, it’s back to school for clinical trials professionals! We are focusing on good clinical practice (GCP) and how to “audit-proof” your clinical trials. While keeping tabs on GCP has always been important, the task has only gotten more complex in recent years. The increased adoption of decentralized clinical trials (DCTs) and technological solutions are among the reasons for this. It is crucial to remain compliant in an area that is highly regulated.

This is also our first issue since our editors attended the 2023 DIA Global Annual Meeting in Boston, MA, in late June. A number of themes emerged through the sessions and interviews, including patient data, regulatory compliance, and diversity. You can visit our 

 to check out our latest event show coverage in its entirety.

, regular contributor and freelance writer Christine Bahls gives an overview of how the industry can raise the bar in GCP adherence. Key industry leaders provide insights on improving training and real-time application, as the list of GCP items is only proliferating amid the rise of digitalization. The end goal is avoiding compliance pitfalls in conducting clinical studies.

 focuses on the International Council for Harmonization’s (ICH) Good Clinical Practice (GCP) E6 guidance. Through the COVID-19 pandemic, drug developers learned a lot from the spike in DCTs—the practical challenges and benefits. However, at the time, ICH’s GCP E6 R2 guidance was out of date and did not address DCT elements. With the draft R3 version being issued in May, there are a new set of principles when it comes to DCTs that sponsors must support their investigators and sites in carrying out.

This issue’s trio of feature articles concludes with a 

 on eSource interoperability in the transfer of data from electronic health records (EHRs) to electronic data capture (EDC). Through a live pilot study, embedded within a Phase III cancer trial, experts were able to conclude that the industry is indeed taking steps toward establishing EHR-to-EDC as a highly effective option for clinical trial data requirements.

 is the president and CEO of Applied Clinical Trials' parent company, MJH Life Sciences

Articles

Publisher's Note

Increased adoption of decentralized trials and new advancements in technology among reasons for evolving regulatory landscape.

'Audit-proofing'  Your Trials

When the Big Pharma giant Pfizer abruptly aborted its relationship with decentralized clinical trial (DCT) specialist CareAccess six months ago, the company issued a terse statement regarding its decision: Pfizer blamed CareAccess for committing unspecified good clinical practice (GCP) violations. Hence, CareAccess could no longer continue recruiting participants for the huge, joint Pfizer-Valneva DCT for their Lyme disease vaccine candidate; those it had recruited were cut from the study. Since then, not a peep out of Pfizer, even after CareAccess told the world, Pfizer was wrong. Of the 96 or so trial sites, CareAccess had 28.

One would expect all hell to have broken loose at CareAccess. Yes, people lost their jobs and the negative press certainly wasn’t welcome. But one also would expect that other CareAccess clients would have broken their ties, or at least conducted audits of CareAccess’ conduct. But the CareAccess website shows numerous recruitment efforts still ongoing; it also shows it is hiring for multiple positions. As one source said, “Projects are continuing at CareAccess and things are still working. It is a strange thing.”

In a statement about its practices, CareAccess said: “Beyond the required GCP course all employees are required to complete, we also provide hands-on training in small groups both when employees are onboarded and every year as a refresher. Further, we run regular simulations at our sites to learn how to adapt to and address challenges that might arise and to ensure high-quality participant care.”

CareAccess declined to answer questions regarding the trial; Pfizer did not respond to email requests for comment.

Pfizer’s decision to begin new recruitment efforts won’t be cheap.

“It is extremely expensive for Pfizer to do this,” says Francis Crawley, executive director, Good Clinical Practice Alliance – Europe. There is “no sense in working with a site if there is no confidence in the data.”

If it’s a question of confidence in the data, then what would help instill that? Training.

Adhering to GCP requires more than just knowing the rules, says Crawley. It is understanding and knowing how to apply them in real time. Like following a recipe. You have an ingredients list, “but if you don’t know how to cook, you can’t do it,” he notes.

The list of GCP items will only get longer due to more digitalization, the move to DCTs, and the use of massive amounts of real-world data to support new molecular submissions.

“We live in a digital world,” says Crawley.

Another good reason for good training: It is likely that many clinical trial sponsors and contract research organizations (CROs) haven’t been fastidious about GCP. One study from 2011 showed that of 80 published trials reviewed, 32% did not report any protocol violations and none reported on all protocol violations looked for in the study, including patient adherence infractions, data collection infractions, enrollment violations, and randomization violations.

Getting through a trial without some sort of protocol violation is a long shot. Jonathan Cotliar, MD, chief medical officer, Science 37, says it is virtually impossible to avoid protocol deviations. Participants and study team personnel are human beings—humans make mistakes, he says. Protocols ask study participants to behave in ways that are not natural, and often create additional challenges beyond the obstacles that present themselves as individuals living with certain medical conditions.

Jerry Chapman, senior good manufacturing practice (GMP) quality expert, Redica Systems, says that protocol deviations are to be expected because clinical trials are about research. “There will always be problems with compliance,” Chapman tells 

. “We ask [clinical investigators] to do an ungodly amount of work.”

A salient point to make here: A clinical trial sponsor spends more money on finding the necessary number of people to prove an investigational drug’s effect than anything else in the study. What determines the second biggest expenditure is the number of visits those patients will make to the clinical site over the trial’s duration.

 Wrote the study authors: “Our statistical model showed trial costs rose exponentially with these two variables.”

DCTs could help with these two variables, but the irony is that to do so will involve copious levels of technology—and the latter will involve copious amounts of training.

Training is an area often overlooked and often used as a checkbox, contends Chapman.

“You have to be able to test someone on their knowledge, to ensure they absorbed it, or they can demonstrate certain skills,” he says. “You can’t read about how to dose a patient and say, ‘I can do it.’” Redica Systems has published an analysis, the data taken from years of FDA 483 inspection reports and warnings, that details the GCP violations made in clinical trials. Just saying that it was a protocol violation doesn’t help, says Chapman.

He has known quality professionals, he adds, who will look at the boilerplate information on an FDA inspection report and the references to the Code of Federal Regulations (CFR) “and not go further. That is a mistake.” It is necessary to read the whole report, because “there are really important parts that let you determine [violation] severity so you can determine how to remedy those violations with action items,” says Chapman. “You can use this data for internal retrospection.”

Whether by coincidence or calculation, FDA, within a span of a few months, has released new guidances covering training, International Council for Harmonization (ICH) E6 (R3), risk-based trial monitoring, and conducting DCTs.

 The agency last addressed the first two topics in 2013. The DCT document, long awaited by DCT providers such as Science 37, advocates for “appropriate training, oversight, and up-front risk assessment and management.” Crawley points out that the ICH GCP guideline includes information on the “appropriate management of data integrity, traceability, and security.”

Another training in waiting: Regulators like real-time monitoring. A 2020 report on a US-European regulators’ symposium said, “The ICH recommends use of centralized monitoring to ID protocol deviations. It emphasizes the need to focus on trial activities that are vital to safety and trial data reliability.”

FDA does not regulate GCP training details—not the scores, not the topics. Sponsors should provide the clinical investigator site team with training specific to the study and their roles as necessary, said an FDA spokesperson via email.

CITI Program is one of many organizations that offers GCP certifications. Jaime A. Arango, EdD, vice president, content and education, said in an email exchange that its subscribers determine their own needs and minimum-score thresholds for GCP training. CITI Program recommends an 80% passing score per module. The core level comprises about 13 modules.

Over the years, CITI has added video case studies, webinars, and new courses, including for clinical trial recruiting, DCTs, and remote and/or centralized monitoring.

Crawley says he has tested online training in which the answers were wrong. It is difficult, he notes, to learn online. GCP requires not only knowing the guidelines, but also being able to apply them, he adds. Classroom training far exceeds online training, but actual experience in a wide variety of situations for applying GCP is really what is needed.

At that 2020 symposium, representatives of FDA and the UK Medicines and Healthcare products Regulatory Agency parsed what GCP is required in preserving data integrity. It’s an important question, considering that data-generation no longer is exclusive to the trial itself, but also includes data from electronic health records (EHRs), real-world evidence and more. For regulators to reconstruct study conduct, a digital hair cannot be out of place.

The attendees, according to that report, said sponsors must monitor use of e-systems, and address issues with data, be they missing, inconsistent, or outliers. They need to fix tech programming issues and “potential protocol deviations that may be indicative of systemic or significant errors.”

In its risk-based approach guideline, FDA said centralized monitoring would allow sponsors to aggregate and then compare data coming from the various sites to “detect potential anomalies more,” including data entry delays and incomplete entries.

In this guideline, FDA is even advising sponsors when to do assessments—early in the morning. This way, if a few protocol deviations are found, they can be, secularly speaking, nipped in the bud.

In practice, risk-based monitoring is, albeit at a snail’s pace, becoming more reality than theory in the field. A 2020 report that reviewed 6,000 published trials found that 77% had at least one risk-based quality monitoring component in play—such as centralized monitoring and key risk indicators —as compared to the prior year’s 47%. Said the authors: “Risk-based approaches have been around for a long time, but adoption has been slow.”

Considering the operational complexity, technical prowess, administrative detail, and skills necessary to help patients, one wonders if a day’s worth of instruction can cover it all, considering the use of telehealth in a DCT.

A passing comment on inspections: They have been down, across the board, over the past few years. But now, thanks to new legislation passed in December, (the Food and Drug Omnibus Reform Act), FDA can request records before a bioresearch monitoring program inspection.

As for the drop in those inspections, while the pandemic is certainly to blame, a US Government Accountability Office (GAO) report from January found there are fewer independent institutional review boards (IRBs) due to consolidation and private equity investment.

FDA, when asked, did not supply a response for the drop in inspections.

Redica Systems, which has designed software to identify regulatory and quality issues so its clients can reduce their own regulatory pitfalls, had been curious about what was behind the reasons for the 483s and the warnings. Protocol violations aplenty, but, says Chapman, the firm wanted to dig deeper. Using artificial intelligence (AI), machine learning, and natural language processing, along with IRB and clinical investigator (CI) reports, they trained their software to look at the violations through a clinical inspectors’ eyes and using their vocabulary. “Based on the IRB and CI, we can drill down on where the issues are coming from,” says Chapman.

They looked at FDA warning letters dated over a seven-year period. The biggest problem they found was that sponsors and investigators were not adhering to their responsibilities. They found that 75% of the data integrity violations concerned issues like attribution or accuracy. They also found a steep drop in voluntary inspections—82 in 2021 vs. 182 in 2017.

Analyzation of the 483s, for which Redica Systems used a data pool from a 20-year period, found that data integrity issues were more common—these included legibility, accuracy, completion, sourcing, and availability issues. Drilling deeper, Redica Systems found enrollment problems such as failure to properly determine subject eligibility. Some participants had supplied bogus names, phone, and social security numbers.

Severity of a violation, according to Chapman, can be difficult to determine and measure.

“A data integrity issue means maybe somebody didn’t save the original document that they transcribed. It may not be faulty, but it means the data is suspect. That gets kind of murky,” he says. “When you talk about a warning letter, beyond a 483, what you will see, for example, is maybe ‘not according to plan.’ That is one of the bigger citations, but how serious is that? That part is in the text that follows. Seriousness isn’t determined by the number of violations.”

Operations at Science 37 seem to reflect regulators’ proposed guidance: one virtual trial site with real-time protocol inspections across all patient data entries—in short, Sauron-like vision from all digital angles. Not necessarily fewer protocol deviations, but if the trends are there, they are easier to identify. One virtual site, says Cotliar, “provides probably a clearer path.”

And that path is pebbled with study team documentation, from the trial investigators to the visiting nurses to those running the platform. “I don’t have to rely on site files to look at other single platforms, to achieve proper oversight,” adds Cotliar.

Training at Science 37, as one would expect, involves various levels, from issues that are protocol specific to getting into the weeds of the technology. “We spend a lot of time in training, its sole focus being, does everybody understand how to use the platform?” says Cotliar.

Is everyone comfortable with it? According to Cotliar, the visiting nurses go through mock visits to trial participants’ homes. They set up the technology that is automatically linked to a unified platform, “to make sure we are complying.” They learn how to handle the technology if the power goes out. All of this, adds Cotliar, takes repeated practice.

Crawley believes that as clinical trials become more digitized, more AI-dependent, attitudes regarding GCP need to advance.

“You have to operationalize GCP,” he asserts. “Training will be important if we are going to have confidence in trials that are increasingly digitized and conducted through different systems of AI.”

 is a freelance writer for medical, clinical trials, and pharma information.

An Efficacy, Safety, Tolerability, Immunogenicity, and Lot-Consistency Clinical Trial of a 6-Valent OspA-Based Lyme Disease Vaccine (VLA15) (VALOR). ClinicalTrials.gov. August 2, 2023. 

https://clinicaltrials.gov/study/NCT05477524?tab=history&a=10

Sweetman, E.A.; Doig, G.S. Failure to Report Protocol Violations in Clinical Trials: A Threat to Internal Validity? 

https://trialsjournal.biomedcentral.com/articles/10.1186/1745-6215-12-214

Moore, T.J.; Heyward, J.; Anderson, G.; Alexander, G.C. Variation in the Estimated Costs of Pivotal Clinical Benefit Trials Supporting the US Approval of New Therapeutic Agents, 2015-2017: A Cross-Sectional Study. 

https://bmjopen.bmj.com/content/10/6/e038863.citation-tools

https://www.fda.gov/media/169090/download

A Risk-Based Approach to Monitoring of Clinical Investigations: Questions and Answers

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/risk-based-approach-monitoring-clinical-investigations-questions-and-answers

Decentralized Clinical Trials for Drugs, Biological Products, and Devices

https://www.fda.gov/media/167696/download

Khin, N.A.; Grandinetti, C.; Dixey, H.; et al. Tackling Challenging Data Integrity Topics in 2020: Update on Good Clinical Practice Perspectives from the US FDA and MHRA UK. 

https://pubmed.ncbi.nlm.nih.gov/34358334/

Stansbury, N.; Barnes, B.; Adams, A.; et al. RiskBased Monitoring in Clinical Trials: Increased Adoption Throughout 2020. 

https://pubmed.ncbi.nlm.nih.gov/35235192/

Thousands of Sites, Less Than 100 Investigators: New Authorities Help FDA Maintain Oversight of Clinical Research 

https://www.fda.gov/about-fda/regulatory-news-stories-and-features/thousands-sites-less-100-investigators-new-authorities-help-fda-maintain-oversight-clinical-research

Institutional Review Boards: Actions Needed to Improve Federal Oversight and Examine Effectiveness 

https://www.gao.gov/products/gao-23-104721

Feature Articles

Stepped-up training and real-time application key to avoiding compliance pitfalls. 

More than Just Rules: Raising the Bar in GCP Adherence 

During the COVID-19 pandemic, the pharmaceutical industry gained experience with the increased decentralization of clinical trial elements, which were traditionally site-based in design and operations. At that critical time, trial sponsors and regulatory authorities turned to the International Council for Harmonization’s (ICH) Good Clinical Practice (GCP) E6 (Revision 2) 

 to find if digital innovations in trial design, emerging technologies, use of service providers, and more were appropriate, ensuring that participant safety and data were protected. Because the document was issued in 2016, R2 guidelines did not specifically address individual decentralized trial elements and related design requirements.

. ICH shifted in direction with this version, going from a process-based approach to one based on principles specific to conducting ethical trial design and quality management. While supporting the use of innovative methods and technologies to improve trial efficiency and success, the R3 guidance focuses on the importance of placing value on patient needs and preferences by designing trials with patients. The ICH GCP guidance will continue to evolve as the industry secures new experiences, solutions, and related insights. In the meantime, it is critical that sponsors, contract research organization (CRO) partners, and site leadership understand what is expected of them as they work to maintain data integrity when using decentralized technologies and processes, keeping patients protected and minimizing burdens for stakeholders.

For investigators specifically, overseeing trial conduct and related data generation, management, and reliability is an expanding responsibility because these key activities can now be done at the site and off-site, such as in the participant’s home or elsewhere and include additional service providers who can access various participant data. Since sponsors have ultimate responsibility for clinical trials, giving investigators and their teams the necessary support to adhere to GCP and regulatory guidance while giving participants flexibility in how they participate is critical. The following are several considerations for sponsors to support investigators and sites as they build a quality trial management system in a rapidly evolving landscape.

Early trial planning: A comprehensive approach

When integrating decentralized elements into clinical studies, investigators take on oversight of protecting the participant’s safety and data while carrying out efficient and quality processes for eConsent, use of wearables, electronic diaries for participant input, data collection via home health providers, and much more. Combine that with diversity in trial population, disease or treatment nuances, phase of development, etc., and sponsors and investigators have quite a bit to think about in today’s landscape. First and foremost is the protection of the participants, which means considering all the regional and national laws and regulations as well as GCP and applicable privacy legislation. Beyond regulatory requirements, incorporating the patient voice into drug development is key to improving engagement and building ongoing trust.

As such, early planning for the requirements noted earlier and more is key to setting up trials on the right track.

Well-defined roles and responsibilities: A starting point

When conducting trial activities off-site, of course, data may be gathered by different methods, including service providers involved, such as mobile nurses or phlebotomists who are accessing relevant participant data, as well as digital technologies that gather data directly from patients. During trial design, clearly communicating who will be responsible for what oversight and at what level is crucial for protecting participant data and the integrity of trial results.

As per the E6 (R3) guidance, trial protocols and agreements should clearly list sponsor and investigator responsibilities during all trial activities, including communication flow and data processing. For example, as home health service providers are assigned specific trial tasks, detailed explanation of their level of involvement and access to specific data should be documented, with the investigator having ultimate responsibility for the trial conduct. The intricate level of nuances included should leave no room for discrepancy on oversight responsibilities. For example, the sponsor can provide a service provider to assist the participant using the technology in terms of set up and ongoing support.

Because this conduct support is contact with the participant outside of tech support, all related activities fall under the investigator’s scope of responsibility. The sponsor can support the investigator by providing and overseeing the service provider’s role on behalf of the investigator. But well-defined explanations of roles and responsibilities are necessary to uphold GCP guidance.

Depending on the trial, the amount of continuous data coming through multiple sources (e.g., wearables, eDiaries, trial platforms, etc.), both remotely and on-site, can be hefty, potentially bringing in millions of data points, which fall on investigators to oversee.

A clear process on how to manage this constant data flow provides a strong foundation for investigators and site teams to effectively take on the task of full data oversight and manage it with reliability in mind. As trials integrate multiple decentralized technologies, platforms and related service providers, a risk-based data management and oversight approach can help them to be audit-ready. This approach can include:

Creating a data flow diagram so all relevant stakeholders can understand the process in detail. How frequently investigators review incoming data is based on how relevant the data is to patient safety and achieving trial objectives, with a priority on capturing safety events in a timely manner.

Developing and having a risk mitigation plan in place in case the digital tool does not work as intended. Laying out a thorough plan for addressing immediate need for medical attention will be critical, including what actions should be taken and by whom.

Regarding digitized tools, sponsors can work with technology partners to ensure these solutions are validated with intended use in mind. This includes:

Making sure digital tools are generating required alerts to the investigator regarding defined safety events.

Giving the investigator continuous and full access to source data via on-site or off-site methods and ensuring data is directly reported to the sponsor, such as electronic clinical outcome assessment (eCOA) or central lab reports.

Minimizing the risk of access to data by unauthorized parties via encryption and other security measures while also defining user rights and methods of access for authorized parties.

The E6 (R3) guidance puts particular emphasis on the need for data reliability or trustworthiness, and understandably so, given the large amount of data to be collected and reviewed and other complexities that come with decentralizing trial elements.

For one, sponsors should plan and account for participants, investigators, and service providers receiving training on how to use the digital tools included in the trial to ensure that data collection, review, and transmission are conducted properly. In other words, the sponsor should enable site teams and participants to be successful. Additionally, sponsors should ensure educational messaging for participants includes key instructions for communications during the trial.

Participants and service providers alike should receive training on what are considered relevant safety events and related reporting process, including who to reach, in what time frame, and how to manage the event. This is especially important because investigators may not review data in real time. Participants should be able to directly contact the investigator site to report any safety concerns.

Though the drug development landscape is evolving rapidly, sponsors, investigators, and other key stakeholders may question whether they know how to effectively translate digital transformations into their programs to ensure patients are more engaged and part of the process while securing their safety. However, just as we shifted from paper-based to electronic case report forms, change is a natural part of the equation. Stakeholders are not alone in the process. As ICH recommends, sponsors are encouraged to seek scientific advice from regulatory authorities and other industry advocates regarding the use of decentralized trial elements and related learnings and best practices.

As the industry navigates the future unknowns of patient-centered approaches to trial design, all of us can keep in mind that we are in it together—evolving while ensuring we comply with legislations and industry guidelines to uphold patient safety standards and stay inspection-ready. Patient-centric and decentralized solutions are not the future, they are part of the here and now. But these solutions are evolving and in flux. So, it is a matter of staying up to date.

, decentralized clinical trials regulatory director, IQVIA

How to support trial investigators through decentralization of trial elements.

Proposed ICH-GCP E6(R3) Guidance: Principles in Action

At DIA 2023, members from FDA updated the audience on decentralized clinical trials (DCTs) and their closely-related enabler, digital health technologies (DHTs). Jacqueline Corrigan-Curay, JD, MD, principal deputy center director, the Center for Drug Evaluation and Research (CDER), noted that under PDUFA VII, a DHT steering committee was 

. One goal of the committee is to accelerate DHTs’ move into the larger environment of DCTs. The hope is to bring trials where patients are, connect DHTs to those who are willing to use them, and ensure that their use is not inadvertently excluding a person
or populations.

Corrigan-Curay said further in regard to DCTs, “We need to understand and to pre-plan. You have to think of the appropriate trial for a DCT. What COVID has done is make us think about what can be decentralized. We’ve always had aspects of it, but what’s new are the sophisticated platforms.”

Another aspect of DHTs was brought forward by Hilary Marston, MD, MPH, chief medical officer, FDA. She remarked that DHTs “provide an opportunity to reflect on patient experience outside of the clinic”—but how that is achieved so that the information is accurate from the device and reflects the intervention on outcome progress. She added, “We need to make sure they are accurately reflecting a clinical endpoint of understanding, and that’s challenging.” Marston then noted that to achieve that understanding, drug developers would have to invest in studies to evaluate the risks; since it’s not their core business, it becomes a difficult area to justify the spend, she points out.

A Q&A on FDA’s website with Leonard Sacks, MD, associate director for clinical methodology in CDER’s Office of Medical Policy, stressed the involvement of sponsors in regulatory processes and directed them to resources, as well as an email to aid FDA in addressing DHT-derived data questions. He said, “We are working on electronic methods to track drug application submissions containing DHT-derived data. We are asking sponsors to use the updated versions of FDA forms 1571 and 356h to indicate when they include DHT data in submissions. This will help us understand the changing landscape of DHT utilization, and the trends, challenges, and opportunities for implementation.”

 is the editor-in-chief of Applied Clinical Trials

From the Editor

Agency provides update on decentralized trials and digital health technologies at DIA 2023. 

FDA Focuses Efforts on DHT

In 2021, University College London Hospitals NHS Foundation Trust (UCLH), IgniteData, and AstraZeneca embarked on a ground-breaking collaboration to evaluate how electronic health record (EHR)-to-electronic data capture (EDC) data-transfer technology would perform in a real clinical trial setting versus traditional data transcription methods. To ensure a true comparison, the EHR-to-EDC pilot would be designed as a live mirror study and use real patient data; it would run in parallel with a live AstraZeneca-sponsored Phase III oncology trial. Furthermore, clear evaluation criteria would be defined in advance, and the results would be benchmarked against the data transcription methods used in the real study.

First off, a rigorous proof-of-concept pilot would stress-test the maturity of IgniteData’s EHR-to-EDC data mapping capabilities. The solution’s connection, authentication, and data transfer abilities would also be assessed: And only on successful completion, would the greenlight be given to the launch of a fully-fledged live mirror pilot.

So how would EHR-to-EDC perform when shadowing a live AstraZeneca-sponsored oncology trial at UCLH? Here, we examine the aims behind this three-way collaboration and consider what the latest evidence from this “pilot within a live trial” reveals.

Understanding the growing impetus for change

This pivotal collaboration was born of the fact that the traditional approach to collecting clinical trial data has long been growing increasingly complex. Over 70% of data currently used in clinical trials is duplicated between research systems and hospital EHRs, and around 20% of the total costs of a study is typically allocated to duplicating and verifying data.

There are, of course, additional drivers for change. Not least, the widely reported health industry data explosion. The healthcare industry generates around 30% of the world’s data

 and is showing no sign of slowing down. Clinical trials are no exception to this trend. Recent studies

 have shown that a Phase III oncology trial typically generates an average of 3.6 million data points. That is three times the data collected by late-stage trials 10 years ago

In such circumstances, replacing the laborious manual transcription of data with technology that enables researchers to re-use the regulatory-grade data already in hospitals’ EHRs offers a compelling way forward.

Getting started: Evaluating tech providers

Attempts to overcome the clinical trial data challenge outlined above were for a long time stalled by the interoperability of healthcare systems. Today, the prevalence of EHR systems that use HL7 Fast Health Interoperability Resources (FHIR) standards and incorporate a Substitutable Medical Applications and Reusable Technologies (SMART) on FHIR application programming interface (API), means that the possibility of electronically transferring patient data to a study database instead of using manual methods has become a reality.

Yet, despite these important technology advances, there remained a lack of hard evidence supporting the efficacy of data-transfer technology in a real setting. Which brings us back to the purpose of the UCLH, IgniteData, and AstraZeneca collaboration.

Between 2018 to 2020, the EHR2EDC Consortium, of which AstraZeneca, Sanofi, and Janssen were founding members—along with a group of European hospitals, and The European Institute of Innovation Through Health Data (i-HD)—set out to determine the optimum technology solution for transferring data between EHRs and EDC.

Having conducted a rigorous review of 20 potential technology providers, the Consortium collectively identified IgniteData as a top-performing technology provider in the EHR-to-EDC space. Following this achievement, AstraZeneca then selected IgniteData as vendor of choice for a landmark EHR-to-EDC live mirror study project at UCLH.

To recap, the aim of this project, which began in 2022, was to objectively quantify the performance of EHR-to-EDC data transfer in a real-trial setting and measure the success of this approach versus traditional data transcription methods. To achieve these goals, and with the site and sponsor selected—UCLH and AstraZeneca—it was agreed that the pilot would specifically evaluate critical factors such as data availability in EHR, data quality and accuracy, data transfer to EDC, perceived healthcare provider (HCP) experience, site burden, and time savings.

The evaluation criteria for the project were defined as per the table below. 

In the first phase of the project, IgniteData’s cloud-based technology, Archer, was embedded within the non-production EHR at UCLH, thus ensuring that there was no risk to the real randomized controlled trials (RCTs) at these sites, nor to live patient data in the EHR. It was also established that the site’s staff could easily select and transfer structured data into AstraZeneca’s Medidata Rave system.

Archer is a virtual research assistant that enables the transfer if clinically-validated data from hospitals’ EHR to sponsors’ research systems. It uses HL7 FHIR through SMART on FHIR APIs to create a data conduit that integrates with many EHRs and EDCs.

Archer has a mapping engine, built in consultation with hospitals and sponsors and designed specifically for mapping healthcare data. This streamlines the mapping data task, helping to eliminate errors and duplication of efforts.

Following the successful completion of the non-production pilot, and with consent gained from participants, ethics committees, and regulatory authorities to push real patient data from UCLH’s EHR to AstraZeneca’s EDC, the collaborative evidence-building project was ready to move into the live mirroring phase by the end of 2022.

At this stage of the project, the most data intensive categories in the Phase III oncology study—vital signs, local laboratory results, and concomitant medication—were mapped by Archer. Four patients from an AstraZeneca-sponsored Phase III cancer study were enrolled into a live mirror study; and data from the first five of their visits were electronically transferred from UCLH’s EHR to a copy of the study database. In all, 6,664 data points were transferred from the EHR to the EDC using Archer during this phase.

The live pilot established that IgniteData’s data- transfer technology, Archer, could map 100% of vital signs and labs data, and was able to successfully transfer 100% of mapped data from these domains.

Transferring mapped data using Archer showed time savings compared to manual methods. Savings were achieved even including the time taken to do extra manual lookups to check data accuracy—which would not be needed in a real trial setting. In addition, Archer could significantly reduce source data verification (SDV) and query resolution time in a live study—a factor not considered here.

IgniteData’s mapping analysis found that the 15% of forms mapped by Archer accounted for 45% of all study data. Overall, 96% of the targeted fields for the selected data domains of the case report form (CRF)—vital signs, labs and concomitant medication—were mapped.

Unscheduled visits were not included in the live mirror study, as this capability was still in development at the time of running the pilot: however, they will be included in subsequent pilots, which will significantly increase the amount of data accounted for.

HCP experience was measured using a 7-Lickert scale questionnaire: for user experience and perceived reduction in site burden, the overall score was positive.

Learnings from the live pilot study and next steps

As anticipated from the outset, running a live mirror study in a real setting provided insights and highlighted opportunities. Overall, Archer was shown to achieve impressive levels of accuracy, and the data transferred by Archer always matched the data in the EHR, a fact with positive implications for SDV in the future.

Unscheduled visits—a requirement for using Archer in a live RCT—has been incorporated into the next pilot, and this capability was also reaffirmed as an important means of increasing the amount of data that could be transferred with minimal effort.

Conducting the live pilot highlighted several learnings in relation to the end-to-end process of transferring concomitant medication data between hospital and sponsor systems—and has allowed the collaborators to formulate a strategy around solving these complexities going forward.

More broadly, new opportunities were identified, such as optimizing CRF design when using EHR-to-EDC, investigating medical coding of EHR medications, and looking at the feasibility of using EHR-to-EDC in other domains.

These learnings will feed directly into the next pilot, which is already underway. There is certainly more to do, but the collaborators are confident that the steps taken to date constitute a major step forward in establishing EHR-to-EDC as the go-to option for clinical trial data requirements. While sites look forward to benefits such as reduced site burden, sponsors are equally excited about driving data transformation for clinical trials in a collaborative way that cements their status as “sponsors of choice” for sites. 

 UCLH uses the Epic comprehensive electronic health record (EHR). This work was supported by UCLH’s in-house EHR team funded by the NIHR UCLH Biomedical Research Centre and Research Data Managers from UCLH’s Cancer Clinical Trials Unit.

, PhD, IgniteData strategy advisor and former global, integration lead for electronic health records (EHR) services, AstraZeneca, 

, PhD, FRCPath, MRCP, formerly the chief research information officer and consultant haematologist, UCLH/NIHR BRC clinical and research informatics unit, 

, EHR deputy delivery manager for research & innovation, University College London Hospitals NHS Foundation Trust, 

, research manager, cancer clinical trials unit, University College London Hospitals NHS Foundation Trust, 

, senior clinical IT nusiness partner, AstraZeneca, 

, associate director, project data manager, AstraZeneca, 

, clinical operations program director, AstraZeneca, and 

The Healthcare Data Explosion. RBC Capital Markets. 

https://www.rbccm.com/en/gib/healthcare/episode/the_healthcare_data_explosion

Rising Protocol Design Complexity Is Driving Rapid Growth in Clinical Trial Data Volume, According to Tufts Center for the Study of Drug Development. GlobeNewswire. January 12, 2021. 

https://www.globenewswire.com/news-release/2021/01/12/2157143/0/en/Rising-Protocol-Design-Complexity-Is-Driving-Rapid-Growth-in-Clinical-Trial-Data-Volume-According-to-Tufts-Center-for-the-Study-of-Drug-Development.html

Evidence from a Phase III cancer trial points to notable advances in data-transfer tech.

eSource Interoperability Between EHR and EDC

A compelling benefit of membership of Critical Path Institute’s (C-Path) Electronic Clinical Outcome Assessment (eCOA) Consortium is the ongoing opportunity to interact in a neutral environment with sponsors within the Patient-Reported Outcome (PRO) Consortium. There is much fertile ground to explore in the context of eCOA implementation, and much of what the eCOA Consortium does is founded on this relationship. What C-Path offers in addition is the pivotal interface with FDA through the public-private partnership between C-Path and the agency, a relationship that has driven the publication of important and authoritative works, such as the recently published 

 on ePRO dataset structure and standardization.

Across both consortia, members have yearned to have open, non-committal, and exploratory discussions on specific eCOA-related matters with regulators. Thanks to the collaborative mindset of FDA colleagues, especially within the Division of Clinical Outcome Assessment, an invitation to join a cross-section of eCOA Consortium and PRO Consortium members to discuss two specific eCOA-related topics was accepted, and the inaugural eCOA Forum was held immediately after the close of the 14th Annual PRO Consortium Annual Workshop in Silver Spring, MD, on April 20.

Two specific topics that were examined; bring-your-own-device (BYOD) and item skipping. The first discussion explored what additional evidence is necessary to allow for BYOD approaches for PRO data collection to be incorporated into registrational trials, assuming PRO measures within an ePRO implementation are fit-for-purpose. The discussion referenced established industry-best practices and their applicability to BYOD models, the perceived risks of this approach, and the importance of usability alongside measurement comparability.

Much of the concern around the BYOD approach focuses on the impact of smaller device screen sizes and the understanding that an element of variability in data may be introduced by BYOD that is mitigable through training and good design principles.

The discussion focused on the fact that the requirements are the same for BYOD approaches as with data collected by other methods to be used in registrational trials. The group consensus concluded that eCOA providers should develop a package of evidence—generated in a population at least similar to that being studied—that usability is assured, as this will be of benefit to sponsors exploring BYOD for registrational trials.

The second more provocative topic asked the group to answer this question: Is it ever appropriate to require a trial participant to complete every item within a PRO measure? In preparing for this discussion, it was apparent that different stakeholders take a range of contrasting positions. The core concern could be reframed as simply not wanting respondents being forced to make up answers. A distinction between the evidence to be gathered during instrument development and then instrument application was also raised because the skipping of individual items is informative during instrument development.

There was acknowledgement of the fact that participants may decline to complete study procedures and should be appropriately consented but also advised of the reasoning and value of contributing their data. Development of novel measures may allow for identification of—and subsequent removal or revision of—potentially challenging questions, and perhaps incorporation of “not applicable” or “prefer not to answer” options, but that isn’t an option for legacy PRO measures.

The counter-argument assessed whether allowing for item skipping actually has an impact on the data obtained, and allowing skipping may help inform the qualitative assessment of those more challenging questions. The use of item libraries that enable very specific and pertinent questions to be selected is a methodology that may negate the issue altogether.

On this matter, the eCOA Forum concluded without a resolution, but collectively accepted that outcome. If good design principles are followed and active skipping is required—to avoid accidental missed responses—data quality impact should be minimized. Moreover, the opportunity to reflect on the perspectives of key stakeholders on challenging issues was both stimulating and productive, and the eCOA Consortium will continue to drive such vital discussions.

Authored on behalf of Critical Path Institute’s eCOA Consortium by 

Data Collection

eCOA and PRO consortiums along with regulators gather for discussion on important data collection topics.

The First eCOA Forum Examines BYOD and Item Skipping

In an era of rapid scientific development, the pharmaceutical industry constantly evolves to meet new challenges and seize emerging opportunities. GeoVax, a biotechnology company specializing in developing vaccines against infectious diseases and cancer, is at the forefront of this innovation.

I recently had the opportunity to sit down with David Dodd, CEO of GeoVax, for an enlightening discussion on the company's unique vaccine development strategy, clinical trials, and approach to serving patient populations often overlooked by conventional vaccines. The conversation sheds light on the company's specialized focus on immunocompromised patients, their clinical trial operations, and their expectations for the future.

Moe Alsumidaie: Can you elaborate on how GeoVax's technology differentiates from current vaccines?

 GeoVax's approach to vaccine development is unique. While current vaccines are designed to elicit a strong antibody response, our technology aims for this and more. For instance, related to SARS-CoV-2, we include another part of the virus in our vaccine, the nucleocapsid protein, which is conserved across all coronaviruses. By incorporating this protein in our vaccine, a robust T-cell response occurs. This antibody/T-cell dual-response, intended to provide a more robust, durable immune response mechanism, has been validated and presented at recent conferences such as the World Vaccine Congress and the Vaccine Summit.

Our approach is particularly significant for patients with compromised immune systems, where a strong T-cell response is essential. We intend to differentiate our COVID-19 vaccines by focusing on immunocompromised patients. This cohort broadly includes people with conditions such as sickle cell anemia, renal disease, HIV, and other morbidities that deplete the body from being able to mount an effective response to antibody stimulation.Hence, the critical importance of inducing strong T-cell responses. Currently, we lead the global program in the clinic development of a COVID-19 vaccine that is focused on these high-risk populations.

Alsumidaie: What challenges do you anticipate in running your Phase II studies from a clinical operational standpoint?

 Clinical trials always present inherent challenges. For example, finding patients to participate in a COVID-19 vaccine trial would be significantly complicated if we were to pursue developing a vaccine for use within the generally healthy population.In other words, as a direct, general competitor to mRNA vaccines. This is because most of these vaccines generally target healthy populations and the vast majority are already vaccinated.

However, our focus is different. We target patient cohorts actively managed by their medical support teams, such as physicians, physician assistants, and nurse practitioners. These include blood cancer patients, whom hematologic oncologists directly manage, and patients with chronic lymphocytic leukemia, for whom current vaccines and monoclonal antibodies are inadequate. Other patient populations, such as those with renal disease, autoimmune diseases such as Lupus, HIV, and others, are actively managed by their medical care teams.

Another trial we're conducting involves healthy volunteers. In this study, we're evaluating our vaccine as a potentially more robust, durable booster among patients who have received mRNA vaccines as their initial vaccine. In this health volunteer booster trial, to overcome the challenges of recruiting qualified health volunteers, we work through a network of physicians' offices that feed into a particular clinical research site.This seems to benefit our patient recruitment process for this more traditional vaccine clinical trial.

Alsumidaie: Can you discuss your strategy for targeting other patient populations like those with HIV or lupus? How does the regulatory approach fit into this?

 We intend to conduct separate studies for different cohorts. For example, we are conducting a Phase II trial among blood cancer patients and have just announced the initiation of a separate Phase II trial for chronic lymphocytic leukemia patients, evaluating our COVID-19 vaccine compared to an mRNA vaccine. We also have a historical and substantial involvement in the HIV community, having previously developed and advanced an HIV-preventative vaccine. We also have a keen interest in the renal disease population, recognizing the critical need for a safe, effective, and durable COVID-19 vaccine for this population.

In general, we believe that an expedited regulatory process is likely in addressing the various high-risk, immunocompromised populations. We don’t necessarily anticipate that a broad approval, addressing all immunocompromised patients is feasible which is why we're conducting separate trials

Alsumidaie: The White House recently launched a new initiative to accelerate vaccine development and distribution. How is GeoVax aligning with this initiative, and how will it impact your strategies moving forward?

 The recent White House Project NextGen initiative aligns perfectly with GeoVax's mission and strategies. The program is focused on the development of new vaccines and therapeutics to better address SARS-CoV-2 viral strains and to prepare for future strains. Funding for the program is $5 billion, enough to support next-generation vaccines through efficacy testing. We applaud the government's increased support for vaccine development and distribution. The initiative's emphasis on innovation, equity, and broad access mirrors our objectives. We are actively participating in this initiative, and anticipate that Project NextGen will bolster our efforts to bring our unique vaccines to as many people as possible as quickly as possible. We look forward to collaborating with other stakeholders in this initiative to achieve a healthier, safer world.

Alsumidaie: What is your projected timeline for bringing these vaccines, as well as your cancer therapy to market?

 We are data-focused and aim to reach various milestones to move us closer to the market. With support from Project NextGen, we expect to accelerate to completion of our Phase II COVID-19 vaccine program. Also, we believe that an expedited approval process is feasible related to our focus on patients with compromised immune systems. Regarding Gedeptin®, our gene-drug therapy for patients with advanced head and neck cancers, we are concluding the current Phase II/II trial this year, which will be followed by discussions with FDA regarding a regulatory path based on an expanded Phase II trial. If we’re successful, we could have a product available for registration in 2025.

Alsumidaie: How are you managing the company's stock price, especially with the ongoing scientific developments and the clarifying timeline?

 Our focus is on reaching certain data milestones. We are in the process of g having a peer-reviewed publication related to initial data from our COVID-19 vaccine in the Phase II program among blood cancer patients. We believe that this update will provide meaningful support for our stock. As we achieve more milestones, this will positively impact our stock price. We also continue to increase our focus and development in oncology, which will be we believe will be of high interest with the investor community.

Alsumidaie: Is there anything else you'd like to share about GeoVax's strategy or upcoming projects?

 In the future, we expect to increasingly highlight progress within oncology. This is an area with significant unmet medical needs and our Gedeptin® technology appears to provide multiple opportunities for addressing additional cancers, both through monotherapy, as well as in combination with other therapies such as Immune Checkpoint Inhibitors. We also expect to highly leverage that our COVID-19 vaccine is focused on numerous patient populations dealing with various cancers, providing the opportunity for us to address such medical concerns both relative to their cancers, as well as ensuring more comprehensive care via our COVID-19 vaccine. In summary, we are focused on contributing broadly to improved healthcare for patients worldwide, leveraging our technology and stakeholder relationships. This will include partnering and collaborations to ensure broad access, distribution, and administration of our products worldwide.

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

In this Q&A, Dodd speaks about GeoVax's vaccine development strategy, clinical trials, and approach to serving patient populations often overlooked by conventional vaccines. 

Applied Clinical Trials-08-01-2023

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