Efficient and compliant data capture can make or break the success of a clinical research trial. Utilizing a comprehensive, site-centric eSource or electronic data capture (EDC) platform can streamline a site’s data capture, management, and compliance.

Defining eSource and EDC

First, it may be helpful to define eSource and EDC.

Typically used for investigator-initiated trials (IITs), EDC is used for transcribing paper source into an application, with a team providing downstream analysis for endpoint adjudication and data submission. In IITs especially, EDC users are responsible for submitting their own data.

Conversely, eSource is used for collecting visit data. This is essentially a fit-for-purpose replacement of the electronic medical record (EMR) for collecting data during visits. eSource users will turn their data over to their sponsor via the sponsor’s EDC application.

Using eSource Instead of Paper

Designed to help sites accomplish necessary data capture activities and workflows, eSource enables research staff to capture all necessary information for both research and standard-of-care purposes. Site staff need a system to help them scale their studies, be efficient, and put the correct workflow structures in place. This helps multiple investigators meet with different participants on different days, while also feeling confident everyone is doing what’s necessary to keep the study moving.

An eSource platform enables easy coordination between staff members as well. With a high volume of information and data coming in, it can be easy for data to get lost in the mix, or for staff to give or receive old data. Keeping everything electronic helps minimize the risk of information getting lost in the shuffle of paper.

Additionally, eSource helps with analyzing data. For example, if there are questions about lab results, staff can work internally with the care team to identify any clinically significant findings. Using an eSource system can improve quality and compliance by ensuring only designated roles such as investigators can identify a result as clinically significant or not significant. Having this capability helps sites maintain efficiency and compliance throughout a study.

There is also oversight when it comes to remote monitoring in eSource. A big advantage of eSource is the ability for remote monitors to easily access and review data, and issue queries when there are questions. This enables both sites and sponsors to monitor data quality, accuracy, and reliability as the study is going on.

Using eSource Instead of an Electronic Medical Record (EMR)

Many sites have an EMR platform in place, but the EMR doesn’t meet their needs to capture and manage source data. This may be due to the burden created for site staff from leveraging an EMR to capture source data, or the EMR’s inability to capture the information in a compliant manner and export the data out of the system in a structured way.

In cases regarding compliance, even though organizations have a system to allow data capture, it doesn’t fulfill the needs and requirements for research trials. Sites need the ability to appropriately capture the clinical research data in a compliant manner, as well as the ability to access data back out of the system in a structured fashion.

Using EDC for an IIT

Primarily, a site-centric EDC platform serves organizations conducting IITs, trials where investigators act as the sponsor. In these trials, there’s no sponsor providing the EDC technology for the site to submit trial data, and instead the organization needs to manage data entry themselves.

While the investigators will perform the clinical research activities, they also need to submit results for Food and Drug Administration (FDA) acknowledgement, guidance, and approval. Using Advarra’s eSource + EDC platform provides the capability for organizations to do their own independent research without a separate industry sponsor related to the study.

Advarra eSource + EDC is a 21 CFR Part 11-compliant system, helping sites:

  • Capture data appropriately
  • Have the necessary audit trail
  • Enable remote monitoring of the study
  • Send accurate, valid documentation to the FDA

As sites and institutions are conducting IITs, typically, they are collecting data on paper. Research staff are going to participant visits with paper forms to collect data, to which they will later transcribe into the EDC platform. Digitizing this information enables staff to export the data, do downstream processing, and complete statistical analyses, while also managing study calendars, visits, and forms. Implementing the appropriate technology platform for data capture is critical to a clinical trial’s success. While different organizations will have different needs regarding the use of eSource and EDC capabilities, any research site can benefit from a purpose-built eSource + EDC platform.

Clinical trials involving investigational in vitro diagnostic (IVD) devices are subject to the Food and Drug Administration’s (FDA’s) investigational device exemption (IDE) requirements (21 CFR 812). Unless the study meets certain IDE exemption criteria, sponsors (or sponsor-investigators) must determine whether using an investigational IVD presents:

  • Significant risk (SR) and is subject to the full IDE requirements, or
  • Nonsignificant risk (NSR) and is subject to the abbreviated IDE requirements

This blog is intended to help investigational IVD research sponsors (and sponsor-investigators) make SR/NSR device determinations and provide study-specific justification for their assessment to institutional review boards (IRBs).

Significant Risk vs. Nonsignificant Risk

A clinical trial is deemed SR when it involves an investigational medical device presenting a potential for serious risk to the participant’s health, safety, or welfare. When an investigational device does not carry this potential for serious risk, the clinical investigation is NSR.

Learn more about SR/NSR determinations in our blog.

In IVD research, device risk determinations are primarily tied to sampling procedures and the consequences of invalid test results. False positives or negatives may lead to a misdiagnosis or mismanagement of a participant’s condition.

Sampling Procedures

In some cases, an investigational IVD will require research participants to undergo high-risk sampling procedures that are not standard of care. In these situations, the use of the IVD is SR and requires an IDE.

Sampling procedures typically presenting SR include:

  • Biopsy of a major organ
  • Sampling requiring general anesthesia or prolonging standard of care surgery
  • Placement of a blood access line into an artery or large vein

When an investigational IVD requires any of these above procedures for research purposes, the study is likely SR.

Conversely, NSR procedures are typically things like:

  • Blood obtained through finger stick or simple venipuncture
  • Saliva collection, buccal swabs, and other non-invasive sampling
  • Skin punch biopsies
  • Biopsy of the upper gastrointestinal tract using endoscopy
  • Use of existing specimens, such as archival tumor tissue or samples from biorepositories
  • Use of otherwise-discarded remnant tissue from standard of care surgical procedures

Although these procedures are usually NSR, researchers should also consider the characteristics of the clinical trial population. Their current health status, comorbidities, and/or medications could raise the risks of certain sampling procedures to SR.

Regardless of how the IVD results are used in the study, if SR sampling procedures are used, the clinical trial is SR.

Impact of Invalid Test Results

If your research does not involve SR sampling, the next step is to assess the nature of potential harm to participants from inaccurate test results.

All investigational IVD clinical trials should consider the impact returning results could have on participants’ clinical care outside of the trial. False positive results could lead to misdiagnosis, ineffective treatments, or unneeded confirmatory testing. The greater the risks associated with unnecessary clinical care, the greater the risk of the investigational IVD.

False positives can also cause psychological trauma if a participant erroneously believes they have tested positive for a serious disease.

False negative results, on the other hand, might lead participants to forego or delay needed treatment, which could have serious implications for their health.

As part of this assessment, also consider how IVD results will be returned to participants and/or their healthcare providers. IVDs intended for home use may present greater risk than a lab-based test because a lay user (rather than a trained healthcare professional) will interpret the results.

Considerations for Investigational IVDs Used in Therapeutic Product Trials

Clinical trials of therapeutic products (like drugs or biologics) should take into consideration additional protections when:

In such studies, the therapeutic agent is a larger factor in the SR/NSR determination. This is because the safety and effectiveness of the therapeutic agent hasn’t been fully established.

There are additional protection considerations sponsors might include when making device risk determinations:

Will using the results from an investigational IVD lead to some study participants foregoing or delaying a treatment known to be effective?

Consider treatments available to participants outside of the clinical trial. The risks of false positive results from an investigational IVD are lower when the study will only enroll individuals who have already exhausted all approved treatments for their condition.

On the other hand, risks of invalid results increase when there are well-established treatments available outside of the clinical trial. In this case, researchers should consider more than just the risks of foregoing or delaying established treatment. Also critical is determining whether receiving an investigational drug could reduce the participants’ suitability for, or the effectiveness of, existing therapies after the study concludes.

Will use of the results from an investigational IVD expose study participants to safety risks (e.g., adverse events from the investigational therapeutic product) that exceed the risks encountered in non-trial standard of care or the control arm therapy?

An investigational IVD’s risk assessment must include the potential side effects of the investigational treatment administered in the clinical trial.

As the severity of side effects increases, so does the health impact of invalid IVD results – which pushes the use towards SR.

Is it likely, based on existing knowledge about the relationship between the biomarker and the investigational therapeutic product, incorrect results from the investigational IVD would present a potential for serious risk to study participants?

Consider not only the analytical validity, but also the clinical validity of an investigational IVD.

For example, a study drug may be hypothesized as more effective in individuals with a certain mutation, but the link is not well-established. Using an investigational IVD to identify and enroll only those with the mutation of interest raises the overall risk of the IVD.

Further Assistance with IVD Risk Determinations

Sponsors and sponsor-investigators of clinical trials involving investigational IVDs should address these factors when crafting their SR/NSR assessment. If the IRB disagrees with your determination, they will provide a rationale based on the factors discussed above.

The FDA also welcomes queries regarding device risk determinations. The traditional way of obtaining a formal device risk determination is through the Q-Submission process. For clinical trials of therapeutic products conducted under an IND, sponsors can contact their program officer for help determining if an investigational IVD is SR and requires an IDE submission.

Finally, it is important for both researchers and IRBs to understand device risk determinations are unique to each study. They may need reassessment over the study’s lifetime if the investigational IVD use changes.

Assessing Risk for Non-IDE Exempt IVD Investigations 

When unexpected events occur during the conduct of a clinical trial, research personnel may wonder if the event is reportable, and if so, to whom. This blog is intended to provide guidance and clarity on reporting such unexpected events.

Who Should I Report Unexpected Events to?

Studies involving engineered genetic materials (such as genetic vaccines, gene-modified cellular therapies, and gene therapies) require institutional review board (IRB) and institutional biosafety committee (IBC) review:

  • IRB assesses the safety and welfare of the research subjects
  • IBC assesses the risks associated with engineered genetic materials, ensuring they are properly mitigated for the research staff, the community, and the environment around the research site

This distinction between the roles of the two committees helps explain what incidents are reportable to which committee.

Which Incidents Should I Report?

In her blog, Reporting to the IRB: What NOT to Report, Advarra’s VP of IRB Operations, Laurie Carlisle, stated:

“A key aspect of whether an event should be reported [to the IRB] is determining if it pertains directly to the safety of the participants involved in the study. Ask yourself:

  • Is the event unexpected (in terms of nature, severity, or frequency) given the information provided in research-related documents and the characteristics of the participant population being studied?
  • Is the event related or possibly related to participation in the research?
  • Does the event suggest that the research places participants or others at a greater risk of harm than was previously known or recognized, typically requiring updates to the protocol and/or informed consent form (ICF)?”

When conducting a trial involving engineered genetic materials, incidents involving occupational safety and environmental protection are also reportable to the IBC. Such incidents include:

  • Occupational exposures involving the investigational product, such as needle sticks or splashes to the eyes, nose, or mouth
  • Spills of the investigational product outside of a biosafety cabinet
  • Environmental releases outside of the research facility

If such an incident occurs, immediately notify the site’s principal investigator (PI) and report it to the IBC.

The incident report should include a description of the incident, how it is being addressed (e.g., spill cleanup, post-exposure medical care, etc.), and what corrective actions are being taken to avoid a recurrence (e.g., review of standard operating procedures [SOPs] and retraining, employing a new type of safety procedure or safety sharp device, etc.).

What Does the IBC do with an Unexpected Event Report?

Once the IBC receives an incident report, they may contact the site for additional information to understand more about the incident. This process is intended to ensure the safety of the research staff, community, and environment around the site and is not punitive in any way. Rather, IBCs seek to collaborate with researchers to identify gaps, develop corrective actions, and protect everyone involved.

The IBC will review the incident in a convened committee meeting to determine if any additional actions are required. Incidents involving overt exposures, spills, or environmental releases of engineered genetic material may also require reporting to the National Institutes of Health (NIH) Office of Science Policy.

The IBC will determine whether the incident merits reporting to the NIH and will copy the site’s PI on the report. The NIH reviews the reports and determines if additional safety measures or corrective actions are required. The Food and Drug Administration (FDA) does not receive any notifications from the IBC.

The Centers for Medicare & Medicaid Services (CMS) released a letter outlining routine costs in clinical trials for patients eligible for Medicaid in April 2022. The letter expands upon coverage options for pediatric patients. However, a year has passed with no further updates on this letter or Medicaid beneficiaries enrolling in clinical trials. How can your institution best prepare for this change and what can you expect for the future?

Background

In 2001, Medicare released the national coverage determination (NCD) 310.1. This NCD provided guidance to not only Medicare beneficiaries, but also all private insurers on what items and services are deemed eligible for coverage. This resource has become a staple for all institutions conducting industry, federally funded, or investigator-initiated trials (IITs). Yet, coverage for pediatric patients or those receiving Medicaid coverage was not described until 2022.

What We Know

Much of the 2022 Medicaid letter aligns with the determinations in NCD 310.1, outlining routine costs in clinical trials. To be eligible for Medicaid coverage, a study must be deemed a qualifying clinical trial. The study must be performed to prevent, detect, or treat any serious or life-threatening disease or condition. In addition, trials must either be funded by a federally funded cooperative group, have an investigational new drug (IND) exemption issued by the FDA, or include a drug otherwise exempt from requiring an IND.

Routine costs include any item or service provided to prevent, diagnose, monitor, or treat complications resulting from participating in the qualifying clinical trial. These assessments include any cost otherwise covered outside the scope of the study as per the patient’s routine care. These routine services may also include items required solely for the provision of the investigational item or service, such as the administration of an investigational drug.

Items and services not covered under the new mandatory Medicaid benefit include the investigational item itself, items/services not otherwise covered outside of the trial’s scope, and assessments solely performed for data collection or research purposes.

What We Don’t Know

A key question for research sites and institutions is how current NCDs and local coverage determinations (LCDs) further affect coverage. Pediatric patients often have a greater need to run additional testing compared to the adult patient population.

A laboratory test, such as thyroid-stimulating hormone (TSH), may be limited in an adult cancer study due to restrictions from NCD 190.22. However, a pediatric patient may indicate this due to their impacted and ever-developing endocrine system.

Research site and institution feedback shows these assessments are routinely covered for Medicaid beneficiaries, but further support from CMS is needed to ensure coverage.

Next Steps

Currently, individual states continue to review the plan and make appropriate legislative changes to account for this new Medicaid clinical trial policy. Research studies involving Medicaid beneficiaries continue to run, leaving the research industry in a state of limbo. Until further information is available, following the guidance from established Medicare policies on clinical trial coverage is the best recommendation.

For sponsors and their sites, adhering to U.S. Food and Drug Administration (FDA) guidelines is critical to the success, failure, or delay of delivering life-changing therapies to market. A successful FDA inspection can pave the way for continued operations, product approvals, and in some cases, even accelerated go-to-market regulatory pathways. This blog provides key insights and guidance for sponsors and sites as they work to mitigate risks and ensure compliance for a successful FDA inspection.

Understanding the FDA Inspection Process

FDA inspections are routine assessments conducted to evaluate sponsors and their sites’ compliance with good manufacturing practices (GMP), good laboratory practices (GLP), and other relevant regulations. The inspections are usually done prior to a first market application for new drug applications or routine inspections for ongoing compliance. It’s crucial to familiarize yourself with the inspection process for effective preparation. It involves the following stages:

  • Notification: FDA provides a notice about the upcoming inspection to the principal investigator (PI) as well as to their sponsor organizations. This notice can be as far in advance as a few weeks or as little as five days.
  • Preparation: Sponsors and sites should conduct a comprehensive self-assessment, review procedures, and all study-related documentation to ensure all relevant documentation is readily available.
  • Inspection: FDA field investigators visit the facility, review records, interview personnel, and assess compliance with regulations.
  • Reporting: FDA issues an inspection report, highlighting any observations or findings.

Best Practices to Becoming Inspection Ready

Maintaining compliance with the regulations means taking a proactive, risk-based approach to safety, quality, and efficacy. Achieving a successful FDA inspection should include the following key preparation activities:

Culture of compliance: Compliance with FDA regulations should be ingrained in the organization’s culture. This includes providing training to employees, creating standard operating procedures, and fostering a proactive attitude toward quality and compliance. Establish mechanisms to capture feedback and suggestions from employees, stakeholders, and previous inspection experiences. Encourage open communication channels and regularly review your processes and procedures to identify areas for improvement. Implement a robust quality management system (QMS) including a formalized process for documenting and addressing corrective and preventive actions (CAPAs). Proactively address any identified gaps or non-compliance issues and ensure appropriate actions are taken to prevent recurrence.

Develop robust documentation systems: Staff must ensure processes, procedures, and personnel training records are accurate and up to date. Whenever possible, it’s beneficial to implement electronic systems to facilitate easy access, traceability, and organization of documents.

Conduct internal audits: To stay inspection-ready, regularly perform internal audits to identify areas for improvement and ensure compliance with regulations. This also helps teams to address any deficiencies promptly and implement corrective actions.

Mock inspections: Conducting internal mock inspections will help identify gaps in readiness, familiarize employees with the inspection process, and enable practice as staff respond to questions.

Train employees: Provide comprehensive training to employees on FDA regulations, quality systems, and their specific responsibilities. Tailoring training programs to each employee’s roles and responsibilities will help put them at ease during the inspection process.

Implement risk management strategies: Conduct risk assessments to identify potential vulnerabilities and develop strategies to mitigate them. This may involve assessing critical processes, supply chain management, and data integrity.

Maintain facilities and equipment: Implement a preventive maintenance program to minimize the risk of equipment failures and product quality issues. Ensure facilities and equipment are well-maintained, calibrated, and validated.

Prepare for interviews: FDA inspectors will likely conduct interviews during their inspection. It’s important staff understand how to effectively communicate with inspectors, ensuring accurate and concise responses.

Responding to inspection findings: If the inspector identifies any observations or deficiencies during an inspection, promptly address them with a robust CAPA plan. Communicate the plan to the FDA and ensure timely implementation.

Sponsors and sites can significantly impact an FDA inspection’s outcome by following the best practices listed above. Each component helps teams understand and more positively contribute to a smoother inspection process. By prioritizing compliance and a proactive risk-based approach, sponsors can ensure regulatory compliance, protect their operations, and uphold their commitment to delivering compliant, life-changing therapies to market.

Research in gene therapies and genetically engineered drugs and vaccines are growing exponentially, and will only continue to become more popular. Per a report from the American Society of Cell and Gene Therapy (ASGCT), gene therapy research is an increasingly important part of an institution’s research portfolio, with over 3,500 therapies in preclinical or clinical.

The accelerating gene therapy market is expected to grow globally by 16.6% between 2020-2027. As human gene therapies enter the research pipeline at a growing pace, research sites need to consider how prepared they are to take on the additional review requirements of these studies in their activation programs.

This was just one of many questions we explore in our comprehensive survey of research sites and their internal activation practices. Diving deeper, this blog explores how research sites are focusing on their institutional biosafety committee (IBC) programs as part of overall study activation time.

Understanding When IBCs are Needed

First, let’s define what an IBC is and when institutions need their approval.

When treatments involve recombinant or synthetic nucleic acids, including messenger RNA (mRNA) or viral vector vaccines, additional IBC oversight is necessary. Some of these treatments potentially make permanent changes to the humans they are introduced into. Additionally, in some cases, gene therapy treatments make permanent changes to a human’s genetic profile, which is different than typical drug treatments.

Further precautions and IBC oversight are necessary when handling and administering these novel research compounds. The U.S. National Institutes of Health Office of Science Policy (NIH OSP) sets the guidelines for research involving recombinant or synthetic nucleic acid molecules.

Activation Insights

Survey results indicated many larger research sites reported they have an IBC in place to review research subject to the NIH OSP guidelines. Not surprisingly, these organizations were primarily large academic medical centers with sizable research portfolios.

However, simply having an IBC is much different than actively managing the IBC review process as part of an overall strategy to streamline trial activation.

Of the respondents who have an IBC at their organization, 54% indicated the review process for human trials exceeds 30 days. Additionally, more than a third of the institutions with an IBC indicated their institutional review board (IRB) and IBC review process for human trials are not integrated, nor run in parallel. For these institutions, human gene therapy trials are likely taking significantly longer to activate than their more traditional drug study counterparts.

Improving Activation for Gene Therapy Trials

Know the Process

First and foremost, researchers and clinical teams need to clearly understand the overall study activation processes at their organization, including IBC and other oversight committee reviews. An IRB tends to get the most attention since all human trials need IRB approval. However, if an organization does not focus on the efficiency and expertise of the additional committees, like the IBC, it does not matter how quickly the IRB moves.

The overall activation time is only as fast as the slowest committee, and that’s assuming the process allows for parallel review.

In the survey, many institutions indicated they don’t have a specific measure for IBC performance. In total, 88% of respondents who have an IBC reported they have no turnaround time goal or key performance metrics for their IBC program. The result is not knowing if a gene therapy-related clinical trial can even be activated within the activation timeline typically given to a sponsor during site initiation.

Build Expertise on the IBC

For many institutional IBCs, the majority of research oversight is preclinical. As more therapies are moving out of the lab and into human clinical trials, this paradigm is changing.

If an IBC does not have the requisite expertise to apply the NIH OSP guidelines to human clinical trials, it is generally advised to not try to do the review in-house. At best, an inexperienced in-house IBC review may result in a delay while the committee seeks additional expertise or due to unnecessary questions from the committee back to the investigators. At worst, an inexperienced IBC review may not apply the guidelines appropriately and introduce regulatory risk for the institution.

In either case, if the IBC does not have experience with human clinical trials, study activation time will likely be delayed.

Defer IBC Review, Keep the Local Biosafety Infrastructure

As human gene transfer trials are increasingly reaching Phases II and III, industry sponsors are routinely selecting a single central IBC and IRB provider to review all sites in a multicenter clinical trial. NIH, and soon Food and Drug Administration (FDA), mandate institutions rely on the single IRB (sIRB) designated by the sponsor. However, according to our survey, most institutions are not also deferring their IBC reviews off to a single IBC in the same way they defer oversight to the designated single/central IRB.

Very similar to how IRB deferrals work, biosafety programs can defer the formal IBC committee review component (e.g., five members convening an IBC meeting, minutes, etc.) to an independent IBC provider. Often, the sponsor will establish the protocol and scientific review at the central IBC and handle billing, both of which reduce burden on the research site staff.

Sites should consider using sponsor-selected, independent IBC services. Not only are commercial IBC services typically faster, but they also allow the biosafety officer to focus their attention on staff training, physical lab tracking, and other local issues. These are keenly important, but can be separated from the formal process of conducting IBC review per the NIH OSP guidelines.

Innovative treatments using gene therapy are growing, and public perception of genetically engineered drug therapeutics is changing due to the mRNA COVID-19 vaccines. An organization should ensure it has an efficient activation process through an IBC, so participants can take advantage of these new, cutting-edge investigational products.

Note: This article was originally published May 17, 2021, and has been updated to include new and clarifying information.

Gene therapy research is exciting and full of promise, but because of the risks involved, it’s also highly regulated, requiring an institutional biosafety committee (IBC) to provide additional oversight and risk assessment. In the clinical research community, we’re already familiar with institutional review boards (IRBs) and their review for ethical considerations and participant risks – so what’s the difference between an IBC and an IRB?

How are IBCs Different from IRBs?

While both committees focus on risk, they have contrasting responsibilities. IRBs are tasked with protecting research subject’s rights and welfare. IBCs, however, seek to protect study personnel, the community, and the environment from exposure to engineered genetic material and other biohazardous agents.

An IBC may also advise the IRB in assessing potential risks to the study subjects and how best to explain the unique risks of gene therapy and other genetically engineered treatments in the informed consent form (ICF).

What Does an IBC Review?

IBCs help researchers apply the necessary safety measures to ensure gene therapy research is conducted safely and responsibly.

Because of the risks involved, gene therapy research requires additional safety measures to ensure research subjects and study staff, as well as the community and the environment surrounding the research site, are not harmed by the modified genetic material or the infectious agents utilized to deliver them. These safety measures go beyond the human subject protection requirements IRBs enforce and include a required site inspection as part of the approval process.

The IBC’s review is intended to ensure a thorough risk assessment is performed regarding the risks associated with the genetically modified materials. The IBC also reviews to confirm a comprehensive risk mitigation plan is in place prior to starting the research.

How is IBC Membership Composed?

While a single IRB (sIRB) can oversee research protections for a protocol being conducted at multiple sites, the IBC uniquely focuses on biosafety at the site level. This means IBCs are constructed to focus their risk assessment locally at each research site.

IBC membership must include involving two local community members who reside within 50 miles of the research site. This local membership requirement provides the IBC with the local community’s perspective and concerns as they assess the risks of utilizing genetically engineered products in research within a community. The IBC’s membership roster is therefore unique to the individual research location it oversees.

For the sake of efficiency, IBC meetings can be centrally coordinated and synchronized similarly to a sIRB. However, each IBC ultimately is its own entity with a unique roster of members who remain responsible for localized risk review.

It’s possible an IRB’s membership might be similar to an IBC’s; however, the committees are composed to conduct their reviews for different purposes. IBCs include members who possess expertise in genetic engineering, biological safety, infectious diseases, and environmental protection. Each IBC is required to have at least two community members who are unaffiliated with the institution or research site and who represent the interests of the community and the local environment.

What do the Regulations Say about IBC Review?

Food and Drug Administration (FDA) and Office for Human Research Protections (OHRP) regulations require IRB review for research involving human subjects. For IBCs, National Institutes of Health (NIH) Guidelines require IBC review for:

  • Any genetic engineering research receiving NIH support
  • Research taking place at sites currently receiving NIH support
  • Research taking place at sites who have previously received NIH support

Even if no NIH support is involved, NIH Guidelines suggest IBC review is a best practice for genetic engineering research: “[I]ndividuals, corporations, and institutions not otherwise covered by the NIH Guidelines are encouraged to adhere to the standards and procedures set forth” in the Guidelines (Section IV-D-1).

IRB IBC
Required when: Research involves human subjects Research involves gene therapy or genetic engineering of the treatments (e.g., mRNA)
Responsibility (oversight for): Protecting human subjects participating in research Protecting human subjects, study personnel, the community and the environment when conducting gene therapy or genetic engineering research
Composition: Minimum five members with varying backgrounds, including:

  • At least one scientific member
  • At least one non-scientific member
  • At least one member not affiliated with the institution/IRB
 Minimum five members who collectively have the expertise to assess risks associated with recombinant DNA research, including:

  • At least two members from local community who are not affiliated with the institution/site
Central vs local:
  • Centralized review of multiple sites by a single IRB permitted
  • Local review by site-specific IRB
  • IBC must be site-specific with local community members
  • Central administration of IBC permitted

In a nutshell: IRBs are concerned with risks to human research subjects, and IBCs are concerned with risks to anyone who might come in contact with a study’s genetically modified material.

Note: This article was originally published September 22, 2017, and has been updated to include new and clarifying information.

The Association of American Cancer Institutes (AACI) recently published a white paper titled Collaboration to Develop Recommendations to Improve Trial Activation Timelines. The paper highlighted findings from a 33-member task force made up of representatives from cancer centers, industry sponsors, and the National Cancer Institute (NCI).

The task force focused on three main areas of study activation: contract negotiation, budget development, and trial start up committee reviews. With this focus, one of the five key areas identified for improving trial activation was creating Medicare Coverage Analysis (MCA, or National coverage analysis [NCA], as the paper stated) for industry-sponsored trials.

MCA is a systemic process of developing a billing plan for a clinical research study, which provides an in-depth analysis of how all the items and services listed in the clinical research protocol are billed per Medicare-provided guidelines. The MCA determines what a patient’s health insurance plan can cover and what a sponsor must pay for. While the MCA process is a critical step to understanding a study’s true cost, it’s often time-consuming for sites. This ultimately increases timelines for sponsors working to activate a study. For sites and sponsors, this disconnect can cause frustration, which is why connecting the dots between each side’s expectations is so important.

Sites and Sponsors Role with MCA

For sites, an MCA can be a labor-intensive task, and according to the AACI white paper, it can take upward of four weeks to develop and complete. To add to these challenges, most sites have limited skilled resources; our survey of clinical research site professionals found 50% of organizations noted the number of staff was the most frequently identified pain point for both budget negotiation and MCA processes. What’s more, many sites fear allegations of Medicare billing fraud, which can lead to fines or legal issues, if Medicare or a private insurer is improperly billed for study procedures.

Sponsors have historically stayed away from getting involved in the MCA process, letting the responsibility fall to each individual site working on the protocol. Bottlenecks in the sites’ ability to complete the MCA can cause frustrations for sponsors waiting to activate trials and are forced to delay the initiation of budget negotiation.

Once the MCA is completed, sites may identify additional fees for sponsors to pay. This can create additional back-and-forth with sponsors, potentially increasing timelines drastically. As evidenced above, the MCA process is a complicated task for sites to complete and a time-consuming barrier to trial activation timelines for sponsors – though it doesn’t have to be.

Rethinking Study Startup

As a key element of study startup, the MCA process is fundamental to developing a draft budget designed to help both the individual research site and sponsor estimate their expenses on protocol-required items and services. One of the main deliverables and recommendations from AACI is sponsors should provide an MCA (or NCA) for each study to improve budget negotiation timelines. This reduces the duplicative work each site is doing individually and removes one of the major barriers to starting the budget negotiation process sooner.

In order to increase efficiency and accelerate the MCA process, sponsors should meet the call of sites and start providing MCAs. Since completing an MCA takes a specific skillset sponsor teams do not currently have, they should consider leveraging specialized service providers or consultants already possessing the needed expertise. Working with an outside service provider also removes the need to train and retain these resources, allowing sponsor teams to focus on tasks they can’t outsource.

Conclusion

The AACI white paper highlights speeding up clinical trial activation timelines requires a change in mindset and an increased understanding of the process for both sides. To overcome MCA-related challenges, working with experts who can expedite and streamline study startup activities by working directly with sponsors helps immensely. The need to complete MCAs in a timely manner is critical to the success of a clinical trial’s activation, subsequently impacting the timeline for when a patient receives access to therapies.

The study startup process is a critical point in research, and oftentimes, can make or break a study’s success. Sites, sponsors, and contract research organizations (CROs) must work together to ensure a streamlined startup process, but oftentimes, there are hurdles to overcome. Understanding the current state of study startup often helps shed light on methods to implement for process improvement.

Identifying, Qualifying, and Selecting Sites

A key component to improving the process is site selection. During this process, communication and personalization are key. Sponsors must be able to communicate with a site’s central office, rather than just specific people on a trial, such as principal investigators (PIs). This encourages the stakeholders most prepared to act and manage resources are informed of upcoming trial opportunities.

Due to a lack of centralized information and access about certain research sites, sponsor study teams will produce and distribute site feasibility questionnaires (SFQs) to sites they may have already engaged or received responses from in the past. While easier for sponsor study teams in the short term, it creates significant redundancies and administrative burdens for sites. Many questions are asked multiple times, and there’s a lot of back and forth with sites and sponsors to ensure feasibility. Leveraging what’s on file to reduce the amount of time you’re asking sites to fill out questions will go a long way.

Excerpt: Advarra Trend Report | State of Trial Opportunity and Selection

Gained efficiencies in the SFQ process are needed – low site response rates exemplify this, as well as sites desiring to receive more study opportunities. Site respondents have various opinions on how repetitive SFQs are within the same sponsor, with 54% stating at least half the questions are redundant with previous questionnaires they have received from the same sponsor. This high rate of perceived redundancy, combined with the response from our sponsor respondents indicating 76% of them keep a repository of answers from previous SFQs, provides an opportunity for the industry to streamline efforts by better utilizing data already collected.

Budgeting, Contracting, and Managing Essential Documentation

The information and document exchange requirements of any research program can be enormous. Generating and exchanging documents through a standardized and repeatable process makes it much easier to systemize programs for faster startup.

A standardized approach to study startup lays an essential foundation for efficiency. Current processes in contracting and budget negotiations require most study and site teams to renegotiate the same terms across each individual trial. Creating a master clinical trial agreement (CTA) with regular partners will streamline processes and instill a sense of trust between stakeholders.

For example, when negotiating a study budget, if your site is charging a specific amount for a procedure or visit and negotiating with the sponsor, it’s important to be as detailed as possible. There are discrepancies between similar procedures and price differentials to consider, and the clearer a site can be about how much money they are asking for and why, instills a sense of transparency between them and sponsors, since everyone is on the same page about what is being funded.

Beyond budgets and contracts, a lot of additional documentation is exchanged during study startup, including essential regulatory documents. This may come in the form of email chains or paper documentation constantly needing updates. Utilizing purpose-built platforms to manage, exchange, and collect various critical documents in a centralized manner, rather than manual workflows required for managing email or paper, can go a long way for your teams during the study startup phase.

Site Initiation, Training, Transparency, and Reporting

As the study activation process leads into initiation and training, organizations are often closing the loop on many activities happening within the startup process – sites are selected, documents are signed, and operations are moving. At this stage, it’s imperative to have proper resources and tools prepared prior to the site initiation visit (SIV).

Typical site initiation activities such as investigator meetings (IMs) and SIVs should be supplemented with engaging training materials and a clear agenda. In addition to study-specific resources, sponsors and sites can streamline the training processes by accepting training programs of others on research requirements like good clinical practice (GCP) and store those certificates for future studies.

As sites and sponsors work together to uphold transparency and reporting across study startup, being able to see what’s happening at sites from an activity perspective is very helpful. Sponsors should ask questions such as:

  • Have sites received our amendment to the protocol?
  • How many sites have completed their training? Are they prepared to conduct the study?
  • How many patients have been pre-screened? Are there any enrollment criteria to adapt?

Although notifications can keep sites on track, sponsors must realize more isn’t always better. Finding the right balance of updates to send to sites will be better than sending too much, or none at all. Also consider who you are sending notifications to – are they the right people who need to see them? Communicating expectations with sites – and being open to receive feedback regarding notifications and communication as well – will only strengthen your relationship with your sites in the long run, which leads to better study startup processes.

To learn more site-centric and collaborative strategies that will improve your research operations, watch our on-demand webinar, “Reducing Site Burden throughout Study Startup”, featuring a panel of industry peers of life sciences and sites alike.

In today’s world of research, using a clinical trial management system (CTMS) can significantly streamline operations, and make for a more efficient research study. Do you know if you’re using your CTMS to its fullest capabilities? Below are some of the ways sites can get the most value from their CTMS platform.

Facilitating Cross Team Communications

Oftentimes, research teams at large institutions such as academic medical centers, cancer centers, and large health systems are very siloed. To keep a study moving, it’s important to remove communication barriers to ensure smooth processes, workflows, and accelerated timelines.

A comprehensive system like Advarra’s OnCore CTMS centralizes communication, proactively facilitating collaboration among internal teams to break down silos. One example of this is cross-team task lists – staff are immediately notified which tasks they need to complete, when they can begin them, and when they are due. In many cases, these tasks are repeatable across studies, further standardizing cross-team collaboration and communication, and making life much easier for site staff. Configuring protocol milestones also triggers notifications for coordinators overseeing many parallel trials.

Single, Centralized Calendar

Research is becoming increasingly complex, and this is often reflected in the study calendar itself. The calendar includes information such as when subjects will be seen, what occurs during each visit, and what data will be recorded during each visit. As a result, centralizing the calendar in OnCore—and leveraging that calendar to drive study-related tasks and downstream workflows—can further streamline communication across teams and keep complex studies on track. A centralized calendar can also provide historical documentation following amendments and changes to the protocol to make sure all participants are receiving the correct level of care.

Financials and Reconciliation

In addition to the benefits noted above, centralized study calendars also help drive downstream financial and billing workflows. As participants move through a study, staff can generate financial items based off of the financial calendar. This leads to having both a budget calendar on top of an existing financial calendar, with room for error.

With protocols in the stage where they are generating financials, it’s important to have a CTMS to keep track of each occurred visits, individual procedures, visit variations, and invoiceable items, all centralized under an individual sponsor for your protocol. Using both a receivable and payable component in a CTMS, allows you to both invoice and receive payments related to the protocol and utilizing vendor payables allows for tracking payments out to other departments through your system.

Study Staff Visibility

Having visibility into a protocol allows staff to track its status and overall health in real-time. This is beneficial at any point in the study – from the time you enter the protocol into the system, you can see where you’re at with the institutional review board (IRB) review process, how accruals are progressing, whether timelines are being met, and more.

Another benefit of this increased visibility is the ability to quickly and easily identify areas of the study where your site isn’t being adequately compensated. Perhaps your site is having to do more standalone procedures for individual visits as the trial has evolved, and there’s a need to get an amendment. The ability to track all aspects of the study, and leverage that visibility in real time, is invaluable to ensure operational success.

Strong User Adoption

Even the best CTMS won’t be valuable to your site unless you have the resources to get the most from the platform. A strong, collaborative user community is key to learning tips and best practices from those who already use the system day in and day out. And comprehensive training and documentation are vital to ensure both a successful adoption of the platform, but also ongoing success as your organization scales the use of the CTMS and onboards new staff. Advarra provides a wealth of documentation and facilitates the Onsemble community for organizations to share best practices.

How Advarra Can Help

For academic medical centers, cancer centers, or large institutions handling large volumes of research each year, OnCore enables you to gain visibility into all aspects of your research operations. OnCore enables staff to automate the flow of information between systems, gain insight with comprehensive reporting and analytics, and effectively manage the entire protocol timeline.

Clinical research aims to produce knowledge in the service of treating diseases and improving human health. In a just and well-functioning society, the benefits of research would ideally be shared equitably among all social groups, regardless of race, age, gender, or ethnicity. This gives the research community (e.g., sponsors, investigators, and institutional review boards [IRBs]) strong reasons to improve research participation access. It also challenges the community to learn how to improve diversity in clinical trials for historically under-represented groups, such as women, children, cognitively impaired individuals, elderly people, and racial and ethnic minorities.

Unpacking why Groups are Historically Under-represented in Research

Historically, clinical research has failed to adequately include certain groups of people. In some cases, this is at least partly because these groups have been deemed vulnerable and in need of protection.

For example, women and individuals of child-bearing potential have tended to be excluded out of concerns about the potential effects of an investigational product on a developing fetus. People with mental illness and individuals who are cognitively impaired have been excluded because of a perceived inability to consent for themselves. Similarly for children. The elderly have also been excluded out of concern of potential co-morbidities and polypharmacy potentially increasing the risks of research or confound the interpretation of the data.

In other cases, the explanation for why groups are under-represented in research is more complex. Racial and ethnic minorities have suffered a long history of exploitation at the hands of researchers, resulting in high rates of mistrust in the research enterprise. Lower enrollment rates among racial and ethnic minority groups may reflect this fact and should come as no surprise.

Ethical Concerns with Research Under-representation

There are at least two ethical concerns with these disparities.

First, when certain groups are not included in research, it can make it difficult to apply the results of research to them. For example, just because a drug is safe or effective in a narrowly defined study population does not automatically mean it is safe or effective in a wider group of individuals who might include people with comorbidities or on various other types of medications. When these and other groups are excluded from research, it hinders them from sharing in the primary benefits of research – the advances in disease diagnosis, treatment, and prevention research yields – and promotes longer term health inequities, with these groups being “left behind” from a public health standpoint.

Second, when certain groups are not included in research, they do not have access to the potential direct benefits of research participation. While the primary aim of research is the production of knowledge, research participation often yields access to promising new therapies. In disease conditions for which there currently exists no cure or standard of care, enrolling in a research study of an investigational new therapy may be the best option for many patients. All individuals should have equitable and fair access to these opportunities.

Addressing Ethical Issues with Clinical Research Disparities

What can the research community do to address these concerns and learn how to improve diversity in clinical trials? The first thing to recognize is restoring trust among groups who have suffered at the hands of research will take time, a commitment from the research community to listen to what these groups are saying, and a willingness to take their experiences to heart and let them shape us. There are no quick fixes for public mistrust in research.

While we as a research community work to build trust, there are things we can do to promote the inclusion of under-represented groups. While these are simple and commonsense actions, they are unfortunately often overlooked and not put into practice.

While the responsibility of implementing many of the following points begins with sponsors and researchers, the role of the IRB should not be overlooked. Indeed, empirical research has shown IRBs see themselves as having a role to play in promoting inclusion and good work has been done to outline a roadmap for the role of IRBs in enhancing the diversity of clinical research populations.

Here are some practical strategies on how to improve diversity in clinical trials while addressing ethical concerns:

  • Design careful study eligibility criteria without unnecessarily excluding certain groups, including women and individuals of child-bearing potential, children, the mentally ill and cognitively impaired, non-English speakers, the elderly, and racial and ethnic minorities.
  • Institute thoughtful, protective measures addressing concerns with potentially vulnerable groups participating in research, short of exclusion. Such measures can include contraception measures for individuals of child-bearing potential, legally authorized representatives to consent on behalf of cognitively impaired people, and thoughtfully designed eligibility and individual withdrawal criteria for older people with comorbidities.
  • Translate documents into languages other than English for non-English speakers. This is basic, and translation costs are minimal enough for this to be a no-brainer for most sponsors. Subject materials should at least be translated into Spanish and other prominent non-English languages in the relevant geographical area.
  • Offer robust reimbursement plans for out-of-pocket costs related to participation, including travel and childcare. Such expenses are among the biggest barriers to research participation among economically vulnerable groups (which often include, unfortunately, racial and ethnic minorities). Additionally, consider offering fair compensation to participants for their time and the burdens they undertake. Determining what counts as “fair” compensation will vary depending on various factors, including the nature of the study and what is being asked of participants, the time commitment involved, and local cost of living.
  • Sponsors, sites, and IRBs should strive to diversify their members and staff. This allows the research world to learn and benefit from historically neglected perspectives and standpoints, which may in turn help under-represented groups feel more comfortable in research contexts.

These points are achievable short-term goals. They can move the research community in the right direction while we do the difficult work of building trust in the wider society, and with historically marginalized and exploited groups in particular.

In vitro diagnostic (IVD) devices are tests used on human biospecimens (e.g., blood or tumor tissue) to diagnose diseases or other conditions, monitor a person’s health, or help manage a current condition. Although IVDs themselves do not treat, prevent, or cure diseases, the data they output can be an important part of disease management.

IVDs are used in almost all clinical research. They can be essential for selecting appropriate participants, identifying potential adverse reactions, and studying how a drug affects the human body. However, the testing itself often occurs in laboratories or some other healthcare setting away from research participants.

Additionally, while the Food and Drug Administration (FDA) regulates all IVDs as medical devices, the agency has generally not enforced device regulations for certain IVDs designed, manufactured, and used within a single CLIA-certified laboratory. IVDs meeting this definition are known as laboratory developed tests (LDTs).

For these reasons, it can be difficult for researchers and institutional review board (IRB) members alike to determine when an IVD is investigational and, if it is, which regulations apply.

Whether you’re new to IVD research or could use a refresher, this high-level overview will help you navigate IRB review requirements for IVDs.

What is a “Human Subject” in the Context of IVD Research?

Under FDA’s medical device regulations, a subject (also called a “participant”) is “a human who participates in an investigation, either as an individual on whom or on whose specimen an investigational device is used or as a control.” This means if your research uses an investigational device on human biospecimens, your project involves human subjects and requires IRB oversight (more on that below).

You may never interact with the people from whom the samples were collected. You might not even obtain identifiable information about the donors. None of that matters: If your IVD study uses human samples, you’re doing human subjects research.

When Does Research Involve an Investigational IVD?

When an IVD is the object of study, it is investigational, regardless of the device’s approval status or intended use in the study.

The IVD may be the primary focus of the clinical trial, or it may be evaluated in a minor, exploratory objective. solely focusing on investigational IVDs (also known as IVD clinical trials) are easy to identify for two reasons:

  • They are clearly collecting data about the device’s safety, effectiveness, validity, or performance.
  • The developer/manufacturer of the IVDs are typically the entity that submits the study.

It may be more challenging to recognize a second type of investigational IVDs: using an IVD to guide therapeutic management of participants in a clinical investigation, when the IVD is not already approved for this purpose. This includes both unapproved IVDs and marketed IVDs used off-label.

When such an IVD is essential for the safe and effective use of a corresponding therapeutic product, it is known as an IVD companion diagnostic device.

An IVD is “guiding therapeutic management” when it is used for any of the following activities:

  • Assessing a potential participant’s eligibility, such as confirming the presence of a particular cancer mutation
  • Assigning participants to a treatment arm; this includes stratifying participants based on IVD results
  • Determining dose level for a particular participant or group of participants
  • Monitoring participants for side effects, such as increased lab values
  • Predicting which participants are most likely to experience serious adverse event

Often used in drug clinical trials, these investigational IVDs are not the primary research focus, and the device developer or manufacturer is rarely involved in the study. Therefore, it is imperative sponsors identify these investigational IVDs for the IRB.

What IRB Regulations Apply to Research Involving Investigational IVDs?

As with all FDA-regulated human subjects research, your study must comply with the requirements for IRB review (21 CFR 56) and informed consent (21 CFR 50).

Additionally, studies involving an investigational IVD may also be subject to the investigational device exemption (IDE) requirements (21 CFR 812). The applicability of the IDE regulations depends on the level of risk the IVD use presents to study subjects and will fall into one of three categories:

  • Exempt from the IDE requirements
  • Nonsignificant risk (NSR): must comply with abbreviated IDE requirements, and the IRB must concur with the sponsor’s NSR assessment
  • Significant risk (SR): must comply with full IDE requirements, including approval by both the FDA and IRB prior to study initiation

If your study involves an investigational IVD, you’ll need to determine which category best fits your research. The FDA is the final arbiter if the study sponsor and IRB disagree. Note: If your IVD meets the definition of an LDT, it falls under FDA enforcement discretion. For such tests, neither the FDA nor many IRBs enforce compliance with the medical device regulations. Thus, an LDT may not need an SR/NR determination, but risks of sampling procedures and invalid results should be disclosed in the informed consent form (ICF).

What Information Does the IRB Need When Reviewing Investigational IVDs?

To ensure an efficient and compliant IRB review, researchers should provide the following information:

  • In the IRB submission form, identify any investigational IVD(s) used in your study, specify its regulatory status, and indicate whether you think its use is IDE exempt, NSR, or SR.
  • Describe the investigational IVD(s) and how each will be used in the clinical trial.
  • Provide the device’s user manual or instructions for use (IFU). Early in an IVD’s development, a formal IFU may not be available; in such cases, the protocol or other supporting documentation should provide sufficient information for the IRB to make a robust device and risk determination.
  • Describe the risks of IVD use (including risks associated with sampling procedures and impacts of false positives/negatives) in the ICF.
  • If the device or its use changes during the clinical trial, submit a modification to the IRB; the regulatory status may need reassessment.

As always, respond promptly to IRB requests for additional information, which may include a request for the FDA’s formal device risk assessment.

Collaboration to Simplify IVD Research Oversight

IVDs occupy a unique position in the array of regulatory controls and guidance that may confound novices in this realm. By working collaboratively with the IRB and FDA, sponsors and researchers can gain the expertise to turn a potentially process into a clear and straightforward pathway to study approval.

Login
Scroll to Top