Reasonably, it takes a village to conduct a clinical trial. And among the many vital contributors to successful clinical research in the U.S. is the institutional review board (IRB) – sometimes known as an independent ethics committee (IEC), an ethical review board (ERB), or a research ethics board (REB).

Under Food and Drug Administration (FDA) regulations, an IRB is an independent group of people who review and monitor biomedical and behavioral research involving human subjects. An IRB’s purpose is to protect the participant rights and welfare of human research. In accordance with FDA regulations, an IRB has the authority to approve, require modifications to, or disapprove research when it believes the participant’s rights or welfare are not properly protected.

According to James Riddle, Vice President of Research Services and Strategic Consulting at Advarra, “Probably the most important thing for an individual to know is that, at least here in the United States, there is an independent group of folks who are overseeing research, looking out for your best interest as a patient, somebody other than the sponsor.”

History and Origins of the IRB

The IRB originated in several landmark efforts to instill ethical considerations into research, including the Nuremberg Code of 1945, stemming from Nazi atrocities in World War II. U.S.-based events that helped inspire the IRB include the Tuskegee Syphilis trial, in which Black men with syphilis were denied treatment. The National Research Act, signed into law in 1974, is the legislation that formally created the IRB. The Belmont Report followed in short order and set forth the basic ethical principles underlying biomedical and behavioral research conduct involving:

  • Respect for persons
  • Beneficence
  • Justice

Today, the IRB’s structure and function is codified in 21 CFR Parts 16 and 56, enacted in 1981.

Who Serves on an IRB?

The people serving on an IRB is surprisingly diverse, as it may include lawyers, accountants, local church members, or any other community member who expresses interest in serving, applies for membership, and is accepted. IRB members may serve on a private IRB, through companies like Advarra, or the academic institution may administer their own IRB.

What Elements of Research does the IRB Review?

Both sponsors and independent researchers working on behalf of sponsors are subject to IRB oversight. Sponsors will submit their protocol and information about the investigational product (IP). They’ll also submit the template consent documents and any other materials patients will receive to explain the trial to them. Once these elements are approved, the IRB will turn to review the individuals conducting the research.

Each research site submits a short application to the IRB to verify the investigator has the appropriate credentials, facilities, and staff to safely conduct the trial. The submission should also include:

  • The investigator’s curriculum vitae and medical license
  • Study information, including:
    • The clinic
    • Staff involved in the research
    • Expected number of participants enrolling in the trial
    • Prior experience with conducting trials in this particular disease modality or similar disease conditions

The IRB’s objective is to confirm each investigator is qualified to conduct the trial per the already-approved protocol.

What is the IRB’s Potential Impact on a Trial?

While the IRB does have the power to derail or even terminate a research project, researchers should understand while it is rare, and is never the IRB’s objective. Certainly not at Advarra.

“We want to see projects move forward, we want to see new cures hit the market, we want to see advancement in human health,” says Riddle. “So, what we are most likely to say to a sponsor is something like this: ‘Look, here are the federal regulations. Here’s where your protocol falls short, in our opinion. Take what we’ve said under consideration, update your protocol, and come back to us.’ If the sponsor disagrees with the IRB’s position, they are welcome to appeal the evaluation or ask for clarification. Very rarely is a protocol ever just killed.”

How do Sponsors and Researchers Interact with the IRB?

Once the protocol and investigators are approved and researchers start enrolling and consenting participants, staff will continue to send periodic reports to the IRB. The Board will want to know the number of participants enrolled and any problems stemming from the study. There is significant interaction between the investigators, the sponsor, and the IRB when the investigated drug or device uncovers new risk information. For instance, if new side effects appear, the IRB will decide how to communicate the information to participants. They will also make sure participants understand they can end their participation based on the new information.

Does IRB Oversight Continue Throughout the Trial?

While most of the heavy lifting occurs during research initiation, an IRB will continue to monitor trial activities as long as there are interactions between researchers and participants. In a typical clinical trial, this includes long-term follow up and data gathering, even beyond the point where participants are taking the IP. As long as there is still communication between participants and the investigators, the IRB will be active. This provides participants with the comfort of knowing that if at any point new risk information is revealed, the IRB will make certain they are informed and given the opportunity to exit the trial.

A special thank you to James Riddle for providing insight into this blog.

For the past two years, the clinical research industry has seen an acceleration in staff shifting to a remote, work from home model. While this was initially in an effort to keep everyone safer from the COVID-19 pandemic, many organizations are permanently moving toward a remote or hybrid work model for their staff. How has this shaped current regulatory trends, and what is it going to suggest moving forward?

First, we need to understand why many organizations are shifting toward a new work environment. There are a couple of reasons for this move. The first, and perhaps most important, is staff-centricity. The ability to work remotely gives people more flexibility in their days. Whether your staff are parents with kids at home or have appointments to get to, working from home allows them to attend to these needs easier than if they were in an office setting.

From the site perspective, moving towards a remote or hybrid work model can attract talent to your institution as you work to fill the gaps in your staffing. Advertising a flexible work model is good for your organization as you try to recruit new team members. It can also expand the geographic area of potential candidates, as there will be less need to commute to a physical location.

For those working in clinical research operations, technology can provide tools to efficiently and compliantly support any type of model: onsite, hybrid, or remote. Working with eClinical solutions such as eRegulatory (eReg) or eSource eliminates the need for physical binders and centralizes management of regulatory documents and other information, ensuring it’s accessible anywhere.

Easing Staff Burden When Shifting to Remote Work

When moving towards a remote or hybrid work model, make sure you are equipping your staff to do so effectively. For example, a single organization often has staff members dispersed across a city. In the past, keeping your trials moving and being at the right place at the right time required a lot of coordination and making sure everything that was needed was in place. In the past, site staff would sometimes drive across town just to have an investigator sign a document. Switching to an eClinical suite eliminates the need for extensive coordination for all staff, as everything is accessible online, with no physical retrieval needed.

Additionally, an eClinical suite benefits more than just your staff. It also greatly reduces the need for onsite monitoring visits. Currently, many institutions have restrictions in place limiting who is on site. For sites without an eReg management system, this requires more planning and coordination to accommodate to this change. With Advarra eReg, sites are easily able to take their binders, designate which materials are available, set a timeframe, and see what the monitor sees. This enables a swift review for monitors, and less stress for research staff to make sure everything was in place.

Considerations When Adopting an eClinical Suite

One key benefit of going from paper to paperless data collection is eliminating some steps you take on paper that actually don’t provide any value. When moving from paper to digital, taking a step back to assess your current workflows will help you understand which steps need to stay in your digital workflow, and which ones can go. One example of this is evaluating your delegation of authority workflows. Moving from paper to digital is a great time to implement a master delegation of authority process, boosting efficiency within your teams and greatly reducing the “PI signature chasing” that’s prevalent during the delegation process.

However, when making the move from paper to digital, it’s important to understand it will take effort on behalf of your staff to get libraries built up and ready to use. Adopting technology to make your research more efficient for everyone is an investment – if you spend time now on building it up, your staff will continue to reap the benefits over and over. In the long run, your studies will become more scalable and efficient, enabling your staff to do more and serve more participants for each study.

Regulatory Trends to Watch in the Future

As we’ve seen the industry move toward adopting electronic technologies to keep their research moving forward, there are key trends to watch:

Patient Centricity

Utilizing an eClinical software such as eConsent enables research staff to find and enroll more participants in their studies, making it easier for them to actually participate once they are enrolled. The easier it is for someone to participate in a study, the more likely they are to continue on with the study, decreasing the dropout rate. In a time where increased trial complexity is making it more difficult to recruit and enroll participants, doing everything you can do to get participants in your funnel and keep them there is important. For this reason, if you’re looking to adopt technology, you also need to make sure your participants also find it easy to use.

Becoming More Site-friendly

Sponsors are seeing the way sites are becoming overburdened as they use multiple technology platforms to enter in data for studies, which causes significant challenges in staffing levels. As a result, it’s in a sponsor’s best interest to become more site-friendly. Part of doing so is letting sites use their own systems when conducting research, instead of sponsor-initiated technology. While there are a myriad of benefits to this, ultimately letting the sites use their own technology will enhance the overall research environment. This will help staff leave behind the one-off workflows that aren’t cohesive once placed in an electronic format, further streamlining their operational processes and making their research more efficient.

While deciding to convert to electronic processes is a lengthy process with many things to consider, it’s often worth the investment. As the clinical research industry continues to evolve to a hybrid or remote workforce, it’s important to consider the best option not only for your staff, but for any participants who they are working with on a trial.

For nearly 10 years, a growing biotech company worked to develop a nitric oxide and delivery device for babies in the newborn intensive care units (NICU). The organization also needed to file the appropriate documents for Food and Drug Administration (FDA) approval to bring this combination drug and device to market.

Confronted with the myriad of complexities of the 510K FDA filing process, this company also had to address the challenges of an unreliable internal infrastructure to advance the development of the product.

Essential Steps to Consider

Engage the right partner: Identify and engage a trusted strategic partner who brings a multi-dimensional perspective – strategic and tactical to your go-to-market plan. Your strategic partner should be able to provide insightful and comprehensive regulatory guidance for meeting the stringent FDA requirements for drug and device combination products.

Identify and assess: Critical to an effective and compliant manufacturing plan is developing and implementing current good manufacturing practice (cGMP) gaps in infrastructure.

For growing biotech companies, an analysis may reveal the need for:

  • FDA filing process assistance: Life cycle FDA regulatory support from experienced, FDA veterans through the FDA regulatory communication process
  • Experienced research and development (R&D) project management: Supplemental and scalable infrastructural support in project management with specific expertise in growing life-sciences companies
  • Quality management: Expert, ready-to-contribute manufacturing personnel to create and implement a quality control system in compliance with cGMP regulations
  • Strategic advisory support: Step-by-step plan for gaining FDA approval and advancing their drug/device combination to market
  • Clinical oversight management structure: The basis for a successful internal infrastructure within the organization
  • Comprehensive R&D expertise: Multidimensional perspectives from seasoned experts in regulatory affairs, clinical research operations, project management, and quality management experts ensured advancement through the entire 510K FDA filing process
  • Seamless implementation: Access to a scalable, flexible team of consultants with experience in implementing quality manufacturing experts; chemistry, manufacturing, and control (CMC); technical writers; and FDA communication practitioners to complete the new drug application (NDA) filing

What is Your Return on Investment?

Accelerate Time-to-FDA Approval and Market Commercialization

Eliminate the usual back and forth with the FDA and advance through a complicated filing process at a much quicker rate.

A growing biotech company obtained FDA approval for their combination drug and device within three years. Five months after approval, this company was able to launch its combination drug and device to the market.

Save Time and Money

Reallocate internal resources and save valuable time and resources through an accelerated timeline.

The most recent Cancer Center Support Grant (CCSG) guidelines released by the National Cancer Institute (NCI) include a new Core component called “Plan to Enhance Diversity (PED)”. Its purpose is to show both the membership and leadership of your NCI-designated cancer center reflect the population you serve. While there are no required data tables or metrics involved at the time, it is an opportunity for your center to show you are leading the efforts to enhance the diversity of your staff. Along with this new component, the NCI is dedicating a budget to enhancing diversity. You’ll be able to grow your diversity, equity, and inclusion programs with these CCSG funds.

More About the Plan to Enhance Diversity

The new narrative requirement asks you to share your center’s plan to enhance the participation of underrepresented populations in the research workforce and center leadership. Underrepresented populations are determined based on criteria set by the National Institute of Health (NIH). Under this plan, you must show your intentions to establish and support infrastructure and resources to support career-enhancing research opportunities for researchers from diverse backgrounds. This could be training or mentoring programs, or acquiring institutional resource commitments. Additionally, you must show how you will evaluate the success of your plan and the progress made.

Consider the Diversity of the Nation Versus Your Catchment Area

Diversity is no longer defined primarily by race and gender, but has broadened to include differences in cultural backgrounds, disabilities, age, sexual orientation, race, and gender. Dr. Henry Ciolino of the NCI indicated they are required to use the NIH definitions at this time, but centers can expand the definitions of underrepresented to discuss other gender categories, sexual orientation, and more distinct race and ethnic backgrounds.

The new guidelines request that you aim to have your membership represent the population of your catchment area and your leadership represent the population of the nation. The makeup of your catchment area and the United States could vastly differ from each other so to plan for both is undoubtedly a challenge. Here are some ways to prepare for this plan:

Leverage Your Institution’s Resources

Your center likely has a wide range of resources in place to help promote diversity, equity, and inclusion (DEI). Some strategies to make the most of these resources include:

  • Working with your university’s DEI office to develop new practices for the cancer center specifically and to show how you leverage institutional resources
  • Joining university-sponsored workshops and events for DEI education
  • Reaching out to learn about the benefits of hiring a DEI administrator specifically for your department
  • Discussing the pros and cons of cluster hiring, a method of hiring used to increase faculty diversity, and how you could potentially incorporate this practice into the cancer center to promote recruitment and retention
  • Requesting funding to support initiatives benefitting the cancer center and the university as a whole

Collaborate With Your Peers

NCI-designated cancer centers are a collaborative group. Institutions are willing to share what has been done well and what remains a challenge. For example:

  • University of Oregon offers the Presidential Undergraduate Research Scholars (PURS) program, emphasizing in engaging undergraduate students underrepresented in chemistry, physics, mathematics, and other subjects
  • University of California – San Francisco (UCSF) provides opportunities for underrepresented minorities through mentorship and training programs and a diversity steering committee. UCSF also works with its community to provide engagement opportunities for underrepresented and under resourced groups age 18 and under
  • Fred Hutchinson Cancer Research Center (Fred Hutch) is one of the first to practice cluster hiring at a cancer center

Members of Fred Hutch also created the Cancer Center DEI Network. Its goal is to “develop diversity, equity, and inclusion metrics, and share best practices on recruitment and diversity programs” in cancer centers.

Use Advarra EVAL to Track Your Efforts

Advarra’s Research Evaluation System (EVAL) offers ways for you to track and narrate your institution’s efforts to promote diversity in your membership and leadership. Whether it’s grants from individual donors or investments from your university, you can track how your dollars are spent to support research and publications, mentoring the future generation, community projects, and more. You will be evaluated based on your commitment to these efforts and the progress you make. Having a robust plan today is your opportunity to set and elevate the standards for future CCSG support.

 

As we step into 2022, the clinical research landscape is rapidly evolving, shaped by the lessons learned from the COVID-19 pandemic and the accelerated adoption of new technologies. This year promises to bring significant changes in study designs, participant engagement, and the integration of decentralized clinical trial (DCT) technologies. Below are key predictions and trends for the clinical research industry in 2022.

Decentralized Clinical Trials Take Center Stage

One of the most anticipated trends in clinical research for 2022 is the continued expansion of decentralized clinical trials (DCTs). These trials, which allow patients to participate remotely, have become a critical component of modern study designs. Rather than requiring participants to visit research sites for each interaction, DCTs offer flexibility, enabling them to participate from their homes or local communities using digital tools.

This year, the focus will likely be on consolidating various trial designs—such as adaptive and decentralized approaches—into more cohesive and participant-friendly formats. This shift is not just about convenience; it significantly broadens the pool of eligible participants, particularly those from rural or underserved areas. For instance, patients living far from major academic centers may only need to travel for initial screenings, with follow-up visits and data collection happening remotely. These technologies make participation easier for a diverse range of people, enhancing inclusivity and diversity in clinical trials.

Advances in Real-world Evidence

The use of real-world evidence (RWE) in clinical research is gaining momentum, with regulatory bodies like the FDA issuing guidance on how to effectively integrate RWE into clinical trials. RWE allows researchers to collect data from everyday settings, offering a more accurate reflection of how treatments perform outside the controlled environment of traditional trials.

This trend aligns with the broader goal of making clinical trials more representative of real-world populations. Remote data collection tools, such as wearable devices, enable researchers to capture real-time data, offering insights that were previously hard to obtain. These technologies allow researchers to measure evidence out in the real world rather than in controlled clinical settings. However, the increased reliance on remote data collection also introduces challenges, particularly in ensuring the validity and integrity of the data.

Innovation in mRNA and Gene Therapy

Building on the success of mRNA vaccines during the COVID-19 pandemic, 2022 is expected to see continued innovation in mRNA technology and gene therapy. These fields are pushing the boundaries of what’s possible in clinical research, offering new therapeutic options for a range of diseases.

As mRNA and gene therapy technologies become more advanced, clinical trials in these areas will likely incorporate more adaptive and decentralized designs. This approach will enable trials to be more flexible, faster, and inclusive. The focus will be on bringing together various biotech innovations and trial designs, helping to push clinical research forward.

The Role of Local Pharmacies and Community Clinics

Another exciting development is the increasing role of local pharmacies and community clinics in clinical research. With decentralized technologies enabling remote participation, there’s a growing need for professionals in the community to support participants. Local pharmacies and minute clinics are well-positioned to assist in this process, providing services such as sample collection and basic health checks.

This integration not only brings clinical research closer to participants but also diversifies the types of clinical research sites. decentralized trials could soon involve locations rather than just traditional research offices. This shift will further facilitate participant access to trials, improving recruitment and retention.

Streamlining Data Collection in Clinical Trials

While the explosion of data from wearable devices and remote monitoring offers significant benefits, it also poses a challenge. The sheer volume of data can be overwhelming, and it’s crucial for researchers to focus on collecting only the most relevant information. This more targeted approach to data collection will help streamline the trial process, allowing for quicker and more efficient studies.

Resurgence of Clinical Research in North America

In 2022, there is optimism in a resurgence of clinical research in North America. The COVID-19 pandemic has brought clinical trials into the public eye, raising awareness and interest in research participation. With decentralized technologies making trials more accessible, the potential for growth in the North American market is high.

Consolidation of Clinical Research Sites

Consolidation of clinical research sites is another trend expected to accelerate in 2022. Similar to the consolidation seen in hospital systems over the past decade, clinical research sites are beginning to merge into larger networks. This trend allows for more consistent operations and improved data quality, ultimately benefiting sponsors and participants alike. Additionally, these larger networks can tap into more resources, enabling them to support decentralized trials more effectively.

With diversity, equity, and inclusion efforts currently at the forefront of the research community’s collective mind, we’re also seeing increased interest in community-based participatory research (CBPR). Advarra’s institutional review board (IRB) members have had many conversations with researchers about how best to approach this type of research from a participant protections perspective. So what is CBPR? And what does it have to do with research diversity, equity, and inclusion? In this blog we define CBPR, explain common ways it is employed in research, and the benefits of conducting CBPR.

What is Community-based Participatory Research?

Also referred to as community-based research (CBR), CBPR is a partnership-based approach to research that takes place in community settings and involves community members in the project’s design and implementation.

Aimed to unite researchers and communities with shared goals, CBPR typically involves diverse community members, organizational representatives, and researchers in all aspects of the process from start to finish.

Dating back to the 1980s, CBPR’s basic principles of participatory research were introduced by:

  • Health Resources and Services Administration (HRSA)
  • Indian Health Service (IHS)
  • Substance Abuse and Mental Health Services Administration (SAMHSA)
  • Centers for Disease Control and Prevention (CDC)

In 1995, the National Institute of Environmental Health Sciences (NIEHS) became the first of the National Institutes of Health (NIH) to support CBPR when it funded 15 CBPR projects.

While CBPR is not confined to research in the area of health, it is most commonly employed in that arena. Typical topics for investigation include public health issues like HIV and violence prevention, mental health issues, and chronic conditions like diabetes and heart disease. In recent years, CBPR has especially been linked to an interest in studying and addressing health disparities and inequities and the conviction that communities that partner with researchers have a unique opportunity to improve their members’ health status. Oftentimes, CBPR is employed in research aimed to reduce or eliminate racial and ethnic health disparities in under-represented populations.

Why Engage in CBPR?

There are many reasons to engage in CBPR, including:

  • Improving research quality and validity by leveraging local knowledge and local theory based on the lived experience of the people involved
  • Strengthening the research and program development capacity of the partners
  • Overcoming the distrust of communities that have historically been the “subjects” of research
  • Working to bridge cultural gaps that may exist between the parties involved

What Does it Take to Succeed in CBPR?

Success with CBPR requires full cooperation between all stakeholders in the study’s design, implementation, and evaluation. Additional requirements include:

  • Open communication among all stakeholders
  • Full transparency and free sharing of ideas and experiences
  • Trust in and among all stakeholders
  • An equal sharing of power across all stakeholders
  • A shared commitment to the benefit for the community

Considerations for IRBs

Note that CBPR introduces a new set of considerations for institutional review boards (IRBs). As a result, it’s reasonable to ask your IRB what experience, if any, it has with CBPR, and what additional or unique considerations it will include in its review of a CBPR project. Some examples include:

  • Asking additional questions (in an application) from the principal investigator (PI) and study team or sponsor to help the IRB understand the roles of community partners
  • Assessing the adequacy of community engagement to ensure respect for the community affected
  • Assessing of adequate training for community partners
  • Gathering conflict of interest disclosures from the community partners, if applicable

Clinical trials are growing increasingly complex, more expensive, and demand patient diversity. Since 2013, trial objectives have increased by nearly 16% in Phase III trials, with data points collected increasing by more than 300%. In addition, sites are experiencing frustration and confusion caused by the multitude of technologies sponsors require, with an average of six sponsor-mandated systems per trial. Frequently faced with managing different technologies for each sponsor and trial, the administrative burden on sites is enormous.

Let me give you an example. We’ve heard from study coordinators at sites who once reported being able to perform six or seven participant visits a day who now report, it’s down to two or fewer. This stems from the multiple duplicative efforts required to enter data and documents into sponsor-imposed systems that sites often already have collected somewhere else.

At Advarra, we’re out to fix this challenge. Our goal is to create a standardized, seamless integration between sites and sponsors or contract research organizations (CROs) – ultimately creating a site-centric connected ecosystem of technology supporting clinical trials. Because, at the end of the day, sites and sponsors have the same goal: bringing treatments to market safely and efficiently.

Here are a few things to know when it comes to Advarra’s BYOT philosophy:

Ensuring Patient-centricity Starts with Being Site-centric

A recent survey led by Advarra and the Society for Clinical Research Sites showed that over 60% of sites report sponsor-provided platforms or portals have increased their operational burden significantly. This is a problem for both sites and participants. When sites are overburdened, they can’t provide clinical trial participants with the level of attention they need, resulting in a lack of overall patient-centricity and an increased risk of participant dropout.

Sites play a central and pivotal role in clinical trials, but their input is often overlooked. Sites must be able to use their own integrated technology to efficiently support both site and sponsor workflows. One of the places where we see delays in clinical trials is study startup. Miscommunication between sites and sponsors is often why these delays occur. This is unfortunate because study startup time is critical to participant well-being, especially those with life-threatening diseases. By seamlessly connecting site and sponsor systems and reducing duplicate workflows, BYOT decreases startup time, accelerates research, and allows stakeholders to bring treatments to market faster.

I’d love for participants to feel more engaged with the research team, because clinical research is, of course, not possible without willing participants. Enabling research coordinators to spend less time entering data and more time with participants will allow them to feel more engaged and a part of the wider team. This can also have downstream impacts to improve recruitment activities, patient consent workflows, and much more.

Sites and Sponsors Both Benefit from a Connected Technology Ecosystem

Technology must be connected and collaborative for sites and sponsors to be most effective. When sponsors prioritize their own needs, sites must take on new administrative tasks, distracting from their ability to focus on process improvement and participant well-being. Our survey with SRCRS also found that 28% of sites spend more than 15 hours a day interacting with multiple, disparate systems, issued to them by the sponsor or CRO; yet 86% of sites prefer to use at least some of their own technology solutions to manage and conduct industry trials. It’s also worth mentioning only 8% of sites prefer to use all sponsor-issued technology.

Sponsors, like sites, are doing the best they can. They have their own processes and vendors working to centralize information across growing global teams dealing with increasing workloads, variable regulatory and data security requirements. The current process isn’t ideal for anyone. That’s why at Advarra, our goal is to standardize and integrate actions, data, and documents between sites and sponsors to make their work more productive.

Sponsors will also benefit from the connected technology ecosystem: Enabling sites to use their own technology allows sponsors to connect with existing site technologies to exchange documents, conduct remote monitoring, track enrollment, and more. As an example, automated sponsor visibility into which documents a site has already uploaded can save a significant amount of time. Sites would only need to upload new documents as a result. This is only one example of how an intelligent, connected ecosystem can be a huge time saver.

BYOT will benefit all research stakeholders from sites to participants, making safer, smarter, and faster clinical trials a reality. We need to start challenging the existing norm for clinical trials because they’re growing more complex. This calls for a process solution, not a point solution.

At Advarra, we passionately desire to have more patients look at research as a viable care option and encourage more clinicians to recognize the value in clinical trials. The increasing momentum around patient-centricity and innovation in clinical research means the time is now to reform and strengthen the site-sponsor relationship.

The BYOT initiative feels like a natural extension of what we’re already working on at Advarra. We play a role in more than 60% of all industry clinical trials and see firsthand how impactful clinical research is. There’s an opportunity to make clinical research easier for those involved, and more effective for those who rely on it for life-saving treatments, and that’s what matters to me.

As many research organizations are becoming more patient-centric and adapting to technological advancements and remote requirements, they are re-designing the way they conduct research. Accelerated by the COVID-19 pandemic, many trials have shifted from being exclusively conducted in a brick-and-mortar site to a decentralized clinical trial (DCT) model. This approach is typically more convenient for the participant, and it allows research to continue despite in-person limitations.

Within the DCT model, there are various labels and definitions to know. These definitions can change and evolve quickly, so it can be challenging to keep up with all the terminology. In this blog, we attempt to clarify the terminology, defining decentralized clinical trials and the various terms falling beneath the DCT umbrella. We also outline what this may mean for the clinical research industry.

What are Decentralized Trials? 

A decentralized clinical trial utilizes technology and processes to create options for participation beyond an exclusive physical presence at research sites. Unlike a traditional clinical trial where data collection and trial procedures are conducted entirely at a physical research site location, decentralized trials can enable telemedicine, remote collection devices, and mobile/local healthcare providers to provide additional options to participants for in-home visits.  

You may have also heard terms like “hybrid,” “virtual,” and “remote trials” used in conjunction with—or as quasi-synonyms for—the decentralized trial concept. What do these terms have to do with decentralized trials? What’s the difference?

Virtual and Remote Trials 

Catalyzed by the COVID-19 pandemic, virtual and remote trials incorporate data collection and participant interaction outside of physical site locations as much as possible. Participants provide informed consent remotely, researchers collect any samples remotely, and data is captured through wearables issued for the research or even through the participant’s own devices or apps. While study staff often remain centrally located, mobile medical providers may visit the participants’ home when the collection of specimens or data requires the presence of a trained medical professional.

Hybrid Trials 

A hybrid clinical trial incorporates a range of decentralized, virtual, and/or remote modalities of a clinical trial. It also integrates elements of a traditional randomized controlled trial, with strategic design elements to support real-world data collection. These design elements typically focus on randomization, can accelerate product development, and help lower the cost of data collection and participant follow-up.

Many organizations across the research community are learning the value of using new and innovative study designs to increase access to research, as well as increase the quality of data and quantity of information. As a result, industry stakeholders are now using the term “hybrid trials” and “decentralized trials” somewhat interchangeably. 

Telehealth Versus mHealth in Research 

Telehealth – also referred to as telemedicine – typically refers to patients receiving care from a healthcare professional without physically entering into a building to see them. There are multiple ways to conduct telehealth, including using video chat, communicating via text messaging or email, and utilizing other remote monitoring technologies (e.g., smart glasses) to conduct research-related interactions with the participant without an in-person visit.

Mobile health (mHealth), on the other hand, is typically used to refer to capturing health data via a smart device and may be useful in clinical research. Examples include electronic patient diaries, electronic patient-reported outcomes, monitoring apps, and devices to measure activity. While participants typically use mHealth to capture and track data about themselves, mHealth may also allow them to access clinical records and communicate with providers as needed.

What Does this Mean for Clinical Research? 

The relative explosion of DCT designs and technology brought on by necessity to deal with travel restrictions related to the pandemic will forever change the clinical research landscape. Sponsors and research sites who embrace these new modalities should see the quality and consistency of their data increase while capturing more data from participants where it really counts: in their natural environment. Eliminating logistical barriers to participation also enables an expansion in the diversity and the sheer number of participants in research. Participants who previously could not travel to the research clinic during weekday business hours are now able to participate through televisits, in-home measurements and specimen collection, and digital mHealth tools which are convenient to use both in terms of time and location.

Conclusion 

No matter the nuances or differences between each of these terms, each of them will continue to play an increasingly important role in clinical research, especially as we continue to adapt to the digital age. When designing a study, it’s important to utilize the best study designs and methodologies for the specific trial and participant population. Remaining as patient-centric as possible should continue to be the main goal for sites and sponsors as they work to advance clinical research safer, faster, and smarter.

As the clinical research industry continues to conduct more and more trials, sponsors and sites alike are faced with the task of expanding their budgets. They are faced with entertaining and requesting costs due to the growing need of bringing the posed drug or therapy through the phases and to market.

However, increased budgets leave room for increased billing compliance violations. In 2020 alone, $2.2 billion was recovered from the False Claims Act. How does this affect the study activation process? What are best practices to put in place to ensure proper billing compliance from the start? Perhaps the first steps are understanding why billing compliance issues occur, and where to start to mitigate risks.

Reasons for Billing Compliance Issues

Even with guidance and acts in place designed to prevent billing fraud, it still happens. The first case of billing fraud related to billing compliance happened in 2005, and we’re still seeing similar cases today. Some common reasons related to billing compliance issues includes:

  • Double billing
  • Inappropriately deeming clinical trials to be qualifying
  • Inappropriately billing items/services as routine costs
  • Falsely billing non-covered items/services as routine costs
  • Falsely billing study team’s time/effort when a participant hasn’t been seen

It may be helpful for institutions to conduct a coverage analysis to help with billing compliance. Designed to break down all items and services required in a clinical trial, a coverage analysis shows what is covered and what is not covered by Medicare.

Where to Start with Billing Compliance

Now that we understand reasons for billing compliance errors, it’s important to know how to start to become more compliant. When starting, it’s helpful to ask the following:

  • Are we compliant with billing practices?
  • Are these costs enough?
  • Are there any costs I’m missing?
  • How fast do I need to move on this trial?

In order to effectively ask these questions, we must dig deeper and ask more questions to get to the root.

Does this Study Meet Medicare’s Requirements for “Extended Coverage”?

Extended coverage is defined as costs that wouldn’t normally be needed outside a particular study. In order to understand if something is considered “extended coverage”, NCD 310.1 is a guide outlining routine costs in clinical trials.

In NCD 310.1, there are two portions to address. The first portion addresses whether the investigational product (IP) or the study falls under a Medicare benefit category, if there’s therapeutic intent, and whether the patient has a diagnosed disease. The second portion to address is more invasive, but it’s important to provide clarity. Staff must indicate if the study is funded by a government-funded center or agency, if the Food and Drug Administration (FDA) reviewed a 6-digit investigational new drug (IND), or if it’s exempt from IND status altogether.

What are the Routine Costs in the Study?

How do we define what a routine cost is in a study? First, you must know if an item or service is covered by the sponsor or if it’s a standard of care (SOC). Defining those upfront will help you understand if it’s routine or not.

Additionally, knowing if NCD 310.1 offers extended coverage, if Medicare policies apply, or if there are any site-specific preferences can help determine if an item or service is considered routine. Another way to look at this question is asking if any Medicare statues affect coverage.

How do I Determine What is a Reasonable Cost for Items or Services?

Determining a reasonable cost for items or services is another way to confirm expenses are met. To understand what cost is referenced, current procedural terminology (CPT) codes are often utilized. This is referred to as “language” between sites and sponsors and is used to determine cost references. These extensive codes are noted on insurance claims, showing specific items or services performed. In addition, Medicare has provided public reimbursement rates for each of these CPT codes.

Staff will likely have to provide input for time and effort costs as well. In these cases, it’s helpful to rely on study staff experience, and use time estimates as well. For any other costs, communicating with departmental teams is an effective way to gain insight as to what estimates should look like.

What Administrative Fees Should I Include?

Lastly, you will need to address any additional fees that may apply to an administration. To understand what types of fees these may be, it’s helpful to identify if it’s only incurred as a result of trial participation, if it’s a “cost of doing business”, if the sponsor is likely to accept the request, or if it’s a reasonable ask. An example of this are costs a hospital incurs to keep staff employed.

Knowing and understanding how to properly route costs and fees in a study will greatly benefit your study team when it comes to staying compliant and avoiding issues such as double billing. This will simultaneously keep your organization’s reputation intact, setting you up for future success.

In the fast-paced clinical research industry, time is of the essence. Maximizing the time you have to efficiently meet with participants, collect data, and organize it is key to keeping your study on track.

Oftentimes, keeping paper records of study visits, participant data, and the like can cause significant delays during research. This may result in added labor hours, misplaced documents, or an increased risk of error. A solution for these roadblocks may be transitioning from paper source to an eSource solution. Knowing the benefits of using eSource, tips for implementing eSource, and maintaining compliance in your eSource solution may make all the difference in an efficient trial.

Benefits to Using eSource

As the research industry continues to move into a more decentralized, electronic age, there are many benefits to transitioning from paper to eSource. Top benefits include:

  • Saving time
  • Easier data interpretation
  • Increased organization

Saving Time

Switching to eSource can improve a study’s accuracy, compliance, quality, safety, and decrease deviations – all of which add up to significant time saved on protocol. Additionally, electronic source records decrease time and effort for source and electronic data capture (EDC) data entry verification. This leverages real world direct data entry and remote monitoring capabilities.

eSource also has the ability to leverage standardized research assessment templates, such as informed consent process documentation templates and clinical research assessment forms. In addition to standard healthcare outcome assessment forms and standard questionnaires utilized across all clinical trials, this also decreases time and effort recreating paper source documents per study.

Adapting standardized templates and forms, and implementing standard research questionnaires strengthens the site’s quality and safety outcomes. In turn, this will decrease protocol deviations and enhance the validity of source data collections.

Easier Data Interpretation

Switching from documents with hand-written notes to everything electronic standardizes writing, making it easier to read for everyone, since no time is spent trying to interpret what’s written out.

Additionally, eSource allows staff to put in order sets, which, due to the shift from paper to electronic workflows, will decrease deviations.

Increased Organization

With paper source, it’s easy to misplace necessary documents for a study, or to lose them altogether. Staples may come loose, or papers may get thrown out on accident. Not only would staff have to spend time retrieving documents if this happened, but it also accounts for the missing organization piece of paper source. Through eSource, everything is in one place, eliminating the risk of misplacing documents or not having everything you need as you collect data.

Additionally, using electronic patient reported outcomes (ePRO) with eSource further automates and improves data quality. Utilizing ePRO to its fullest extent also contributes to increased organization because it holds everything for a study subject, including standard forms they need. This not only keeps everything organized for study staff, but for participants as well, since everything is in one spot for them.

Tips for Switching Over to eSource

When transitioning source documents from paper to eSource, it can be helpful to implement standard templates across the organization for everyone to utilize. When looking for consistencies across studies, it’s helpful to use two buckets: research categories and therapeutic lines. Research categories include components such as serious adverse event (SAE) or adverse event (AE) logs, device tracking methods, or informed consent forms (ICFs). Therapeutic lines include head-to-toe assessments, vitals, or lab draws.

While there may be more consistencies than just the ones listed above, this provides a good basis for what goes into electronic source forms. By making short and simple form templates, you can reuse the templates from study to study, further saving time on repetitive tasks.

Think About the Assessment Flow

Keeping everything electronic eliminates the hassle of flipping through pages to find the correct documentation. Rather, you can set up a documentation flow, ensuring you fill out the correct documents in the correct order. eSource enables staff to set up requirements around documents – dictating which documents are essential to fill out, which are optional, or which ones to fill out in a specific order. Additionally, you can embed certain fields as “required”, ensuring critical information is collected, ultimately helping you avoid deviations.

Once everything is filled out, sending documents to the principal investigator (PI) is easier via eSource, because all you will have to do is send them a link, directing them to the specific documents they need to review and sign. This saves time on their end, and ensures everything needing their signature is filled out properly.

Maintaining Compliance in eSource

When transitioning to an eSource system, it’s imperative to remember the system needs 21 CFR Part 11 validation and conformance. If you are going to store and maintain a Food and Drug Administration-regulated (FDA) essential record, such as a delegation of authority log, a 1572, or a signed ICF that the FDA can ask for during an audit, the system needs to be validated. Incorporating electronic signatures on the signature process and program also need to meet 21 CFR Part 11 requirements per regulation guidelines.

Keep in mind, there are two parts to Part 11 regulation. The first part covers electronic records – if any FDA-regulated information is created, maintained, or stored in electronic format, Part 11 applies.

The second part entails the electronic and digital signatures piece. This second part outlines the FDA’s requirement for authentication, non-repudiation of the signature, meaning it has to be the legally binding equivalent to the manual signature. When transitioning to an eSource system, the institution employing the eSignatures needs to notify the FDA in their Part 11 regulation of their intent to use eSignatures in lieu of paper signatures.

While there are many parts to consider during the transition from paper source to eSource, the transition enables researchers to conduct their research more efficiently by allowing them to focus on tasks that matter most to them: interacting with participants and advancing science.

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A clinical research trial can only be as strong as the participant population it’s actively reaching and serving. Additionally, the participant population should also match the population of those who need treatment. However, many research teams still struggle to improve access and retain participants in clinical trials. While there may be multiple factors involved in this challenge, location greatly affects a person’s ability to participate or not.

In fact, more than 70% of Americans live more than two hours away from a trial site. If someone were to live that far away and travel to a site on a weekly basis, that’s four hours each week they are giving up to participate – and that’s just on the commute.

Additionally, the industry is seeing a challenge in recruiting enough clinicians to participate in recruitment efforts. This is due to a high cost, low incentive ratio to participate in finding patients for trials. Since providers aren’t opting to participate in recruitment efforts, it’s increasing the challenge to find eligible patients, or even making patients aware of options available to them.

Addressing Common Challenges

The COVID-19 pandemic has given the research industry the workflows and infrastructure to address these challenges and change how research is conducted through decentralized clinical trials (DCTs). Defined as a non-traditional clinical trial model, DCTs utilize technology and processes to create options for participation beyond an exclusive physical presence at research sites. A decentralized model encompasses hybrid, agile, virtual, and remote study designs.

Shifting to a decentralized model can reap many benefits and help solve the industry’s biggest challenges. From a participation standpoint, we can remove the requirement to conduct all visits at a physical research site and allow patients from various parts of the country or world to participate. By doing so, we can allow ourselves to potentially condense the overall trial timeline, increase representation, and decrease trial costs.

Additionally, if we expand participation beyond just clinicians at sites, we can include more clinicians at various locations and organization types. This will also aid in broadening patient access by introducing clinical research to organizations normally without the option of providing a trial as a care option for their patients.

Designing an Adaptive Clinical Trial

When we move toward a decentralized model, we are moving away from limiting trials with labels. The key to success in a decentralized landscape is designing your trial to be adaptive and deployed in different ways depending on participant preference, technology, therapeutic area, and more. In this approach, patients and providers are in the middle, and surrounding them are various aspects going into a clinical trial, including:

  • Home
  • Site
  • Care Providers
  • Telemedicine
  • Sponsors

Bringing all of these components together allows the patient to participate how they want to and in manners that work best for their lifestyles. By enabling the most efficient modality for that specific intervention, everyone can participate, in turn strengthening representation across the industry.

Planning Ahead

It’s paramount to appropriately design and support a DCT on both a macro- and micro-level. Thinking of what the participant could expect, how the study may unfold, and what communication methods to deploy during a trial will help ensure it runs smoothly. Similarly, it’s important for the site or provider to understand what the trial could look like at their location, as well as what it will look like for in-home activities. Outlining these details will help everyone understand what options are available to them. Outlining these details will help all study stakeholders understand what options are available for them to provide, or participate in, connecting more patients to the care they need.

Advarra experts Joan Versaggi and Leslie Paul answer questions from the first in the webinar series – FDA Updates: BIMO – What Sponsors Need to Know.

Q: How are inspections assigned domestically in the United States (US) versus outside the US?

A: The BIMO CPGM (Bioresearch Monitoring Compliance Program Guidance Manual) addresses in Part III (Inspectional), section V (International Data) what a Food and Drug Administration (FDA) investigator looks at during an inspection. Section B. 2. notes the Centers (e.g., CDER, CBER) issue sponsor inspection assignments. Domestic inspection assignments are issued through the ORA OBIMO headquarters to the appropriate ORA BIMO division. Foreign inspection assignments are issued to ORA OBIMO headquarters

Q: What are remote “assessments” and how do they differ from the “regular” inspection (i.e. no 482, no 483 etc.)?

A: This webinar covered the changes to the BIMO CPGM 7348.810 (Sponsors and CROs) and how the FDA conducts “regular” inspections. For details regarding the conduct of remote interactive evaluations of BIMO facilities, see FDA’s Guidance for Industry Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities During the COVID-19 Public Health Emergency.

Q: Where is the complete response letter in the chain of events?

A: After the FDA conducts their review of the sponsor-provided information, a complete response letter is issued indicating they will not approve the application at that time. This is outlined in 21 CFR 314.110.

Q: Can you give an example of a sponsor-investigator?

A: A sponsor-investigator is an individual who initiates as well as conducts the clinical investigation. A sponsor-investigator must comply with regulatory requirements applicable to both sponsors and clinical investigators.

Q: How transparent should a sponsor be with the FDA investigator during a pre-approval inspection (PAI) when there were issues in unblinding (e.g., mistake at sponsor)? Should the sponsor inform the FDA up front during the inspection? Or just be prepared to talk about it *if* the FDA investigator finds it?

A: Our advice is to be transparent with any quality issues, such as unintentional unblinding. While sponsors should have reported this in the clinical study report, they should be forthcoming with a serious issue and provide an explanation as to what happened, why it happened, and what was done or what controls are now in place to ensure the non-compliance does not occur in the future.

Q: Given that many sponsors are now working remotely due to COVID-19, can we expect that FDA would reach out in advance to schedule inspections, versus coming to a sponsor location unannounced?

A: Inspections under this program are generally pre-announced, unless otherwise instructed in the inspection assignment and at the discretion of the ORA BIMO division. Pre-announcements are generally no less than five calendar days in advance of the inspection.

Q: Can you please comment on FDA collecting more and more data on USB drives? Sponsors have started putting standard operating procedures (SOPs) in place restricting USB drive use due to security issues.

A: It’s best practice to have written procedures governing how electronic data is provided to a regulatory authority if they request it during an inspection. Chapter 5 of the Investigations Operation Manual (IOM) section 5.3.8.3.1 – Electronic Records, provides specific instructions to the FDA Investigators on the collection of electronic records. The IOM states in part, – If there are no mechanisms available for a firm to securely transmit the data electronically to the investigator, the data may be provided to FDA on a CD, DVD or a USB…The information obtained from the firm is commercial confidential information (CCI) and as such must be protected to the greatest extent possible. It is the responsibility of the investigator to make sure the physical data source remains secure. Likewise, data obtained from extra-governmental sources may contain viruses or malware that may be included with the information provided to the investigator either on purpose or accidentally. The transfer of electronic data must be evaluated along with concerns related to safeguarding the security of both FDA and firm information.

Q: What is the expectation of evidence for a sponsor to show oversight for a vendor’s subcontracted services as required by ICH E6 R2?

A: New Section F – Outsourced Services specifically states the following:

Review and evaluate the sponsor’s oversight of outsourced services as appropriate and as defined in contracts, written processes and procedures, and SOPs. Focus on the outsourced services playing a significant role in the clinical trial (e.g., management of primary efficacy endpoint or safety data) and/or were involved in any significant FDA regulation deviations. Determine if the sponsor has processes and procedures (e.g., SOPs, plans, or other work instructions) for selection of outsourced services and activities, and determine what criteria were used to select the CRO (and as applicable, other individuals or organizations providing outsourced services) and whether they meet those criteria.

Q: What documents are available to inspectors prior to the BIMO audit visit?

A: Centers will provide background materials when they issue sponsor inspection assignments, such as:

  • Study protocol
  • Case report forms (CRFs)
  • Data line listings
  • Complaint summary
  • Any additional information

Q: In providing the list of SOPs, should we provide only current SOPs or all versions in effect during study conduct?

A: The FDA investigator should receive SOPs in place during the conduct of the clinical trial(s). If you have updated SOPs addressing any deficiencies in the SOPs in place at the time of the study conduct, they can demonstrate the sponsor’s improvements.

Q: What’s the thought/guidance for providing a BIMO reviewer’s guide in a marketing authorization application (MAA)? Is it a best practice as it’s optional?

A: I have never provided this with an application, I suppose there may be a good reason to provide one. For example, if the drug has gone through several owners and the sponsor wishes to clearly outline who was responsible for what, when? Further I found the Bioresearch Monitoring Technical Conformance Guide, which is referenced by the Draft Guidance Document: Standardized Format for Electronic Submission of NDA and BLA Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for CDER Submissions.

To learn more about recent BIMO changes, watch the on-demand webinar FDA Update: BIMO – What Sponsors Need to Know.

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