In 2020, the SARS-CoV-2 coronavirus has infected millions and resulted in death for hundreds of thousands. It has also negatively impacted clinical trials of all types, includingmedical device trials. Traditionally, clinical trials collect data at physical healthcare facilities. In-person data collection is challenging when travel restrictions are in place and if participants and staff are fearful of contact with others. This situation is likely to continue past the height of the present crisis as restrictions and behaviors change permanently, and will lead to protocol deviations for in-progress studies.
As a crisis response, many sponsors applied decentralized and hybrid clinical trial technology where possible to support remote interactions, including using telemedicine to conduct remote visits to replace those previously done at a site. They also used tactics such as mailing equipment (e.g., pulse oximeters and spirometers) to participants for home data collection.
Sponsors discontinued or suspended many trials not feasible to continue. If you continue your trial during this time, you need to pay even more attention than usual to how you capture data to ensure it is high quality. This article discusses how.
It’s all about the data quality
Data quality directly impacts the success of a clinical research study. Common data quality issues in clinical research data collection include lack of data standardization, missing or incomplete clinical data, and incompatible representations of data types and elements. Protocol deviations can cause many of these data quality issues and are more plentiful in a crisis in a disrupted environment.
Review study endpoints as a first tactic when rethinking study design through a crisis. Defer any less critical endpoints if they require in-person visits or travel. You create a higher risk for protocol deviations when you do not streamline study protocols appropriately.
Protocol deviations complicate the picture
A protocol deviation is any change from the approved study design or protocol that is under the investigator’s control and not authorized by the IRB/ethics board, so long as it does not affect the participant’s safety, rights, or welfare and the completeness, accuracy, and integrity of the study data. Aprotocol violation, by contrast, may affect the participant in those negative ways and is considered much more severe.
If the protocol is updated appropriately for the current conditions, you should have fewer protocol deviations long term. Proper site training and preparation also reduce the number of deviations by helping to ensure that participants and staff follow the protocol. However, the environment changes dramatically in a crisis when travel, social distancing requirements, and the introduction of new technology all increase the probability of a deviation.
Protocol deviations that may occur with global travel restrictions and social distancing guidelines in place include:
Failure to show up for a scheduled visit
Failure to provide adequate samples (such as blood)
“Out of window” visits, meaning the participant did not show up within the required timeframe
If a deviation occurs, report the deviation to the IRB/ethics board on the Deviation Summary Log and submit it at the time of continuing review. The IRB reviews the Deviation Log to determine if there is ongoing noncompliance. Remember that the sponsor must investigate potential adverse effects and decide whether or not they might be related to the study drug before reporting to the IRB.
TheFDA issued updated guidance on dealing with reporting of protocol deviations caused by the crisis. However, it is unclear how or if the guidance will adjust to the still-uncertain situation.
Three data considerations for continuing studies in progress
Quickly assess if you need to make protocol changes to ensure participant safety. If you do not change the protocol to accommodate participants, there may be an increased risk of missing data and participant dropout.
Consider if it is safe, feasible, and reliable to collect endpoints remotely. With the data you need, can patients self-assess and report results electronically, or must a clinical professional be present? For example, collecting data for an endpoint of worsening heart failure might require a high level of clinical judgment, and cannot be self-assessed by a participant.
Understand the regulatory considerationsof in-home data collection.FDA regulations allow for expedited changes when submitting amendments to IRBs for active study protocols that relate to immediate hazards to human subjects.
Your data quality action plan
Keep these data collection quality best practices in mind as you move forward through this crisis and beyond:
It’s not easy to stay on track with compliant data for a clinical research study at regular times. In a crisis, it is even more challenging. Be prepared: rethink your study design for the future, find new ways to collect and monitor data, and commit todecentralized or hybrid clinical trial technology as a way to stay flexible.
For existing and new Castor customers
Castor will continue to deliver its services without interruption. Our teams have always been equipped to work from home, and can do so effectively. Phone lines have been routed to two applicable team members per phone line. Our availability during business hours will not be affected nor will the availability of our platform.
How Castor’s technology is supporting the fight against the Coronavirus outbreak and COVID-19 Castor has joined the global fight against the Coronavirus by making our research data capture system available for free for all COVID-19 research projects. As of June 30, Castor is supporting more than 250 COVID-19 studies in 22 countries across 1,750 hospitals. 62,000 participants are enrolled in these trials and more than 10,000,000 data points have been captured. Since time is of the essence, we have enabled these studies to go live within 6.5 days on average.
We have developed ready for use eCRFs based on the WHO standard CRFs, to help researchers start their study or registry in less than an hour. The lack of quality data should not be the reason for a delay in developing vaccines and treatments.
When novel strains of viruses like the Coronavirus (which causes COVID-19) emerge, data quickly becomes our most valuable asset. This was true during the recent Ebola outbreak, where we already had decades of research into the effects and possible treatments, and it is doubly true when considering the new strain of Coronavirus.
So what can we do to help? As a leading medical research tool, it turns out we can do a lot, and frankly we have a moral obligation to do so. We can helpdrive access to standardized data in real-time, enable the use of AI across standardized datasets, and accelerate the discovery of evidence that can help manage the Coronavirus outbreak.
To effectively fight the new Coronavirus, we need to ensure our technology is available to anyone joining the fight, and that we’re contributing as many additional resources as possible to researchers involved. With this in mind, Castor will be doing the following:
Castor is committed to supporting researchers worldwide to understand this disease and find treatments and vaccines. We are therefore providing researchers with free access to our platform and an upgraded level of service (Gold SLA). To be able to provide you with the billing code and upgraded account, we ask that you provide us with information on your study by filling out this form. This will help us organize all of the ongoing COVID-19 research projects in Castor, and foster effective collaboration.
Free access to Castor for COVID-19 studies during 2020 includes Castor’s base platform and may include more. Please contact us for more details.
Bas is one of our Senior Software Engineers. Having recently joined our team of Castorians, I wondered how he’s been experiencing working as a Back-End Engineer at Castor? What does a “day-in-the-life” look like? How has his role been impacted by COVID, and why would he encourage other Engineers to join us on our purpose-driven mission?
Firstly, a little insight to what our Engineers use at Castor (yes, our stack is stacked!)
Knowing what you know now, if you could look back to 8 months ago as you were applying to join Castor, what would you tell yourself?
I would tell myself not to worry about not having domain-specific knowledge. The field Castor operates in might seem daunting at first, but you’ll start learning the ropes on day one and never stop!
Coming into the role, what did your first 3 months look like as a Senior Software Engineer?
I was started off with a week of onboarding sessions in which I learned more about the company and its different departments. In between those sessions I got to know my team members and together with Volker (our awesome Engineering Manager) they got me set up with all the tools and access that I needed.
Quickly thereafter, you’ll find yourself exploring the EDC codebase and working on your first ticket. Mine was a nice vertical slice in which I got to work on multiple layers of the application.
You’re part of the regular day-to-day much quicker than I had expected and that’s because of the great support you get!
How would you describe the culture and working style in Castor’s Engineering team?
Supportive is the first word that comes to mind. Everyone is always willing to help you out whenever needed. Be it pairing up to do some code ‘spelunking’, or giving background info on decisions that were made in the past. You’re immediately treated as an equal and your opinion matters right away, which made me feel at home within the first week.
What does Castor’s product release process look like?
We have around 4 big releases per year and a smaller release every 2-3 weeks. A cycle is kicked off by determining what should be in it. After that a development cycle of about 2 months. Following that we do a feature freeze in which we only do fixes
And, would you say there’s a good balance between new features and refactoring?
It varies but overall I would say, yes there is. We mainly apply the boy scout principle, leave things behind a little nicer than you found them, in the regular day-to-day. If a bigger refactor is needed to make it easier to fit in a new feature then it’s highly encouraged.
Castor has been doing a lot to support researchers during the COVID crisis. Has this meant new opportunities or new initiatives for you and the Engineering team?
Definitely, it was a bit hectic when we had a short-term shift in priorities. We had to expand our API on the EDC to support a mobile app that was developed over the span of two weeks. The app is meant to record COVID-19 symptoms in a healthy group of participants. The below infographic shows how Castor is working to support the fight against coronavirus!
That all sounds really exciting and truly purposeful. With all of this work, have you been given much support by Castor to keep working through the crisis?
The support-system that is in place has been wonderful. People that lacked stuff at home to work comfortably got items delivered by our awesome People Team. Since most of us already worked from home one day a week, the transition has been quite smooth.
With all this in mind, why would you encourage other Engineers to come and join the team?
If you want to be able to flex your ‘tech-muscle’ while working on something that will benefit a lot of people, within a company that is open, inclusive, and full of people that are passionate about what they do and how they do it, then you should come and join us!
Through the Medical Device Regulation (MDR) and new version of ISO 14155, the regulatory landscape for clinical investigations with medical devices will significantly change. In contrast with previous regulations, all Post-Market Clinical Follow-up (PMCF) clinical investigations will have to be conducted in compliance with the ISO 14155 standard. Although some PMCF investigations may be exempted from a number of requirements, the basic necessities remain applicable, such as implementing written quality procedures, monitoring and document management. Another necessity is using a compliant method of data collection and processing such as Castor EDC.
On 26 May 2020, EU regulation 2017/745 (MDR) was scheduled to come into full effect, thus amending the Medical Device Directive (MDD). Although this regulation may be delayed due to the COVID-19 pandemic, now is the time to get organized and prepare to hit the ground running with clinical data collection.
The introduction of the MDR triggers significant changes to the regulatory landscape for medical devices and adds new requirements for clinical investigations. Namely, the MDR specifies that clinical investigations should be in line with ISO 14155:2011 on good clinical practice (MDR (64): p. 9) and that sponsors should provide evidence that clinical investigations are conducted in line with good clinical practice (MDR Annex XV Chapter III Point 6: p. 172). In addition, under the MDR both pre- and post-market clinical studies count as a clinical investigation, which extends the requirement to comply with good clinical practice to post-market trials, both interventional and observational types.
A new version of ISO 14155 is expected to be released in the near future, and a draft has recently been presented although not formally implemented (ISO/DIS 14155:2018). In its new version, ISO 14155 reinforces that its applicability extends to “post-market clinical investigations” and in Annex I further defines applicability for the various post-market types, including observational PMCF investigations. Because applicability of ISO 14155 extends to all clinical investigations that involve human subjects, this also impacts Investigator Initiated Studies (IIS) and registries. In addition, Annex I of the new ISO 14155 describes the clinical development stages of medical devices, including the applicability of the standard to every specific stage. For post-market observational studies, possible exemptions are indicated for device accountability, labeling for clinical investigations, need for an Investigator Brochure, reporting to regulatory authorities, full informed consent, and CVs of members of the investigation site team.
Because of the wide applicability of ISO 14155, this article discusses the impact of ISO 14155 on post-market studies, and specifically on observational post-market studies.
Annex XV of the EU MDR discusses a sponsor’s obligations with respect to clinical investigations. Per ISO 14155 section 9.1, sponsors are responsible for clinical quality assurance and quality control, and therefore have to implement and maintain written clinical quality procedures to ensure that clinical investigations are fully compliant with ISO 14155, other applicable laws and regulations, as well as the Clinical Investigation Plan (CIP).
Relevant quality procedures may be integrated in the sponsor’s overall quality system. Examples of processes to be captured in these procedures include essential document creation (such as the CIP), document management, data collection and processing (data management), training, and monitoring. A set of well-written quality procedures is of great value to the clinical investigation as these procedures provide a clear workflow and distribute responsibilities within the clinical team. The key to successful procedures for post-market studies is to keep them flexible and practical.
Clinical quality procedures can be created by sponsors and implemented internally, however this may be a time-consuming and costly process. Alternatively, these procedures can also be acquired from an external source, as long as it is clear from the clinical investigation documentation which procedures were exactly used.
Clinical Investigation Plan (CIP)
According to the MDR Annex XV as well as ISO 14155 Annex A, when conducting a clinical investigation the CIP must include certain specific elements. These include a single identification number of the clinical investigation, identification of the sponsor and information on the Principal Investigator (PI), a description of the funding used to execute the investigation along with a synopsis, device description along with its clinical risks and benefits, aim and design of the investigation, information on the subjects, a description of the measures taken to minimize bias, details of the monitoring and data management plan, compliance statements, a description of the safety reporting procedures, etc. In addition, it is crucial that the CIP is written clearly to avoid possible misinterpretations. Finally, the investigation’s endpoints and parameters must be well described to facilitate CRF development.
To ensure the quality of the CIP, different stakeholders should review the plan prior to document finalization. For example, experienced monitors will be able to identify potential problems with in/exclusion criteria, whereas data managers may be able to provide input on endpoint description and timepoints for collection.
Because post-market studies may be designed as observational studies, the issue of informed consent can be difficult to navigate in certain circumstances. Generally, the notion of informed consent implies that study subjects must be informed of the risks associated with the investigational procedure and available therapeutic alternatives. However, with observational studies informed consent may not be fully required, but subjects must at least consent to sharing of their medical data—even though pseudonymized—for the purpose of the clinical investigation and for a sponsor representative to have access to their original medical records (ISO 14155 Annex I point 7d). Such a consent form is often referred to as a data release form. For European citizens and residents, the data release form must comply with GDPR requirements. Per GDPR, subjects must be informed on who the data processor and controller is for the clinical investigation and must receive contact details of a Data Protection Officer for the investigational site, the Sponsor, or both. Furthermore, subjects must be informed about their right to review their data as these are collected, make corrections, and be removed from the system if desired.
Data collection and processing
According to ISO 14155:2011 (6.8), all data shall be generated and maintained in a way that enables control and traceability of the data. The new ISO 14155 (7.8) adds reliability and integrity to these requirements as well as validation of electronic clinical data systems used to evaluate authenticity, accuracy, reliability and consistent intended performance of the data system. These requirements impact both the data generated and held by manufacturers and those generated in the setting of an IIS. As a result, both sponsor-generated and IIS-generated data must be collected and processed using compliant data capture systems and CRFs. In this context, using an established EDC vendor that offers a fully validated and compliant system as well as the opportunity to validate study-specific CRFs is of crucial relevance.
Data Monitoring and Document Management
According to ISO 14155, monitoring of clinical data is the act of overseeing the progress of a clinical investigation and to ensure that it is conducted, recorded and reported in accordance with the CIP, written procedures, ISO 14155, and other applicable regulatory requirements. Sponsors are responsible for identifying and using qualified professionals for this function and should evaluate the nature of monitoring that is appropriate for the specific clinical investigation. In addition, monitoring plans (MP) that outline the activities done per visit type (site initiation visit, interim monitoring visit, close out visit) as well as the type of reporting must be compiled. In exceptional circumstances such as for certain registries, centralized monitoring may be sufficient. For most post-market studies monitoring of primary endpoints may be sufficient, however this should be adequately justified in the MP (ISO/DIS 14155:2018 section 6.7; EU MDR Article 71 point 2).
The results of the assessments must be written in the monitoring plan (MP). The MP also describes the outline and activities done per visit type (site initiation visit, interim monitoring visit, close out visit) and the type of reporting required.
In exceptional circumstances (which may include certain forms of registries) centralized monitoring, without actual source data verification may be sufficient. For most post-market studies only monitoring of primary endpoints is considered sufficient but this differs on a study by study basis and needs to be justified in the MP.
Similarly, clinical investigation documents also must ensure control, traceability, reliability, and integrity per the new ISO 14155 Annex E. As a result, clinical investigation documents must contain a version and date for every revision made, as well as a description of the potential impact of the change on safety and performance endpoints and data sources identifiable to the subjects. These documents should be located at both the Sponsor’s and the investigator’s sites, as per overview provided in ISO 14155 Annex E. While maintenance of the Sponsor’s regulatory files is expected of the Sponsor, maintenance of the site files pertains to the investigator. The investigator is also responsible for the accuracy, attribution, completeness and legibility of the source data and the timeliness of data entry into the CRFs. All copies of source documents must be certified by signature of a member of the investigation site team. According to the new ISO 14155 (7.8.3), If an electronic system is used as the primary location of document storage and filing, the system must be validated in order to evaluate authenticity, accuracy, reliability, and consistent intended performance of the system. In Castor EDC, all validations can be easily performed and documented.
The implementation of the new EU Medical Device Regulation (MDR) just got a plot twist: COVID-19. This pandemic is impacting all areas of health care and is particularly troublesome for the medical device industry.
With the EU Commission putting out the proposal to delay the MDR, and the EU Parliament voting in an overwhelming majority to extend the MDR by one year, this has the industry wondering, “what can I do now to be ready for the new regulation?”
In this article, we discuss a few hot topics to consider as you assess impacts to your organization.
There’s no doubt that clinical trials will be heavily impacted. Between elective surgeries being canceled and an “all hands-on deck” mentality for health care providers around the world, research unrelated to COVID-19 treatment and vaccination is taking a back-seat to the pandemic spotlight. Inevitably, this means Post-Market Clinical Follow-up (PMCF) studies will suffer due to decreased opportunities for patient eligibility and collection of postoperative data.
Several regulatory authorities have released guidances (FDA, MHRA, EMA) on how to shift to remote monitoring for clinical trials. Even if the MDR is delayed, now is the time to get organized and prepare to hit the ground running with clinical data collection.
Immediate Action: Reassess clinical data readiness and apply released regulatory authorities’ guidances. Look for ways to integrate remote means of clinical trial operations and be sure to clearly document COVID-19 impact (e.g. sample size, change in methods, statistical considerations).
Opportunity: If you haven’t started filling your clinical data gaps, you should begin this now! With clinical trial delays an unfortunate reality, it’s an opportunity to catch up on planning activities such as PMCF plans. During the delay, consider if there are any untapped data sources that can be collected remotely while waiting for the pandemic to pass and how you will prioritize data collection after it does.
COVID-19 is having a significant impact on supply chains. During this pandemic, it is not “business as usual.” With non-essential sales and elective surgeries on the decline, manufacturers may be feeling supply chain disruptions as critical resources are prioritized over other products. Additionally, manufacturers are likely seeing a dip in sales for devices used primarily for elective procedures and surgeries (e.g. non-emergency joint replacements, hernia repairs, etc.). On the other hand, the growing demand for Personal Protective Equipment (PPE) and devices needed to identify, monitor, and treat COVID-19 patients may have tipped the scales for some products to continue to be supported under the MDR regime.
Working from home and safety protocols will also impact workforces. Some companies will see that their employees have more time to spend on activities other than their normal day-to-day duties. This may open up temporary resources for planning and maintenance of MDR programs while social distancing is being practiced.
Immediate Actions: Reassess marketing and sales projections with regard to MDR priorities. Consider how safety measures will impact production lines, as well as any impacts to resourcing and funding for MDR tech doc remediation programs.
Opportunity: What do the MDR and new product development teams have in common? They’re cross-functional. Likewise, COVID-19 has cross-functional impacts, meaning that now is an opportune time to think about who is working from home and perhaps unable to perform their duties at full capacity. Can you temporarily leverage these skill sets to expedite MDR remediation? (e.g. risk assessments, pulling documents, filling in gaps in the technical documentation, etc.)
Notified Body Readiness
With COVID-19 and the proposal to delay the MDR by one year, uncertainty remains regarding Notified Body (NB) readiness. The recent MDCG Guidance describes how NBs are to adapt their procedures during the pandemic, including guidance on implementing remote audits in some cases. With travel restrictions possibly being extended until there is a widespread vaccine available, it is advisable to plan on remote audits becoming a reality for longer than just a few months.
Given the result of the EU Parliament Vote on April 17, there is a chance that some manufacturers will have a bit of breathing room prior to being required to submit under the MDR. What does this mean? Moving the MDR date of application gives NBs an opportunity to continue being designated under the new regulation and ready to accept applications from manufacturers. This would be extremely beneficial as currently there are only 12 NBs designated!
Immediate Action: Check-in with your NB. Several have released COVID-19 responses (e.g. TUV SUD and BSI). Regardless, manufacturers should expect NB availability and reviews to be further delayed by the COVID-19 situation. With the MDR delay likely to be approved, consider if this changes your current approach for QMS procedure changes and audit schedules. Note the Medical Device Directive (MDD) certificate expiration dates and plan on submitting well in advance of the deadlines.
Opportunity: Take a second look at your submission plan—what’s your plan B, C, D, etc? Are you ready to implement Post-Market Surveillance (PMS) requirements? Will your Class I products be ready by May 2020? If the MDR is delayed as expected, does it make a difference? Leadership will be expecting that you understand the impact of these questions in order to secure MDR program funding.
The COVID-19 pandemic impacts clinical trials, manufacturing, and supply chains, as well as Notified Body readiness and other regulatory concerns. However, the takeaway is that the medical device industry must still be EU MDR compliant in a short amount of time! With most manufacturers reporting that they would not be able to meet MDR compliance by May 2020 and a significant NB shortage to support the implementation date, this delay may offer temporary relief to regroup and recharge. But don’t be fooled—delay does not equate to inaction. Rather, the industry should use this opportunity to take a fresh look at their MDR plans to ensure that all gaps have been identified and a solid, defendable plan is in place for when the time comes to submit their MDR-compliant technical documentation.
Don’t wait! The MDR delay only “kicks the can” one year and doesn’t address the bottleneck of MDR applications that will need to occur between 2021 and 2024. Now is the time to continue filling MDR gaps through the creation of PMCF plans and executing remote clinical data collection. It is imperative to strategically prepare and submit applications based on the business priority.
The impact of COVID-19 will extend beyond a few months. Expect (and plan) for the worst, and hope for the best. Communicate clearly to upper management that the one year delay does not extend the “grace period” for valid MDD/AIMDD (May 2024 at the very latest, depending on your MDD certification expiry date). Keeping MDR program funding as a priority will allow appropriate preparations to be made and increase the likelihood of a successful transition from the MDD to the MDR.
The ongoing COVID-19 pandemic is one of the most serious health crises in modern history, affecting an unprecedented swathe of society. Hospital overcrowding is an alarming consequence of SARS-CoV-2, requiring careful allocation of limited resources to ensure the most grievously ill patients receive the highest level of care.
An impediment to accomplishing this allocation is the broad diversity in symptoms and severity between patients, and clinicians often feel that even a previously-stable patient could become critical at any time. This dangerous uncertainty highlights the difficulty doctors face in deciding which patients should enter the intensive care unit (ICU), and which are likely to improve despite being ill enough to require hospitalization.
Amidst the chaos, Dr. Martijn Beudel along with researchers at Amsterdam UMC and Maastricht UMC+ are pioneering a new kind of patient risk assessment to combat the crisis: machine learning.
How COVID-PREDICT is using Castor
Castor is supporting COVID-PREDICTby providing its electronic data capture (EDC) system free of charge to help the team easily capture data from multiple sources. Algorithms for predicting disease outcomes are being created and tested with data that are retrieved in real-time through Castor’s API, which enables integrations with a wide range of other tools. These algorithms will assist in predicting the probability that a patient will require intensive care, and if so, what the likely outcome will be. These algorithms will be organized into dashboards as seen below:
Castor’s Enterprise Tableau integration is used to pass data to Tableau, a widely-used business intelligence tool. Thanks to hosting with TRUE, this tool built and managed by The Information Lab has been granted free licenses from Alteryx and Tableau to assist in studying COVID-19. The dashboards will give an overview of admissions to the ICU, MCU (medium care unit), and hospital wards, as well as visualize the outcomes, comorbidities, and complications.
The Dutch healthcare system has mounted a committed effort to keep its citizens safe, but despite the brave actions of doctors, nurses, and healthcare workers across the country, intensive care facilities are reaching capacity well before the number of infected peaks. The vital task of deciding who is transferred to intensive care, how long they must remain there, and who can wait out the disease in general care is a significant impediment to effective patient flow given the recency and lack of data about the virus. Currently, it is virtually impossible to direct intensive care transfers at the level of precision necessary for the crisis, when the lives of thousands of critically ill people are at stake, and this is where COVID-PREDICT aims to help.
Study Design and Methodology
Researchers at Amsterdam UMC and Maastricht UMC+ under the direction of Dr. Beudel have designed a system using machine learning to determine likely outcomes for individual patients; that is to say, who is at greater risk of requiring intensive care among those hospitalized. To accomplish this, Dr. Beudel and his team are entering retrospective cohort data from COVID-19 cases according to the WHO-COVID-19 standard CRF into a national database, and analyzing it using a machine learning system. Outcomes at 1, 2, 3, and 6 weeks are recorded along with responses to treatment.
Their project, which is expected to last between March and June of 2020, aims to make optimal use of the existing capacity within the Dutch healthcare system, improve patient flow within the hospital system, and deliver critical care services to the patients who need it most.
About the Team
Dr. Martijn Beudel is a neurologist with a special interest in movement disorders and neuromodulation (Deep Brain Stimulation (DBS). Since the COVID-19 crisis emerged, Dr. Beudel temporarily shifted focus to COVID-19, and has mobilized members of his DBS research team to assist with the COVID-PREDICT project:
Clinical trials are experiencing significant disruption worldwide due to the COVID-19 pandemic. Medical research is not immune to the effects of physical distancing, strained healthcare systems, and an emotionally volatile environment affecting trial participants. Clinical trial teams are facing regulatory changes, participant safety issues, funding issues, and a tech crunch as they flip from in-person to remote trials.
As of this publication, there are 262,366 recruiting clinical trials globally which may be affected. The full impact in Europe, America, and elsewhere remains to be seen. So far, we know that there has been a slow response to “flatten the curve” and epidemiologists are already warning of a fresh spike of cases in the fall. Realistically, we can expect that clinical studies may be significantly disrupted for at least 12 months.
Additionally, COVID-19 is consuming healthcare resources for both treatment of the ill and trials. Study sponsors will likely be forced to prioritize between COVID-19 and in-progress clinical trials. Existing trials may be slowed down or even stopped, especially where trial sites are located in hospitals. A number of EU sites, such as Poland, France, Italy, and UK, have suspended trial activities with the exception of treating ongoing patients to prevent missed treatments. Trial participants in many areas are not allowed to travel to clinic sites or are uncomfortable doing so.
Currently, the biggest challenge in the EU is the lack of site staff availability to do anything trial-related as many are being re-deployed to Emergency Rooms. Other sites are not allowing Clinical Research Assistant (CRAs) on site, putting current trials at risk of shutdown unless they quickly find a remote strategy. And, of course, due to quarantine and social distancing orders in effect almost all clinical trials are suffering from slowed or stopped enrollment of participants. Trials are also grappling with delayed investigational product shipments.
As we observe China slowly get back to business, we will be looking closely at their clinical trial progress for clues about the future of other research.
The Initial Response
As a first step, it’s essential to limit exposure risk to research participants, clinicians, and study coordinators. Investigators also need to pivot how they are conducting studies and may need to adjust protocols.
Now’s the time to differentiate between what visits are essential to be done in-person and what can be done remotely. Minimizing exposure for study participants may require a reduction of in-person appointments and any other circumstances that would require the participant to engage in non-essential travel. As we’ll discuss further on, this may involve using local labs or monitoring patients from home.
Some patients involved in medical device trials may be chronically or critically ill and at risk of harm if the trial is paused without a contingency plan. Consider arranging private transportation for the participant to come to the trial site, if it is open, and the participant would otherwise take public transportation. And if a patient simply doesn’t feel comfortable participating in a trial right now, their wishes must be respected.
Protecting staff may mean restricting non-essential staff from being on-site. If this is the case, drastic work-from-home measures will be needed. As leaders are no doubt aware, this requires a tremendous amount of change management as individual workers respond differently to change depending on their personalities. There is also the need to establish alternate ways to engage all team members, whether it’s through daily huddle, connecting via video, installing Slack channels, etc. Regardless of the challenges, research leaders must step up to manage their teams from afar.
During this time of upheaval, it’s important to review what regulations have been changed or loosened to accommodate trials impacted by COVID-19.
“The regulatory guidance, from my perspective, offers a lot more flexibility than we’ve seen before,” says Baljit Samra, Castor Advisory Board member and former COO of the Duke Clinical Research Institute. “I’d certainly encourage you to read both the FDA and EMA guidance in particular.”
After reviewing the material and deciding what protocol changes might be necessary, try to fast-track the process as much as possible to keep your study moving forward. There may be a need to report to the institutional Review Boards (IRBs) and Regulatory Bodies with whatever changes you make. Admittedly, it can be hard to pinpoint right now where changes can be made without explicit approval, so we recommend that you follow the guidance from these regulatory bodies to ensure that you don’t make any changes to your trial that will not be allowed.
Doubtlessly, notified bodies will consider deviations from business-as-usual when they are considering clinical trial results. However, the onus remains squarely on investigators to record protocol modifications, deviations and missing data. In order to meet quality and compliance challenges, document reasons for data and the impact of delays. Record stoppage, reduction or modified inspections and/or audits. Capture risk logs for COVID-19 with CROs and partners.
“Whatever approach you take within the boundaries of the regulatory guidance, I would document it so that you are in a position to really justify your approach,” advises Baljit.
Conduct Trial Risk Assessments
Each and every trial is different and only its researchers will know that trial intimately. Regulators are therefore asking researchers to conduct detailed risk assessments, giving priority to the safety of trial participants. When doing so, factor in the many disruptive aspects caused by COVID-19 and prepare for inevitable deviations to processes and to protocols.
The first big question: Is my trial regulated by FDA, EMA or any other regulatory bodies? The more tightly-regulated the trial, the fewer protocol changes that you’ll be able to make without explicit approval. On the other hand, if a study is being conducted in an academic setting or it is an investigator-initiated study, there may be more options.
While conducting a risk assessment, be sure to review the risk to participants. If the trial itself is beneficial to the health of participants, then traditionally the trial would need to continue so as not to endanger patients’ health. This might be true of oncology studies or rare disease studies, where the patients may derive great benefit from continuing treatment. Conversely, if visiting the hospital site would be detrimental to a patient’s health, that might be a point where you stop enrollment. In short, take a common sense and ethical approach when deciding whether your trial should continue.
When considering how to proceed with a trial, divide clinical data into three categories:
Must-have and needs to be collected on-site
Must-have but can be collected remotely
Now is the time for protocol simplification and a focus on collecting essential data. In deciding how specific clinical studies should be handled during this pandemic, John Hopkins advised the following guidance:
Leverage Technology to Modify a Study
Potential modifications may be possible to keep a trial alive through the pandemic. Look at your entire protocol and think about where you can start to plug in technology. Dip deep and get really creative by looking at both in-the-box and out-of-the-box options.
Before implementing any new tech solutions, review the original trial consent form—did you explicitly state which technology you’d be using? If so, that would significantly restrict your flexibility because the patient consented to a very particular approach. Most consent forms that we see, however, do not have such restrictions and would allow you for flexibility in introducing new technology.
If you have access to a data protection office or legal department in your company or at your institute, try to involve them early. For example, if you are thinking about adding videoconferencing or a new document management solution or any new technology platform, get the experts involved right away to go through the approval process. And if you work at a big company or an academic institution, collaborate with others so you only need to work with a single vendor and only go through one approval process to get the tech you all need.
Activate remote enrollment
The biggest question here is whether decentralized enrollment is possible: Can you enroll patients without them actually visiting the site? Over 85% of researchers expect moderate to significant impact on recruiting new study participants, according to a recent survey by Castor, so if that’s a possibility, you may be able to continue enrollment. This might involve a video call where you go through the consent form with the participant, followed by the participant filling out an e-consent form. Stay as close as possible to the original process. Regulatory bodies will consider alternative consent options, but they will still require approval. Contact our team to learn how we can support implementation of remote enrollment.
Mail Equipment to Participants
There are a lot of measurements typically done on-site that could potentially be done remotely. Enable virtual clinical trial data collection by mailing user-friendly diagnostic devices to your participants such as pulse-oximeters, spirometers, glucose meters, etc. If there’s a large enough budget, consider switching to IOT devices which can provide plug-and-play in-home measurements. Look at endpoints and assess whether there is a device that you could ship to the patient which would be plug-and-play where they can start sending these measurements to an EDC system such as Castor EDC.
Use Existing Tech Tools
Based on your local regulations, you may be able to use mainstream options like Confrere or similar platforms to connect with patients. For example, video calls can be a great way to do assessments while observing the patient. Look into what secure messaging tools are available through telehealth platforms. Be sure to incorporate the use of these tech tools into your protocols to promote patient engagement and collect data. Look for certifications such as HIPAA, HITRUST, ISO-270001, SOC-2, NEN-7510, and GDPR compliance. Go for brands that are already operating in healthcare because they will likely already have necessary certifications in place.
Leverage Local Resources
Consider the use of local facilities or laboratories for study visit procedures where the principal investigator is in agreement and the patient is in agreement. Even in places with emergency measures in place, specimen collection centers are likely considered essential services and may remain open.
Issue Lab Slips Remotely
Prepare lab slips for blood draws and urine specimens remotely so that a participant does not need to enter a clinic in order to get the lab slip made. This may be done through e-mail, fax, or other means. The patient can go directly to the specimen collection centre and skip a clinic visit.
Engage with Participants
Set up a content feed or blog to keep subjects up to date on study status. Engage with trial participants by:
sending regular updates via email
using ePRO for additional measures outside of protocol
using social media for engagement (while respecting anonymity)
using video calls to stay in touch
“Historically, I’ve always seen that our industry tends to be a more conservative industry,” says Baljit. “As long as we are conscious of the regulatory requirement around privacy and security, at this point in time, it’s going to be a blank sheet of paper as far as how we address research needs in both a technological and virtual manner.”
Nearly 50% of researchers surveyed by Castor say they will be looking for technology to support them in remote source data validation and remote monitoring, so consider what tools are needed to ensure monitors are effective while working remotely. Processes must remain compliant with regulations (e.g. no unencrypted PDFs with personal data being exchanged), and researchers should carefully assess whether they are using compliant technology for this purpose, such as HIPAA-compliant screen-sharing technologies. A round-up of recommendations from Castor Advisory Board member Craig Lipset can be found here.
Our Castor team has been busy surveying our clients’ needs. From our conversations, we know that what clinical trials need right now is technology allowing investigators to observe participants, instruct them to complete assessments, and record their observations directly into an eSource form. In a nutshell, they need technology to support data collection as it moves from an onsite environment into a virtual one. Learn how Castor supports research continuity here.
Real-time reporting across the enrolled population
The above are all integrated into Castor’s Electronic Data Capture (EDC) system and are available for use with all trials. We are also working to launch other remote-friendly features as quickly as possible. As a company, we are intently interested in supporting our clients to keep their studies running and our entire team is working hard to support those efforts. Now is the time to implement robust strategies to mitigate any issues with ongoing studies as a result of the COVID-19 crisis.
As of early April 2020, over 1,000,000 people have been confirmed infected with the SARS-CoV-2 coronavirus, and governments are scrambling to contain its spread. The high R0 value (a measure of contagiousness) of SARS-CoV-2 means that those infected copiously spread the virus and develop complications suddenly. As a result, health care systems are overwhelmed, and effective delivery of medical care to all patients has become a challenge worldwide. Inadequate personal protective equipment (PPE), overcrowding, and difficulty protecting existing patients are key challenges the medical industry is grappling with. The most common measure implemented to contain the spread of the virus before it impacts health systems is social distancing, which in turn has resulted in shutdowns across many industries.
Medical device manufacturers have not escaped the pandemic’s impact. Similar to pharmaceutical companies, medical device manufacturers rely heavily on healthcare facilities for their clinical trial data collection. Most medical device products must undergo clinical trials both pre- and post-market before manufacturers can obtain certificates for market approval.
While certain trials such as Investigator Initiated Studies (IIS) are necessary for the broad healthcare system to come to a consensus around efficacy of certain therapeutic options, other clinical trials are initiated by sponsors to investigate the safety and clinical performance of devices in order to satisfy regulatory requirements. For instance, in the EU, the Medical Device Regulation (MDR) requires manufacturers to conduct Post Market Clinical Follow-Up (PMCF) studies to demonstrate the continued safety and performance of their devices, as well as capture any emerging risks these may carry. However, the COVID-19 pandemic has delayed clinical trials and disrupted processes.
In an effort to relieve healthcare systems from all non-urgent medical requests during the COVID-19 pandemic, many clinics have been postponing non-critical surgeries and/or appointments as well as banning visitors. These restrictions include ambulatory visits, under which research studies typically fall. From a logistics perspective, Phase I units in many hospitals around the world—where extensive monitoring of volunteers during first-in-human studies generally take place—are being reserved for the monitoring of COVID-19 patients.
Clinical investigations are mandatory for many medical devices that carry a certain level of risk, such as implantable devices. While planning a clinical study, manufacturers must navigate complex and costly processes such as those that require review by Ethics Committees and Competent Authorities. These authorities are currently concentrating their efforts on responding to the COVID-19 pandemic while their staff is working remotely, resulting in delays to initiation and subsequent execution of clinical trials.
For instance, delays in patient enrollment for non-COVID-19-related clinical studies are resulting in timeline shifts and budget adjustments for manufacturers. Overwhelmed clinical sites and healthcare professionals may have little to no interest in maintaining clinical routine and clinical trial schedules, and milestones may therefore be impacted. With large medical device manufacturers managing diverse product lines, these delays will likely impact entire pipelines and product launches unless these new medical devices are involved in the effort to contain COVID-19.
The medical device industry often relies on data from IIS, which are initiated by clinicians to investigate the clinical performance of certain therapeutics including medical devices, usually in the form of comparative studies. The clinical evidence derived from these IIS plays an essential role in the clinical evaluation reports (CER) that manufacturers are required to compile in order to obtain market approval in the EU. As a result of the widespread impacts of the COVID-19 pandemic, IIS are currently on hold or delayed with potential consequences to market access for all non-COVID-19-related medical devices. This could mean innovative, life-saving devices may not reach patients on time, or that legacy devices are unavailable for restock. Both of these scenarios carry significant risk of harm to patients worldwide, and could bring additional chaos to overwhelmed healthcare systems.
Post-Market Clinical Follow-up Activities
In addition to sponsor-driven clinical trials and IIS, PMCF projects are also likely being impacted by the COVID-19 pandemic. In the EU, PMCF activities are required to demonstrate conformity of subject devices with respect to their continued safety and performance parameters. PMCF studies are gaining momentum under the MDR as an increasing number of these follow-ups will be required to achieve compliance in the EU.
However, PMCF studies are not currently seen as attractive undertakings to clinicians and manufacturers for a variety of reasons. Many perceive post-market studies as bare regulatory necessities for products that often have a long market history, and these are therefore less appealing from a research perspective. Under this light and in the midst of a pandemic, investigators may risk neglecting these PMCF studies.
According to Henk Snyman, Medical Director (EU-MDR), Medical Affairs at Cook Medical, “Data collection for PMCF at sites will be severely impacted during the pandemic. Many clinicians have other priorities now and don’t want to discuss PMCF projects. The MDR extension is certainly welcome, but we still need to see the finer details.” However, if PMCF data collection is pushed out or unfulfilled, this could have harmful consequences such as loss of certificates for certain devices that are considered healthcare commodities.
What Are Some Things Manufacturers Can Do Right Now?
Implement Strategy to Mitigate COVID-19 Impact
Mitigating the effect of the COVID-19 pandemic will require a comprehensive evaluation of the study protocol, beginning with a risk assessment. Clinical trials that pose a benefit to the participant (such as “humanitarian use” designated devices in the US) pose a question of whether the trial can be safely suspended or discontinued entirely, and will need to be addressed according to the specific circumstances therein.
Second, for traditional, phased trials, the risk to participants should be assessed in terms of reporting obligations to sites, consequences of discontinuing the trial abruptly, etc. To facilitate study continuity, many manufacturers are implementing telemedicine solutions. This can range from mailing a patient user-friendly equipment (e.g. pulse oximeter, spirometer) for collecting data in the home, to in-person home nurse or technician visits supervised remotely by a clinician. As long as proper infection control measures are followed, the risk to the participant and study staff is significantly reduced when compared with entering a hospital or clinic.
Some medical devices can be configured to transmit data directly to your electronic data capture (EDC) solution, and can eliminate both the manual data entry as well as the need for a participant to visit a site. Speaking more broadly, principal investigators (PIs) should assess study endpoints pragmatically, and consult their ethics board to determine whether less important endpoints could be deferred if they require in-person visits or travel.
Decentralized technology will be a key component of the research community’s response to the pandemic. Over 85% of researchers reported in a recent survey that they expect moderate to severe effects on participant engagement in a recent survey, highlighting it as an area of significant concern. Thankfully, research technology has never been easier to use or simpler to implement. Electronic patient reported outcomes (ePRO) can reduce the travel burden on participants and study staff while continuing to capture data. Additionally, guidance issued by regulatory agencies in both the EU and US have enabled studies to rapidly transition from wet-signature informed consent to eConsent platforms.
For more information, see this article summarizing key considerations for mitigating COVID-19 impacts on research.
Prepare for Future Projects
Due to the COVID-19 pandemic, the European Commission recently adopted a proposal on April 3, 2020 to postpone the application date of the MDR for one year. “As the coronavirus crisis increases demands for certain vital medical devices, it is crucial to avoid any further difficulties or risks of potential shortages or delays in the availability of such devices caused by capacity limitations of authorities or conformity assessment bodies related to the implementation of the Medical Devices Regulation,” the Commission wrote in a statement.
With delays to the MDR and clinical trials, manufacturers should use this extra time to fill their clinical data gaps and catch up on planning activities such as their PMCF plans. To learn the steps needed to put together a PMCF plan that will pass Notified Body scrutiny, watch this webinar.
In addition, manufacturers should repurpose newly-freed schedules to peruse published scientific data that may suggest additional indications and possible fields of usage for their products. Stay in touch with the clinicians who support you (or may support you in the future) with research, development, or medical expertise.
Prepare also for the execution of future clinical studies by identifying areas for improvement in your data solutions and trial operations. When research resumes, having technology solutions and processes that better fit your needs will expedite the return to operational normalcy.
For instance, now is a good opportunity to improve how you capture data for medical device trials. The ability to electronically perform clinical data collection and monitoring has a competitive advantage when compared to old-school, paper-based methods or legacy systems (Excel, SPSS, Access, etc) that not only require physical presence at sites but also create greater opportunities for errors.
Identifying the right electronic data capture (EDC) system that is best suited for your complex needs is crucial to success. When choosing your EDC, select the solution that will enable seamless data collection for you and your sites. This will minimize inaccuracies in the data while optimizing processes. Using the right EDC system can improve the overall quality of your clinical data and help your clinical research run more smoothly and efficiently.
Use Your Network to Think Outside the Box and Support Clinicians.
The COVID-19 pandemic is an opportunity to strengthen the partnership between manufacturers and clinicians. Take the time to speak with your products’ end users—especially with key opinion leaders—and ask what their greatest need is in their specific field and organization, hospital or private practice. Use your network to find solutions or satisfy these needs. Also find ways to help others who do not have the same knowledge or expertise as you or do not have the reach of your network. Click here to read how Castor enables research continuity during the COVID-19 pandemic.
Contact us to learn how we can support your medical device trials during this pandemic.
Today’s increase in the incidence of heart failure is due to an aging population and therapeutic advances that have lengthened the lives of cardiac patients. Despite advances in treating ambulatory patients who have heart failure, symptomatic relief through an optimal agent, optimal dosing schedule and optimal administration route have yet to be found. Castor Research Award Nominee #11 ADVOR study is researching the use of acetazolamide as a booster of diuretic efficacy.
Both an aging population and modern therapeutic innovations which have prolonged the lifespan of cardiac patients, have led to an increased incidence of heart failure (HF). During the last two decades, important progress has been made in the treatment of ambulatory patients with heart failure with a reduced ejection fraction (HFrEF). Despite these important advances, many patients still are frequently hospitalized with decompensated HF demonstrating most often signs and symptoms of systemic congestion and volume overload, which is associated with a worse outcome. Treatment in these cases focuses mainly on symptomatic relief through the administration of diuretics, although clear evidence on the optimal agent, dosing schedule and administration route is lacking. Loop diuretics, that act at the ascending limb of the loop of Henle in the kidney, are by far the most commonly used agents to achieve decongestion in patients with decompensated HF. However, from a pathophysiological point of view, targeting sodium reabsorption in the proximal tubules of the kidney–rather than solely at the loop of Henle–has several potential benefits in patients with HF. The carbonic anhydrase inhibitor acetazolamide (Diamox®), which is approved for the treatment of mountain sickness, inhibits sodium reabsorption in these proximal tubules. Some studies suggest that adding acetazolamide might be an efficient booster of diuretic efficacy in combinational diuretic therapy with loop diuretics.
Marlies Dictus: Since June 2018, working as a scientific co-worker in ZOL Genk for the ADVOR study.
Katrien Tartaglia: Since January 2018, working as a scientific co-worker at the Clinical Trial Unit of ZOL Genk.
Liesbet Van Brussel: In April 2018 joined the dynamic ADVOR-team at the Clinical Trial Unit of ZOL Genk as a scientific co-worker.
Ward Eertmans: Since November 2018, working as a scientific co-worker in ZOL Genk for the ADVOR trial.
Elly Vandermeulen: Since the beginning of 2017, working as a scientific co-worker at the Clinical Trial Unit of ZOL Genk.
The ADVOR study team takes care of the practical aspects of the ADVOR study. The team gets medical input from the scientific team, which consists of two cardiologists with expertise in heart failure (Prof. Dr. Wilfried Mullens and Dr. Matthias Dupont) and one cardiology Ph.D. Fellow (Dr. Jeroen Dauw). All members of our study team perform the same role as a scientific researcher with each member having specific focusses and being responsible for different participating sites: project manager, data manager and on-site monitor.
Study design and methodology
The ADVOR study is a double-blind, randomized, placebo-controlled, Phase IV, prospective multi-center clinical study. 519 patients will be randomized (using permuted block randomization) in either the active group (high dose loop diuretic in combination with Acetazolomide) or the placebo group (high dose loop diuretic in combination with placebo), stratified for center and left ventricular ejection fraction percentage. In total, 24 Belgian centers are actively participating in the ADVOR trial and the trial will soon expand with seven additional sites. Eligible patients receive a maximum of three days of treatment or until decongestion is achieved. Three months after the first study medication is given, a follow-up visit takes place.
The ADVOR study will examine if the addition of acetazolamide to loop diuretics will lead to a better decongestion in decompensated HF patients with volume overload. It is assumed that a more thorough decongestion should translate into fewer readmissions for recurrent decompensation, better renal preservation, and eventually, lower mortality. The primary endpoint is treatment success (decongestion achieved) on the morning of Day 4 without the need for escalating diuretic strategy (doubling loop diuretic dose, the addition of chlorthalidone, or ultrafiltration) on the morning of Day 3.
How ADVOR study team uses Castor
The study uses Castor for the collection of study data and electronic query management. As it is a multi-center study, centers across Belgium can enter the data online. The ADVOR study team reviews the data in the system and also verifies the data are consistent with the source documentation on-site. During this process, manual and automatic queries are managed in Castor EDC. At the end of the study, exporting these data allow the study statistician to do the final analysis.
“None of us has advanced programming skills,” said researcher Marlies Dictus. “So the user-friendly form builder was of great help when building the eCRF.”
The possibility of mandatory and conditional fields assists site users in knowing which data are necessary to complete and avoids the completion of unnecessary data and consequently avoids the creation of queries.
Reports and the combination with repeated measures give the data manager and site users a clear view of which data should be and have been completed.
The “User missing” option gives various options to indicate that certain data fields/steps/phases are, for example, not done or not applicable (instead of leaving them empty and generating queries to ask why the field is left empty).
The automations and validations are useful in relieving the manual work for the data manager.
The SDV verification tag (used in ADVOR as a data management verification tag) and the data lock feature allow the data manager to have a visual overview of which data have been verified and locked for a certain patient.
The sign function gives the possibility to electronically sign off the data by the investigator instead of doing administration on paper.
Summaries help the data manager in the manual review of the data. We combined several summary data fields in “summary forms” per topic. For example, patient summary to verify the consistency of dates and visits, laboratory summary to check for outliers over time.
Hide phases/steps to document data management findings (for example, summaries, AE coding, documentation of protocol deviations) that are not visible for the site users.
The import function assists the data manager in entering data in batch (for example, at the end of the study to import the unblinding information per patient from an excel file).
The export function helps the data manager provide a status of the study, exporting data for the data management review, and as a way to provide the data set to the statistician for final analysis.
Stay tuned on the Castor EDC blog for more 2019-2020 Castor Research Awards nominations. We wish the nominees good luck and smart science—and encourage all researchers to share their projects for the chance to win €3000!