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The processes necessary to support regulatory compliance require valuable time and resources within a clinical research institution. Regulatory tasks in particular require frequent coordination between multiple roles and stakeholders to be efficient and successful. Those same workflows can be applied when referring to eRegulatory systems. Direct communication and integration between key operating systems like email, local and central IRBs, Clinical Trial Management Systems, and other eRegulatory instances all contribute to a more efficient and compliant trial.

Email Integration – Accelerate Study Start Up

Correspondence and supporting documents between sponsors, IRBs, and other stakeholders are essential to house in a protocol binder. However, manual workflows associated with downloading and uploading email messages and attached documents hinders efficiency, especially during study start up. By leveraging an email integration with your eRegulatory system, you can easily save correspondence (the emails themselves) as well as any attached documents to quickly review and associate them with the appropriate protocols in the system.

The industry’s most integrated eRegulatory system, Advarra eReg, allows you to seamlessly upload documents by utilizing unique email addresses for each protocol binder. For example, imagine a regulatory manager or coordinator receives a protocol update or important correspondence from the IRB or sponsor via email that was necessary to house in the protocol binder. Rather than having to download and then manually upload the information into the system, they’re now able to simply forward that email along or better yet, cc or bcc the eReg system to capture correspondence and attachments as you are working in your email. Once complete, your correspondence and attachments are stored in the protocol specific to your communication for easy long-term filing or additional routing. This not only eases the day-to-day file management burden for your staff but is especially impactful when applied to all studies across the organization.

IRB Integration – Increase Compliance while Reducing Effort

Documents shared between your IRB and organization are an essential component of your long-term binder storage and are often updated and routed throughout the lifecycle of a study. By utilizing integrations from both central and local eIRB systems to your eRegulatory system, you can reduce manual effort and increase compliance by syncing important documents via central intake processes.

Advarra eReg supports integration with Advarra’s Center for IRB Intelligence (CIRBI) Platform. In addition, Advarra eReg supports connections with your local eIRB system. With this IRB integration, all approved documents can be immediately accessible for your regulatory and clinical staff in eReg to take the necessary action. This also allows you to decrease time and effort needed to download documents from an external system and upload them into your regulatory binder across your institution’s research portfolio, maximizing time and effort saved.

Clinical Trial Management Systems Integration – Accelerate Study Start Up

An organization’s clinical trial management system (CTMS) is often the source of truth for all protocol and participant information. Minimize duplicate effort within regulatory workflows through integration with Advarra’s OnCore Research Enterprise System by pulling CTMS data related to protocols, contacts, and organizations, into a new protocol in eReg to support accurate and efficient binder building during study start up. This integration allows for organizations to level-up their technological workflows including streamlining the administration of staff training and delegation of authority. Connecting your CTMS and eReg systems through intentional, purpose-built workflows ensures your processes remain in sync across systems and match real-life workflows without the parameters of the applications.

eReg to eReg Integration – Efficiently Coordinate Multi-Site Trials

If you are the coordinating center for a multi-site trial, you can ease regulatory burden not only across your organization but across participating sites by leveraging the Advarra eReg-to-eReg integration. When coordinating multi-site trials using Advarra eReg, the sponsor or coordinating center can house not only their own documents related to studies, but also the site files of all participating sites, structured in a site-specific folder structure. Facilitated by a multi-site protocol connection, the coordinating site can request documents from the participating site, and the participating site can easily send the appropriate documents as requested.

While significant efficiencies occur through the eReg-to-eReg integration, for those participating sites operating on paper or not using an electronic system, the participating site can log into the coordinating site’s instance of eReg to upload their documents into the regulatory binder. With a simple review and routing workflow, the coordinating site can efficiently manage protocol documents across multiple sites to ensure study compliance, and effectively manage essential correspondence, amendments, and more.

Conclusion

Just as communication and coordination amongst regulatory staff, principal investigators, sponsors, and other stakeholders improves the efficiency of a trial, so does communication amongst your technology systems. As clinical research continues to move towards a remote environment, centralizing and integrating your regulatory management process and technology is vital to your institution’s success.

2020 changed everything, including training and learning.

Did you switch your training strategy to eLearning or web-based this year? With limited options, many organizations implemented virtual or on-demand training this year because of travel restrictions and limits on group events during the COVID-19 pandemic. Some organizations are still weighing the benefits or effectiveness of eLearning but haven’t taken the plunge yet, and a few organizations are just waiting until in-person training can resume.

Advarra went all-in on eLearning this year. With cases still growing near all Advarra offices, we have fully embraced our 100% virtual learning strategy to keep customers and staff safe. We started investing in our eLearning program in 2017, so Advarra’s Training Team was ready and equipped to convert all of our training to fully virtual learning this year when it became clear that COVID-19 was going to prevent us from conducting classroom training safely.

Why should you consider eLearning?

Some of the advantages of an eLearning program are clear – eLearning is accessible whenever it is convenient, staff can review it at any time, and it can (should!) include assessments or knowledge checks to make sure learners are really “getting it.” eLearning can be assigned to hundreds or thousands of staff at the same time – getting the message out about new processes or policy changes to everyone immediately. eLearning provides a consistent message and allows learners to work at their own pace. Have you ever been ten minutes from the end of a two-hour class with too much material left to cover? eLearning won’t ever have to cram, rush, or skip content due to time constraints.

There are other advantages to running an eLearning program. Consider a scenario where you have 300 staff to train on a new electronic software program, or who need to satisfy their requirement for annual human subjects protection training. What does it look like to train these 300 people? In the traditional manner of classroom training, it becomes a complex mathematical equation based on the number and size of your computer-equipped classrooms, the number of trainers on your team, the number of staff away from the clinics at one time, and the number of classes a trainer runs each week without collapsing from exhaustion. Sure, it might make sense to offer a morning, afternoon, and evening class so staff can choose a time to fit their schedule, but if one trainer is expected to teach all those classes, they’ll be running around from sunrise to sunset.

Now imagine your only computer training room seats 20 people. You’ll need to schedule at least 15 training sessions for 300 staff, which will require at least two to three weeks. What does that look like if you use eLearning instead? A series of eLearning modules provided in a learning management system (LMS) and completed by all impacted staff within a few days prior to go-live. No training room is needed.

Sounds great. What’s the catch?

Creating custom eLearning is a big project; creating the content, writing scripts and storyboards, designing the modules, incorporating feedback from subject matter experts (SMEs), and developing assessments require just as much time and effort as designing a classroom training program. You might choose to assign a project manager, one or more eLearning Developers, plus SMEs who know the content. An eLearning project might take 3-6 months or more. Calculate 6 months’ of an eLearning Developer’s salary, plus a Project Manager’s salary, appropriate software licenses, and time from subject matter experts – that will cost your organization $100,000 or more.

Sounds expensive. Are there any other options?

Advarra’s in-house team of eLearning developers can create custom eLearning for your organization for a fraction of the cost. We have internal experts on Advarra technologies and clinical research topics who can kickstart your eLearning projects, plus a team of full-time eLearning Developers with experience creating scripts, storyboards, interactive and engaging modules, and assessments. Using your workflow documents, standard operating procedures (SOPs), or existing training materials, we can start on your custom eLearning project today.

Is eLearning really worth it?

Someone is going to ask you about the return on investment (ROI) of eLearning. What is your department or organization’s ROI? Is it really wise to spend all this money on eLearning software, audio equipment, and new staff? If we hire eLearning Developers, how long will it take for them to onboard and learn your workflows and policies?

You will realize value from your eLearning program. On-demand training is more convenient; you won’t have to pay your staff to travel to and sit in a classroom. Knowledgeable staff will complete their tasks more efficiently with fewer errors.

eLearning provides the greatest ROI when it saves your organization time, so evaluate what training is required for many, several hours long, and offered frequently. You’ll see greater ROI if you reduce your costs – use Advarra’s custom eLearning services to launch your training program and realize value faster.

Don’t wait.

Organizations slow to adopt new training strategies will fall behind. Partnering with ACRP in spring 2019, we conducted a survey of over 1,500 clinical research staff. Our results found 1 in 3 respondents said they did not receive adequate initial training on the technologies they use regularly, and more than half said they didn’t receive any ongoing trainings for these technologies. Even more compelling, 80% of respondents found on-demand training (like eLearning) helpful. Your staff want on-demand training, and it can be just as effective as in-person training, so we encourage you to try it out.

Would you like to see some samples of our work? Learn more about our custom eLearning content.

A key component to the success of a clinical trial is opening a site for recruitment, which requires accelerated startup times. Delays in budget negotiations and site startups can dramatically alter these timelines. For a closer look at clinical trial budget development, read our blog Developing a Clinical Trial Budget Following Medicare’s Clinical Trial Policy and Device Regulations.

From the sponsor’s perspective, managing budget negotiations at multiple sites is a monumental task, addressing numerous, often conflicting funding requests from sites. In this blog, we’ll describe a case study of how clinical trial budget negotiations can be viewed by both parties: sites and sponsors.

In this example, Sites A, B, and C are selected to participate in the same clinical trial. However, each site has its own unique methodology to develop and negotiate a clinical trial budget that meets their specific site’s needs.

	Budget Preparation on Site	Budget Negotiations with Sponsor
Site A	US-based site in the same city as Site B Prepares budget based on internal coverage analysis process (understanding what items may/may not be covered by Medicare and other insurers)* Notes not all standard of care (SOC) items/services are covered by Medicare and requests additional sponsor funding to cover these items/services	Budget negotiations become challenging due to the requested coverage for SOC items/services After numerous rounds of back-and-forth redlines in emails (time delays) the site and sponsor reach a standstill; negotiations are escalated, and a conference call is scheduled
Site B	US-based site in the same city as Site A Requests higher rates for items/services in the budget, including fees for conducting the actual procedures and inflation costs over the life of the trial Requests additional funding for a specific lab test not performed locally Does not address SOC items/services and accepts what is noted on the sponsor’s budget	Budget negotiations are “quick and easy” Budget is approved, and the contract is executed in a timely manner
Site C	US-based site in a different state on the opposite coast from Sites A and B Prepares budget based on local coverage analysis process, understanding what items may/may not be covered by Medicare and other insurers* Notes many SOC items/services are likely to be covered by Medicare except for a few	Budget negotiations are smooth as the site is only asking for a few additional SOC items Budget is approved, and the contract is executed in a timely manner

*Medicare is considered the “Gold” standard and, oftentimes, commercial healthcare insurers follow its coverage decisions.

To prepare for the conference call and provide justification for their budget, Site A pulls together Medicare’s rules and regulations, applicable local coverage determinations (LCDs), and copies of correspondences with their local Medicare Administrative Contractor (MAC) regarding coverage for items and services for this clinical trial. Sometimes this type of discussion will be effective, and the budget is negotiated. Other times, there is further escalation to the sponsor’s legal department and senior leadership, where the same documentation and discussion occurs again before deciding whether to provide the requested funds.

What Is Really Going on in the Above Scenarios?

Site A creates great delay and frustration on both sides. What went wrong with Site A’s negotiations? How can two sites from the same city request such different budgets, and how can Site A and Site C vary so much in what is considered SOC?

LCDs vary by region, explaining the difference in SOC coverage for Site A and Site C.

The difference between Site A and Site B stems from institutional processes—Site A appears to have a consistent process in place to evaluate Medicare’s coverage of items and services for the conduct of a clinical trial. On the other hand, Site B may not have a process in place to evaluate Medicare’s coverage of items and services for the conduct of a clinical trial, or their process may be less well-defined, or they may have different interpretations of what is covered.

The sponsor may not understand Medicare’s coverage and impact on drug and device clinical trials and the differences in LCDs. It’s also possible they cannot afford to provide this additional funding to the site. This disconnect can create angst and negative financial implications for both sides. At best, the site and the sponsor agree on a budget, and, at worst, the sponsor or the site opt not to participate in the study. This is a disappointment for all parties, including potential participants interested in participating in the clinical trial.

Education and communication are key components a site can use when working with its sponsors. Sites can prepare a resource toolbox for sponsors and provide it as early as possible—sometime after the confidential disclosure agreement (CDA) is executed and before budget negotiations commence. This toolbox helps maintain positive working relationships, prevents surprises for both sides, and avoids wasted resources in developing and negotiating a budget that may not get approved. Possible resources for the toolbox include copies of the regulations, summary statements, white papers, journal articles, and a flow chart/diagram of your institution’s specific processes. While the toolbox takes time to develop up front, it saves valuable time during budget development.

Conclusion

The negotiation of a clinical trials budget is a time-consuming and often daunting task for sponsors and sites. Inaccurate budgets result in astronomical financial losses for both sides. Moreover, budget negotiation delays themselves can have negative financial impacts, creating frustration and loss of goodwill. And we cannot forget participants may also incur losses: if a study they planned to volunteer for is significantly delayed or will not open at all, this could negatively impact their health and hope. If communication is open and expectations are addressed early in the site selection process, budget development and negotiations can be streamlined and virtually seamless.

There are many challenges involved in developing and negotiating a clinical trial budget that applies Medicare’s rules and regulations for device and drug clinical trials. In this blog, we’ll discuss these challenges, and suggest strategies to assist with this process.

Medicare and Clinical Trials

There are three regulations addressing Medicare coverage in clinical trials:

Medicare Coverage Related to Investigational Device Exemption (IDE) Studies
Clinical Trial Policy: National Coverage Determination (NCD) for Routine Costs in Clinical Trials (310.1)
Coverage with evidence development (CED): Centers for Medicare & Medicaid Services (CMS), as part of the national coverage determination (NCD), may determine coverage of an item or service only in the context of a clinical study, which typically also involves a registry. The NCDs requiring CED are listed here.

All three of the regulations allow Medicare beneficiaries to participate in clinical trials, as Medicare payment (coverage) is no longer precluded. However, rules must be followed to prevent triggering the False Claims Act and other fraud and abuse laws arising from noncompliance.

Medicare Claims Management

A Medicare Administrative Contractor (MAC) is a private healthcare insurer awarded a jurisdiction to process Medicare Part A and Medicare Part B claims. Currently, there are 12 A/B MACs. In addition to processing Medicare claims, MACs address coverage decisions, which includes developing local coverage determinations (LCDs) following specific guidelines.

Medicare Coverage Analysis

Early adopters of the NCD for Routine Costs in Clinical Trials set the stage with a process to work with the policy, which is called a Medicare Coverage Analysis (MCA) or Coverage Analysis (CA). While the three regulations addressing clinical trials have specific unique requirements, the MCA process works well with all three.

Sponsors and Clinical Trial Budgets

Sponsors have the daunting task of developing a study budget template. Typically, this is a line item budget with some pass-through costs; however, some budgets are a per-participant lump sum. Budget template considerations include the number of participants required, the number of sites, and whether the study is conducted within the US. The budget typically provides funding for items and services to conduct the clinical trial (to meet study objectives and ensure participant safety) and include time and effort, study startup fees, IRB fees, laboratory, and pharmacy costs. Other factors include the cost of healthcare within the US, standard of care (SOC) items and services billed to healthcare insurers, items/services required for research purposes only, and the concept of fair market value (FMV). A budget must be fair but not excessive; both too high and too low of a budget negatively impacts the clinical trial’s outcome.

Once completed, each site receives the budget template, along with the Clinical Trial Agreement, protocol, and informed consent. The site is expected to review the template and modify it based on the site’s charge master/research fee schedule and other specific terms/fees applicable to the site. All these costs vary by institution.

Site Budget Development

The site must consider FMV as well as the cost of providing healthcare at their site, resources needed to adequately conduct the study, pharmacy costs, laboratory costs, indirect costs, etc. If the site accepts governmental healthcare insurance funding (e.g., Medicare), they must also factor in the rules and regulations regarding drug and device clinical trials; for example, many items and services associated with clinical trial conduct (even if considered SOC) cannot be billed to Medicare.

With this in mind, payment of SOC items and services is often a big surprise for both sponsors and sites. The sponsor may assume the site will bill healthcare insurers for these items/services, so these are not line items on a study budget. For the site, if they are unable to bill Medicare for these items/services not covered by the sponsor, participation in the clinical trial can be cost prohibitive—the site may not be able to participate in the trial. Losing a participating study site affects accrual, which impacts the clinical trial meeting specific timelines/endpoints. If this occurs with many sites, and the sponsor is not equipped to address these issues, the study risks failing due to lack of accrual. This is a devastating scenario for all involved (sponsor, site, and participants).

The development of a good clinical trial budget is time-consuming and challenging for everyone involved. But it’s not an insurmountable challenge. Many sites and sponsors focus on potential participants to enroll in the study, but it’s important to also address budget needs and negotiations early. Through education and communication, sites and sponsors can address potential pitfalls early in the process before they become major issues.

In our next blog, we will address how to talk through clinical trial budget negotiations outlined in a case study scenario. Need assistance in developing or negotiating your next clinical budget? Contact Advarra for global virtual and on-site support.

When you work for a company that values collaboration, it puts you in a position to wear many different hats and provide a wealth of unique experiences. For 12 years I have helped Advarra customers with support, training, and advice, allowing me to speak frequently about technology adoption and best practices. Staff augmentation gives me the opportunity to take those experiences and put them in action, empowering our customers to make big changes.

During a recent project, I worked with a customer site on a financials roll-out, which included centralizing financial services. I worked with a team of intelligent, motivated, and dedicated staff determined to help their research teams find new cures while keeping trials financially successful.

Walking Through the Steps

Our first step was to accelerate the billing grid integration between their OnCore Enterprise Research System and their Epic electronic medical record (EMR). Since they were in the middle of an implementation, I worked with the team to rebuild their charge master. This helped minimize the risk of double billing errors and streamlined the overall process to reduce billing holds. These early steps gave me the opportunity clear up any confusions surrounding the charge master. When the connection to Epic went live, our customer viewed the project as a success.

While on site, I also noticed there were very few documented processes, and offered a Workflow Workshop to key stakeholders. The workshop is designed to evaluate the current state of processes in place and work to establish best practices in the organization. Hosting this workshop brought stakeholders together to analyze each process from beginning to end. We walked through processes involving protocols, budgets, and subjects. By the end of the workshop, everyone understood each process and the roles involved.

The next phase came with writing and updating current manuals and process documents to help staff understand OnCore best practices. My experience with the system enabled me to capture key workflows, and I helped create functional documents for each staff role, including updated software information, process details, and tip sheets.

After the manuals and process documents were updated, I then provided training and working sessions for the finance teams. Since the study team used OnCore and already understood the subject workflow, I tailored the training to focus solely on the financial workflows that were a priority for the customer. Each training included a demonstration of the financial workflow, the purpose behind it, and why it was necessary to implement. Additionally, I trained study teams in centralized sessions, helping teams move away from visit spreadsheets to documenting actual visit data in OnCore. We shared best practices and tips for making the requirements easier to follow with OnCore’s time-saving features. In the end, it was great to see these features work as expected in reducing staff time.

Next, we worked on adoption, an important (but often forgotten) step to all software roll-outs. We focused on in-person team visits, and found the benefits greatly outweighed the travel time. Face-to-face time with those who will use the system is invaluable, providing an ideal setting to address concerns and resistance to change. During adoption, there were a few skeptics and many great questions. Team leadership talked about the purpose and the importance of these changes, which go a long way to build trust and acceptance. There were also large group sessions with all research teams, giving us another great opportunity to reach people with information, process details, and expectations.

Finally, we went live with real trials and budgets. The start of a new project is a great time to demonstrate how this process works and to build even more trust through action. Our goal is to make a quality, consistent presentation to each study team and prove these workflow processes work. I also assisted with creating initial study calendars and budgets, and gave the budget team a checklist to QA, ensuring they worked properly. My last step was giving the team a list of future projects to consider once they were comfortable with the new workflows.

Through this process, we learned staff augmentation can help in many ways. Through the experience and best practices I brought to the customer team, we were able to optimize their use of OnCore, maximize the efficiency of study startup and financial processes, and put them on a path to success.

Advarra Staff Augmentation Services allows your organization to meet staffing needs, setting your team up for long-term success.

In a recent webinar, Advarra IRB and research compliance experts discussed key areas to consider as we look to ramp up research in the COVID-19 pandemic’s “new normal.” Presenters discussed challenges such as how to communicate with stakeholders, how to prioritize the research portfolio, and ways to ensure compliance and participant and staff safety. Due to time constraints we weren’t able to answer all audience questions during the Q&A period, so our experts have answered some of the most popular questions in this blog.

Note: IRB policies vary; please contact your IRB regarding any specific questions.

Q: How should participants be consented via phone or email?
A: There is no prohibition on consenting by phone or by email. If not consenting in person, you must be able to verify the identity of the individual with whom you are communicating, provide an opportunity to answer questions, and assure that the informed consent form (ICF) is signed and returned. For more information, see question 11 in FDA Guidance on Conduct of Clinical Trials of Medical Products During COVID-19 Public Health Emergency.

Q: Do you have any guidance on witness to signatures when consent is conducted over the phone or email?
A: When using a witness in the consent process, it is best practice to have an objective, unbiased individual serve as witness. The witness should attest that the prospective participant received the consent, that the individual had an opportunity to have questions answered, and that the individual stated he/she signed the document and would return it.

Q: Should research participants be notified—or consent be sought from them—if a sponsor requests all participants’ COVID-19 test results be provided as part of the study data/case report form (CRF) for a non-COVID-19 study?
A: Yes, if the data is going to be part of the research data set, then the protocol and ICF should be amended, and participants should be notified and sign the amended ICF.

Q: What are your thoughts about keeping studies open that can be conducted virtually?
A: From a site perspective, the program’s entire portfolio should be assessed and various factors considered. The purpose of research is to answer a scientific question, which requires quality and complete data collection. At the same time, the participant and staff safety must be considered. If safety cannot be maintained or the scientific question can no longer be answered, then the study likely needs to be paused or suspended. If the study is almost complete and procedures can be done virtually, then there is likely a compelling reason to keep it open.

Consider include the organization’s scientific priorities, the needs of the patient population(s) served, the ease of research conduct, the ability to move procedures virtually, and the study’s status. Additionally, the statistical analysis plan and possibly the data analysis plan will need to be amended to reflect changes in what data is collected and how it is collected.

Q: Do you have any suggestions for multisite study recruitment during this time?
A: Modes of recruitment can be specific to the research participant population and should be considered study by study. Take into account the participants’ age, socioeconomic status, technologic ability, and requested interaction with recruitment. Broadly speaking, different generations have different skills with technology tools. Depending on socioeconomic status and/or age, access to or use of cell phones (especially smartphones) may be limited. People may have the ability to answer phone calls or answer basic surveys online but may not interact well with uploading documents or pictures. Not all people are active on social media. The study may target minors which is a sensitive group to reach online. Security access on their devices may prevent them from being able to access sites or videos.

Q: Any suggestions for assessing participants’ technology access to be able to virtually participate in a study?
A: As discussed above, consider the participant population’s demographics. Certain populations may be more or less comfortable with electronic tools for virtual study conduct. Also consider geographic and socioeconomic factors for your site’s community and the target participant population; not everyone has regular, reliable high-speed internet access.

Q: Can IRBs require that sites/sponsors implement safety processes to decrease the risk of COVID-19?
A: An IRB has jurisdiction over the research. If the safety procedures are not specific to the research with data collected about those safety procedures, it is unlikely the IRB has authority to require general safety precautions.

Q: If patients must be screened for COVID-19 per hospital standards when coming for clinical trial-specific visits only, could this be reimbursed by sponsors?
A: This is worth discussing/negotiating with the sponsor, particularly if the person is only coming to the site for the clinical trial visit. If the participant is expected to cover the cost of the testing, then it should be disclosed in the ICF; that could impact people’s willingness to participate. Also consider to what extent the COVID-19 testing cost is covered by the local/regional health authority. If the jurisdictions provide testing at no cost (including coverage for facilities and practitioner time), it wouldn’t be appropriate to have the sponsor cover the cost.

Q: If the sponsor requires COVID-19 results be reported in an ongoing study, should participants be consented or reconsented?
A: Yes, if the data will be part of the research data set, and this is not part of the original protocol and ICF. The protocol and ICF should be amended, and participants should be notified and sign the amended ICF.

Q: Can you provide any budget-proof strategies around restarting research (e.g., adjusting costs for remote modalities vs the “old normal”)?
A: We suggest evaluating budgets as research resumes. Consider costs associated with additional technology, time, training, etc., and open conversations with the sponsor to help account for those costs. Also ask the organization’s/program’s administration and IT teams if existing technologies already exist that can be applied where possible, and find out whether multiple departments/units can combine efforts to spread the implementation impacts (and increase effectiveness). Think about organization/program-wide answers rather than study-specific answers.

Sponsors may recommend certain technologies, which may be the best solution—but if a technology is already in place that will speed transition to a remote/virtual environment, make sure it will meet study’s needs. Example: A sponsor may be able to provide “X” communication solution for conducting video visits. But if your organization already has solution “Y” in place (including IT vendor assessments, compliance assurances, policies, and processes), it may be better to tell the sponsor about that available technology so research can continue.

Q: Could confidentiality issues arise if participants being screened according to university-wide procedures answer COVID-19 screening questions that are reported to local public health authorities?
A: The screening procedure, which presumably is being conducted as part of research, should include information regarding privacy and confidentiality protections.

Q: Who should sites/sponsors consult with to determine if e-signature is legal in their setting?
A: Electronic systems used to generate electronic signatures on clinical trial records, including ICFs, during the COVID-19 public health emergency must comply with the requirements outlined in FDA regulations at 21 CFR part 11 (Part 11) when applicable. Compliance with Part 11 should be discussed with your technology team and potentially your legal department. Depending on the systems being used, your technology team will help identify if the necessary steps and documentation are in place. If you use a commercial off-the-shelf solution, the vendors may be able to provide sponsors and other regulated entities with information regarding Part 11 compliance. See FDA Guidance Use of Electronic Records and Electronic Signatures in Clinical Investigations Under 21 CFR Part 11 – Questions and Answers for more information.

Many clinical trial protocols include plans to compensate participants for their contribution to the research. According to FDA’s information sheet Payment and Reimbursement to Research Subjects, participant payment is a recruitment incentive and “is not considered a benefit that would be part of the weighing of benefits or risks.” Additionally, in its Informed Consent FAQs OHRP states that “remuneration to subjects may include compensation for risks associated with their participation in research and that compensation may be an acceptable motive for agreeing to participate in research.”

IRBs are tasked with reviewing the amount of payment, as well as the method and timing of disbursement, to ensure that the payment plan does not present potential undue influence. Participant compensation is often a complicated matter, so in this blog I’ll attempt to clarify some issues by shedding light on what an IRB considers during its review.

Definitions

Bear in mind that compensation is not the same as reimbursement. Consider the following definitions:

Compensation
Payment to subjects for participating in a study. It may be considered a recruitment incentive or a way of acknowledging the time and burdens imposed on subjects. Compensation plans require IRB review for assessment of whether they present any undue influence.

Reimbursement
Re-payment for actual costs accrued by the subject while participating in the study (e.g., parking, transportation, mileage reimbursement, childcare, etc). This often requires the submission of receipts. Reimbursement does not generally raise the same concerns as compensation regarding undue influence since participants are being “paid back” money they have spent.

Compensation should be based on time invested and inconvenience. It may also be based on types of risks and procedures. However, compensation should not be considered a way of offsetting risks. The term undue influence is critical here; according to OHRP, undue influence “often occurs through an offer of an excessive or inappropriate reward or other overture in order to obtain compliance.”

IRB Review of Participant Compensation

IRB review should focus on whether the payment plan may compromise a participant’s evaluation of the risks or may affect the voluntariness of his or her decision to enroll and/or to remain in the study. Such concerns may arise, for instance, where an excessive and inappropriate amount of money is offered to participants.

When the research targets economically disadvantaged participants, payment proposals are typically subject to a higher level of IRB scrutiny. Payment may be more important for those to whom it will make a significant financial difference, so this participant population may be more susceptible to undue influence. On a similar note, for studies that enroll minors as participants, the IRB will want to know whether the compensation is intended for the parent/guardian, the minor participant, or both. When providing compensation to minor participants, the IRB will consider what is age-appropriate: for instance, gift cards may be appropriate for older children, while toys/gifts may be more appropriate for younger children.

Notably, the regulations do not define standard compensation limits. Because IRBs are tasked with evaluating compensation plans without defined regulatory standards, many IRBs have developed internal standards to provide for consistency in reviewing compensation. It is important to understand your reviewing IRB’s standards and provide a rationale for your proposed plan.

Considerations When Developing a Compensation Plan

As mentioned earlier, each IRB maintains its own policies on participant compensation, so it’s important to know what is and is not permissible according to the study’s IRB of record. With that in mind, here are some general considerations for researchers developing a compensation plan:

In determining the amount of compensation to provide, take into account the amount of time each visit takes and the procedures to be performed at each visit. For instance, it may be appropriate to compensate participants a higher amount for study visits that require them to stay in the clinic overnight. Outside of the study visits, it may also be appropriate to compensate participants if they will be expected to complete detailed and time-consuming activities such as lengthy survey or study diary entries.

Credit for payment should generally be prorated, accruing as the study progresses, and payment should not be contingent on maintaining compliance over the course of the entire study. The reason for this is that withholding payment until completion of the study may adversely impact a subject’s right to withdraw from the study at any time. Payment may not always need to be exactly evenly prorated among study visits, but the overall plan should be assessed for potential undue influence. A completion bonus may be permissible as long as it is not so large that it unduly induces participants to stay in the study when they would otherwise have withdrawn. IRBs may have different policies for how large completion bonuses may be, based on, for instance, a percentage of the overall compensation.

Note that small incremental increases in compensation are not necessarily an indicator of potential undue influence and may be acceptable. Additionally, large differences may be acceptable if more involved and burdensome procedures are performed later in the study. Let’s look at a couple examples:

In a study where all study visits include similar procedures and risks, a researcher proposes paying $100 for visit 1, $200 for visit 2, $300 for visit 3, and $1000 for the final visit.
- An IRB might consider this unacceptable, as it could unduly influence subjects not to withdraw from the study.
In a study where later visits include more burdensome procedures, a researcher proposes paying $50 for visit 1, where only a blood draw is done, and $300 for visit 5, where a biopsy is performed.
- An IRB may accept this proposal, as the compensation increase is commensurate with the increased invasiveness and burden of the visit 5 study procedure.

When developing any potential compensation plan, always measure it against the potential for undue influence and how it may impact a potential participant’s voluntariness and willingness to participate in the research.

If you have specific questions about your compensation plans for an upcoming study, contact Business Development or your Coordinator.

Clinical research continues to grow throughout the world, with researchers looking outside the US for new and diverse subject populations to help develop and improve investigational therapies. Requirements for research ethics review vary considerably country to country, and the regulatory variety can be daunting for a researcher new to working outside the purview of US regulatory agency requirements.

While it’s not possible to cover the many unique regulatory requirements of each nation in a single blog, I will discuss the basics of ex-US research ethics review for US-based researchers. For those seeking information on a particular country’s clinical research requirements, the International Compilation of Human Research Standards compiled by HHS is a good place to start.

Review by a Non-Local Ethics Committee

In many parts of the world, research ethics review is conducted locally by institutionally based ethics committees. Some countries may require additional layers of review at the local and/or national level, and most nations do not permit oversight by ethics committees that are not based in that country. Centralized research ethics review, like the US central IRB model where a single committee oversees research at multiple sites, is not common outside of North America.

There are some exceptions: for example, Canadian research regulations share similarities with US regulations and permit centralized non-Canadian research ethics committees to oversee some research, provided certain requirements are met (like including a majority of Canadian citizens as committee members).

Check with the country’s research ethics agency and/or the local institution to understand what is and isn’t possible. When non-local oversight is not permitted, researchers must work with local regulatory agencies and research ethics committees to ensure they comply with all local requirements.

How Can a US-Based IRB Help with Ex-US Research?

Research ethics committees do not exist in all countries, and when there are research ethics review requirements, not all local committees are alike. In some cases, it may be helpful to provide the local committee with a US-based IRB’s study review summary. While the regulations may not be the same, the perspective of a US-based ethics committee may be a helpful resource for the local committee’s own review deliberations. The ethical standards applied by the US-based ethics committee should be no less stringent than they would be for research conducted in the US.

Some ex-US research ethics committees may also accept dual oversight, where both the local ethics committee and the US-based ethics committee review the study and maintain oversight as the regulations permit. This may be an option for studies with sites in the US as well as in another country. Dual oversight may not work in every scenario, so check with the research ethics committee of record to understand what is possible.

Contact an Expert

Navigating a new set of regulatory requirements can be tricky, to say the least. Language and cultural barriers can exacerbate an already complicated situation. If you’re new to conducting research outside of the US, it may be beneficial to contact an expert for support. Some consulting groups and CROs may have resources based in the ex-US country who can help navigate the local requirements and processes.

Need auditing or quality support for an international study? Contact our consulting team.

We all know there are numerous acronyms and abbreviations used in clinical research. While some can be easily deciphered, others may take some searching to find their meaning. Particularly with the recent surge in electronic systems and regulations, it can be hard to keep track of necessary abbreviations and terms.

Whether you’re new to the clinical research world or need a refresher, here’s a condensed list of common acronyms and abbreviations you may come across.

AACI: Association of American Cancer Institutes

AAHRPP: Association for the Accreditation of Human Research Protection Programs

ABSA: Association of Biosafety and Biosecurity

ACRP: Association of Clinical Research Professionals

ACTS: Association for Clinical and Translational Science

ADME: Absorption, Distribution, Metabolism, and Elimination

ADR: Adverse Drug Reaction

AE: Adverse Event

ALCOA: Attributable, Legible, Contemporaneous, Original, Accurate

AMC: Academic Medical Center

API: Active Pharmaceutical Ingredient

API: Application Program Interface

ARO: Academic Research Organization

ASCO: American Society of Clinical Oncology

ASCPT: American Society for Clinical Pharmacology and Therapeutics

ASGCT: American Society of Gene & Cell Therapy

BA/BE: Bioavailability/Bioequivalance

BLA: Biological Licensing Application

BSM: Biospecimen Management

caBIG: Cancer Biomedical

CAPA: Corrective and Preventive Action

CAR-T: Chimeric Antigen Receptors and T cells

CBER: Center for Biologics Evaluation and Research

CBRN: California Board of Registered Nursing

CCEA: Complete, Consistent, Enduring, Available

CCOP: Community Clinical Oncology Program

CCR: Center for Cancer Research

CCSG: Cancer Center Support Grant

CCTO or CTO: Centralized Clinical Trials Office or Clinical Trials Office

CDASH: Clinical Data Acquisition Standards Harmonization

CDER: Center for Drug Evaluation and Research

CDM: Clinical Data Management

CDP: Clinical Development Plan

CDRH: Center for Devices and Radiological Health

CDS: Clinical Data System

CDUS: Clinical Data Update System

CFR: Code of Federal Regulations

CMO: Contract Manufacturing Organization

CMS: Centers for Medicare & Medicaid Services

CRA: Clinical Research Associate

CRC: Clinical Research Coordinator

CRF: Case Report Form

CRMS: Clinical Research Management System

CRO: Contract Research Organization

CRPC: Clinical Research Process Content

CSO: Contract Safety Organization

CSR: Clinical Study Report

CTA: Clinical Trial Authorization

CTCAE: Common Terminology Criteria for Adverse Events

CTMS: Clinical Trial Management System

CTRP: Clinical Trials Reporting Program

CTSA: Clinical and Translational Science Award

DDI: Drug-Drug Interaction

DHHS: Department of Health and Human Services

DM: Data Manager

DMC: Data Monitoring Committee

DSMB: Data and Safety Monitoring Board

EC: Ethics Committee

eCOA: Electronic Clinical Outcome Assessment

eCRF: Electronic Case Report Form

EDC: Electronic Data Capture

Learn more about Advarra’s electronic data capture system, Advarra EDC.

EHR: Electronic Health Record

EMR: Electronic Medical Record

ePRO: Electronic Patient-Reported Outcomes

eTMF: Electronic Trial Master File

FAIR: Findable, Accessible, Interoperable, Reusable

FDA: Food and Drug Administration

FE: Food Effect

FIH: First In Human

FWA: Federalwide Assurance

GCP: Good Clinical Practice

GCRC: General Clinical Research Center

GDP: Good Documentation Practice

GLP: Good Laboratory Practice

GMP: Good Manufacturing Practice

GVP: Good Pharmacovigilance Practice

HIPAA: Health Insurance Portability and Accountability Act

HRPP: Human Research Protection Program

IBC: Institutional Biosafety Committee

ICF: Informed Consent Form

ICH: International Council for Harmonization

IDE: Investigational Device Exemptions

IEC: Independent Ethics Committee

IHCRA: In House Clinical Research Associate

IIT: Investigator Initiated Trial

IND: Investigational New Drug (Application)

IP: Investigational Product

IRB: Institutional Review Board

ITT: Intent to Treat

IVRS: Interactive Voice Response System

IWRS: Interactive Web Response System

LTFU: Long Term Follow Up

LRAA: Local Regulatory Affairs Associate

MAC: Medicare Administrative Contractor

MAD: Multiple Ascending Dose

MCA: Medicare Coverage Analysis

MRN: Medical Record Number

NCI: National Cancer Institute

NDA: New Drug Application

NHV: Normal Healthy Volunteer

NIH: National Institutes of Health

NLM: National Library of Medicine

OCT: Office of Clinical Trials

OHRP: Office for Human Research Protections

OSR: Outside Safety Report

PAC: Post Approval Commitments

PC: Protocol Coordinator

PD: Protocol Director

PHI: Protected Health Information

PI: Principal Investigator

PK/PD: Pharmacokinetic/Pharmacodynamic

PRE: Prompt Reporting Event

PRMC: Protocol Review and Monitoring Committee

PRMS: Protocol Review and Monitoring System

QC: Quality Control

QCT: Qualifying Clinical Trial

QMS: Quality Management System

SAD: Single Ascending Dose

SAE: Serious Adverse Event

SC: Study Coordinator

SDR: Source Document Review (Also Source Data Review)

SDTM: Study Data Tabulation Model

SDV: Source Document Verification

SIF: Site Investigator File

SMO: Site Management Organization

SOC: Standard of Care

SOE: Schedule of Events

SOP: Standard Operating Procedure

SPOREs: Specialized Programs for Research Excellence

SRB: Scientific Review Board

SRC: Scientific Review Committee

SUSAR: Suspected Unexpected Serious Adverse Reaction

SVT: Subject Visit Template

TMF: Trial Master File (also eTMF)

TMO: Trial Management Organization

UADE: Unanticipated Adverse Device Effect

UADR: Unexpected Adverse Drug Reaction

UAP: Unanticipated Problem

Is there an abbreviation or acronym you see regularly in clinical research that isn’t listed here? Let us know.

To learn more about the fundamentals of clinical research, check out these free resources:

Food and Drug Administration (FDA) regulations and the Common Rule require that the selection of participants in research is equitable. “Equitable selection” generally refers to the idea that no one group should bear all the burdens of research or reap all the rewards. This term also refers to the idea of ensuring marginalized populations have access to research.

These regulations also require that research include additional safeguards when some or all of the study participants are likely to be vulnerable to coercion or undue influence.

The principle of equitable selection and the requirement for additional safeguards for certain vulnerable groups can seem at odds. We see this tension in the example of adults with impaired decision-making capacity. While these adults might be considered vulnerable to coercion and undue influence, and thus in need of additional protections, institutional review boards (IRBs), sponsors, and investigators must also be cognizant of not unduly limiting these individuals’ research participation in an effort to protect them.

Putting It Together: Neurological Disease Research Example

Consider the example of research on neurological diseases. Researchers continue to chip away at this challenging field, seeking new treatments and potential cures for these conditions. This research is urgently needed: In the U.S., neurological diseases create nearly $800 billion annually in healthcare costs. The economic, social, and emotional costs of these conditions will continue to grow with our aging population.

When conducting clinical research on neurological diseases, researchers often must provide additional safeguards for the research participants. Conditions like Alzheimer’s disease, Parkinson’s disease, and others can cause both physical and mental impairment, making individuals vulnerable to coercion or undue influence.

Researchers must be careful to ensure individuals with impaired decision-making capacity (and, if appropriate, their legally authorized representatives) are fully informed about a study and can provide legally effective informed consent to participate in research. A legally authorized representative (LAR) is any individual, judicial body, or other body who are authorized under applicable law to consent to research participation on behalf of a designated person (45 CFR 46.102(i)). Depending on where the research takes place, an acceptable LAR might be a health care proxy, medical power of attorney, or a caregiver.

Understanding “Capacity”

In this context, “capacity” refers to a potential research participant’s ability to:

Make and express a choice
Understand relevant information
Appreciate the significance of the information relative to the participant’s own situation
Reason with this relevant information in making decisions

Decision-making capacity is a spectrum, with some individuals more capable of understanding and reasoning than others. With this in mind, “impaired decision-making capacity” can include anyone who is incapable of giving legally effective informed consent. This could be because of a neurological condition that affects an adult’s decision-making capacity, a developmental disability (e.g., autism spectrum disorder), an injury leading to temporary incapacity (e.g., an injury that causes someone to become unconscious), or even because a person has been put under legal guardianship by a judicial body.

Don’t assume that just because an individual’s decision-making capacity is diminished that he or she cannot provide legally effective consent. Decision-making capacity is variable within groups and may change throughout the course of a study: Someone with early Alzheimer’s disease may be capable of providing consent, but as the disease progresses, their capacity will likely diminish.

Regulatory Guidance

In its draft guidance Informed Consent Information Sheet: Guidance for IRBs, Clinical Investigators, and Sponsors, the FDA recommends additional safeguards for participants with diminished decision-making capacity, such as:

Using an independent “qualified professional” to assess the consent capacity of potential participants at the time of consent and in an ongoing manner
Establishing a waiting period to allow additional time for decision making
Using methods to enhance consent capacity, such as repetition, simplification, and/or enlisting a participant advocate or trusted family members
Using questionnaires to assess understanding
Reassessing a participant’s decision-making capacity for progressive disorders
Involving LARs as cognition declines
Including an assent mechanism
Involving the IRB or another third party to observe the consent process and/or the research

Vulnerabilities like impaired decision-making capacity are critical aspects of clinical research. Vulnerabilities have driven the regulations governing research, and honoring that mandate gives us continued permission to conduct research.

Regulations can’t cover every person or situation, so it’s essential for research professionals to have a working mental construct for identifying vulnerability, along with practical ways to mitigate its influencing factors.

Note: This article was originally published on August 30, 2017, and has been updated to include new and clarifying information.