In addition to other responsibilities, human subjects protection programs (HRPPs) and IRBs are tasked with ensuring a research protocol’s lifecycle is compliantly captured. To help support compliance initiatives, an eIRB system can provide study teams with necessary guidance when submitting research requests to the IRB. Such a system may also assist in identifying the appropriate research regulations. With an eIRB system, all necessary information and data is in one location, making for a simplified process from protocol submission to review.

Regardless of the organization’s size or specializations, shifting from paper-based processes to electronic systems is a significant undertaking. This blog outlines five considerations when selecting an eIRB system for your organization.

Easy Setup and Configuration

We live in a world where regulations can (and will) change. The revised Common Rule went into effect in 2018 and changed several longstanding regulations and guidances; going forward, we anticipate other changes in research regulations, such as those recommended in the 21st Century Cures Act. IRB systems need to be flexible to help staff better navigate and support compliance with any future regulatory changes. eIRB platforms don’t have to be one-size-fits-all; research staff should have the opportunity to configure a system to their organization’s specific needs in a way that benefits them.

When evaluating, consider if a system has an option for smart forms, which are intelligent electronic forms, built with digital elements or logic, designed to gather research protocol information. Smart forms capture the pertinent information through initial study submissions, modifications, continuing reviews, and reportable events. The system should allow IRB staff to not only create new forms but also update a form’s existing logic.

Streamlined Processes and Workflows

Ultimately, an eIRB system should be able to streamline operational processes and workflows. For example, consider whether the system helps to improve your current turnaround times, or if fewer clicks are required to complete a common activity.

Additionally, the system should be transparent. Communication tools should be available within it, and multiple people should be able to access the system at any time, from any device. Keeping everything within the eIRB system helps move submissions along to the next point person without anything getting lost in an individual’s inbox during the review process.

Keeping everything electronic also makes it easier for staff to manage necessary protocol documents. Take the informed consent form (ICF) for example. Every time it’s updated or changed, the ICF can be archived or added to the history of the electronic folder in the eIRB system, with version updates intact. Staff are able to see previous ICFs and compare versions along the way. Contrast this with keeping ICF versions in a paper format or in a standard computer file folder: sifting through versions could not be done nearly as easily and efficiently.

Enhanced Human Subjects Protection and Compliance

With eIRB systems, a new protocol submission starts with the research team, including the principal investigator (PI) and study coordinator. From there, it typically goes to a general queue for the IRB analyst to pull. As they pull information, there’s a lot to consider as they analyze a new project, including:

  • Eligibility for expedited review
  • Eligibility for exemption
  • Compliance with the Common Rule
  • Compliance with FDA regulations
  • Informed consent compliance with protocol and IRB policies

Using an eIRB system to its fullest extent will help this analysis process. The system should enable users to identify which regulations apply to the specific research they’re analyzing.

Additionally, smart forms can be configured to identify whether the study involves greater than minimal risk, includes minors, vulnerable populations, waiver of signed consent, is subject to HIPAA, if it involves a drug or device, etc. Depending on what’s been selected in the application/smart forms (such as greater than minimal risk research, expedited, or exempt, for example), research staff can respond to questions tailored to their specific submission. Making sure the system is set up to ask these questions will also help with institutional compliance initiatives, helping ensure all necessary information is properly captured. Staff can require answers to questions to ensure necessary information is collected at initial submission, rather than having to go back and forth with the study team.

Encouraging Transparency Throughout Study Navigation

During a study, research staff should see everything – from when the study was originally approved and when the activation process started, to when reportable events occurred. Looking at all pieces of information is important, and staff need a clear picture and understanding in order to navigate the study. The system itself should have one location for materials such as:

  • Archived consent forms
  • Investigator’s brochure
  • Recruitment materials
  • Device manual

Navigating these documents is important, as it gives the user the ability to see historical changes within a study and view currently approved study documents. Having an easy-to-navigate system ensures the correct approved study documents are utilized to properly conduct a study. It also assists with ensuring study documents are accessible for site audits.

Easily navigating a study will also make processes and procedures more efficient, since staff will spend less time digging through stacks of paper or reaching out to colleagues to locate certain documents. Additionally, by putting source documents in the eIRB system, it will show an electronic stamp of approval, current consent forms, and up-to-date documentation. Securely navigating a study, ensuring appropriate access, and transparency is key for study navigation.

Easy to Roll Out and Train Users

Even though there are many benefits to adopting an eIRB system for your organization, change can be difficult for many people. When implementing any system, it’s important to minimize the impact on HRPP staff members and those conducting research. When testing a system, consider going into the sandbox or test environment to play around with it so it makes sense to users. The system should have the capability to allow for user testing and validation. User testing and validation is key to a successful rollout as system bugs can be identified and fixed prior to rollout. The more it makes sense to users, the easier it will be to roll out organization-wide and train users.

Invite research coordinators, regulatory staff, and others who will be completing the application to focus groups where you can begin socializing the new system. In focus groups, subject matter experts should identify and discuss areas of change and how it will impact workflow.

When a system is updated, internal support documents need to be updated to align with system features. Having a clear understanding of the upcoming changes is critical to ensure that resources are in place to support users post rollout.

The final step in implementing an eIRB system is the rollout stage. Creating a rollout plan with minimal impact on users is key to a system’s success. During the rollout, subject matter experts and project managers should be available to answer system questions, address bugs, and facilitate communication between the eIRB vendor.

As this blog outlines, there’s a lot to consider when selecting an eIRB system. This shift can be a big undertaking for your organization. Seeking external expertise and guidance can be beneficial when shifting to an electronic system.

Over the past two years, Operation Warp Speed brought mRNA-based vaccines into the spotlight, as organizations like Moderna and Pfizer/BioNTech raced to develop a COVID-19 vaccine. While scientists have worked on messenger ribonucleic acid (mRNA) for years, these successes have enabled researchers to use mRNA technology to develop vaccines against a number of other infectious agents, as well as to develop potential therapeutics for a number of other disease indications.

Curious about mRNA technology and the regulatory requirements for its use in clinical trials? You’re not alone—our biosafety team frequently receives questions from study sponsors, contract research organizations (CROs), and sites. Read on as we respond to our most commonly asked questions.

What is mRNA?

mRNA is a biological molecule used by cells to serve as an intermediary between the genes encoded in DNA and the proteins those genes code for.

According to the Central Dogma of Molecular Biology, cells contain all the instructions for producing proteins in DNA-based genomes, as shown in the figure below. It’s impractical for cells to make protein directly from DNA, so cells use a process called transcription to reproduce the “blueprint” for making a single protein into mRNA. A separate process called translation reads the genetic instructions in the mRNA and uses it to make protein.


Illustration of translation and transcription processes

Making mRNA is akin to photocopying a single page from a standard operating procedure (SOP) manual (i.e., the DNA genome) to carry out a single procedure (i.e., making a specific protein). Cells can make many mRNA “photocopies” of the genetic blueprint, which allows for efficient mass production of the desired protein.  

mRNA contains genetic information (i.e., nucleic acids), and the U.S. Food and Drug Administration (FDA) regulates mRNA technology as a biologic.  

How do mRNA Vaccines Work?

Typically, mRNA-based vaccines are delivered within lipid nanoparticles in oily casings designed to protect the mRNA. The lipid nanoparticles have similar chemical makeup as cell membranes, so once injected into recipients, the lipid nanoparticles merge with the recipient’s cell membranes to allow the mRNA to enter their cells at the injection site.

Once inside a cell, ribosomes read the mRNA and follow the instructions found in the mRNA to make protein – a process called translation. mRNA-based vaccines present that protein to the immune system, stimulating an adaptive immune response against the protein encoded in the mRNA.

mRNA-based vaccines against SARS-CoV-2, the virus that causes COVID-19, encode the virus’ spike protein. This approach is comparable to a subunit vaccine, in the sense that the vaccine only delivers the key target antigen for the immune system to attack, without the added risk associated with utilizing a live attenuated virus or a heat or chemically inactivated dead coronavirus.


Illustration of how an mRNA-based vaccine works against SARS-CoV-2

As successful mRNA-based vaccines helped prevent severe COVID-19, the technology is also actively under study for use against a number of other infectious agents such as Zika virus, respiratory syncytial virus (RSV), influenza, herpes viruses, and others. The vaccine platform is also utilized to develop anti-cancer vaccines.

What are the Regulatory Requirements for Clinical Trials of mRNA Vaccines?

Since FDA regulates products utilizing mRNA as biologics, sponsors must submit an investigational new drug (IND) application through the FDA’s Center for Biologics Evaluation and Research (CBER) and receive a biologics IND number prior to initiating any human clinical trials. Assuming human trials are successful, sponsors can seek approval to market an mRNA-based product through the CBER biological license application (BLA) process.

Due to the public health crisis posed by the COVID-19 pandemic, Pfizer/BioNTech’s and Moderna’s mRNA-based COVID-19 vaccines initially received emergency use authorizations (EUAs). However, later BLAs provided full approvals for both.

Prior to initiating a clinical trial involving human research subjects, a research ethics committee called an institutional review board (IRB) must provide approval. In Canada, the committee is called a research ethics board (REB), and in the EU it’s an ethics committee (EC). The Japanese equivalent is the ethical review committee (ERC).

Do Clinical Trials Involving mRNA Delivery to Human Research Subjects Require IBC Review?

Research involving engineered genetic material may also require an institutional biosafety committee (IBC) to review the research. So, in a word, yes – if there are ties to National Institutes of Health (NIH) support.

NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines) Section III-C-2d calls for IBC review of research involving the deliberate transfer of engineered genetic material into human research participants, where the engineered genetic material “can be translated or transcribed.”

mRNA functions within a cell by being translated into a protein. In the case of mRNA-based vaccines, that protein is the antigen used to trigger an immune response.

Why Do Trials Involving mRNA Need IBC Review?

NIH provides the standard for oversight of research involving genetic engineering and gene therapy. The NIH Office of Science Policy (OSP) promulgates the NIH guidelines and calls for local oversight at the research site by an IBC reporting to the NIH OSP.

An IBC is charged with protecting study personnel, the community, and the environment from exposure to engineered genetic material. An IBC may also advise the IRB in assessing risks to the study participants.

For more information on IRB and IBC responsibilities, check out our blog IBC vs IRB: What’s the Difference?

The IBC review requirement applies to research involving engineered genetic material taking place at sites receiving support from the NIH or participating in NIH-supported research. Sponsors or sites receiving any NIH support are obligated to comply with IBC review, regardless of whether the support is associated with the particular gene therapy study in question.

In cases where the agency did not provide monetary support, NIH may still require IBC review if the agency collaborated in the research of the study agent or provided materials for its development, as stated in NIH Guidelines Section I-C-1-a-(2).

Even if there are truly zero NIH funds or collaboration involved, IBC review is considered a best practice: “Individuals, corporations, and institutions not otherwise covered by the NIH Guidelines are encouraged to adhere to the standards and procedures set forth in Sections I through IV” (Section IV-D-1).

As the name implies, endpoint adjudication committees adjudicate, or pass judgment, on endpoints in a clinical trial. But what else do these important committees look at? This blog outlines some of the critical events where endpoint adjudication committees (EACs) – also known as clinical event committees (CECs) – can be used to look at more than just “endpoints” in clinical research.

EAC Versus CEC

If you are not familiar with what an EAC does and the value they bring to clinical research, read our blog DMC vs EAC: What’s the Difference? to learn more.

In its March 2006 guidance, Establishment and Operations of Clinical Trial Data Monitoring Committees, the U.S. Food and Drug Administration (FDA) solidified and reinforced the need for clinical trial sponsors to consider establishing certain independent committees to provide independent oversight and insights for clinical trials.

Thus, EACs were introduced to industry, highlighted as a way for sponsors to ensure their research plans incorporate appropriate independent medical assessments and adjudication processes. However, some sponsors already had individuals or committees formulated to look at clinical events during research, and the CEC terminology stuck around.

At Advarra, we primarily use the terminology of EAC, as that is what’s used in the regulatory guidance. In practice, EAC and CEC are synonymous.

Adjudicating Certain Research Events Requires Medical Judgment

Many clinical events result in clear determinations, are easily discernible, and are measurable with defined thresholds by calibrated instrumentation and lab test. Defined thresholds may answer questions such as:

  • Did the blood pressure exceed a certain amount?
  • Was the creatinine level in the blood under a certain number?
  • Did the person test positive via a polymerase chain reaction (PCR) test for the virus on or over day 15?
  • Has the person taken a certain drug in the last 90 days prior to enrollment?

None of these examples would require medical judgment to discern; they are all binary yes/no, easy to document, and are definite questions.

Undoubtedly though, not all events occurring in clinical trial conduct are this clear cut. Just as the practice of medicine is multifaceted, many times in research, substantial medical judgement needs to be applied.

In medical practice, there is room for practice, opinion, or judgment. When you are talking about clinical research, regulatory guidance makes clear that those decisions in the trial requiring medical judgement to adjudicate should be independent.

Unlike in medical practice, where a physician may make their own judgment and then proceed to treat based on that opinion, these research decisions should be adjudicated or reviewed by someone besides those sponsoring, organizing, or conducting a trial.

Common areas where EAC or CECs would get involved as an independent adjudicator of events to provide expert assessment back to the sponsor include:

Eligibility and Randomization

Inclusion and exclusion criteria often contain determinations on ranges of disease progression, comorbidity severity, and other judgments requiring medical expertise. There are occasions where potential participants are on the cusp of the inclusion and exclusion criteria – in these cases, judgment helps determine if the protocol is safe for them.

Increasingly, sponsors are turning to trusted independent EAC/CECs to make these determinations, rather than the local principal investigator (PI) or the sponsor’s medical director. The PI and medical director aren’t unqualified; rather, by using an EAC/CEC, the sponsor can eliminate the perception of bias in the evaluations.

Because the EAC/CEC is comprised of therapeutic experts, the level of expertise is increased for these decisions. Not only can eligibility and randomization decisions profoundly impact a participant’s safety, they can also skew the overall trial data if judgments are not consistent or are influenced by the bias to include more participants.

Adverse Event Causality

Was an adverse event (AE) or some other event caused by the study drug or device? A lot goes into those assessments. A participant’s overall medical history, comorbidities, concomitant medications, and environmental factors will potentially influence the event’s causality evaluation and relatedness to the investigational product (IP).

These evaluations, to the extent medical judgment is needed, should be done by an independent committee, looking at the clinical event and adjudicating a determination. Side effects and unexpected events play a critical role (along with efficacy) when regulators are considering approval. Using an independent committee to reach consensus and eliminate the perception of bias in the evaluation may influence how regulators view the data.

Safety and Continuation

EACs and CECs can also evaluate overall participant safety and ongoing participation in a research trial. These types of assessments are more common in oncology and other conditions where participants are dealing with severe illness. An EAC/CEC is primarily responsible for evaluation of defined clinical endpoints. These endpoints help the sponsor evaluate continuation for a participant in the study.

The PI has the primary authority and responsibility to monitor participants and pull them from the study if there are safety concerns. However, having a periodic independent assessment regarding a participant’s safety as they continue in research can add value to the study, aiding in eliminating the perception of bias.

Having a trusted independent group of experts involved in the study can add expertise, reassure investigators they are making the right calls, and eliminate the perception of bias. All are good and necessary activities to support public trust in research and provide appropriate safety oversight for participants.

Sponsors should plan early for how they can leverage an independent EAC or CEC and work with that partner to develop and define a charter that complements the protocol design.

For more than 20 years, Advarra’s endpoint adjudication committee (EAC) team has seen a lot. Over that time, one key element for successful collaborative engagement with clinical trial sponsors is clear – you need top-level experts, and a good technology-enabled system.

Access to top-level experts is standard for us, as we’ve been carefully cultivating our worldwide network of over 1,500 medical and research professionals over two decades. That said, the expertise in the network is facilitated through the technology system, enabling all those experts around the world to work together efficiently and deliver timely and accurate assessments back to the sponsor. In this blog, we take a closer look at how and why Advarra leverages proprietary, custom, and intelligent technology in our EAC program to move clinical research along safer, smarter, and faster.

What is an EAC/CEC?

In a nutshell, an EAC is an independent group of experts who evaluate clinical trial data to determine if individual participants meet certain endpoints as defined in the protocol. Complex studies often require professional judgment to determine if an event meets the endpoint criteria or if it was caused by underlying medical conditions, comorbidities, or other environmental factors. If you are not familiar with what an endpoint adjudication committee (EAC) (also known as a clinical event committee [CEC]) does and the value it brings to clinical research, read our blog to learn more.

How do EACs/CECs Really Operate?

To understand the important role technology enablement plays in endpoint adjudication, we have to first start with the core activities and functions of an EAC. At a foundational level, EAC members evaluate and issue judgments (i.e., adjudications) regarding medical events occurring in drug and device clinical research. If the adjudicators do not all agree, a formal committee is convened, the members deliberate, and they potentially come to a consensus.

The process sounds easy until you start to consider the myriad types of disparate information necessary to properly evaluate a complex medical event, including information from worldwide sources in any number of languages. To make their determinations, the EAC/CEC members may need the following:

  • MRI/CT scans
  • Medical photos
  • Medical record histories
  • Clinic notes
  • Defined research metadata elements or other eSource information

Members may also need narrations from the frontline principal investigator (PI) who has seen the participant and can explain the circumstances. Any of those pieces of data may come securely through data feeds originating within multiple systems at the sponsor, clinics, and imaging providers. So it’s important to have a process of identifying datasets, setting secure communication integrations with sponsor systems, and getting the elements into the adjudication platform.

The professional adjudicators need this information organized in a meaningful presentation so they can accurately and rapidly assess an event and provide a judgement using the criteria outlined in the EAC charter. For global trials, the materials must be translated quickly from eSource language into the adjudicator’s language. Adjudicator questions regarding the materials must be curated by the EAC administration team and communicated to the appropriate party. Any updated information received must integrate into the overall adjudication dataset. Adjudicator determinations regarding the event are then securely transmitted back to the sponsor’s platforms, so the clinical trial can continue without interruption or delay.

If the various adjudicators do not come to unanimous consensus after their individual reviews, then the EAC administration team will convene an EAC meeting to deliberate. This involves meeting organization and scheduling, minutes, motions, votes, telepresence systems to connect worldwide members, and incorporating sponsor representatives for the open session discussion. To keep the process organized and efficient, all of this should be managed within the EAC platform, with the adjudication meeting results sent back to the sponsor.

Throughout all of this, the sponsor needs to have appropriately masked dashboard access so they can see the status of the various adjudication events moving through the system in real time, without impacting or influencing the adjudication work being done. The EAC software should also provide various levels of system access and visualization for the different EAC administrator and adjudicator roles.

And to keep things interesting: the EAC must do all of this rapidly in a way without hindering the research progress or putting participants at risk. If it sounds complicated, it’s because it is.

Flexible Platform Allows for Rapid Customization and Validation

There is a common adage in research: “If you have seen one clinical protocol, you’ve seen one clinical protocol.” Each EAC project is unique, and that’s why our adjudication platform needs to be massively flexible to ingest disparate types and sources of metadata. The core platform is validated; we work with the sponsor during charter development to define what elements will be incorporated into the adjudication and what systems house the information.

Once we’ve established the project’s specific needs, our configuration and validation teams work with the sponsor to stand up the various secure connection “pipes.” Some projects require first establishing the secure transfer pipes with the multiple vendors who house the source data. A return pipe exists to place the masked adjudication decision back into the sponsor’s clinical trial management system (CTMS) or similar system. For our strategic partners with existing secure data feeds to their eSource and clinical record keeping systems, we can move rapidly. At the end of the project when closed session records are returned to the sponsor, we may also feed those resulting materials into the sponsor’s electronic trial master file (eTMF) through a secure integration.

Simultaneously, we work directly with our adjudication experts to organize the information presentation and progression and make the adjudication process comprehensive, efficient, and, perhaps most importantly, as easy as possible for the adjudicator to digest the materials and render an opinion. Workflow is also configured depending on the charter and sponsor requirements. Some projects have two adjudicators, some five or more; all need to render a unilateral opinion separate from the other adjudicators.

When meetings are necessary, some projects require unanimous agreement, some are supermajority, and others allow for simple majority. Workflow and adjudication parameters are all unique to each project and defined collaboratively with the sponsor during charter development.

Once it’s been configured specifically to a particular clinical protocol, we then test the platform following our computer system validation policies and procedures for compliance with U.S. Food and Drug Administration (FDA), Part 11, EU Annex 11, and any sponsor requirements. Since each project is based on the same core platform, validation activities typically focus on the secure data transfer and the customized configuration.

It’s complicated, but since our platform is designed to ingest all manner of disparate datasets, we can get new projects set up and through validation in as little as a couple weeks. Advarra also has amazing worldwide technology resources to help set up any necessary secure data transfer pipes with sponsors.

Security and Compliance

In the world of international privacy regulations, your EAC/CEC administrator needs to satisfy an acronym soup of regulations governing the movement and handling of a data subject’s information: GDPR, PIPEDA, HIPAA, CCPA, and more.

The same team who supports Advarra’s global software compliance program also supports our proprietary EAC/CEC platform. We routinely review the international privacy landscape to ensure systems comply with the latest encryption, data governance, data security monitoring, and other associated regulations.

Part of our charter development process involves working with the sponsor to define which regulatory frameworks apply to the data being exchanged, and then applying the appropriate mix of standards. Sometimes that means configuring the secure cloud environment for regional data storage and segmentation. In certain locations, (e.g., EU zone, Israel, China) it may mean verifying the appropriate government filings and local privacy official representative disclosures are completed either by Advarra or the sponsor, so Advarra can be the data processor.

Summary

A truly successful endpoint adjudication technology platform has to work fluently with the study sponsor, EAC/CEC administration team, translators, and most importantly, the adjudicators. It’s not enough to just use basic clinical workflow software or bolt on a module to an existing data management system. To recognize all the benefits of a technology-enabled service, you start with the core service elements and then build the platform around the service and people.

The result of this approach? A compliant, efficient, and successful EAC/CEC service which can spin up new projects quickly and rapidly deliver consistent adjudications from worldwide experts—all while providing the sponsor/CRO full transparency on their adjudication statuses.

Digital transformation.

We’ve heard about it for years, but now all of us have experienced a dramatic technological acceleration as the pandemic forced us to embrace digital to meet our everyday needs, from online shopping to remote work to telehealth.  

And we’ll continue to see this trend: a recent McKinsey survey found eight out of 10 organizations have embarked on a digital transformation journey in the last five years. And tech research firm IDC predicts businesses will spend $2.3 trillion per year on digital transformation in the next four years, with worldwide technology investments hitting $7.4 trillion.  

So, what does digital acceleration mean for clinical research, a traditionally risk-averse industry (and for a good reason)?  

At Advarra, embracing and implementing technology isn’t new. In fact, as a digital pioneer leveraging our industry-leading review platform for the last 15 years, Advarra has improved the user experience, increased regulatory compliance, and further connected the ecosystem through digital innovation and technology. 

When we look at what technology enablement means for the industry in more detail, we see benefits ranging from radical and real-time transparency to game-changing efficiencies to more secure workflows and data sharing. In fact, our technology products provide value across the entire review services ecosystem. This includes our foundational Center for IRB Intelligence (CIRBI) platform, which facilitates real-time communication across research programs, to our Biosafety Portal, which simplifies study submissions and reporting, to our SOAR technology, which makes endpoint adjudication easier and more transparent.  

Technology makes us a stronger partner to our clients – and while we’ve already seen a lot of digital progress in recent years, there’s so much room to grow. We’re continuing to bolster our technology platform and can expect even greater success and benefits with additional adoption, including: 

  1. More consistency of determinations across Advarra’s various committees and offerings. Ensuring the quality and dependability of decision making is a major part of the institutional review board’s (IRB’s) work, and technology allows us to do this more precisely. A consistency of decision making across all of our panels creates a better client experience.
  2. Faster turnaround times and more compressed workflows. This allows multiple components of our review services to operate simultaneously, rather than assembly style. 
  3. Increasing transparency and accountability. It’s important for us to share turnaround times and service-level agreements (SLAs) with clients. There are no guessing games with Advarra, and technology enables us to share more of that journey with clients. 

The power and promise of technology is exhilarating, but we also know we need to be trusted stewards of that technology in an industry like clinical research, where safety is the ultimate priority.  

With digital transformation continuing to change almost everything in our lives, we understand the importance of precedent and industry knowledge. This ultimately makes us the only partner who can help the industry transform and embrace new technologies without compromising on safety, quality, or outcomes.  

The future is exciting – and innovation will help us continue to achieve even greater things for the industry, to not only improve performance and efficiency to get therapies to market faster, but also improve safety and enhance clinical trial protocols. 

In its March 2006 guidance, Establishment and Operations of Clinical Trial Data Monitoring Committees, the U.S. Food and Drug Administration (FDA) solidified and reinforced the need for sponsors to consider establishing certain independent committees to provide independent oversight and insights for clinical trials. The term “endpoint adjudication committee” (EAC) (also known as a “clinical event committee” or CEC) started to infiltrate the device research world, and FDA began encouraging device developers to ensure their research plans incorporated appropriate independent medical assessments and adjudication.

So why would a device clinical trial need an EAC or CEC? This blog explains how device developers utilize EACs and CECs to enhance their development team’s expertise, protect participants, and move research along through regulatory approval safer, smarter, and faster.

What is an EAC/CEC?

In a nutshell, endpoint adjudication committees and clinical event committees provide expert medical judgment to determine if a research participant has met a protocol-defined endpoint. Complex clinical trials often require a professional assessment to determine if an event truly meets the protocol endpoint criteria, or if it was caused by underlying medical conditions, comorbidities, or other factors.

This oversight may also be necessary when specific therapeutic expertise is needed beyond what the principal investigator or sponsor’s medical monitor can offer. The number of participants meeting an endpoint is essential to evaluating the safety and/or efficacy of an investigational compound or device. To learn more, check out our blog DMC vs EAC: What’s the Difference?

A Quick Note on the Regulatory Term “Devices”

This blog specifically refers to “devices” in research. Keep in mind that in the regulatory worldview of the U.S. FDA and EU European Medicines Agency (EMA), the term “devices” covers a lot of different items. According to section 201(h) of the Food, Drug, and Cosmetics (FD&C) Act,  a “device” can be “an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part” which meets certain criteria regarding the device’s intended purposes and how primary intended purposes are achieved (namely that the device “does not achieve its primary intended purposes through chemical action with or on the body…and which is not dependent upon being metabolized for the achievement of its primary intended purposes”).

What specifically does the FDA regulate as a device? We know it covers instruments and contrivances, but let’s talk specific examples. Some common items include, but aren’t limited to:

  • Digital therapeutics (e.g., mobile health [mHealth] apps)
  • Diagnostic assays
  • Laboratory developed tests (LDTs) (e.g., advanced genomic analysis)
  • Traditional devices, including:
    • Pacemakers
    • Cranial stimulation
    • Laser surgery tools
    • Electronic toothbrushes

So when we talk about “devices,” it can sometimes be challenging to apply the regulations to a specific device, because we’re describing a pretty diverse landscape.

Enhance Device Developer’s Medical Expertise

Most device developers likely do not have a worldwide team of medical experts on staff with experience in all possible therapeutic disciplines. However, it is critically important for developers to have access to such diverse therapeutic expertise.

For instance, say you need to determine if your digital therapeutic device caused a participant’s seizure, or if it occurred because of some underlying medical condition. You would likely need an experienced neurologist to evaluate the event. Or, for example, you may need an experienced neuropsychologist to determine if your mHealth app was responsible for a participant’s improved cognitive function, or if it was the result of concomitant medications they were on or other environmental factors.

Many device developers are skilled in application development, design, and manufacturing. But they may not necessarily have all the requisite medical expertise to evaluate adverse event causality, or to adjudicate complex endpoints where medical judgment is needed. Yet, in order to secure regulatory approval from the agencies to conduct research – and in some cases ethics approval from the institutional review board (IRB), research ethics board (REB), or ethics committee (EC) – device developers must have access to this deep and broad medical expertise.

Independent EACs and CECs provide device developers with the necessary expertise to augment the research team for a given protocol or broader development program. CECs and EACs are specifically and carefully designed with the appropriate experts who work with the sponsor according to the committee’s charter in the evaluation of research events. They can make determinations regarding adverse event causality, relatedness, and seriousness, as well as provide an evaluation of complex endpoints requiring medical judgment.

And importantly, independent EACs provide a mechanism for device developers to demonstrate to regulators that appropriate safety oversight is in place for the device research.

Independent Assessment Eliminates Perception of Bias

Today’s devices can be highly complex with unique modes of interaction within the body. The human body is a complicated place; each of us has unique physical environments we live in, various comorbidities, and different concomitant medications and medical histories – all of which affect how devices may impact us.

Determining if a device is working as intended, or if some other confounding medical issue is driving the outcome, can be difficult. Medical judgment is often needed to determine if a certain medical event was related to the device or some other confounding factor. Specific endpoints in the trial may also require expert medical judgment to determine if the participant’s results meet the protocol’s pre-defined endpoint.

The evaluation of events and the subsequent determination of relatedness or endpoint completion can profoundly impact the statistical calculations regarding the investigational device’s safety and efficacy. A few adjudication decisions one way or the other by the medical experts can mean the difference between potential product approval, or not.

Given the importance of these individual endpoint judgments in demonstrating safety and efficacy, both FDA and EMA have guidance strongly encouraging sponsors to have an independent group of experts separate from those sponsoring, organizing, or conducting the trial to conduct this important adjudication activity. By engaging an independent EAC, sponsors can eliminate the perception of bias and confidently reassure regulators regarding the medical evaluations and judgments incorporated into the research results.

Whether you are developing a digital therapeutic for ADHD, precision genomic assays, the next life-altering medical device, and any type of device in between, someone needs to provide an independent assessment if your investigational device is working as anticipated.

CECs and EACs provide device developers with an independent mechanism to both expand the therapeutic expertise of their own research team and eliminate the perception of bias when interpreting endpoints. With the help of a qualified EAC/CEC and access to a worldwide network of clinicians in all therapeutic areas, sponsors can move device research forward more quickly and with greater confidence.

The updated European Union (EU) pharmaceutical legislation for the Clinical Trials Regulation (CTR) entered into application on January 1, 2022. The CTR aligns processes for the assessment and supervision of clinical trials throughout the EU. These updated requirements were designed to ensure a standardized approach for conducting clinical research, while emphasizing clinical trial participant safety and heightened public transparency requirements. These new regulations have significant implications for sponsors submitting trials in the EU. This blog outlines these changes and their implications.

Transitioning to EU CTR

EU Clinical Trial Regulation 536/2014 (EU CTR) replaces the EU Clinical Trial Directive (Directive 2001/20/EC). There is a three-year transition period:

A chart showing the transition to EU CTR over time from Initial CTAs submitted in 2022 to trials conducted under EU CTR in 2025.

Previously, sponsors had to submit clinical trial applications separately to national authorities and ethics committees (ECs) in each country to gain regulatory approval to run a clinical trial. Over the next three years, the Clinical Trial Information System (CTIS) will become the single-entry point for researchers and companies conducting clinical trials in the EU. Sponsors can apply for authorizations in up to 30 EU and European Economic Area (EEA) countries through a single application. Effectively, the single application becomes a one-stop-shop.

Submitting New Trials

Within the first year of the implementation, sponsors will have the option of submitting new trials under the current directive (2001/20/EC) or to the EU CTR before submissions under the EU CTR becomes mandatory. The EU CTR will allow sponsors to submit one combined CTA to the competent authorities (CAs) and Ethics Committees (ECs) for all EU countries intending to participate in each trial, via the CTIS. The application will entail a two-part process:

  • Part I: A reporting member state (RMS) coordinates a scientific assessment
  • Part II: Member state specific assessment

A chart displaying a timeline of clinical trial approvals with steps between application submission and single decision notification for each MS

Understanding the Timelines of Clinical Trial Approvals

Parts I and II of the dossier can be reviewed in parallel or sequentially, depending on the sponsor’s preference. Clinical trial approvals will be released as a single member state opinion following both the CA and EC assessment per country, rather than the current process of separate CA and EC approvals, in accordance with individual country processes and timelines.

Transition of all ongoing clinical trials to the new EU CTR needs to be completed within three years of its implementation as part of a clinical trial development plan. Documents such as the protocol, investigators brochure, and investigational medicinal product dossier will need harmonization or consolidation across the EU prior to transition.

The EU CTR will have less flexibility in the way substantial modifications (SMs) are submitted. Under the new regulations, SMs will take about three months for approval. No additional SMs can be submitted during this time. This includes the addition of EU member states, making a country selection, and the associated submission strategy key factors for success.

In addition to significantly simplifying submission processes for trials taking place in multiple countries at the same time, it also facilitates participant recruitment through the easy expansion of a trial to additional member states. CTIS includes a public portal, showing which trials are open to recruiting participants, giving contact points for further information. This will make it easier for participants to find opportunities to take part in clinical research.

Additional Developments

Building on the CTR application, the launch of CTIS, and the Accelerating Clinical Trials (ACT) EU, these new requirements will strengthen the European environment for clinical trials, while maintaining high safety standards for trial participants and improved public transparency for EU citizens or diagnose diseases.

References:

At Advarra, we are passionate about enabling the industry to become more site-centric. To achieve this, it is especially important to equip sites with the proper technology to conduct studies. One way to do so is encouraging sites to seek buy-in from their sponsors as they advocate for using their preferred technology platforms on studies. Not only will this reduce the amount of technology platforms needed to conduct a study, it will also accelerate trial timelines, benefitting both sites and sponsors.

Benefits to Having Control Over Your eClinical Systems

Ultimately, since sites are the ones conducting research, they are responsible for the quality of items such as documents, consents, and data. With staff on the front line of clinical research, it’s only natural to want sites to have the best tools and technology available to enable them to produce their best work. Making it easiest for those on the front line will ultimately make any study more successful.

There are tangential benefits to making tasks such as collecting signatures, managing documents, or assisting in the startup process easiest for the staff conducting them. By letting staff use technology they are most familiar with, they can collect this information and complete tasks at a quicker rate. The trial will, in turn, cost less, have a shorter startup timeline, and give sponsors quality data and documents. Protocol deviations are expensive; empowering sites to do what they do best with fit-for-purpose technology will benefit all parties.

Common Challenges When Asking for Sponsor Buy-in

When trying to gain sponsor buy-in, there are several things a site can do before approaching their sponsor. It’s almost guaranteed their sponsor will ask if the system is compliant and validated. Outlining if the system is 21 CFR Part 11 compliant, where it will be hosted, and answering additional security questions before sites approach sponsors will save time on both ends.

Additionally, gathering basic materials beforehand and assembling them into a “frequently asked questions” package will benefit sites. This may include standard operating procedures (SOPs) or other material you think the sponsor may want to know. Just as they are doing their due diligence in asking these questions, you should be ready to answer their most common questions.

Advocating for Using Your Own Technology

Oftentimes, sponsors will come to sites with a specific technology platform for them to use, which typically does not align with the technology platform that site uses regularly. For example, a sponsor may mandate an eRegulatory (eReg) management system despite the fact that sites typically have their own already-implemented eReg system. Sites using a platform different from the one they regularly use or are familiar with may negatively impact the trial. Staff will first need to be trained on how to use the sponsor-mandated software, which can delay activation timelines. Additionally, staff will most likely need to input data into their site-preferred system as well. This duplicative data entry makes data errors more likely, and results in more time spent on a protocol than what is necessary.

Even if sponsors suggest specific technology, sites should feel comfortable pushing back if they have a different system they feel would be better suited for successfully conducting the trial. There are many reasons a site might want to consider advocating for using their own technology. Using their own technology allows a site to following already-documented workflows and SOPs, which in turn saves money for both the site and sponsor. The less time needed for training new systems in general will save time overall, resulting in an accelerated study activation and, ultimately, delivering life-changing treatments to market more efficiently.

While artificial intelligence and machine learning are not new concepts in science, in the last decade the clinical research community has seen tremendous growth in these areas. Researchers are developing new applications at a rapid pace, and while it is exciting, it is also maybe a bit scary at the same time.

But what do “artificial intelligence” and “machine learning” really mean?

  • Artificial intelligence (AI): A feature where machines learn to perform tasks, rather than simply carrying out computations that are input by human users. (NIH)
  • Machine learning: An approach to AI in which a computer algorithm is developed to analyze and make predictions from data that is fed into the system. (NIH)
  • Algorithm: An overarching term describing any processes or set of rules to be followed in calculations or other problem-solving operations. An algorithm takes some input and uses mathematics and logic to produce the output. Broadly, it refers to a step-by-step procedure for solving a problem. (Merriam-Webster)

Technically, “if/then” is an algorithm. Statistical tests are also algorithms, but they are different than AI algorithms, which are a continual process of providing new inputs.

AI algorithms take both inputs and outputs simultaneously in order to “learn” the data and produce appropriate outputs when given new/unfamiliar inputs. AI algorithms typically consist of a collection of algorithms. In machine learning, AI algorithms are “fed” data and are asked to process it. An AI system can make assumptions, test, and learn autonomously.

Those AI “assumptions” have to be managed or confined; in other words, there must be some human control over the assumptions. In 2017, Facebook Artificial Intelligence Research (FAIR) trained chatbots on a collection of text conversations in English between humans playing a simple trading game involving balls, hats, and books. When programmed to experiment with the English language and tasked with optimizing trades, the chatbots seemed to evolve a reworked version of English to better solve their task.

To quote recent thoughts on ethics and machine learning, “Academia and wider society have laid down ethical principles as a way to ward off a repeat of bitter historical events, but it certainly seems that these will be eroded by uncertainties about consent, harm, and even what constitutes a human subject.”  Such statements suggest a need for more specific guidelines in this space, which are currently scarce.

The Department of Defense (DoD) has developed guidance suggesting research involving AI should be designed to be:

  • Responsible
  • Equitable
  • Traceable
  • Reliable
  • Governable

With that guidance in mind, institutional review boards (IRBs) may want to include the following additional considerations when reviewing research involving AI and machine learning:

  • Remember the regulatory concepts of “identifiable” and “private” information. Navigating these provisions can be complex when you consider the large amounts of human data needed for AI development.
  • Preserve informed consent to use private, personal identifying data as much as possible.
    • Informed consent is important when using private or personal identifying information.
  • Review the potential for bias in the algorithms used for “learning” and the “assumptions” used to learn, such as:
    • Obtain scientific review to assess potential bias
    • Avoid algorithmic bias by documenting and defining how the data is selected
    • Show how bias is mitigated
  • Exempt research (such as use of data) must still comply with the Belmont Report.

Recently, the DoD changed the provision for scientific review of research to include minimal risk research. It could very well be because of the increasing volume of AI research, as more research into AI is developed. While this idea seems scary, IRBs are well equipped to handle ethical review and oversight of artificial intelligence research: after all, it starts with human data.

Learn more about IRB oversight of innovative research modalities in this podcast:

Clinical trials can be complex. Multiple treatments arms, various dosing schedules and regimens, placebo controls, multifaceted endpoints, blinded study staff, pragmatic design elements, and multinational sites all fuel the complexity. In its March 2006 guidance Establishment and Operations of Clinical Trial Data Monitoring Committees, the U.S. Food and Drug Administration (FDA) solidified the need for sponsors to consider establishing independent committees to oversee certain aspects of clinical trials.

Around the same time, the terminology of data monitoring committee (DMC) and endpoint adjudication committee (EAC) started to infiltrate the clinical trial world. These committees had been around prior to guidance, but the March 2006 FDA guidance and similar guidance in July 2005 from the European Medicines Agency (EMA) solidified the need for these two groups. Over fifteen years later, most involved in clinical research have at least heard of EACs and DMCs, also known as clinical event committees (CECs) and data safety monitoring boards (DSMBs), respectively.

So what’s the difference between an EAC and a DMC? This blog outlines the requirements for each committee, what they do, and the critical roles each plays in keeping research participants safe and in advancing clinical research.

DMCs: The Macro View

It’s important to look at the aggregate, big picture during a clinical trial to understand how things are going overall. As the study goes on, researchers may be wondering:

  • How do we know if the investigational product is working better than the placebo or comparator arm?
  • Is the investigational product not working well, and the trial should stop early?
  • Are more adverse events coming up than expected, causing us to change the protocol design or take a pause while we evaluate why this is occurring?

In many studies, researchers and sponsors do not have access to unmasked study information and so have no way to begin answering questions like these. As the trial continues, someone independent from those conducting the trial needs to monitor the unmasked data in a thoughtful, pre-planned, and unbiased way. This is usually the job of a DMC or DSMB.

The DMC is an independent group of experts conducting periodic review of the accumulated interim data during a clinical trial. Particularly in trials with a blind or placebo control, a DMC’s purpose is to review the unmasked, aggregate, worldwide trial data as it is collected. From there, members can detect and report safety concerns, early evidence of benefit or harm, and/or treatment futility using criteria outlined in the clinical trial protocol and DMC charter. Usually made up of five or six members, DMCs include biostatisticians and clinicians who all must be independent of those sponsoring, organizing, or conducting the trial.

In short, DMCs use statistical models to oversee research safety at a macro level. All the data is unmasked, aggregated, and analyzed per the protocol’s data safety monitoring plan and the DMC charter. If the DMC detects safety issues, futility, or other pre-defined criteria, they may recommend the sponsor halt the trial early or make safety changes in the protocol.

EAC: The Micro View

Converse to DMCs, EACs focus on the opposite end of the spectrum at the micro level. Today’s modern drug, biologic, and device treatments are highly complex with multiple and complicated modes of interaction within the body. The human body is also complex, each of us living with unique physical environments, various comorbidities, and different concomitant medications and medical histories.

Just as the practice of medicine is far from simple, in many clinical trials it can also be difficult and require a fair bit of medical judgment to determine if a certain medical event was related to the investigational drug or device – or some other confounding factor. Specific endpoints in the trial may also require expert medical judgment to determine if the participant’s event met the protocol’s pre-defined criteria.

The event evaluation and the subsequent determination of relatedness or endpoint completion can profoundly impact the statistical calculations regarding the investigational product’s safety and efficacy. Especially in rare disease or similar small population studies, a few adjudication decisions made one way or the other can mean the difference between potential product approval or denial.

Given the importance of these individual judgments, both FDA and EMA guidance on monitoring committees strongly encourage sponsors to have an independent group of experts conducting this important adjudication activity, to remove any perception of bias. This is where the independent EAC comes in.

EACs evaluate individual medical events to determine if the event characteristics meet the protocol’s defined endpoints or adverse event criteria. The committees are comprised of multiple medical experts who evaluate events occurring in the trial through a pre-defined adjudication process outlined in the protocol or EAC charter to render an option on the event. Depending on trial requirements, EACs may look at medical histories, various scans and images, and other participant information available from the sponsor or research site. Adjudication determinations about the individual events are then incorporated into the overall trial data, ultimately impacting the DMC’s analysis of aggregate trial-wide data.

A Note About the Regulatory Basis for DMC and EAC

U.S. FDA and the International Conference on Harmonisation Good Clinical Practice (ICH GCP) E6 (R2) require sponsors to monitor the safety of their trials. In the March 2006 guidance, FDA strongly suggests DMCs and DSMBs are an appropriate way for sponsors to fulfil this requirement. Additionally, EMA guidance from July 2005 has similar recommendations. Both regulatory agencies cover the importance of appropriate independent assessment and adjudication of certain outcome events in the trial and intimate independent endpoint adjudication committees as an appropriate framework.

Both FDA and EMA guidance do not prescribe operational specifics for the committees other than to strongly suggest the DMC and EAC oversight committees must be independent from those who sponsoring, organizing, or conducting the trial. In other words, the sponsor or contract research organization (CRO) is not in the best position to administer and control the DMC or EAC. As such, Advarra’s independent DMCs and EACs play an important role in providing independent oversight and both operate in accordance with both U.S. FDA and EU EMA guidance.

Completing the Research Oversight Environment

Both DMCs and EACs play an integral role in clinical research oversight and evaluation. DMCs take the worldwide, high-level perspective using advanced analytical methods to evaluate aggregate data. EACs dive deep into the micro level evaluation of specific events to make critical assessments, contributing to the broader trial data and ultimately determinations on safety and efficacy used by the regulatory agencies to determine approval.

Ensuring proper billing compliance within clinical trials is often a confusing, but a very consequential task for research teams. Knowing applicable regulations and policies (e.g. national coverage determinations [NCDs]) and how certain items or services fall under these policies can greatly impact an organization, as well as their trial participants. This blog provides a beginner’s overview of clinical trial billing compliance and best practices to ensure charges and claims are properly routed to the correct billing entity.

What is Clinical Trial Billing Compliance?

Clinical trial billing compliance is the act of ensuring charges – such as therapies or treatments – in a clinical trial are routed to the responsible party. This may be a third party or a research account in accordance with applicable federal rules and state laws. Essentially, clinical trial billing compliance ensures you are charging the right party when someone is enrolled in a trial.

Why we Need Clinical Trial Billing Compliance

If clinical trial billing compliance is conducted improperly, sites may face financial penalties as a result. Furthermore, incorrect billing may trigger the False Claims Act at the federal level, as well as other fraud type occurrences at the state and local levels. It’s important to get billing compliance right to put participants who are volunteering for a trial at ease. They should not be burdened with an additional item that they don’t have much control over. While many are giving their time and effort to be part of a trial, if they get an unforeseen bill, that’s another hurdle or burden that’s put on them, and it shouldn’t have to be that way.

What are the “Rules” to Clinical Trial Billing Compliance?

In 2000, the Centers for Medicare and Medicaid Services (promulgated a rule stating Medicare will cover some charges for those beneficiaries enrolled in clinical research. While this rule was updated in 2007, prior to 2000, this wasn’t allowed, but Medicare now ensures costs are covered if someone were to enroll in a clinical trial. This new rule uncovered an entirely new allowance on coverage and reimbursement, as well as opened up new demographics for sites seeking new trial participants.

Medicare and Medicaid have provided the most specific rules to date, and as a result, most insurers comply with these rules. Generally speaking, if you are billing in compliance with Medicare rules, you are compliant everywhere.

In addition, in 2010, the Affordable Care Act provided provisions to allow third-party payors to cover some items and services in the context of a clinical trial. This allowed for further clarification from both Medicare and commercial payers to outline what exactly they will or will not pay for.

Best Practices to Following These Rules

Becoming aware of these rules can save your institution and your participants money and time in the long run. The best thing you can do is educate yourself on the rules surrounding research billing compliance. In addition to Medicare, there are state-level and Medicaid rules to understand, although for the most part, they mirror Medicare rules. However, there may be nuances between the different levels, and it’s important to understand where those nuances may apply.

It’s also helpful to identify when your participants are being treated. There’s no way to bill properly if you don’t know if a patient is coming in for research purposes or a normal healthcare visit. Once you have identified each visit, make sure the charges flow in accordance with the established Medicare and Affordable Care Act rules.

Lastly, release the charge in a manner the payor accepts. Medicare has specific rules on what types of codes and modifiers need to be added to a charge when it’s submitted for reimbursement. Knowing these ahead of time will save you time, as well as advance timely payments for submitted charges.

For the most reliable information on clinical trial billing compliance, it’s helpful to check first with the organization’s billing entity. If they aren’t able to provide clarity, the next step is to seek guidance from a compliance official or a general counsel.

What does Regulatory Enforcement Look Like?

There haven’t been a lot of for-cause audits specifically due to research billing from the government. Since 2000, the government put other checks in place, such as coding and modifiers to append. Through these mechanisms, they can monitor compliance at institutions.

Instead of anticipating a for-cause audit specifically for research billing fines, there’s a more pragmatic approach to take. Putting your participants first will change the focus on how to conduct proper billing compliance.

One way to develop an effective regulatory compliance framework is having an easy-to-use set of tools ready for your team. Developing coverage analysis to identify responsible payers for treatment in a clinical trial is a good start. In addition, healthcare providers can use their electronic medical record (EMR) and billing system as well as leverage their clinical trial management system (CTMS) patient tracking functionality. Through a CTMS, staff can identify the patient and their research items or services before they walk through the door. A good CTMS tool can enable staff to identify what can be billed through the coverage analysis process.

While billing compliance may seem like a complicated task, research operations teams taking the time to stay educated on local regulations as well as Medicare rules will equip their organization for billing compliance success. Keeping the participant’s safety at the forefront of a regulatory compliance framework ensures accurate and timely billing is always conducted.

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