Moe Alsumidaie

Clinical trials will continue to play a crucial role in the future of medicine. With the rise of the Millennial and Gen Z generations, it is important to consider how these demographic shifts will impact the design and execution of clinical trials. As technology advances and our understanding of medicine evolves, the way clinical trials are conducted is also changing. In particular, the future of clinical trials will likely significantly impact Gen Z and Millennials, who have grown up in a digital age and have different expectations of healthcare and research.

One key factor to consider is that Millennials and Gen Z are more tech-savvy and connected than previous generations. This means that they are more likely to be open to using digital tools and platforms for clinical trial participation, such as electronic consent forms and remote monitoring devices. Additionally, these generations are often more accustomed to engaging with health information online and may be more likely to seek out and participate in clinical trials advertised through social media or other digital channels (i.e., Google Ads). I’ve personally found that online advertising works very effectively at recruiting patients within that age group.

Another important consideration is that Millennials and Gen Z are more likely to value personalization and transparency in their healthcare. This means they may be more interested in participating in trials that offer personalized treatment options or provide detailed information about the trial process and potential risks and benefits in an easy-to-understand way. Additionally, these generations have a great interest in expressing their personal values, such as social impact, which may increase the likelihood of clinical trial familiarity and willingness to participate.

One of the biggest changes in the future of clinical trials is the shift towards decentralized trials (DCTs). While the concept is relatively new in the industry, it has gained ground, and 

regulators have written a recommendation paper

. Data collection methods typically used in DCTs can include using smartphones and wearables to collect data and telemedicine to monitor patients remotely.

The benefits of decentralized trials for Gen Z and Millennials are numerous. For one, they allow for greater flexibility and convenience for participants, who can participate in the trial from the comfort of their own homes. This can make it easier for people to participate in trials, particularly those who may have mobility issues or live in remote areas. Additionally, decentralized trials can also help to increase diversity among participants, as people from different backgrounds and locations can participate. All of these factors 

Another important aspect of the future of clinical trials and DCTs is the increasing ability to use artificial intelligence and machine learning due to data digitization. For one, they can help increase the speed and accuracy of data analysis, leading to better treatments and faster drug development. Additionally, AI and machine learning can identify new potential drug targets and predict which patients are most likely to respond to a particular treatment. Say goodbye to the tasks of conducting interim data analyses if you can visualize your study’s endpoints and predict them in real time on a dashboard.

However, there are also risks associated with decentralized trials, particularly regarding data security and privacy. As more and more personal information is collected and stored digitally, DCT companies may become the target of hackers and data breaches. Additionally, there may be concerns about the accuracy and reliability of data collected through remote monitoring devices and apps, which could lead to inaccurate results and false conclusions. Furthermore, decentralized trials can make it easier for professional trial participants to participate in multiple trials simultaneously, especially if there is no database to track multiple trial participation.

There are also risks associated with using AI and machine learning in clinical trials. One of the biggest concerns is that these technologies may perpetuate existing biases and disparities in healthcare, as they are only as unbiased as the data they are trained on. Additionally, there may be concerns about the transparency and interpretability of the results these technologies generate, as it can be difficult to understand how they make decisions and predictions, especially for people who need to be trained in data sciences.

In summary, the future of clinical trials will likely significantly impact Gen Z and Millennials and will look very different. Decentralized trials and the use of artificial intelligence and machine learning are likely to become more prevalent, bringing many benefits such as convenience, flexibility, and increased diversity among participants. However, there are also risks associated with these changes, particularly regarding data security and privacy, as well as the potential for existing biases and disparities in healthcare.

, 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.

Articles

Recent industry advancements such as DCTs, AI, and machine learning are shaping the future of clinical trials.

Clinical Trials in the Millennial and Gen-Z Era

The paper focuses on three major areas: patient safety, patient and investigator inclusion, and evaluating DCT risks and benefits. Trial participants' rights, safety, dignity, and well-being should come first, and decentralization in clinical trials should not increase participant safety, rights, and well-being risks. While this concept is not new, the paper emphasizes that early participant and investigator involvement in clinical trial design increases the scientific value and boosts trial trust, recruitment, and adherence. Moreover, patients' perspectives on living with a condition may influence the selection of decentralized elements, such as the feasibility of videoconference appointments, the use of digital tools, the measurement of meaningful endpoints, and the selection of the right population. A risk-benefit assessment should consider decentralized elements that may affect scientific validity, data integrity, benefit-risk ratio, or trial participant rights. Decentralized trials should follow general medical rules to protect patients, especially when away from traditional patient care centers. A responsible investigator with a trial population-specific medical background should assess each patient's risk profile, including anamnestic, physical, and laboratory or imaging data.

Study oversight includes delegating study tasks, vendor quality agreements, and establishing effective lines of communication. When parts of the clinical trial are conducted off-site, and additional service providers like home nurses or technology providers are involved, the sponsor, investigator, and any other parties must clearly define their roles and responsibilities before the trial begins. Additionally, when trial participants visit the clinical trial site less often, alternative methods of clinical monitoring of their health status and data collection may need to be deployed. Decentralization introduces unique risks to participant rights, safety, dignity, and results, necessitating oversight requirements for investigators and sponsors. Hence, the study's plans and procedures should show that the sponsor and investigator fully control their responsibilities, such as data processing, communication flow, and trial participants' rights, safety, dignity, well-being, and data reliability.

When sponsors outsource to vendors, all tasks must be documented in a quality agreement with the vendor. Suppose the sponsor selects a service provider, and the investigator is not involved in the contractual arrangement. In that case, the sponsor-investigator contract should document the contractual arrangements with the service provider for tasks under the investigator’s responsibility, and the investigator should be able to request additional information, require changes to the agreement or service, and have the option to reject a service provider’s trial-specific medical care tasks. The sponsor should also ensure that the contracted service provider is qualified and experienced in delegated trial tasks.

Effective lines of communication should be established, documented, and shared with all relevant parties, including trial participants, investigators, sponsors, and service providers. All parties should have access to the clinical trial information they need at any time, and an emergency communication plan allows all relevant parties to act quickly, and trial participants should receive contact information for acute cases, device failures, home visit questions, and more. Processes to recognize duplicate AE reports must be established since data tends to reside in multiple sources when deploying multiple DCT vendors. Digital tools, like wearables, increase data frequency, and hinders the investigators' time; hence, a clear process should be in place to handle constantly emerging data, and the investigator's review frequency should depend on the data's relevance to trial participant safety and efficacy. Risk-based safety data review should consider the IMP safety profile, indication, and known risks.

Investigational medicinal product home delivery

IMP home delivery was another topic reflected in the paper and included four main areas: authorization, responsibility, delivery, and dispensation and administration. Suppose the site investigator or delegated healthcare professional does not dispense the IMP to the trial participant. In that case, the vendors delivering it should be authorized and qualified to distribute or dispense medicinal products, and transportation steps should be minimized, per good distribution practices (GDP).

The investigator is ultimately responsible for the participant and must document the treatment decision before delivering IMP to trial participants' homes. Delivery to the participant's home or another suitable address is allowed as long as regulatory requirements are met, risks of exposure to conditions that could affect product quality and integrity are minimized, and the GDP guidelines for medicinal products for human use are considered.

The investigator site pharmacy, a delegated pharmacy, or a depot can deliver the IMP. The sponsor should manage the process and contracts, and the clinical trial protocol or Investigational Brochure (IB) should describe IMP delivery to trial participants. Only the trial participant (or a representative) or a clinical trial healthcare professional should receive the IMP if applicable. Sponsors need to establish IMP delivery and receipt procedures, and if the pharmacies and labeling requirements are met, and national regulations allow, local pharmacies could dispense the IMP to trial participants instead of delivering it to their homes.

If an IMP needs medical supervision, shipping directly to the trial participant may not be appropriate. Suppose IMP must be shipped directly to the trial participant. In that case, clear instructions for storage and administration should be given to the participant; trial participants should be instructed in IMP preparation and administration if the protocol requires it, must be provided via a leaflet with easy-to-understand instructions. Visiting nurses can also be delegated to administer IMP, and either the investigator or delegees should regularly check in with participants to ensure they are taking the IMP correctly. Additionally, IMP accountability and trial participant treatment compliance procedures should be established, as safety regulations require the IMP to be returned and accounted for from trial participants' homes for destruction.

Sponsors should consider clinical trial suitability, patient risk, training, and patient monitoring when implementing DCTs. The investigator should determine if the trial participant's home is suitable for trial-related procedures and evaluate personal/social circumstances that may preclude home visits. Inclusion/exclusion criteria should include home adequacy for critical trial procedures, and the informed consent should explain home trial procedures. Only qualified and trained individuals should perform trial-related procedures at home. For instance, if a healthcare professional collects biological samples at home, the professional should be qualified, trained, and authorized to collect, document, and ship sample collections and ensure proper sample handling and storage throughout the process. Participants who perform trial-related tasks at home should be trained and considered for any additional burden, including digital data collection, and the sponsor and/or investigator should ensure that the delegated person(s) receives proper guidance and training for home tasks. The investigator (or delegee) should monitor trial participant compliance given the decrease in face-to-face visits/meetings with the investigator and/or delegated staff. Trial participants should be able to visit the investigator in person and have a direct line of communication if they need help with a trial-related task or data collection. During home visits, the trial participant or any delegated person should report and manage adverse events, and if a trial participant cannot or will not use their mobile device, the sponsor should offer alternatives.

The EMA paper elaborates on the importance of informed consent procedures if done remotely. Face-to-face communication between the potential trial participant, the investigator, or a qualified person is essential for informed consent, and if this discussion is done in a digital/virtual meeting, it is recommended that this takes place in real-time where the parties can both see and communicate with each other via audio and video. Remote face-to-face contact should allow for questions, and the investigator should make every effort to verify the participant's identity if they don't know them. The participant should also have the right to ask for proof of the investigator's identity if they haven't met before. If trial participants and investigators prefer on-site informed consent interviews, the sponsor should allow them to be conducted in person. The investigator should evaluate participant-related factors affecting decentralized elements of the clinical trial during the informed consent interview (such as the patient's ability to use technology), and the method should be reliable and confidential. Informed consent interviews should use encrypted communication channels to protect confidential information. While providing patient information via brochures and leaflets is helpful, the sponsor should also consider that electronic methods may unintentionally discriminate against participants who cannot or prefer not to use them and should have alternatives, such as paper or physical media, and trial participants should be able to store and retrieve the information provided to them easily and at any time.

Latest recommendation places great emphasis on patients.

Summary of EMA’s Recommendation Paper on Decentralized Clinical Trial Elements

Syneos Health and Medable recently partnered to offer comprehensive technological and clinical operational support in clinical trials. In this interview, Gillian Livock, SVP & general manager, customer engagement at Medable and Noolie Gregory, VP of DCT operations at Syneos Health discuss how combining technology with clinical operations delivers better data and clinical trial patient oversight.

Moe Alsumidaie: How will the Syneos Health and Medable partnership take steps to bring clinical trials closer to the patient?

Our partnership is founded in our mutual effort to apply technology that supports patient engagement and reaches those patients that wouldn't normally be able to participate in research. We collaborate on how to best leverage the power of the Medable platform to keep patients engaged while collecting meaningful real-time, real-world data that gives sponsors actionable insights.

 Yes, absolutely. It’s about bringing the trial to the patient and ensuring they know they can participate in trials in different ways. Gill’s last point is key: the data we can generate because of these approaches is much more real-time. It's much more accurate and, therefore, can drive many more patient insights that we can garner.

The daily interactions patients have with the clinician in real-time tells you how the patient feels right here, not a recollection of what happened three weeks ago. This data that we generate is much more meaningful not just to sponsors but to patients as well. On the front end, we are improving accessibility; on the back end; we are generating better data that is more meaningful to the patient.

 That is the impact of our partnership. The collaboration doesn’t start when we get a protocol from a sponsor. Does it begin before we do critical pre-work to consider how to collaborate most effectively with sponsors to think about designing digital fit protocols? Syneos Health provides that medical and operational expertise, and we deliver the technology.

We think about how to design a better patient journey upfront. What does it mean to have to continue to visit sites every month for a patient for the next 12 months? How can we intelligently assess the data and the insights we need to collect to support this protocol in a way that reduces the burden on the patient and improves site effectiveness? We consider ways to screen patients remotely and reduce costs for sponsors. We look for unique ways to have ad-hoc communications with the patient through televisits. Together, it’s like a white-glove approach to patient engagement.

At the recent DTRA meeting, regulators expressed concern about data fragmentation associated with DCTs

. What oversight infrastructure and tools do you have to help integrate the data better to promote better study oversight?

 This is where the Medable platform makes a big difference because it is end-to-end. If you have e-consent from one source and wearable data from another, that can create fragmentation. Medable’s end-to-end platform enables a unified collection of data. The bottom line is that we can't sacrifice patient safety or data integrity, so we work closely to ensure that doesn't happen in our joint studies.

 It can be challenging for the industry to bring together siloed data sources and modular technologies. Our platform has been designed for interoperability from the ground up and to bring the core modules seamlessly together. At the same time, the platform can connect with other systems to unify the data streams and support a more holistic view.

MA: Thank you. Can you provide an example of a DCT where you work together, what aspects Syneos Health and Medable bring to the study, and where they overlap? How has the partnership benefited both parties?

 Sure, here is an exciting example of a 10-year follow-up clinical trial. As you can imagine, a lot of things happen to a patient in 10 years, so a decentralized approach is critical to capturing robust data over that long period while maximizing patient engagement and retention to get the endpoints we need.

In our partnership with Medable, Syneos Health serves as the CRO—so we are doing the site selection, site contracting, data monitoring, and pharmacovigilance. Medable provides the end-to-end technology backbone.

Again, where we have strived in our partnership is how we collaborate to continue to innovate, adapt, and remain focused on patients and customers to ensure we're meeting the needs of that sponsor. Medable and Syneos Health are in lockstep, working together to ensure a seamless experience.

 As Noolie mentioned, there are many challenges in such a long-term follow-up study. We needed to think about how to ensure the patient stays connected to the trial for a long time without being intrusive into their daily life and supporting our sponsors in collecting the meaningful data they need.

One way is to bring consumer-grade technology to patients they are familiar with—like how they use these tools for mobile banking and shopping. This is one way to reduce the burden of trial participation by making it easy. We can collect rich data about the patients via their internet connection or cell phone throughout their everyday life. The data is available in real-time so we can see whether the patient has completed a task, and if not, we can re-prompt them meaning we continue to collect valuable data when needed. The patients don’t have to remind themselves or visit the site continuously. We can follow these patients in a way that does not impact their lives but continues to allow the sponsor to get the information they need to support the study.

Patients know that, even with a long-term trial, they can easily continue and complete tasks digitally with limited impact on their daily lives. At the same time, sponsors are confident that their patients will still contribute data in line with their clinical trial requirements. This can also be more cost-effective when we eliminate multiple site visits.

MA: Thank you. So I understand that oncology is a therapeutic area that Syneos Health and Medable have collaborated on a lot over the past 18 months. Still, this area is often tough to decentralize essentially. Could you speak about the approach and working for oncology trials?

 At Medable, we think about the best way to digitize patient engagement and data collection. And oncology is a prime therapeutic area for our partnership with Syneos Health to make a difference because oncology is such a complex, lengthy, and arduous process for patients. We want to reduce the impact of multiple site visits and data collection points. We identify ways to minimize site visits by bringing a digital questionnaire, for instance, a patient diary or wearable that collects data remotely. The site, too, has visibility so they can monitor how their patients respond in between visits and contact them with our televisit module for pre-arranged or ad hoc engagement.

This is particularly important for some of these patients post-acute care when they're more comfortable being treated at home—having a digital framework and decentralized architecture allows patients to stay comfortably at home while giving investigators the confidence that they still have oversight of their patients.

 If you think more about Syneos Health’s decentralized capabilities—we even have a home health nursing service to provide in-home nursing for patients. That's a perfect example where you've got the digital backbone, but then you'll be able to support patients in their homes, even in person.

Remote screening and digital recruitment tools allow us to look for specific biomarkers in small patient populations. For example, if you're looking for a biomarker only prevalent in 10% of patients, sites are limited in their geographic reach, but a DCT opens the study to a broader population. For example, you can use digital advertising to identify patients and work with local providers or pharmacies to screen patients for inclusion/exclusion criteria. That benefits the trial because pre-screened patients know that they will be eligible when they go to their first site visit. Our patient concierge services help too.

MA: And presumably, the patients are more willing to participate in a study if they can contribute to the trials from their home or local clinic. Are there additional advantages of a DCT model for clinical research that may need to be more widely discussed?

 You started the question by saying that patients are presumably more willing to participate in a DCT than a traditional trial, but that is only sometimes true for all patients. Some patients prefer an onsite visit with their trusted healthcare professional. But, to answer the first half of your question, one of the most interesting additional advantages of a DCT approach is that there is much flexibility which yields creativity in terms of protocol design and solutions. By partnering with Medable, we have two great minds collaborating and thinking about novel ways to solve old problems using new technologies. This way of working opens doors to solutions that have never been considered.

 That is so true, Noolie. DCTs also offer the benefits of real-world evidence. Leveraging connected wearable devices and other technologies, we can now capture more real-life experiences around what patients feel in real time without overburdening them. Your data becomes much more patient-centric.

 And again, there are some operational efficiencies around remote monitoring. We need to monitor all of this data from the patients. We need to check for compliance. We need to check for anomalies and trends. Being able to do that in a decentralized trial where you have data held within the Medable platform allows us to do that more seamlessly.

 When we think about our partnership governance, we find areas where we can bring operational effectiveness and efficiencies. For example, aTufts Center for the Study of Drug Development study shows that, on average, DCTs can achieve net financial benefits ranging from five to 13 times for Phase II and Phase III trials, equating to roughly $10 million ROI and $39 million ROI, respectively.

MA: What are some of the difficulties typically involved with executing a DCT?

 The biggest challenge for me is change management—getting people to change their mindset and thinking. Many companies say they want to push the boundaries, but then they want 15 case study examples of a study done in that therapeutic area.

We have learned a lot but still need to learn. As an industry, we need to work together. Earlier, you mentioned DTRA, of which we are both members, and this is a way where we're trying to make sure we deliver change as an industry and build that confidence around the innovation.

MA: From a clinical operational standpoint, what are some of the challenges you've been through?

 In some disease areas where patients need high-touch, concierge-like services, there can be some unique challenges. And there are always some things to work through with software, but that’s just a standard aspect of delivering new software.

 There are a few classic issues to manage, like language translations. We have worked hard to manage all those translations across 60+ languages. Delivering clinical trials is challenging under any circumstance, so you need solid partnerships with experienced companies. More recently, and from a broader industry-wide challenge, we've seen a movement away from the slow study-by-study approach to a more scalable enterprise-wide approach like the work we are doing with GSK.

There will be country-by-country challenges, whether regulatory variability, different data security considerations, or device choice limitations. Syneos Health and Medable have successfully worked together to identify such challenges on a global scale and looked at ways to navigate that risk.

 One more point—we have a strong feedback loop, so all lessons learned are being applied again and again in future studies. We are growing and learning together for the benefit of patients, sponsors, and the industry.

Gillian Livock, SVP & general manager, customer engagement at Medable and Noolie Gregory, VP of DCT operations at Syneos Health discuss how combining technology with clinical operations delivers better data and clinical trial patient oversight.

Clinical Operations and DCT Tech Merge for Better Patient Oversight

I’ve written previous articles on the CRA shortage, and recently, the Tufts CSDD published more information on the shortage, indicating 

the two-year minimum CRA experience expectation is dissipating

. But how can CROs and sponsors mitigate risks by onboarding CRAs with less experience? In this interview, Tim Bray, chief sourcing and training officer at Virb discusses his perspectives on the topic.

Moe Alsumidaie: How do you choose candidates for the Virb program, and who has the best educational and professional background?

 Our process looks for both hard and soft skills. We work with our clients to provide the skills and background they prefer in a fresh candidate. We do a comprehensive series of interviews and personality testing. We want a demonstrated ability to assimilate complex information and a strong detail orientation. We also look for a strong mix of achievement drive, influencing, and relationship-building skills. We also like to find students who have shown through their major and work that they can multitask and have shown leadership capability.We prefer students that have already bridged the gap in working with healthcare professionals, particularly nurses and physicians. Many of our students have had pharma internships, medical assisting, medical scribing, and/or pharmacy experience. Our most recent batch had students with PharmDs, neuroscience, biotechnology, biology, and chemistry backgrounds. We like exposure to patient care through internships and actual work experience. One of our students had worked in the eCOA space, and another worked as a CRC. Another grew up in Ghana and coordinated a healthcare program with physicians through her church every summer. She has experience in hypertension, diabetes, and glaucoma. It is candidates like these who have excelled at becoming a CRA.

MA: What distinguishes Virb training from other clinical research training programs?

 Traditional CRA training courses frequently resemble college-style learning modules in that you learn and are tested on concepts. For example, you may spend a week on informed consent and then take a test. Then you spend another week on another topic, and so forth. Often that training employs low-level instructional design tools, such as pre-recorded lectures and PowerPoint slides created by a trainer. This methodology fails because students usually cram for exams and forget the content. In many cases, the students pay for the training courses themselves. Also, since the students sign up for the courses, there is no selection or interview process.

Novel methodologies, such as spiral learning, help students thoroughly understand and master the content. Virb employs spiral learning. Spiral learning teaches concepts gradually and repeatedly, with each successive encounter reinforcing ideas by building on earlier ones, increasing in complexity and scope. Concepts are revealed piece by piece, continually going deeper as the curriculum progresses. Learning science shows that spiral learning results in up to 60% better retention than traditional mastery learning methods. Practice that is spaced out, interleaved with other learning, and varied produces better mastery, longer retention, and more versatility. In Virb’s CRA curriculum, students learn while doing—while practicing how to monitor clinical trials.

At Virb, we get students into practice monitoring from their second week. We don’t just teach principles and concepts and then test them. We teach them to do the work of monitoring through advanced simulations, role plays, and coaching. They will not only learn to uncover all the relevant issues at the site, but we teach them and test them on having conversations with site staff. They produce actual clinical artifacts like site visit reports, letters, and follow-up in critical mistake analysis so they do not repeat the most common errors in site monitoring. We use closed clinical trial data as the basis for our training, and we use cutting-edge AI-enabled online educational technology that can alert instructors if a student is having difficulty. It can also send students more targeted content to assist them in learning more effectively. We also have a very intense final process to Virb certify the student as ready to monitor.

MA: What skills do clients look for in CRA candidates?

 Many clients believe that achievement drive, relationship-building, and influencing skills,s distinguish an average CRA from an exceptional one, so that is why we begin with assessments and interviews. We want to ensure the DNA is already there and do it in a way that removes inherent bias to get more diversity into clinical trials. During training, candidates are provided with a scorecard that evaluates their performance beyond patient safety and protocol; these evaluations include technical compliance and soft skills. In addition, clients receive a final scorecard outlining the candidate’s strengths and development areas. When evaluating our candidates, clients are interested in audit findings and the most frequent CRA errors, such as informed consent, investigational product care, inclusion/exclusion criteria and patient qualification, and patient compliance.

MA: How do you match CRA skills to what the industry currently needs?

We focus our training on building skills our clients say the new CRA will use immediately and then provide the other skills as needed on an ongoing basis. For example, our clients will use new CRAs on cardiovascular outcome studies, dermatology studies and/or remote-based monitoring. We evaluate the effectiveness of our training based on the skills that new hires will need in their first few months and then add skill components as the CRA gains experience.

MA: How does the program address the CRA shortage in clinical research?

We are here to fill this void through efficient and effective training programs and by matching highly qualified and trained candidates with available positions. We are expanding our selection criteria to include personnel interested in lateral moves to fill this vacancy. For instance, we recently recruited a candidate whose business development and proposal work for a DCT technology company provided her knowledge of decentralized clinical trials (DCT). She majored in science, desired a career in the field, and satisfied all of Virb’s qualifications for CRA training. We’re also bringing on people who have some exposure to patient recruitment. We have one candidate who coordinated all vaccines administered by a state Department of Health and assisted in patient recruitment. We are also focusing on recruiting candidates from diverse backgrounds; this is important because cultural diversity is necessary for CRAs and clinical research personnel to represent underrepresented patient and investigator communities. We believe the 2-year experience requirement can adversely impact diverse candidates. I might add that we are beginning to partner with companies in the space to source and train diverse CRCs, as there is a huge need there, and many CRCs become CRAs.

Moe Alsumidaie received funding from Virb for this interview.

Tim Bray, chief sourcing and training officer at Virb discusses how CROs and sponsors can mitigate risks by onboarding CRAs with less experience.

Novel CRA Training Methods Emerge

With the update of the Bioresearch Monitoring Program (BIMO) Sponsors and Contract Research Organizations Compliance Program Manual, FDA provides a comprehensive overview of inspection activities with significant revisions to Part III–Inspectional section. Michelle Webb, vice president of the WCG Avoca Quality Consortium, discussed her perspectives at Momentum Events’ Clinical Quality Oversight Forum.

Moe Alsumidaie: How do different parts of FDA operate when identifying and conducting clinical trial inspections?

 BIMO is a thorough FDA-wide program for on-site inspections and data audits created to monitor every step of the execution of clinical trials.The Center for Drug Evaluation and Research (CDER) and the Office of Regulatory Affairs (ORA) are two critical organizations within FDA who shoulder the responsibilities for Sponsor and CRO Inspections. These two divisions share important information related to inspections through an electronic program called eNSPect. CDER issues inspection assignments and makes decisions regarding the type of inspection and who to inspect, whereas the ORA conducts the inspections, and recommends the initial classification.

MA: What does FDA look at during sponsor and CRO inspections?

 The BIMO compliance program manuals were created to provide standardized instructions for the conduct of inspections. In the spirit of transparency, this information is publicly available for those who will be inspected so they can be better prepared.If you want to understand exactly what inspectors will be assessing during a particular type of inspection, you can simply reference the relevant manual.Essentially, FDA is giving us the test before taking it. What we see with this update to the Sponsor and CRO Compliance Program Manual is in alignment with the changes we have seen in the clinical trial ecosystem over the last 4 years since the previous version.Inspectors will have an increased focus on the selection and monitoring of clinical investigators; sponsor’s oversight of CROs and other vendors, especially those linked with patient safety or data integrity services; the selection of monitors and monitoring procedures; and a deeper examination of data collection and handling as well as electronic records and signatures.

MA: How are clinical trial inspection findings categorized?

 Clinical trial inspection findings are detailed in follow-up reports:

No one wants to get an official action, which occurs when there is repeated or serious noncompliance. However should deviations result in the issue of an FDA 483, the updated guidance reminds the inspector to advise the sponsor that an adequate and timely response to an FDA 483 could affect FDA’s decision for further action.

MA: What are a few things sponsors should prepare for inspectors?

 A notable difference between this version and the previous one is regarding the review and collection of written agreements.Previously the inspector was required to ‘review’ written agreements and the focus was very much on SOPs. The updated language is quite specific, noting that inspectors are to review written monitoring plans/guidelines/procedures/reports and obtain copies of all versions of written agreements.It will be important for Sponsors and CROs to ensure they have complete documentation readily available in time for the inspection.

Among many things, before an inspection, sponsors should prepare a list of clinical investigators which includes site number, location, who completed Form FDA 1572, if investigators were terminated or placed on enrollment hold and reason, and all healthcare providers who provide patient health data or deliver health care to support the marketing application. Additionally, inspectors will be following the flow of critical data. Something we have heard within our member experience focus groups is the value of a data flow diagram, while not required, it will be collected if available. I can tell you from experience that while it’s best to have the data flow prepared prior to study start, even creating this retrospectively before the inspection may reveal vulnerabilities. It is never too late to address them.

MA: Can sponsors use investigators included on the debarment list in clinical trials?

 A new step in this update is reviewing sponsor procedures for checking FDA debarment list. You are still allowed to use an investigator if they are on the debarment list, but you must ensure that you have sufficient documentation assessing the level of risk and clearly outline your level of oversight.

MA: How is FDA assessing sponsor oversight?

 A brand-new section of this compliance manual is dedicated to outsourcing services. The addition of this section provides insight around FDA’s expectations for having strong, proactive vendor management and oversight.With so many different vendors, oversight entails a lot of responsibility. Sponsors and CROs should have written agreements defining roles, obligations, and tasks within a document or SOP—here is where a quality agreement or joint quality management plan could be important. Monitoring, drug management, training, and data handling are activities where inspectors will request documentation for review, to ensure effective oversight is in place

MA: What are common findings during FDA inspections?

 Failure to select qualified investigators and/or monitors as well as failure to maintain adequate records were common inspection findings found in BIMO 2021 metrics. What is interesting is that many of the focus areas highlighted in this updated guidance document very closely align with these.Increased scrutiny on the selection and monitoring of clinical investigators and monitors, and monitoring procedures as well as data collection and handling activities are evidenced by the enhancements made in this update.

MA: What advice would you give to sponsors?

 In alignment with ICH E6 R2, the Sponsor and CRO Compliance Manual highlights the importance of establishing a solid Quality Management System which allows for risk assessment and issue detection.Also having robust vendor oversight, quality metrics and processes for knowledge management are vital. Focusing on building quality into the clinical trial process through proactive compliance, including having a clearly stated protocol, risk identification, and robust, clearly documented processes and procedures will ultimately help you succeed in your inspections.

Michelle Webb, vice president of the WCG Avoca Quality Consortium, discusses her perspectives on FDA's revised overview of inspection activities.

Tips on Sponsor and CRO FDA Inspections

The concept of decentralized clinical trials (DCT) is still in its infancy in the industry, although the pandemic has facilitated its adoption. FDA has issued a 

guidance document for operating under the pandemic

 which outline several characteristics of DCTs, including remote study visits, clinical outcomes assessments (COAs), monitoring and inspections, to name a few. Although FDA 

, formal guidance has yet to be issued regarding the concept. At the second annual meeting of the 

Decentralized Trials and Research Alliance (DTRA)

, regulators discussed their perspectives and experiences on DCTs. This article will summarize key points made by Leonard Sacks (Office of Medical Policy, CDER at FDA), Ditte Zerlang Christensen (EU Project Manager at DKMA Danish Medicines Agency), and Catherine Ela, Head of Clinical Trials Department at the Medical Technology Health Information Innovation & Research Directorate of the Israeli Ministry of Health.

Much discussion surrounded digital tools, such as eConsenting, to promote DCTs. While FDA has been encouraging the use of eConsenting for some time, Sacks observed the rapid adoption of eConsent during the pandemic, which helped the agency evaluate its adoption on a large scale. eConsenting allowed patients to maintain social distance and encouraged remote visits. Ela indicated, however, that regulators at the Ministry had differing perspectives on eConsenting and that the adoption of eConsenting by sponsors in Israel was limited. All regulators agreed that DCT is an ecosystem and that sponsor engagement with regulators is essential.

During the pandemic, regulators learned that DCTs can introduce data fragmentation and inconsistency (due to many technology systems and vendors being used), which could increase study risks. For instance, when patients conduct procedures away from the investigator (e.g., entirely electronic procedures or remote procedures performed by vendors), the investigator's ability to evaluate the patient holistically may be compromised. Sacks suggested a supervisory structure, such as a traveling nurse, to ensure data consistency and quality; without proper supervisory infrastructures, data inconsistencies and missing data increase study risks. Another factor to consider is the preparation and organization of data sources during regulatory inspections; for example, Sacks observed that travel nurses report medications differently than hospital or pharmacy records. If there are disparities in interpreting patient discharge or adverse event reports, regulators are highly concerned. Consequently, integrating data from multiple data sources into a single location and aggregating them to ensure consistency during inspections is beneficial.

Supervisory infrastructures must be built

Regulators concurred that infrastructures for patient supervision must be designed so that investigators and site personnel can oversee patient safety in a DCT environment. Roles must be clearly defined and documented. In addition, regulators suggested implementing integrated technological infrastructures and data centralization to enable staff to supervise patients and regulators to draw a comprehensive picture or storyboard of staff activities and roles.

The regulators emphasized the importance of study oversight. Christensen indicated that a stakeholder meeting hosted by EMA discussed the significance of sponsor oversight in DCTs, explicitly ensuring the centralization and consistency of data across multiple DCT platforms. Other factors include implementing risk-based approaches to patient and study monitoring and establishing communications plans and systems to maintain contact with patients, sites, and study personnel.

Before releasing guidance documents, all regulators were in accordance with harmonizing the DCT concept. In particular, regulators want sponsor organizations to test more DCT concepts, collaborate with regulators, and share their experiences, which will aid them in drafting guidance documents. FDA should soon release a DCT guidance document; however, for the time being, FDA recommends adhering to its 

guidance document on the use of digital health technologies in clinical trials

While the DCT concept is still in its infancy, the fact that regulators encourage DCT practices indicates it is here to stay. Much work between the industry and regulators will need to occur before DCTs can become a harmonized approach and guidance; while EMA expects to issue guidance on DCTs soon, FDA has yet to commit to a defined date for releasing its guidance, and other agencies, such as Israel, want to wait and see how other agencies roll out their DCT guidances.

Insights from second annual DTRA meeting indicate DCTs are here to stay.