. One example is artificial intelligence (AI). This technology is being evaluated to create a digital twin to help predict how a patient would react if they had received a placebo. By eliminating the need for a placebo cohort, AI can lower recruitment requirements, reduce trial length, and increase patient access to the active drug.

Logistics is also an area ripe for smart technology integration. Modern packaging options provide far more than a shipping box for a clinical trial kit. Consider savvier technology, like packages enabled with near-field communications. Equipped with radio frequency identifiers, these packages can communicate with an app that not only tracks the package during shipment, but also provides updates on when the patient opened the package. If the patient must access the kit at specified intervals, this type of data can indicate whether the patient is adhering to protocol schedule.

Clinical trial partners increasingly rely on a menu of technology suites to support their trials, particularly decentralized elements, like remote monitoring or mobile visits.

 Without reliable data collection that’s accurate and repeatable, clinical trials face potential delays that waste time and money.

One aspect of creating an ecosystem for reliable data involves asking up front: what’s the right data set and data detail required for our protocol? While this has always been a core question, technology has added additional considerations. Wearable and other technology can inundate investigators with an ocean of data, especially with devices that offer continuous monitoring. And while all that data can be attractive and relevant, it must still be managed and analyzed. If it’s not essential to the protocol, the data—and the management it requires—adds complexity, time, and costs.

In contrast, it’s also important to ask the question: can any data we collect now be used for future drug development? Reliable storage of not just the physical but the digital sample can help bring future treatments to market without the time and cost associated with new patient enrollment.

Streamlining processes to reduce the rate of data errors also supports reliability. For example, the Clinical Trials Transformation Initiative (CTTI), an association that aims to create a vision for the future of clinical trials, recommends that clinical trials be fully integrated into existing health systems. Doing so would potentially allow a clinical trial to access—with consent—a patient’s EHR and eliminate the need to collect data already in the existing record.

3. Develop data management for the full workflow

The scope of available technology demands more robust data management systems than ever before. From start-up to closeout, data management must span the lifecycle of the clinical trial.

Data management requires coverage across the full clinical trial workflow—and that includes long-term sample storage, which sometimes isn’t fully considered until the end of the sample’s lifecycle. Long-term sample storage must include considerations around tracking and tracing of samples at the storage unit level globally. In addition to the track-and-trace technologies that support the sample, technology is critical for biorepository temperature monitoring, maintenance, and kick-off, or redundancy systems in any event that could risk sample integrity.

Clear data ownership at every step of the clinical workflow is critical, from patient recruitment to drug supply to sample processing to long-term storage. If there are questions at approval submission, the sponsor will need to have clear guidance regarding ownership of each data piece.

Seamless data flow between all partners is equally important. Each partner now has a responsibility to make the investment in front-end and back-end integration that supports data management across the clinical trials workflow. While there is still work to be done in regard to seamless data integration, CROs, suppliers, and other partners are making strides to drive this transformation.

The evolving technology landscape and the COVID-19 pandemic’s impact on clinical trials has enabled and accelerated decentralization of clinical trials, creating an experience that brings the trial to the patient. However, these advances can present a challenge: patient-facing technology is only as powerful as its usability to patients. Devices and other technology that are hard to understand or inconvenient to use can negatively impact patient experience—and that can take a toll on everything from patient enrollment to data reliability.

One aspect of building a patient-centric experience is ensuring patients are comfortable with the digital tools that they will be required to use for the duration of the trial. Patients may require training to use some wearable health devices, so it’s important to consider how they will access effective training. For example, in addition to collecting data, a clinical trial app installed on the medical wearable can offer instructions, such as videos that guide a patient step-by-step through a particular process.

Another, sometimes overlooked, technology challenge is aligning device choice to regional preferences where the clinical trial is being conducted. Consider a clinical trial that will collect data, like cardiovascular rhythm or body temperature, via a smartwatch device. If you choose a wearable brand that patients in that region are not familiar with, you risk reduced enrollment and lower adherence—even if the technology in the unfamiliar brand mirrors the regionally familiar smartwatch.

Using technology to support patient-centric clinical trials also requires consideration of what’s referred to as the digital divide. Depending on the population, factors like age and educational differences can impact technology use and adoption.

Despite the challenges, one of the most exciting aspects of the clinical trial technology evolution is that we could soon conduct trials in which the patient will use just one app to manage their full experience, from participation consent to device management to kit receipt to sample packing and shipment instructions. A scenario like that has the potential to not only increase adherence but also further enhance the patient-centric experience.

5. Understand the regulatory framework around technology

Just as regulations for clinical trials, as a whole, have evolved, regulatory frameworks across the globe now increasingly address the use of clinical trial technology. For example, if the study will rely on a consumer device, like a smartwatch, choose a brand that aligns with relevant regulatory standards of that region. A specific wearable device might monitor functions like heart rate but not provide the level of secure data transmission required in the region where the clinical trial is taking place.

The regulatory consideration extends beyond medical wearable devices to the full clinical trial workflow. Consider data and cybersecurity in logistics. In the traditional clinical trial site setting, partners like suppliers and logistics companies didn’t have access to patients’ personal information. Now, a single decentralized clinical trial can require kits to be shipped to thousands of patients’ homes, exposing a patient’s name, address, and perhaps even the type of equipment they receive and trial they participate in. As a result, all clinical trial partners must be ready to navigate GDPR in Europe and HIPAA in the US, as well as other regional data privacy and security regulations.

Conducting trials in emerging regions can require special consideration. In areas like the BRICS block (Brazil, Russia, India, China, and South Africa) and the Middle East, clinical trial regulations have improved in the last several years, helping better harmonize research standards globally. However, like Western countries, they are now challenged with bringing regulatory framework around factors like data and privacy up to speed.

As these nations continue to build and evolve their regulations, it’s critical for CROs, sponsors, and suppliers to work with local experts familiar with that specific region and any evolving standards. Partnering with a local CRO can help ensure proactive and flexible use of the right clinical trial technology to run a smooth trial that stays on track, on budget, and in good regulatory standing.

6. Consider technology when choosing clinical trial partners

Technology cannot be an afterthought when selecting CROs, suppliers, logistics services, and other partners. As you select partners, ask:

Do I already have a formal integration with this partner? And if so, are we already transmitting data seamlessly back and forth, or do we need an improvement?

Who owns the data at any given stage of the workflow?

If the partner’s technology is already integrated with their own suppliers, how quickly can we react if we have an urgent need for equipment in, for
example, Zimbabwe?

If the clinical trial is held in an emerging region, do we have the right level of local expertise to guide technology integration with that specific population? And do we have compliant tech integration for that region at all levels, from patient recruitment to supply chain?

Are all my suppliers and partners fully integrated in a way that makes technology—and data—easy, seamless,
and reliable?

Technology is a powerful tool that helps clinical trial teams get life-changing treatments to market faster, but all partners must work together to create tech integration that’s reliable, patient-centric, and compliant.

McKinsey & Company. No place like home? Stepping up the decentralization of clinical trials. (Online) Available at: 

https://www.mckinsey.com/industries/life-sciences/our-insights/no-place-like-home-stepping-up-the-decentralization-of-clinical-trials 

Clinical Trials Transformation Initiative. Transforming Trials 2030. (Online) Available at: 

https://ctti-clinicaltrials.org/who_we_are/strategic-vision/ 

Marquis-Gravel, G. Technology-Enabled Clinical Trials. Circulation. (Online) Available at: 

https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.119.040798 

Articles

Feature Articles

Six best practices and three key mistakes to avoid in new technology space.

Tech Integration for Clinical Trials 

Complex study designs are fast becoming the norm—but integrated clinical trial technology can make even the more complicated of data collection requirements a breeze.

IDDI worked on a Phase I/II trial for people with cancer who were ineligible for induction chemotherapy.

High risk participants, complex protocol design, and COVID-19 risk mitigation were among the multiple challenges faced by the sponsor, but all were overcome thanks to the utilization of a range of eClinical tools.

In this case study, we look at how integrated eClinical tools can accelerate study implementation, help to determine a recommended dose safely and accurately, and reduce burden on site staff. We will also look at how to foster effective collaborative partnerships with clinical monitoring teams during a study.

The trial was a Phase I/II open-label, dose-finding, safety, efficacy study, in patients with cancer who were ineligible for induction chemotherapy. It ran across six centers for a total of 32 months.

Phase I, which involved 18 subjects, consisted of dose exploration, and escalation strategies were used to establish the recommended Phase II dose and schedule.

Phase II enrolled 175 patients on an open-label 2:1 randomized design, to evaluate the effect of treatment at the recommended dose.

Participants in both phases were adults. In Phase II, additional constraints were added the eligibility criteria.

Sponsors were faced with a multitude of challenges conducting this dose exploration trial.

To protect participant safety and quickly move from Phase I to Phase II, the team needed to rapidly access all captured data from a variety of sources. These included the electronic case report forms (eCRF), laboratory reports, randomization, and trial supply management (RTSM), and a range of external systems.

This was a complex protocol design. During Phase I, subjects were started on an initial dose of the targeted drug in combination with another product. The dose was then escalated and evaluated for the occurrence of events, using a standard 3+3 dose escalation protocol.

In addition, specific data collection requirements included the dose-escalation algorithm, and tumor and radiological assessments. All of this posed a huge potential to place additional burden on sites, and sponsors wanted to ease the
administrative pressure.

Implementation during COVID-19 was another challenge for the team, who were aware that the pandemic could result in missed visits and missing data. They wanted a robust mechanism, which recognized the importance of risk-based monitoring, to ensure study goals could still be met.

The sponsor selected IDDI as its biometric partner, and we provided our fully integrated eClinical suite, which features electronic data capture (EDC) and RTSM, as well as data collection, data cleaning, and data analysis. Using a single vendor to provide these tasks and services, the client felt, ensured data quality and coherence with trial design.

The solution helped overcome many of the traditional challenges of EDC, delivering data according to the protocol, collecting only those data necessary for the statistical analysis, and collecting data in an accessible format during study analysis.

In terms of tumor assessment, investigators simply entered information such as lesion type and location at the screening visit, and this information was systematically copied over into the relevant response assessment visits. This allowed investigators to accurately follow tumor evolution throughout
the study.

Another vendor was selected to perform clinical and medical monitoring, which enabled a clear separation of tasks.

The eClinical suite is fully integrated, removing the need for repetition of tasks in multiple systems. Date of birth, for example, need only be entered once, and is then displayed across systems. This reduces site burden and the potential for error, while streamlining the process and protecting data quality and integrity.

This approach enabled the sponsor to implement the complex dose-escalation algorithm into the eCRF, which contributed to the rapid and accurate determination of the recommended Phase II dose.

Tumor and radiological assessments were accessible within the eCRF. Calculation functionalities within the system copied the target and non-target lesions, documented at baseline, into post-treatment visits. This ensured consistency in lesion identification across the entire study and reduced data entry.

Linking the RTSM to eCRF and payment sheets to schedule visits also reduced administrative burden, and the creation of precise edit checks limited time-consuming, expensive data cleaning.

The team applied a monitoring plan to the EDC, which guided site staff through source data verification to avoid missed data, and were given rapid access to data via 

 reports, based on their own study element and timeline interests.

While joint working was imperative, it was also important to keep a clear separation between the IDDI’s biometry and the monitoring vendor’s team for a number of reasons. First, it enabled each to focus on their own areas of expertise and gave the biometry CRO the ability to act as an unbiased, independent partner when conducting statistical monitoring and data quality assessment.

This balance was achieved in several ways. For example, while the clinical data management (CDM) and biostatistics services were linked, monitoring data was kept separate to give each vendor an independent view of the information. In addition, key data management and biostatistics milestones were integrated into the planning to enable effective co-working. It meant, for example, that the CDM team was able to start programming the study data tabulation model (SDTM), as soon as the eCRF had been finalized as per the analysis data mode datasets (ADaM).

The protocol amendment process was also carefully managed. The lead CDM, biostatistician, and sponsor managing director all reviewed the protocol to make sure everyone knew the schedule of assessments and the data to be collected. Once the protocol was finalized and eCRF had been developed, the biostatisticians carried out another review, to make sure all endpoints had been included, and that all captured data could be
easily analyzed.

IDDI’s integrated eClinical suite and expert team successfully were able to rapidly implement this study design in just three months, and then quickly and accurately determine the recommended Phase II dose.

Key to this achievement were the weekly coordination meetings with the CDM and biostats departments. As a result, resources were planned on almost real-time trial status, thus reducing time- and resource-wasting activities.

It´s also worth noting that CDM staff do not always have the necessary understanding to ensure the data being collected is appropriate to meet study endpoints. This can jeopardize an entire trial, but we were able to assure appropriate data collection by having the eCRF reviewed by a statistician.

, MS, Chief Commercial Officer, IDDI Group

Phase I/II study in cancer patients showcases eClinical effectiveness.

Integrating Technology and Expertise 

Our 2022 Clinical Research Industry Salary and Employee Satisfaction Survey Report, a biennial survey of clinical trials professionals, conducted with our survey partner SCORR Marketing, shows no overwhelming deviations this year from previous years. However, our 

 was conducted and published prior to the COVID-19 lockdowns. This update, conducted and analyzed in Q4 2021, included questions to highlight some of the concerns regarding clinical research employees’ salary and job satisfaction in light of the pandemic.

Keep in mind that this is an open survey to subscribers of 

, which is a very diverse representation of roles, types of organizations, and locations. In Figure 1, you can see the various functional areas and, expectedly, a higher proportion of clinical operations respondents, as that is our core content focus. This is also a similar representation from our 2020 survey.

Diving into the types of organizations our respondents work for was as follows:

The remainder of the respondents were employed as consultants, with service providers, medical device companies, and other, which included manufacturers, non-profits, government, and healthcare. This compares roughly equally to our 2020 survey, with growth in pharma/biopharma and loss in the academic institution representation.

When we look at levels of responsibility, our respondent comparisons from 2020 to 2022 are listed in Figure 5 below. Again, these surveys are completely voluntary and confidential, but this information comes to bear when we examine job satisfaction levels, and more impactfully, salary levels.

In our 2020 survey, we presented salary data in the aggregate. This year we segmented it by the levels of responsibilities and salary plurality, which is listed in Figure 2 below. Not surprisingly, when we look at the numbers of professionals that received supplemental income, such as bonus or commissions, the 40% majority do not. And the combined 30% that do receive that income average less than $10K. In addition, 75% of the respondents do not receive non-cash compensation such as a car, stock options, or mobile phones.

Coincidentally, BDO publishes its annual CRO Industry Global Compensation & Turnover Survey at this same time each year. This survey collects data for 268 positions in the US and 55 countries outside of the US, and is designed to help clinical research outsourcing companies develop confidence in their pay levels by providing data necessary to gain insight into their compensation practices relative to the market. Its 

When we last checked in with Judy Canavan, managing director and Compensation Surveys leader in BDO’s Global Employer Services practice, it was regarding their 2020-2021 insights 

. The main takeaway then was the continued high rate of employee turnover within CROs, particularly for the clinical research associate (CRA) role. Average turnover in the US for clinical monitoring from 2015 to 2019 was 26%, which Canavan ascribed stagnant compensation levels relative to employee competency development as the main culprit. By mid-2020 with COVID in full swing, Canavan said employee resignation was signaling a growing concern. From a BDO-sponsored poll of 15 CROs year-to-date, US turnover was over 21% as of early November 2020.

The most recent 2021/2022 report better highlights the impact of COVID on CRO roles. Canavan tells 

 that globally, at the early time of COVID, companies were not budgeting huge pay increases because of the uncertainty. “This is understandable,” says Canavan. “There were some layoffs, merit increases were either non-existent or lower than previous years. As the pandemic progressed, and companies figured out how employees could work from home, how they would be handling travel, and managing risk with patients, they became comfortable and business continued.”

But this is where CROs, as well as other industries around the world, missed the boat. Says Canavan, “Companies didn’t have a crystal ball and by continuing the compensation practices from April 2020, they didn’t catch up. It’s not just CROs.” Canavan notes ADP data that shows that people are switching jobs and getting bigger salary increases than in the past. This is occurring even with the raises that come with the Great Resignation, because inflation is up, and thus buying power is reduced. Canavan continues “…inflation is up, it’s affecting the wages, our economy. It affects how each individual sees their paycheck. For roles that receive less money, that will be more noticeable. The impact of the current inflationary economy varies by individual, it depends on their career stage and life stage whether they will feel those impacts more.”

CROs, which historically increased average pay from 1%-2% yearly, last year averaged a 4% increase. And Canavan notes increases targeted at the CRA and project manager levels. “Statistics broadly find that employees tend to switch jobs or companies after three to seven years and get the largest percentage increases to their salaries. In the later years, the percentages don’t go as high,” explains Canavan. “But this is tough on CROs. They lose the consistency and continuity of staffing for their studies.”

This turnover in the CRA and project-manager job families has been an age-old problem in the industry. It is a source of angst among pharma sponsors when they lose that primary relationship on their study. But COVID made an already existent turnover issue much worse. The solution? Canavan says that CROs are in catch-up mode.

In the BDO report, Canavan is quoted: “CRO companies face a unique dilemma: turnover is high and salary demands are increasing. However, multi-year contracts with plan sponsors may limit their ability to increase compensation levels as much as needed. As companies negotiate contracts, they may want to reconsider assumptions regarding pay increases for certain key positions in order to stay abreast of the market.”

She explained that CROs have to make assumptions over these multi-year studies and contracts regarding the average costs for the project managers, and if you assume a 2% increase over a year, that is built in. But now, with the escalating salaries, Canavan is suggesting that CROs have plans in place to account for the enhanced competencies of an individual. In the first five to seven years, employee value increases much more quickly than 3% a year (a typical merit increase).

“Because the leaving and onboarding process is time-consuming and costly for employers, why not look to increasing the base pay via merit increases for current employees? You are going to have to find the money somewhere,” says Canavan. She is also pushing CROs to invest in their HR departments to help implement budgets, career ladders, and compensation/benefit levels the right way. “They are having a problem implementing some of these proactive practices,” says Canavan. The BDO report outlines in more detail how CROs can better help employee recruitment and retention.

As Canavan noted, the BDO survey is CRO-specific and is based on over 60,000 lines of data that are instructive to the CRO survey members to make decisions on overall job market roles and structure. Our survey explores respondents on an individual level. As such, our survey found that participants are more likely to receive supplemental income (e.g., a bonus) than non-cash, but the majority is $5k or less. However, we did not dive deeper to uncover if this was a sign-on bonus trend, or a stay-on-job bonus.

We found that the majority of respondents answered “No” to the question, “Has your company reduced its workforce in the past year?” at almost 75%. And as far as the “Turnover Tsunami” effect listed in Figure 3 below, there were different levels of waves, with a little over 20% finding no turnover. Anecdotally, an indeed.com search of jobs in clinical research brought back 32,727 positions available.

However, for individuals looking to change jobs this year—which was in the minority at 44%—reasons listed in order of response were better compensation, professional advancement, and better career development options and “better utilize my skills” tied for third. “Other” responses varied from work/life balance, low resources, and managerial issues.

For another COVID perspective, respondents felt their companies performed well with COVID in reducing the spread of the virus; providing remote work options; encouraging employees’ physical well-being; addressing employees’ mental well-being; and managing employee workloads.

One final note on the effects of COVID on job roles. Our survey did explore the effect of the pandemic and the impact on skills sets, which is shown in Figure 4 below. When we asked what the biggest challenge was outside of COVID, many said COVID was the challenge, with answers ranging from lack of travel or face-to-face meetings; working from home; and not being able to visit investigational sites.

Clearly, the moves of clinical trials, working from home, and inability to visit sites sits squarely in the CRA role. With the increased use of remote monitoring, as well as other decentralized strategies coming to bear on clinical trial conduct, those roles will be evolving. Canavan believes we really can’t determine right now what the CRA job description will resemble in five years. However, with technology pushing to telehealth and remote monitoring, Canavan says there will most likely be a restructuring of the role. Turnover rates with CRAs could be tied to their very grueling travel schedules, she adds, demands that could potentially be de-stressed with those technologies. However, with the crisis of COVID hopefully soon over, time will be the true marker.

Download your free copy of the SCORR Marketing report. 

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

With large shift to decentralized strategies, industry roles appear set for change.

Salary Survey: The Age of COVID

“The beginning of an exciting new phase for clinical research in Europe” is how the European pharmaceutical industry has greeted the latest initiative from the European Union to boost clinical trials. The cause of the excitement is the announcement early in the new year of “Accelerating Clinical Trials in the EU,” a bid by the key EU medicines authorities with the explicit aim “to transform how clinical trials are initiated, designed and run.”

The European Medicines Agency, the European Commission, and the Heads of Medicines Agencies have come together with a plan to develop the EU “as a focal point for clinical research” and to better integrate clinical research into the European health system. Priorities for the next two years are enabling innovative trial methods, and setting up a platform where all the many stakeholders–from patients and payers to regulators and academia–can come together to support this evolution, taking account of the demands both of innovation and of patient safety.

 is a concrete response to the evident changes in which clinical trial designs are becoming more innovative, with new formats offering possible efficiencies and a more patient-centric approach. Attention has been rising in Europe to complex clinical trial designs, decentralized trials, artificial intelligence, and the use of machine learning, digitalization, and the links of growing importance with 

 diagnostic devices, as well as to the potential of digitalization for patient monitoring and data generation. Until now, however, the disparate groups affected have been lacking the coordination and collaboration that is increasingly seen as necessary on all sides.

The plan is to strengthen leadership and coordination on clinical trial authorization and execution, and at the same time to optimize ethical oversight, integrating ethics committees more closely into clinical trials and the related regulatory activity. This, it is expected, will also support the conduct of large-scale multinational clinical trials with broader geographical scope, and reduce administrative burden while
increasing efficiency.

In a candid assessment of the need for change, the launch document for “ACT-EU”—as it is already coming to be known—admits that even after two decades of EU legislation aimed at improving the environment for clinical trials, “disharmony of regulatory requirements between member states complicate the submission of multi-state trial applications,” and “the resulting slower trial authorizations could negatively affect research responsiveness,” while “the expenses to conduct trials are high.”

Specific objectives range widely, and include protection of trial participants, ensuring data robustness and transparency, tackling unmet medical needs and rare diseases, and helping development of vaccines and therapeutics as insurance against public health crises and pandemics. Additional aid is foreseen for health technology assessment bodies as well as for academic and smaller-company sponsors of trials, and the plans extend to better-coordinated scientific advice and—at the most ambitious—to enhancing “capacity in all aspects of drug development and
regulatory science.”

The expectations are that the first two years of ACT-EU will be taken up with preparatory work, building on the implementation of the EU’s new clinical trials regulation and clinical trials information system, while engaging the full range of stakeholders and expert groups involved across the clinical trials community, modernizing good clinical practice (GCP) in line with the development of guidance at the International Conference on Harmonization, and developing a clinical trials training curriculum for wide use.

The January announcement of ACT-EU is often rebarbative, with its reliance on buzzwords–leveraging, matrix structures, mapping and dashboards—and with what looks like a parody of management consultancy-speak in its plan for “a framework of Do, Require, Influence, Support.” But the evidence is largely undisputed of the genuine need for some greater European coordination in improving the environment for clinical trials.

For the industry, the desire for change is widely documented. Eucope, the European body representing smaller research companies, has told the European Commission that for newer technologies such as the cell and gene therapies that concern many of its members, “it is essential to generate evidence through pathways other than the classic approach reliant on pre-authorization randomized clinical trials.” Many such technologies would benefit from post-licensing evidence generation through real-world evidence (RWE), it says—as well as from “an appropriate process for early and regular engagement with the EMA.”

View from Brussels

2022 EU initiative provides hope for improvement of trial regulations.

A(nother) New Start for Trial Regulations in Europe?

Many signs point in the right direction for the potential to increase the dismal numbers of patients participating in clinical trials. The lessons regarding remote and hybrid clinical trials during COVID, the increased response to Clinical Research As a Care Option (CRAACO), and a growing number of companies—be they analytics or integrated research organizations—seek to place patients as participants in trials, closer to their physician and diagnosis.

Recent changes, coupled with existing policies, to the largest single payer of healthcare in the United States, The Centers for Medicare and Medicaid Services, could also positively impact the numbers of people participating in clinical trials. First up, learned through this 

 written by Scott Gray, co-founder and CEO of patient support services provider Clincierge, are legacy Medicare changes.

Medicare, the largest single healthcare payer for Americans aged 65 and over, required routine costs associated with clinical trial participation be covered. This year 2000 mandate led to increased clinical trials participation in patients over 65, from 25% to 38% between 1993 and 2003. Ten years later, the 2010 Affordable Care Act required all private insurers and health plans to provide the same coverage for clinical trial participants. These covered costs include fees for hospital stays, doctor and lab visits, diagnostic testing, and other medical services routinely covered if the patient was not enrolled in a clinical trial.

It was only Jan. 1, 2022, that Medicaid, funded by both the federal and state governments, granted clinical trials coverage to its 76 million American beneficiaries—mostly underrepresented populations. Sixty-one percent of Medicaid beneficiaries identify as Black, Hispanic, Asian American, or another non-white race or ethnicity.

Though this does offer sponsors and CROs new opportunities to diversify and increase patient populations, it is not without its challenges. There remain ever-present obstacles to recruiting patients, as well as retaining them.

One can only assume that Medicaid patients will need navigation help through site assistance to achieve clinical trials coverage. However, a recent experience leaves me slightly pessimistic as to the ability of the healthcare system to help improve clinical trials. If true changes to help patients navigate all healthcare systems, which includes their caregivers, family, and support systems, are to help clinical trials, healthcare needs a lesson in patient centricity learned from clinical trials.

From the Editor

Looking to US Medicare/Medicaid to increase patient participation.

A Lesson Learned in Patient Centricity

Hennessy spent his career turning his passion for building businesses and creating jobs into a run of successful ventures and brands. Following his graduation from Rider University in 1982, he started his career in medical publishing as a sales trainee. In 1986, Hennessy became chief operating officer of Medical World Business Press, which was part of the launch of medical newspapers and other media products. The company prospered and was eventually sold to a Boston-based venture capital firm.

Hennessy launched Multimedia Healthcare, LLC, in 1993 and built a portfolio of award-winning clinical journals. In 2001, Freedom Communications, Inc., acquired Multimedia Healthcare, about the time that Hennessy was pioneering a new approach to print and digital publishing with Intellisphere, LLC (now part of MJH Life Sciences). Guided by the principles of innovation and entrepreneurial spirit, and reflecting its founder’s dedication to improving quality of life through health care research and education, Intellisphere publishes a variety of integrated print and digital products focusing on a range of topics in research and clinical medicine.

To build a comprehensive multimedia and education platform, Hennessy added additional companies to the MJH Life Sciences portfolio. In 2004, he acquired Healthcare Research Analytics, which has been the leader in health care market research for over 30 years. In 2005, Hennessy acquired ArcMesa Educators, LLC, leaders in online certification for physicians, pharmacists, nurses, and other health care professionals. Reflecting his lifelong interest in politics, Hennessy acquired 

 magazine in 2005, publishing the journal through Political World Communications, LLC. He sold the publication to Biteback Media Ltd in 2011.

In February 2008, Hennessy acquired the rights to the journals 

, both recognized in their respective markets as authoritative, trusted media platforms that provide essential information to a large audience of health care professionals.

In April 2011, MJH Life Sciences acquired Physicians’ Education Resource, LLC (PER), an accredited continuing medical education company that is an industry leader in producing high-quality, first-rate oncology and hematology meetings and conferences. The PER acquisition included a variety of multichannel enduring educational activities, as well the rights to legacy medical meetings, such as the annual Miami Breast Cancer Conference.

Hennessy’s commitment to improving the lives of patients with cancer is deeply rooted within the halls of MJH Life Sciences. As a complement to the industry leading OncLive platform, he developed the Giants of Cancer Care awards to recognize the leaders and pioneers who often go unrecognized for their contributions to advancing oncology care. He further strengthened his commitment to education by acquiring CURE Media Group in 2014, followed by the purchase of the Chemotherapy Foundation Symposium, in his quest to provide oncology professionals with focused education on innovative cancer therapy.

In 2019, MJH Life Sciences made its largest acquisition to date when it acquired the Healthcare and Industry Sciences divisions of UBM Medica, nearly doubling the size of the organization and adding legacy titles such as 

 to his already impressive portfolio. This acquisition made the organization the largest independently owned medical communications company in North America. In addition to acquisitions, Hennessy organically developed ancillary in-house agency divisions with Proximyl Health, Truth Serum NTWK, and MJH Global Medical Affairs.

Later in 2019, Hennessy elevated his own role to Chairman while naming his son, Michael J. Hennessy Jr., to assume the leadership role of the organization and carry on the family legacy. Under his son's leadership, the company enhanced its global potential by entering into a long-term partnership with BDT Capital Partners, LLC in November 2021.

Due to his broad business and educational experience and understanding of the challenges facing New Jersey, Hennessy’s counsel and insight had been sought by several organizations, including his alma mater Rider University, where he served on the Board of Trustees and was elected to the executive committee. In addition to being active in state and national politics, Hennessy also had a long record of service at the local level, where he was a strong advocate for veterans and environmental issues.

Hennessy was preceded in death by his wife, Patrice Hennessey, who bravely battled cancer for almost 10 years until her death in January 2020. Hennessy donated $4 million to Rider University to expand the Science and Technology Center at their alma mater. The Mike & Patti Hennessy Science and Technology Center is set to be completed in 2022.

Michael J. Hennessy, Sr., was the beloved chairman and CEO of MJH Life Sciences, parent company of Applied Clinical Trials.

In Memoriam: Michael J. Hennessy, Sr. (1960-2021)

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Applied Clinical Trials January/February 2022 Issue (PDF)

Delays in sponsors providing post-approval evidence of effectiveness for therapies benefitting from streamlined FDA regulatory pathways, along with high launch prices on many of these quasi-experimental medicines, is generating pressure for further review and reform of the agency’s accelerated approval (AA) process. FDA reports that only about half of AA products have completed research to confirm benefits, including many leading oncology treatments carrying “dangling” indications. The agency’s approval of Biogen’s Aduhelm Alzheimer’s treatment last year based on questionable surrogate endpoint data, moreover, has heightened calls among legislators and researchers for tightening study timeframes and clarifying program requirements.

Deliberations by FDA’s Oncologic Drugs Advisory Committee (ODAC) accelerated the debate with its April 2021 meeting to assess the lack of confirmatory evidence for added uses of several leading cancer therapies. Since then, members of Congress, officials at FDA and other federal health agencies, sponsors and research organizations have weighed in on both the benefits in facilitating early patient access to effective treatments, along with the need to reform the process and timeframes for fully evaluating early evidence of effectiveness. Since then, several biopharma companies have withdrawn certain uses for therapies unable to provide that confirmatory data. Most recently, Gilead Sciences pulled two indications for the cancer drug Zydelig, acknowledging difficulties in providing evidence to support those uses since approval in 2014.

Now AA revision tops FDA policy reform lists. While sponsors often experience difficulties enrolling patients in clinical trials once a therapy is available on the market, weak FDA penalties for delay, as well as incentives for a firm to provide an approved therapy for as long as possible, contribute to perennial delays in submitting follow-on results. The need for better systems to generate reliable information on medical product safety and effectiveness was cited as a top priority by Robert Califf at his Senate confirmation hearingin December, and he is expected to tap his expertise on providing timely and valid clinical research data in addressing these issues. The discussion is slated to involve appropriate use of real-world data (RWD) to support post-approval studies, as well as requirements for sponsors to design and launch confirmatory trials at the time of application approval, an approach that has become a regular discussion point in FDA-sponsor preapproval meetings.

Also up for debate are proposals to penalize sponsors for excessive delay in launching and conducting these studies and for the Centers for Medicare and Medicaid Services (CMS) to limit Medicare reimbursement of a drug until the manufacturer confirms early indications. While such requirements raise concerns about discouraging investment in innovative R&D, additional public-private collaborations could expand the infrastructure and lower the cost of conducting post-approval studies. And wider acceptance of RWD in confirmatory studies would be particularly helpful for small biotech companies that lack resources to prepare for or conduct post-approval studies before gaining initial market approval. These and other issues were discussed by Califf at others at a January conference organized by the UCSF-Stanford Center of Excellence in Regulatory Science and Innovation (CERSI).

The current debate builds on considerable discussion of the AA program in recent years. Richard Pazdur, director of FDA’s Oncology Center of Excellence (OCE), has provided strong support for breakthrough and other accelerated development and review programs for cancer drugs, along with proposals for improvement: OCE’s Project Confirm seeks better compliance with post marketing requirements for oncology therapies benefitting from accelerated program.

 A white paper from the Institute for Clinical and Economic Review (ICER) in April 2021 presents proposals for revising and strengthening the AA process.

 And a broader reform proposal prepared in 2020 by the Friends of Cancer Research (FOCR) set the stage for identifying ways to maintain early access by addressing AA concerns.

Additional information on FDA’s accelerated approval process is available

, as well asa useful summary of the agency’s four similar, but different, programs to facilitate patient access to new medicines.

https://www.gilead.com/news-and-press/company-statements/gilead-statement-on-zydelig-us-indication-for-follicular-lymphoma-and-small-lymphocytic-leukemia

https://www.fda.gov/about-fda/oncology-center-excellence/project-confirm

https://icer.org/wp-content/uploads/2021/04/Strengthening-the-Accelerated-Approval-Pathway-_-ICER-White-Paper-_-April-2021.pdf

https://friendsofcancerresearch.org/sites/default/files/2020-11/Optimizing_the_Use_of_Accelerated_Approval-2020_0.pdf

https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/accelerated-approval

https://www.fda.gov/patients/learn-about-drug-and-device-approvals/fast-track-breakthrough-therapy-accelerated-approval-priority-review

View from Washington

Uncertainty over experimental medicines calls for review of AA process. 

Concerns Mount Over Limited Evidence for Accelerated Approvals

Asia’s biopharmaceutical enterprises are seeing massive market penetration opportunities in the West. Their ability to conduct early-phase trials in Asia at a lower cost and then obtain funding to run later-phase trials in the US puts them at an advantage. As a result, they can enter the Western marketplace with lower-priced medical products. In this interview, Dr. Harish Dave, CEO of Singapore-based AUM Biosciences, discusses evolving strategies for Asian biopharmaceutical enterprises.

Moe Alsumidaie: What is AUM’s vision of bringing affordable cancer treatments and more agility in clinical trials and go-to-market strategy?

 The traditional arena for clinical research has been the US, Western Europe, Japan, and other “westernized” countries based on the robust regulatory framework, capable investigators, and strong research facilities. As the number of clinical trials has increased over time, so has the cost of clinical research. The number of patients willing to participate in clinical research has remained flat or even declined, hampering recruitment and timely study completion. Additionally, facilities and researchers are at a saturation point resulting in further delays.

We have seen several countries in the Indo-Pac region develop a more robust health care and research infrastructure, with highly regarded investigators at the helm of affairs. Patients in these regions are more willing to participate in clinical research, while the population size enables speedy recruitment. Labor and cost arbitrage between regions means we can conduct world-class research cheaper and faster than is possible in the US and EU. The critical element, of course, is that there can be no compromise on trial design, execution and data collection to deliver a robust drug development package. These advantages can be used to carry out Phase I rapidly and, to an extent Phase II studies before incorporating US and EU sites into global Phase II and III designs.

This approach led to the rapid conduct of Phase II and II oncology trials at premier centers and at a global standard before involving many sites and countries, including the US and EU. The time savings results in a longer market time before patent expiration, and there is also the direct cost savings from labor and cost arbitrage.

AUM’s executives are an experienced and diverse group of individuals who have spent time in almost every major region of the world and have the experience and knowledge to use the Indo-Pacific region to accelerate drug development. This translates directly into going to market strategies that do not rely on extracting the maximum price the market will bear but, instead, on a realistic price. More patients stand to benefit from this affordable drug development strategy. AUM hopes to do its part in reducing health care inequities that continue to plague the modern world.

The traditional flow of drugs from the West to the East brings “western costs.” AUM’s strategy is to reverse this flow and go from Asia to the West, satisfying the need of the Asian population for innovative and affordable drug development and reducing the cost of health care in Western countries by introducing drugs at an “Asian” price point.

MA: What challenges have you faced in your Oncology trials?

In a sense, this is not dissimilar to other areas of clinical research but is perhaps more of an issue in oncology. The advances of the last 2-3 decades have resulted in a great deal of segmentation within oncology diseases. Many of our newer therapies address small subsets of patients with inclusion criteria requiring documentation of a particular mutation or biomarker and, sometimes, exclusion of other mutations or biomarkers. This segmentation means we are looking to identify relatively rare subsets for study entry which slows the recruitment process. A classic example is Phase I oncology work. The traditional 3+3 design recruiting “all-comers” with solid tumors can quickly recruit. But if only certain tumor types or certain biomarkers are required, that can greatly slow down fulfilling recruitment goals for each dose cohort.

The second issue is compliance, especially as we move to oral therapies self-administered by patients. Even with a potentially terminal diagnosis, patients may not take their medication on time, or in a fasted or fed state as required, or forget to take medicine altogether. As a general rule, the longer someone is on therapy and the greater the adverse events (AEs), the lower the compliance. This leads to gaps in data and impact outcomes, necessitating a larger trial size to overcome this obstacle. Paradoxically, having a good response may also lead the patient to become non-compliant.

Study retention also can be difficult in a cancer population. Many patients are already debilitated from their underlying disease. Adding to that, AEs of our medications, frequent clinic visits, blood draws, imaging, and other invasive procedures make retention challenging.

The COVID pandemic has also resulted in additional challenges–our patients are reluctant to venture out and risk infection in their immunocompromised state. Many clinics and hospitals are not allowing caregivers to enter the facility to minimize the risk of contagion. And several doctors stopped seeing patients or relied heavily on telemedicine which may not be entirely satisfactory to the patient. From the investigator and pharma perspective, clinic visits were disrupted with missing data and delayed imaging, and Clinical Research Associate’s (CRA) inability to get on site (though this has been mitigated by remote access to Electronic Medical Record (EMR) EMRs). As the omicron variant has demonstrated, we will continue to see newer and potentially more infectious variants emerging, making it difficult to go to the status quo.

MA: How is the pandemic posing challenges for your clinical trials?

 AUM Biosciences were fortunate that our Phase I study had completed recruitment just before the pandemic started. However, the dislocation in services from widespread lockdowns resulted in significant delays in data collection and management of research samples. Critical plasma and serum samples were left to languish at research sites for many months with potential degradation of analytes and loss of valuable clinical research information. Even when we could transfer them to appropriate laboratories for analysis, the staff shortages, backlog of samples, and supply chain disruption of critical reagents and parts caused troubling delays in obtaining and analyzing data. From discussions with other, similarly situated biotechs, we know that recruitment on studies ground to a halt and has only barely started to recover. Investment capital dried up rapidly–many investors became gun-shy and preferred to hold on to dry powder rather than invest when the level of uncertainty was high. And what investment dollars remained made a beeline to COVID-related research and mitigation strategies. This was particularly punishing for small biotechs heavily dependent on ongoing capital raises to fund their research burn.

This was a tremendous learning experience for many of us. It showed how critical the global supply chain was for clinical trials, not just for large companies and medium to heavy industries. Established vendor relationships were crucial to helping many of us weather the cash crunch we faced–their tolerance and willingness to extend credit and offer favorable payment terms helped many biotechs stay afloat. The lesson that cash is king was driven home by the shortage of investment capital during much of the pandemic. It served to emphasize the importance of securing enough financing, including debt financing, to survive such a significant global dislocation.

We, at AUM, were undoubtedly fortunate in that regard. As a company built by industry veterans in the clinical trials space, our extensive and deep connection with contract research organizations (CROs) and other vendors at their highest levels allowed us to secure favorable terms when money was hard to find. Despite omicron, there is a sense that we are emerging from this crisis and, to an extent, have learned to live with it allowing business to go on and research to go forward.

MA: Out of all the small-molecule drugs developed by AUM Biosciences, can you cite a case study wherein AUM Biosciences managed to overcome challenges in a unique way?

 AUM has a portfolio approach to drug development and has worked hard to build out a pipeline of drugs at various stages of development, from pre-clinical to Phase I (and now Phase II). While all aspects of business activity slowed down and clinical research almost ground to a halt, we were able to reprioritize our work by shifting the focus to earlier stage drugs and testing in cell culture and animal models instead of human subjects. This allowed AUM to retain staff (and even grow) during the pandemic and progress the portfolio to a point where we could rapidly go back to the clinic once the research facilities opened up for business. Such risk mitigation would not have been possible with a single molecule company–not only would that have delayed us significantly, but it likely would have necessitated a reduction in force. Once disrupted, carefully assembled teams can be hard to put together again and lead to the impaired outcome for many months or years after the event.

Most small companies in our space are far too busy managing their day-to-day activities to pay attention to global risk management. However, COVID has taught us that proactive global risk management is critical, perhaps even more so for small than large businesses. The C-suite must contemplate black swan events and strategies to mitigate against them.

MA: Tell us more about your clinical trial pipeline and if you have any specific strategies to ensure success in times of a pandemic that has impacted investments, focus as well as the speed of clinical trials.

 AUM has two advanced candidates entering Phase II trials and additional candidates in late pre-clinical, all backed by an AI-driven drug discovery platform and a biologics platform. Our approach is to drug the undruggable and avoid or overcome resistance through combination therapy approaches. Drugs in our portfolio are selected for their activity against a single cancer type and, ideally, multiple cancer types, thereby giving us various shots on goal. A consequence of this “one drug many targets” approach is the scalability of our research enterprise. This is amply demonstrated with the AUM001 MNK inhibitor. This selective translation inhibitor has activity in several solid tumors, which allows us to scale our research effort to explore one or multiple tumor types as determined by the availability of capital and availability of clinic resources during the COVID pandemic. Newer trial designs like basket trials allow us to efficiently explore multiple disease targets cost-effectively, channeling investment into the successful arms and pruning the unsuccessful arms. Using Indo-Pac countries as our home ground advantage, we can execute our studies more rapidly than many of our West-focused counterparts. Speed is of the essence in drug development as the patent clock is ticking–every week saved in development is an additional week of patent-protected marketing of the drug.

, MBA, MSF, is a thought leader and expert in the application of business analytics toward clinical trials, and Editorial Advisory Board member for and regular contributor to Applied Clinical Trials

Dr. Harish Dave, CEO of Singapore-based AUM Biosciences, discusses evolving strategies for Asian biopharmaceutical enterprises.

Asian Biotech Clinical Trial Demand Moves to the West

Digital transformation within the life sciences industry has triggered massive shifts in clinical trial operations. As a result, team member roles and functions are rapidly evolving at all stages of therapeutic development, particularly for organizations running decentralized trials (DCTs).

As the pandemic continues to accelerate the transition to hybrid and fully virtual trials, the need for specific competencies and mindsets to suit DCT business models is creating new challenges and opportunities in team building, training, and development.

ObvioHealth has been conducting decentralized and hybrid trials for almost five years, and thus has first-hand experience in the evolution of digital trial teams. We are a virtual research organization striving to deliver better clinical trial data while reducing the burden on patients. This mission, along with rapid sector growth, has attracted a dynamic team of young and talented individuals. In 2021, we onboarded 71 team members, mostly in product development but also in clinical operations, sales, marketing, and finance.

The industry’s transformation is driving a shift in the skillsets we need to design, recruit for, and operate studies. A raft of new clinical trial roles has emerged—from front-end developers to virtual study coordinators. Many of these roles require unique cross-functional competencies spanning clinical operations, project management, and software engineering. For example, clinical operations team members need to be able to optimize a study protocol for the virtual environment. To accomplish this, they must partner closely with software developers to configure the platform so that it can accommodate all necessary specifications.

These cross-functional roles require a departure from traditional, top-down working models. Those who have worked previously at large organizations with rigid structures have learned a form of risk aversion within this heavily regulated industry. They frequently carry these behaviors into their next roles. But, working in DCTs requires an openness to learning and a willingness to challenge the status quo. Our teams are developing technologies that augment the capabilities of clinical trial sites and patients. As they innovate, their expertise is also helping regulatory bodies to evolve certain guidelines and regulations that no longer apply in a DCT environment.

In our fast-moving environment, we make strategic decisions quite quickly and often need to pivot in order to seize opportunities, from new technologies to new partnerships or new geographies. We need to arbitrate wisely when weighing options so that we don’t run off in too many directions at once, striking the right balance between agility and strategic clarity. It’s critical to align departments often, so we can ensure the team is headed in the same direction. In this environment, the most successful team members must have the intellectual flexibility to pivot when necessary. They must understand the “why” behind a given process and to apply those principles in innovative ways.

To address the constant evolution in health and clinical research, companies may need team members to shift responsibilities—for example, moving from the Clinical Operations department to Product Development. Some team members at ObvioHealth have transitioned from running and managing trials for clients to designing the company’s app and trial platform.

While these roles might seem distant cousins, pivoting across functions has become standard, and even desirable, in organizations like ours. The industry requires adaptable talent. Lateral-thinking clinical researchers, when working within highly matrixed and cross-disciplinary teams, are in an excellent position to design effective products.

Team members who come to a role with previous experience bring with them the ability to tailor study protocols and design to meet sponsor objectives. One ObvioHealth colleague, Joshua Lowndes, previously managed projects for the National Cancer Institute at a publicly funded CRO. He joined ObvioHealth’s Clinical Operations department and now works in product tech.

Lowndes remarked on his career progression: “I joined the company as a scientist focused on publications and realized I needed to position myself for the next role, and this one happened almost as a lucky accident,” he said. “In my academic career, I designed and implemented studies. In my previous roles, when writing protocols, I’d always think about the participants and their needs. This job enables me to lean on that experience and perspective in product conversations. The opportunity to do that here, in a very intentional way, really resonated with me.”

Another colleague, Senior Product Manager Kamalia Sazali, has a clinical background and has worked in implementation, bridging the gap between science and real-world data. She recently transitioned into a new role developing ObvioHealth’s next-generation product and platform.

“This job is the furthest out of my comfort zone I have stretched in my career, but it’s the most exciting,” Sazali said. “We’re taking our learnings and improving the participant journey. We’re asking: Can we start with the tech and see how it improves the protocol and drives interactions and engagement? We’re taking a more product-driven approach that uses all of our clinical expertise.”

When parameters change over the course of the study, an experienced DCT team has the knowledge and flexible thinking necessary to pivot. In some cases, this may require changes in recruitment parameters. In other cases, the team may identify tools that can capture new endpoints and potentially lead to novel outcomes. Clinical research experience gives these team members a big-picture perspective on decentralized trials, enabling them to accelerate certain decision processes. Their access to real-time, granular data puts them in a position to capture insights that may influence a study’s direction. For instance, in a recent study, they were able to simplify and streamline an ongoing trial by reducing the number of outcomes captured through digital devices to make the study completion easier for participants. This willingness to challenge the status quo is key to success in categories like ours.

The benefits of varied experience and open-minded thinking are equally relevant for business development representatives who must have a deep understanding of protocol requirements but are also able to think outside traditional boundaries. The BD team plays a key role in working with clinical experts to design studies that integrate new digital instruments and processes that can more accurately capture data while addressing any regulatory hurdles.

Creating a participant-centric experience

Clinical expertise drives benefits for patients as well. Virtual site clinicians who have held previous roles at traditional sites know the importance of engaging with patients. Brick-and-mortar site clinicians have always assisted participants in person, but decentralized trials have introduced a new and burgeoning category of virtual support teams.

The need for specific capabilities to suit DCT business models is creating new challenges in team building, training, and development.

Applied Clinical Trials-02-01-2022