Applying for a clinical trial grant can sometimes feel like turning in a high school English paper. You could turn in the same exact paper on a different day of the month and get very different grades based on factors that seem out of your control (like whether the teacher is having a good day). However, some critical ingredients can help an application stand out to Federal regulators (e.g., FDA and NIH). Organizations who select eClinical technology partners prior to submitting their application can strengthen their case by detailing data flows, risk mitigation measures, and proven best practices. Demonstrating familiarity and competence with identified technology partners shows that the applicant has the knowledge and experience needed for success in their efforts.
What are some best practices regulators look for?
Excite Your Audience – Present the research in a way that will drive curiosity and interest from peer reviewers. The bigger the research’s impact, the more exciting the project will be. Look to quantify in large terms the level of impact the investigative product will have on the broadest number of recipients. Like a tech startup seeking venture funding, tell your audience how you are going to change the world.
Study Planning – Demonstrate your preparedness by talking about the study build, site onboarding, and enrollment strategies. What is your plan and how will this process be monitored? What are the risks and how will those be mitigated? Have you identified any tools that will help you measure and track your progress? Lay out your plan in detail and include discrete sequential steps.
eClinical Technology Partner – Once your audience is excited about the project and understands your preparedness, they will need to be convinced that the right team is in place for successful project execution. Who will you be collaborating with and how are they specifically qualified for this trial? An eClinical technology partner will provide more than the software that houses the clinical data. They are someone who knows how to leverage technology to minimize execution risk throughout the trial, from designing CRFs and facilitating site training to maximizing data quality and removing human error almost entirely.
Prelude Dynamics has been an eClinical technology partner for many Federal grant recipients. We routinely provide language for applicants to include in their applications and have also provided letters of support for clients. In our experience, early collaboration with researchers adds detail, depth, and substance to Federal clinical applications – streamlining the award/approval process.
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CVM’s Office of New Animal Drug Evaluation (ONADE) has launched an initiative that will greatly increase the efficiency of the study submission process. They will now allow submissions through read-only access to online databases in lieu of the submission of copies of the data. Prelude Dynamics is participating in this pilot program with two study sponsors, and we are optimistic for successful outcomes in both. The primary advantages of allowing CVM direct study access as opposed to the submission of copies of the data are:
- For CVM: With access to the online database they will be able to view the data in a more natural, intuitive way. Spreadsheets do not provide the context that the full database can and are therefore not as suitable. With access to the database, CVM can view all the audit trail information right alongside the source data.
- For Sponsors/CROs: Online access eliminates problems with multiple file uploads and file size restrictions that make the current submission process cumbersome. The burden of “packaging up” study data in a eSubmitter-ready format is removed. Submissions will be faster and less costly.
Preliminary results with one EDC system are promising. Both CVM and pharmaceutical companies are enthusiastic for the future of the study submission process.
For studies to participate in the program, some documentation is required up front. Prelude Dynamics has also removed this burden from Sponsors and CROs by offering prepared templates for interested parties. If you are interested, ask your Prelude project manager for a template today! They can help you submit your information to the right people at CVM.
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What does it mean to conduct effective remote clinical monitoring? It’s critical to be using an EDC in order to accomplish this, but what else is necessary? Keeping the primary goals of the monitor in mind, we will outline several techniques for streamlining this process.
What are the primary goals of the study monitor? First, and most critical, is to ensure the safety of all study participants – including clinical personnel. Second, is ensuring data quality and integrity.
Let’s discuss the EDC features that can help in each of these areas.
Ensuring Safety
Monitors are relied upon to use their knowledge and expertise to recognize potential safety risks, and to report them when discovered. The EDC can’t replace monitors, but it can assist them greatly in their daily workflow.
Use of Notifications. The EDC can be configured to automatically notify monitors when certain events occur. Examples of this include the entry of adverse events, the reporting of out-of–range lab results and new subject enrollment. When automatic notifications are used, monitors are informed in real time and the need to continually review eCRFs for potential issues is eliminated – saving valuable time. Think about the potential risk factors for a study and consider how notifications can be configured to assist the monitor.
Use of Reports and Graphs. Some EDCs support flexible, configurable reporting tools that facilitate the aggregation of data for review. Graphs can be used to more intuitively spot outliers and aid in understanding trends. If such tools are not available, consider asking your EDC provider for custom summary reports that can be used to review study endpoints, exam results and adverse events in a comprehensive way.
Use of Study Dashboards. Dashboards that aggregate reports from multiple sources can provide a convenient starting point for a monitor’s daily workflow. Monitors can log in to the EDC and navigate to a central page to review notifications, study metrics and risk-aware reports.
By proactively thinking about the types of information monitors need, each study can be configured to provide tools such as these before the first subject is enrolled. With the VISION™ EDC system, mid-study updates can easily be made to support data monitoring needs that weren’t anticipated at study build time.
Ensuring Data Quality and Integrity
Sophisticated EDC systems support automated data cleaning in a variety of ways, which naturally improves data quality. Monitors and data managers can contribute their expertise at study build time to make sure that this automation is included as comprehensively as possible.
Use of “Completeness” Checks. Completeness checks answer the question “is all required data on the eCRF?”. This is especially important when some data can be entered conditionally (e.g., only if another data entry element has a certain value). A related question is “why wasn’t this form been filled out?”. It’s a good practice to implement a “Not Done” checkbox on forms such as Adverse Events and Necropsy that are (hopefully) not often used. This practice lets monitors know in a proactive way that the form is intentionally blank, which effectively reduces the amount of questions from the monitor.
Use of “Correctness” Checks. Correctness checks help answer the question “is the data correct and in the right format?”. While study protocols usually provide information about the resolution (e.g., number of decimal places) of data to be collected, they don’t always specify things such as the expected range for data points. Enlisting the support of data managers at study build time will help ensure these checks are in place and are as complete as possible.
Use of Visual Error Indicators. When visual error clues are present and easily viewable, monitors don’t have to spend time manually reviewing each form for errors. They can focus their efforts on strategic reviews instead. Such indicators also provide immediate feedback when data is entered, which prompts clinical personnel to correct entries in real time.
Use of Document Uploads. When it is necessary to transcribe data from paper forms, it’s good practice to provide an upload mechanism for those forms so the transcription can be reviewed more easily. This mechanism, along with Source Data Verification (SDV) functionality, is also useful in converting a paper study to EDC. VISION’s SDV functionality allows the monitor to sign off on each data entry field individually or at the form level.
Use of Integrated Query Functionality. Having the ability to enter queries directly into the EDC system, and to easily see whether queries have been resolved, is an enormous aid to monitors. It eliminates the need for them to revisit queries that have been resolved and move on to more important work.
Qualify the EDC Vendor’s Infrastructure. We’ve defined mechanisms for ensuring the completeness and correctness of data, but how secure is it? EDC vendors should be asked about their backup strategy. How often is data backed up? How much data could I potentially lose? How long does it take to restore data? How long is data retained? These are some good questions to ask your EDC provider before your study commences. Prelude recommends (and performs) hourly backups. Questions about barriers to system access are also important. Ask your vendor what their average up-time is. If clinical personnel can’t enter data in real time, data integrity could be impacted.
Monitor Workflow – Continuous Monitoring
Here are some recommendations for conducting remote clinical monitoring using VISION™.
- Identify a monitoring schedule and stick to it. For slow-enrolling studies, this might be once or twice a week. Larger, more active, studies may require full time monitoring efforts.
- Create focused reports that highlight potential risk areas and promote identification of outliers or undesired patterns. Configure the Dashboard to include these reports and share them with other clinical personnel to promote awareness.
- Consult the Dashboard to make sure notifications have been handled and to get an idea of emerging trends that require analysis.
- Review forms that have been submitted by clinical personnel and use the Query function to call attention to questionable data.
- Review recent lab results for out-of-range results and determine if those relate to Adverse Events.
- Review fields with changes to see if there are any patterns and clarify their use with clinical personnel.
It’s important to perform these activities continuously. Contemporaneous identification of issues is critical when safety is concerned and helps clinical personnel recall specifics they are likely to forget after time passes. Also, when monitoring is done continuously, study close-out activities can be completed much earlier since most of the work has already been done!
Conclusion
Monitors who understand the capabilities of their EDC provider and the automation that has been included in their study have an advantage. They can rely on the EDC system to handle the “grunt work” and concentrate instead on critical outcomes and analyses that can’t be automated.
We were excited to see that the Great Ape Heart Project (GAHP) was featured in an episode of Animal Planet’s “The Zoo – San Diego”!
Cardiovascular disease has long been recognized as an issue for Great Apes, and the GAHP registry is used to record and monitor the cardiovascular health of Great Apes in zoos, parks and preserves around the world. Prelude Dynamics is the proud provider of the EDC database used for this valuable repository, which provides an ever-growing set of normals that are used to compare animals in the wild with those in managed care. This information helps animal health care professionals better understand the underlying causes (such as genetics, diet and stress) that contribute to cardiovascular disease in these magnificent creatures.
The episode follows a Western Gorilla, Mandazzi, whose sire passed away from complications associated with heart disease. Because of this relationship, a full cardiovascular exam for Mandazzi is performed in addition to his routine physical exam. Ultrasound images of his father’s heart stored in the GAHP EDC were compared to those of Mandazzi. Great News! Mandazzi did not exhibit any of the symptoms that were present for his father.
Interesting Facts. Human ultrasound sonographers can capture images for Great Apes since the procedures used are very similar. Not only that, Great Apes can be trained to participate in their own ultrasound exams. But they don’t like the gel!
To find out more information about the GAHP project, click here.
You can also view the full “The Zoo – San Diego” episode here.
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There are so many ways to design electronic CRFs. Perhaps by looking at how NOT to design them, we can come up with some fresh ideas for how to make your next study a smashing success.
Fail to consider how well the forms will function on handheld devices.
The sun us setting on big screens and desktop workstations. Soon a new day will dawn, and the sun will shine solely on small screens. They provide mobility and greater access across the board. They are the key to conducting business in the information age.
Take, for example, form layout. Regardless of whether you are viewing it in landscape or portrait, a long list of fields is not conducive to the thought-processes of the human brain. Fields need to be grouped together in a way that makes sense to the person filling it out. And news flash: the person filling out the forms for your study is guaranteed to be relying on a human brain.
Put simply: don’t shortchange the design process of the study build in favor of a quick turnaround. You will thank yourself later when you are parsing through the raw data for usable statistics.
Require users to navigate extensively to do their jobs.
Do not bury important fields at the bottom of the form. Don’t force your sites to have to dig deep to get what you need. Cater the form configurations to quick and easy navigation.
Employ checkboxes instead of radios.
Simplify the investigators’ jobs before they even begin. Give them less options when possible. Dummy-proof your study to the point where the patients themselves could fill out their forms.
Don’t provide options for “Neither,” “N/A,” “Not Done,” or “Other.”
Bottlenecks happen when a field is lacking necessary options. The investigator will simply leave it blank if they do not see the option they need. Then the monitor goes in and queries the blank field. The investigator responds that they didn’t perform that particular test. The issue gets shunted up the line until it gets to Prelude and a mid-study update is requested to add the pertinent option to the field in question. This takes time, causes confusion, and costs extra support hours, depending on the complexity of the request. There will always be mid-study updates. It’s a normal part of the process, but some things can be prevented. Do your best to predict issues before they happen, and your study will run much more efficiently. Just don’t overthink it…
Assume that the data will be entered in a certain order.
After taking into account all of the above, we’ll leave you with this: You can’t predict everything. Put as much thought into your eCRF’s as you can, but first you have to learn the difference between what you can control and what you cannot. Providing a radio in place of a list of checkboxes is all well and god, but don’t assume they will fill out the first item on the form first. Don’t go overboard with field suppressions and calculations. Try to think the way a clinical would. That’s all you can do.
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