For research sites whose communities include large populations of non-English speakers, it may be standard operating procedure (SOP) to obtain a translated version(s) of the study’s informed consent document at the beginning of each study. That way, when a non-English speaking potential study participant shows interest in the trial, researchers can help the potential participant learn more about the research without missing a beat.

But what about situations where a non-English speaking potential participant shows up unexpectedly, and there isn’t enough time to obtain a translated study consent?

Enter the short form consent.

Regulatory Perspective on Short Form Consents

The regulations require presenting study information in a language understandable to research participants—this includes, of course, the informed consent document and process.

45 CFR 46.117(b)(2) and 21 CFR 50.27 allow researchers to provide non-English speaking potential participants with an oral presentation of the informed consent information in conjunction with a written short form consent document and a written summary of the oral presentation.

A witness must be at hand for the oral presentation, and the participant must receive copies of the short form and summary documents. The long form English consent may serve as the written summary.

FDA and Office of Human Research Protections (OHRP) guidance documents suggest the agencies clearly prefer a non-English speaking participant review a translated version of the complete study consent. But we know this may not always be possible.

How do You Use a Short Form Consent?

For those unexpected situations, some institutions and institutional review boards (IRBs) maintain an approved short form consent translated into multiple languages. This way, researchers don’t have to turn away a potential study participant just because the study consent is not available in the non-English speaker’s language.

Keep in mind: The short form consent isn’t the perfect solution—an interpreter must also be present to assist with the oral consent presentation. Documentation requirements still must be followed as well. This includes:

  • The short form consent should be signed by the study participant or the participant’s (LAR)
  • The written summary should be signed by the person obtaining consent
  • The witness (who may also be the interpreter) should sign both the short form and the summary
    • While not required, OHRP guidance and best practice suggest the witness should be fluent in English as well as the participant’s language

The short form consent can be a useful tool for unexpected situations, but it should not be used when investigators already anticipate non-English speakers will enroll in the research. If you expect non-English speaking participants, be proactive and have the study consent translated into the language(s) commonly used in your community.

Remember, informed consent is an ongoing process. While the short form consent can help during the initial consent discussion, researchers still need to assemble the proper communication tools to ensure the non-English speaking participant understands matters things throughout the study.

Non-English speaking study participants require additional support throughout the course of a study, but with the right tools and a little regulatory know-how, researchers can help ensure these participants are able to provide meaningful research contributions and reap potential benefits.

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

To protect human subjects in clinical research, the Food and Drug Administration (FDA) maintains and enforces specific regulations. Research stakeholders must track, document, and store the required information for trial oversight and monitoring to comply with regulations. This blog identifies applicable regulations and outlines regulated documents and data in clinical research and the systems used by sponsors, contract research organizations (CROs), monitors, and research sites to collect, exchange, and store them.

Introduction to Required Research Documents and Regulatory Compliance

There are three primary regulations impacting trial documentation:

  • ICH Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording, and reporting for trials involving the participation of human subjects. In short, GCP dictates what data and documents need to be collected, stored, and audit-ready.
  • FDA 21 CFR Part 312 describes specific roles, responsibilities, and documentation requirements for investigational new drugs (INDs).
  • FDA 21 CFR Part 11 (commonly known as Part 11) “applies to records in electronic form that are created, modified, maintained, archived, retrieved, or transmitted.” Since many clinical research teams leverage electronic systems to manage clinical trials, ensuring compliance with 21 CFR Part 11 is essential.

Additional Resource: Regulatory Fine Points: What Sites Need to Do for Part 11 Compliance

What is an Electronic Master File (eTMF)? 

An electronic trial master file (eTMF) is a technology solution designed to organize, collect, store, track, and archive required and essential study documents. The eTMF is an electronic version of the trial master file (TMF) that is now industry standard. Historically, the TMF was organized in paper form.

The TMF is the collection of required documents associated with a single clinical trial that demonstrate the trial’s compliant conduct and all associated activities for evaluation by regulators. If you think of the clinical trial process as a journey, with a start and a finish, each step along the way must be captured and updated in a central location: the TMF.

According to FDA and international GCP guidelines, TMFs are required for every study but are not required to be electronic. By regulation, sponsors are responsible for the maintenance, accessibility, and accuracy of the TMF. If a sponsor chooses to utilize an eTMF, they are responsible for ensuring the system is secure and 21 CFR Part 11 validated.

What Documents are Collected and Stored in an eTMF?

GCP guidelines dictate which documents need to be included and categorized in the eTMF. For example:

  • Essential study documents:
    • Protocol, protocol amendments, investigator’s brochure, procedures and manuals, visit guidance, etc.
  • Training documentation and materials:
    • Certificates, videos, supporting content, etc.
  • Funding documentation:
    • Contracts, budgets, negotiations, etc.
  • Safety documentation:
    • Safety letters, serious adverse event (SAE) reports, etc.
  • Ethics committee’s documents:
    • Protocol amendments, approvals, communication, etc.
  • Audit or monitoring documents:
    • Onsite visit records, audit findings, etc.
  • Participant information:
    • Informed consent forms, visit guidance, brochures, recruitment materials, patient diaries, etc.
  • Site-specific documents:
    • Site CVs, training documentation, site standard operating procedures (SOPs), etc.

What Systems Integrate with an eTMF?

Most of the documents required for collection and storage within an eTMF originate outside of sponsor systems. If a research site stores study documents in an electronic investigator site file (eISF), those documents would need to be routed to the corresponding eTMF.

Software and platforms such as an electronic IRB (eIRB) system, eRegulatory (eReg) management system, email programs, and clinical trial management systems (CTMS) can integrate with an eTMF. Integrating systems reduces the amount of work needed to manually move documents from one system to another, and it also reduces the risk of mistakes.

What is an Electronic Investigator Site File (eISF)?

An electronic investigator site file (eISF) is a technology solution designed to organize, collect, store, track, and archive required and essential study documents for an individual site involved in a particular research study.  The eISF is an electronic version of the ISF, which was historically organized in paper form. The eISF at an individual research site works together with the sponsor’s eTMF, which collects and stores data associated with each research site involved in the clinical trial. A research site is also responsible for storing and archiving their ISF.

Additional Resource: 12 Items Auditors Look for When Reviewing an Investigator Site File

What Documents are in an eISF?

Like an eTMF, an eISF collects and stores clinical research regulatory documents, but only related to a particular research site. For example:

  • Essential study documents:
    • protocol, protocol amendments, investigator’s brochure, procedures and manuals, visit guidance, etc.
  • Site-specific documents:
    • site CVs, training documentation, site [SOPs], etc.
  • Site-specific participant recruitment and engagement information:
    • informed consent forms, visit guidance, brochures, recruitment materials, patient diaries, etc.
  • Site-specific monitoring or audit records

What is the Difference Between an eTMF and eISF?

An eISF is a subset of documents required to be collected and stored in an eTMF. An eISF is compiled by an individual research site, while all eISF documents within the eTMF are collected and compiled by the research sponsor.

How Long Must Essential Clinical Research Documents be Archived for?

The records in both an eISF and eTMF for each clinical trial must be stored and accessible for 25 years after a study closes. Regulators, monitors, and other auditors may access the documents over time to review trial conduct and data.

What is Secure Document Exchange?

Secure document exchange describes the workflow for exchanging regulated research documents between research stakeholders. Secure document exchange can help reduce administrative burden, improve data accuracy and security, and automate document collection and updating.

Most document exchange activities happen during the study startup process of a clinical trial. To start a clinical trial, sponsors, CROs, and research sites need to work together to make sure everyone is ready to do the research and meets all the regulatory requirements. Historically, these processes have been burdensome to both sites and sponsors due to lack of communication between technology systems.

Advarra enables efficient and compliant document management for both sites and sponsors. Secure document exchange between Advarra’s eReg and Study Collaboration Platform provides end-to-end integration for automated, seamless exchange of research documents between sites, sponsors, and CROs. Longboat also allows sponsors to manage documents and provide a site eISF to global research sites without their own regulatory management system.

As a drug successfully makes it through the development process, sponsors will inevitably need to submit a new drug application (NDA) to the Food and Drug Administration (FDA). While it may seem like a straightforward process to some, there’s room for many elements to be missed as sponsors prepare for the application submission.

Failure to Have a Pre-Investigational New Drug (IND) Meeting

There are a myriad of regulations coming into play during the drug development process. Because of this, the FDA understands sponsors may need help making sense of regulations. The FDA issued guidance on when formal interactions should occur between them and a sponsor. One such meeting is the pre-IND meeting.

The pre-IND meeting is a sponsor’s opportunity to interact with the agency before initiating the clinical study. In this meeting, they’re able to receive insight and feedback regarding critical issues. There are benefits to holding a pre-IND meeting, such as:

  • Verifying the appropriate animal model is used to determine product safety
  • Determining if the toxicology data is sufficient to justify a first-in-man study
  • Discussing data concerns or potential roadblocks
  • Developing a relationship with the agency team reviewing the submission

Even though it’s only recommended for an organization to take a pre-IND meeting with the FDA, there could be consequences if sponsors fail to take the meeting. If a sponsor chooses not to take advantage of the FDA’s pre-IND meeting, it can potentially lead to FDA rejection of the IND or result in a clinical hold.

Too Much Data or Unnecessary Information

Including unnecessary information, disorganized data, or dense text are common missteps when sponsors submit IND applications. Committing these errors increases the amount of time it will take the FDA to review your IND. Additionally, it makes it easier for errors to slip through the cracks, risking outright application rejection.

Providing too much information in your application may reveal a lack of cohesive strategy within your company, and including large amounts of data without explaining it will slow down the review process. Conversely, failing to present the information concisely is a major flaw. Providing brief points to serve as a guiding point throughout the documents helps reviewers know what is relevant in the application.

Poorly Written or Unorganized IND Application

Oftentimes, IND writers will make the mistake of focusing solely on the science and will disregard everything else. If a submission is difficult to read, reviewers are more likely to place it on hold or reject it outright. As you write your application, think of the FDA reviewers evaluating the document. Not only should you include the appropriate amount of data, but what does your grammar and formatting look like? Having a poorly written IND application will frustrate and confuse the reviewers.

In order to avoid a study placed on hold or rejected, there are best practices to abide by:

  • Operate under the guise of your reviewers may know the basics of your therapeutic area but may not be as familiar with specific details.
  • Similar to adding the right amount of data to your application, don’t overload the IND with unnecessary information. As you write your IND, stay focused.
  • Use common words whenever possible, and if you need to use abbreviations or technical terms, accurately define them.
  • Break up large paragraphs of text with figures and tables to make it more visually appealing.

Before submitting the IND, have one person review the full document to ensure consistencies. This is especially important if there are multiple writers contributing to the IND; one reviewer helps ensure consistency among writing styles.

Leaving Out Pertinent Chemistry, Manufacturing, and Controls (CMC) Details

Using nonclinical data or manufacturing information that doesn’t adequately support the clinical protocol hurts the IND application. It’s critical to ensure all nonclinical data supports the clinical design and provides adequate justification of the desired labeling claims – including basic exposure data. In order to achieve this, teams must undergo detailed planning and have a strong knowledge base of IND regulations.

In your IND application, you must specify how your organization will assure patient safety. Including information such as a drug or biologic’s quality, purity, and strength will help with specification, as well as help reviewers assess production’s adequacy and consistency.

Leaving out data pertinent for evaluating testing procedures will make it difficult for reviewers to determine the proposed study’s quality. Ensure your study has evidence to support the robustness of the assay used in evaluating the clinical trial. Include representative output data such as chromatograms and procedural details in the form of standard operating procedures (SOPs).

Inadequate Support

One of the biggest reasons sponsors receive a clinical hold is the IND lacks organization and clarity. An IND application should provide reviewers with clear data and explanation for results. Make sure these results match your protocol and avoid irrelevant information, because that can reduce your impact.

Additionally, not clearly stating the drug’s or biologic’s potential risk in the submission may raise a red flag. Potential issues of concern need to be presented in a forthcoming and transparent manner during and following the regulatory review. Failure to do so will impact the sponsor’s credibility. It’s the sponsor’s responsibility to provide the FDA with the information in a manner to help them understand the safety issues raised, as well as how they will be mitigated.

The sponsor must also provide all the information related to the application. Common errors in IND preparation include:

  • Forgetting to provide relevant explanations or supporting data for the results
  • Failing to properly match results to the protocol

Sponsors must note: study data standards are required for commercial INDs as of December 17, 2017, for both nonclinical and clinical studies. This is a specific requirement to comply with the Clinical Data Interchange Standards Consortium (CDISC).

Lack of Experience

Many organizations lack experience in compiling an IND submission. It takes a highly skilled team and resource sharing to produce high-quality work, as well as hands-on experience successfully submitting IND applications. With experience comes a deep understanding of the IND submission process and up to date FDA guidance to the table. Previous experience meeting with FDA personnel can help with every step of the IND process.

It’s also important to pay attention to the details. Making inadvertent mistakes in the IND submission is the most common reason for technical rejection of the electronic common technical document (eCTD) filing. Double-check the application to make sure the correct eCTD format is followed, and all pre-clinical data and documents are included. It’s also worth it to look over the submission twice to ensure it is sent to the correct center.

It’s easy for someone to underestimate the time required to develop an IND application and complete the submission – especially if they don’t have much experience preparing an application. It may take 12-14 months to complete the IND package, not including the time commitment for the pre-IND. Keeping this in mind, it’s in your best interest not to wait until the last minute to begin preparations.

Study startup is a complicated, multi-faceted, and time-consuming component of the clinical research lifecycle, one notoriously prone to delays. The key challenge of successful, timely study startup requires careful coordination across multiple constituencies within and external to a research organization. As a result, it is easy to lose track of all the various steps necessary to activate a study efficiently and compliantly.  

With this in mind, we have outlined a checklist for researchers who are looking for guidance on study startup activities. We’ve included suggestions for optimizing each step to minimize delays and set your study on a clear path for success.   

About This List 

Careful planning from day one is essential for study success. The primary goal is to reduce the amount of time and resources required to activate a study.  Lists of various study startup activities vary widely depending on the level of detail provided. These elements are most critical and demand the most attention from sponsors, contract research organizations (CROs), monitors, and sites. 

Key Stakeholders 

Sponsors: The trial sponsor is primarily responsible for many study startup activities including but not limited to:  

  • Writing the protocol  
  • Funding and managing the budget for the study  
  • Engaging a CRO to assist in the execution of the trial 
  • Overseeing startup activities 
  • Collecting, storing, and submitting the data and documents associated with the trial  

CROs: Some sponsors may involve a CRO to manage components of the study. Typically, CROs are responsible for:  

  • Budget negotiation 
  • Engaging and selecting sites 
  • Identifying patient populations and supporting recruitment 
  • Overseeing training, conduct, and other processes across the study 

Monitors: Typically affiliated with the sponsor, monitors ensure appropriate and safe study conduct, as well as overseeing the progress of activating a study. Whether they monitor remotely or in person, they require detailed access to key study documents, standard operating procedures (SOPs), and more at each research site involved in the study.  

Research sites: Staff and investigators at the research site play a critical role in planning and conducting a clinical trial. They are responsible for but not limited to:  

  • Conducting clinical trial visits and procedures 
  • Collecting data during the visit 
  • Connecting with patients to recruit and retain participants 
  • Securing oversight committee approvals (IRB, IBC, SRC, RSC, COI, feasibility) 
  • Executing billing and financial workflows to maintain operations and compliance 
  • Communicating information to study stakeholders include status updates, essential protocol documents, and more  

1. Sponsors: Design and Optimize Your Protocol 

The clinical trial protocol organizes and dictates every component of study conduct. While each detail of the protocol is essential to study success, it also must holistically and realistically support study outcome goals. While many believe study startup is entirely reactive to the protocol, optimizing the protocol before it is ever in motion can greatly impact trial success. This may include reevaluating inclusion and exclusion criteria, enrollment goals, complicated or costly procedures, or other components. 

Early conversations with sites and patient groups will help ensure the visits and procedures are reasonable and achievable as study theory moves to the real-life setting. 

2. Sponsors: Build Your Budget 

Regardless of the type of study you are planning, building the budget is step one. You must get a handle on all the costs for activities happening throughout the life of the trial. Now is the time to thoroughly consider all the potential tasks and associated fees required. Consider the following: 

  • Do you need help writing the protocol?  
  • Do you need a data monitoring committee?  
  • Do you need endpoint adjudication?  
  • Do you need assistance or consulting help on any other matter?  
  • Do you need specific technology to collect or exchange data across stakeholders?  

All of these, and many others, will impact your study’s budget and should be accounted for at the outset. 

Let data inform your budget building process. Explore our resource: Study Activation Survey Results: Budget Negotiation 

3. Sponsors and Sites: Submit Materials to Your IRB for Approval 

Partnering with an experienced IRB increases opportunities to streamline the activation process. As you’re beginning your partnership with your IRB, setting clear expectations for each organization is beneficial during study startup and will also help maintain the relationship for future studies. 

Setting up a study kickoff call can ensure any key milestones or special requirements are understood. Scheduling this conversation upfront with an IRB will save both the sponsor and IRB time during review time. 

Need additional guidance on review requirements?  

4. Sponsors and CROs: Identify the Right Sites for Your Study 

To streamline startup activities, it is important to identify the most efficient and appropriate sites to conduct your study while your team might have a great relationship with a physician at a particular institution, it does not mean they have the appropriate patient population to achieve enrollment goals for the trial, or their institution has the resources to efficiently launch and run a study.  

Unfortunately, finding sites is a perennial problem—mostly because it is difficult to identify and connect with sites with the appropriate patient population for a study. Or once found, the sites are shown to lack sufficient staffing or resources to take on additional trials.  

5. Sponsors, CROs, and Sites: Conduct Feasibility Evaluation 

Protocol feasibility is the process of reviewing clinical trial logistics to determine if the site’s available resources are sufficient for trial conduct.

Site selection is informed early and most significantly by the feasibility questionnaire, a survey sent to all prospective sites. But if those questionnaires are deployed blindly to sites before diligent site planning occurs, it can result in responses failing to tell sponsors enough about the site’s feasibility for that specific protocol. 

A feasibility evaluation should include: 

  • Financial viability 
  • Available resources 
  • Past performance and ability to accrue 
  • Alignment with the study timeline 
  • Current staffing and turnover 
  • Competing trials and populations 

Sites are also responsible for completing and returning site feasibility questionnaires to inform selection and identify opportunities to take part in new studies. However, many questionnaires are redundant, or may not accurately capture a site’s ability to successfully conduct a study.  

6. Sponsors and Monitors: Conduct Pre-study Site Visits/Screening Visits 

Pre-study visits are the final and most crucial step in selecting appropriate sites. These visits are especially vital in cases where the research team has had no prior experience with the site. 

7. Sponsors and Sites: Initiate and Negotiate the Clinical Trial Agreement (CTA) 

The CTA is a legally binding agreement executed between sponsors and sites; one meant to protect both parties’ rights and interests. It covers delegation of responsibilities, obligations, allocation of risk, and financial commitments. Expect negotiations around this critical document and allocate time for them. 

8. Sponsors and Sites: Collect and Exchange Regulatory Documents and Critical Submissions 

Collecting and exchanging what are sometimes called the “essential” documents of the study startup process, is another place where teams will typically encounter issues slowing their progress, especially as these documents are numerous and complex. They fall into three general categories:  

  1. Federal/National Regulatory (i.e. FDA-USA, BfArM-Germany) 
  2. Institutional review board (IRB)/ethics committee (EC) submissions 
  3. SOP requirements 

Optimizing this process centers on removing redundancies and centralizing communication and exchange. For sponsors, leverage a centralized location – like in Advarra’s Study Startup Platform – to distribute, monitor, and retrieve documents across your sites globally. Centralization also minimizes requests for redundant information, or for documents you’ve already received like CV’s, training certificates, and more.  

For sites, it is important to leverage site-centric technology connected with the sponsor to ensure you’re receiving essential study communications like protocol amendments or updated informed consent forms (ICFs). By bringing your own technology to this critical step in study startup, you can maximize internal workflows when deploying documents to internal teams like quickly routing for investigator signatures and sign off, as well as returning documents quickly back to the sponsor

Learn more about how Advarra is streamlining document exchange across sites, CROs, and sponsors.  

9. Sponsors and Sites: Deploy and Complete Training 

Before a study begins enrollment, all relevant site staff must receive training and completely understand their roles. Any misunderstanding—or a lack of understanding—among site staff is a main contributor to delaying study startup progress or increasing timelines due to protocol deviations. Make sure your clinical team members thoroughly understand all the procedures, clinical and administrative, required of them by providing engaging and efficient training for each study.  

Pre-screening potential participants for a clinical study is common practice at most research sites. It can save time by quickly identifying those who may qualify for a study prior to having them move on to the informed consent process. Pre-screens can be done in person, over the phone, or in some cases, even online. The role technology can play in this process is important not to overlook. Regardless of the collection method, the questions and any accompanying script must first be reviewed by the IRB to ensure the materials presented are not beyond the scope of the inclusion/exclusion criteria.

Often, low accrual or delays in clinical trials stem from an undersized pipeline of potential participants. When site staff must manually find participants for trials, or even when automated recruitment solutions don’t deliver as promised, it puts the trial’s viability at stake, with sites and sponsors in the hot seat.

If more trials made pre-screening a fixed part of the study lifecycle in a way that optimized both personnel and technology, many of these problems might be avoided. But too often, comprehensive pre-screening is overlooked in favor of more familiar, but also more outdated, manual tactics. Here’s why that’s a mistake — and why pre-screening is the great missed opportunity for modern day trial enrollment.

What is Pre-Screening in Clinical Research?

Pre-screening activities take place at the outset of a trial, before informed consent. In this critical time, sites review the inclusion and exclusion criteria to determine a potential patient pool for the study. This information then gets reported to the sponsor so they can assess enrollment feasibility.

Ultimately, sponsors and sites aim to start with as many pre-screened patients as possible to maximize the participant pipeline. However, there are several different approaches to pre-screening and no true standard.

“Typically, sites conduct pre-screening manually through paper-based logs or printed spreadsheets that get emailed to sponsors,” said Gillian Barron, Senior Project Manager at Advarra. “This outdated method leaves ample room for incomplete information, typos and other human errors that delay reporting and inevitably, delay enrollment.”

As Barron adds, such manual workflows place too much expectation on overworked site staff with minimal optics for sponsors. But on the other hand, automated solutions place too much expectation on technology — without considering human capacity and strengths.

Who is Responsible for Pre-Screening?

When time is a precious commodity at a research site, it can be advantageous to delegate the pre-screening process to a non-clinical team member. Since the pre-screen itself cannot include any research procedures, it’s quite practical for anyone at the research site to conduct the pre-screen. It is important, however, to ensure the script used is well written and followed as closely as possible. A good script should:

  • Identify the staff member conducting the research and inform the subject of the type of the questions asked – that they are to determine eligibility only, and some may be sensitive in nature. If the staff member is not on the clinical team, it is best to disclose this so as not to give the subject the false impression they are speaking with a medical professional directly related to the study.
  • Tell the patient how long the call is expected to take, and offer the option of completing the pre-screen in person or at another time that might be more convenient.
  • Let the subject know they can stop the interview at any time if they don’t feel comfortable continuing.
  • When possible, a closing statement should inform the subject of what the next steps will include with a timeline. It should also indicate what will be done with the information collected (destroyed or stored, and for how long and where).
  • Concisely disclose applicable information to minimize future dropout rates.

As pre-screen questionnaires are completed, either manually or electronically, it is equally important to have an action plan to ensure eligible subjects don’t slip through the cracks and the information from those who didn’t meet the criteria are handled appropriately. Who will follow up with those who are eligible and when? Who will be responsible for managing the information collected? If the initial collection was done on paper, consider the advantages of maintaining this information electronically:

  • Easy information retrieval
  • Quick updates to answers or ability to complete unanswered questions at a later time
  • Analyze ineligible forms to modify questions if enrollment has slowed to a stop
  • If storing for a period of time, eliminate excess paper around the clinic
  • If using a clinical trial management system (CTMS), easily transition the subject from pre-screen to enrolled

The Role of Staff and Technology in Pre-screening

Given the coexisting barriers and opportunities of pre-screening, the optimal approach is to engage a platform designed to gives sites the tools they need for a more efficient process while also providing more transparency to sponsors.

Solutions like the pre-screen navigator within Advarra’s Study Collaboration platform is one example of a solution doing so with a cloud-based, multi-device platform. Built to standardize the complexities of pre-screening questionnaires, the Study Collaboration platform provides easy yes/no toggles for the most important eligibility criteria.

The completed form then gets presented in real-time to sponsors, who can see pre-screening activity on a global, regional, and site basis. Study teams can see where the patients are located across each country and gain early insights into which of the inclusion or exclusion criteria are causing most prospective patients to fall out of the funnel. This removes the delays inherent in paper-based logs.

“It’s so important for sponsors and study teams to have this information available to them in real time,” Barron said. “With that insight, they can more quickly identify trends, discover pre-screening failures, monitor site performance and consider amendments to expand the participant pipeline — all at the very beginning of a study.”

Case Study: Increased trial enrollment via Pre-screen Navigator

Boosting Trial Success with Pre-screening

As sponsors look to expand their participant pipeline, pre-screening is an essential part of the clinical trial ecosystem. However, not all pre-screening methods are effective. Failure to optimize this critical process can impact study timelines and ultimately, delay commercialization plans and treatment to patients.

Pre-screening is a common strategy to add to any patient recruitment campaign. Fortunately, there’s a better way to do pre-screening. To maximize your pre-screen activities, make sure you have a well-written script, ask the right questions, and have a follow up plan in place.

Additionally, using technology to help manage your pre-screen paperwork and records can serve many purposes. With streamlined technology like the Study Collaboration platform’s pre-screen navigator, site staff can more easily do their jobs while getting back to what matters: their patients. In turn, sponsors can have the real-time insights they need to make decisions that affect the success of current and future research.

This blog was originally published Jun 21, 2013 and has been updated.

Optimizing clinical trial access for potential patients is a critical goal for researchers and sponsors. How can we make clinical research more accessible to anyone who wishes to participate? Decentralized clinical trials (DCTs) can meet that need, but they come with some challenges.

The concept of DCTs brings the trial activities to non-centralized places, closer to participants, so they have better access to the interventions and measures involved in conducting a trial. Ways to accomplish this include engaging home health groups to come to the participant’s home to collect or administer study tasks, or bringing interventions into the community by setting up a common place for interventions (e.g., collecting blood pressure at a barbershop). Utilizing remote technology is another way to aid in convenience and accessibility.

These activities provide more flexibility for participants. Designing a DCT comes with certain challenges of course, particularly when proposing to utilize outside groups or locations for the trial. Funding, sponsorship, tasks to be conducted, and the legal structures of entities may impact sites and the study overall.

Why do Funding and Sponsorship Matter?

Who sponsors a study and how the study is funded are key drivers for determining the trial’s regulatory oversight framework, as well as the framework used by the IRB to review it. This means the requirements will vary slightly depending on which entities fund the trial.

For example, consider a trial funded by a Department of Health and Human Services (DHHS) agency such as the National Institutes of Health (NIH). Trial activities and places where the trial is conducted must also have IRB review if they meet the definition of “engaged” in research under the DHHS/Office of Human Research Protections (OHRP) framework.

In contrast, if a study is sponsored by industry (e.g., a pharmaceutical company) and involves no federal funding or support, it would fall under the Food and Drug Administration’s (FDA’s) oversight—and the concept of “engaged” is not included the FDA framework. However, sites and individuals conducting the industry-sponsored trial could be required to be listed on the Form FDA 1572—if this is the case, those sites and individuals would be subject to the FDA regulatory framework which require IRB review of the activities.

The concept of “engaged” in research is not easy to decipher. It can be further complicated by the types of activities and determining if they “engage” a site in the research, or if the site or individual conducting the activity should be listed on the 1572.

How Does Legal Structure Impact the Decentralized Clinical Trial?

Another consideration to explore is the legal structure of the site, sponsoring site, or entity where the research occurs and who can provide oversight. This concept is a bit more nuanced, but it could make a difference in how trials are set up and conducted with respect to IRB oversight.

For example, an academic medical center (AMC) may employ its investigators as staff. Since investigators are employees of a larger entity, they may not have the authority to delegate trial oversight to another entity, such as a home health group. If the home health group is conducting research activities, they would need some authority or oversight to be able to conduct their activities, such as a separate IRB review, either by the AMC’s local IRB or by a separate independent IRB.

There would have to be an agreement between the home health group and the hospital on which IRB (the AMC’s IRB or the home health group’s IRB) would review on behalf of and provide oversight for the home health group and their activities. It is important to know how your site is structured to be sure everyone can be covered in the most effective way in DCTs.

Compliant, efficient document management during the various phases of a clinical trial is essential. Yet, throughout a trial, as documents are added to different systems for the investigator/institution and the sponsor, a great deal of time is spent managing those documents; and, of course, as with any manual process, there’s risk of error.

That’s why direct communication and integration between key technology systems like email, electronic institutional review board (eIRB) systems, clinical trial management systems (CTMS), and other eRegulatory (eReg) platforms all contribute to a more efficient and compliant trial. With hundreds or even thousands of files part of a trial’s documentation, an integrated eReg solution can facilitate vital time savings per document and ensure improved data quality – yielding a valuable return on the investment in the integration.

This article outlines common eReg management system integrations, and highlights a new integration already allowing sites to save hundreds or thousands of dollars per protocol.

Current eReg Integrations

As clinical research continues to move towards a remote environment, centralizing and integrating your regulatory management process and technology is vital to your institution’s success. There are common eReg integrations clinical trial sites are currently implementing.

CTMS Integration

An organization’s CTMS is commonly the source of truth for all protocol and participant information. CTMS data includes information related to protocols, staff, and your organization as a whole. This integration allows for organizations to level up their technological workflows, such as streamlining protocol creation within the system, associating staff with those protocols, and facilitating delegation of authority.

Email Integration

Correspondence and supporting documents between sites, sponsors, IRBs, and other stakeholders are essential to house in a protocol binder. However, manual workflows associated with downloading and uploading email messages and attached documents hinders efficiency, especially during study startup. By leveraging an email integration within eReg, you can easily send emails, as well as any attached documents to quickly review, and associate them with the appropriate protocols in the system.

eReg-to-eReg Integration

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

Sponsor/ Contract Research Organization (CRO) Systems Integration

These integrations ensure sites to compliantly and confidently execute the protocol, empower and inform study participants, and efficiently manage and monitor studies within one intuitive platform.

The challenge for sites and sponsors is ensuring these interfaces connect with one another and with technology across the enterprise. If they do not, they may encounter duplicate or disconnected data, affecting outcomes and efficiency.

Advarra eReg-eIRB Integrations

To achieve connectivity and support clean data, optimized workflows, and compliance, a unified eReg integration is essential. Advarra eReg provides integrated protocol, staff, and institution documentation to streamline regulatory process and enhance compliance. Advarra offers two system options:

  • eIRB integration: Documents shared between your IRB and organization are an essential component of your long-term binder storage and are often updated and routed throughout the study’s life cycle. By utilizing integrations from both central and local eIRB systems to your eReg system, you can reduce manual effort and increase compliance by syncing important documents via central intake processes.
  • CIRBI integration: In addition, Advarra eReg supports integration with Advarra’s Center for IRB Intelligence (CIRBI) Platform and connections with your local eIRB system. With this IRB integration, all approved documents are immediately accessible for your regulatory and clinical staff in eReg to take the necessary action. This also allows you to decrease time and effort needed to manually download documents from an external system and upload them into your regulatory binder across your institution’s research portfolio.

ROI Benefits of CIRBI Integration

By eliminating manual document management, trial teams can save upwards of five minutes per document.[1] With an average of 200 documents per protocol that would leverage this type of integration, that amounts to 16 hours saved per protocol. For sites with a significant research volume, this can amount to tens or hundreds of thousands of dollars in full time exempt (FTE) savings over time.

The time savings are generated by the automation behind Advarra’s CIRBI Platform, which enables real-time communication among sponsors/CROs, research sites, study staff, and IRB members. For example, following the initial submission, all IRB-required documentation and submissions are readily available in the CIRBI Platform, and you’ll receive instant notification of and access to IRB correspondence and the ability to view the original regulatory documents 24/7.

With the CIRBI integration, you can accelerate your clinical trial’s startup phase and be confident in the quality of your document data throughout the course of the trial as you save valuable staff time.

[1] According to Advarra data based on a top 10 biopharmaceutical company

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).

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.

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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