Effective participant recruitment is crucial to a successful clinical trial, but recruiting eligible participants in sufficient numbers has long been a challenge. As trials become more complex, and calls for appropriate diversity in participant populations increase, the problem is intensifying. Smaller sites often have the most difficulty, and fewer resources for meeting the challenges.

Strategically using the right tools and technologies can streamline your recruitment, helping to establish a clear process and making it easier to identify potential participants, enroll them, and efficiently manage them throughout a trial’s course. There are also many associated benefits for site teams struggling with burdensome workloads that too often take them away from the core business of providing care.

Having tools and technologies to provide efficient processes and support effective communications is essential for success. Unfortunately, many sites are still struggling to work effectively with inadequate tools like Excel spreadsheets. Those sites may be surprised to learn the capabilities and relative affordability of a clinical trial management system (CTMS).

Establish the All-important Process

When it comes to sites and recruitment, a fundamental problem is often the process. The beauty of a CTMS is it goes beyond simply providing a tool, offering a ready-made process with a solid foundation for recruiting activities. Sites without a centralized solution may find recruitment can be a chaotic, fragmented process. Traditional approaches like tracking potential participants in spreadsheets or emails are tedious, prone to error, and lead to difficulty measuring the campaign’s success. In some cases, they can even hamper recruitment and participation.

Consolidate Functionality in One Place

Another great advantage of using a CTMS platform is it consolidates vital functionalities, enabling sites to leverage one system for multiple purposes and integrating workflows to save staff time. This streamlines and simplifies the work associated with operating a clinical trial site. After all, managers may be hesitant to introduce unnecessary systems, and no team member wants to be responsible for learning and using more systems than necessary.

While integrated workflows within the site technology ecosystem can provide significant time savings, sites can also leverage integrations with outside platforms to boost recruitment efforts. For example, sites can integrate with social media platforms such as Facebook to manage recruitment campaigns and track prospective participants directly within the CTMS. And, using an API, a CTMS can connect to other databases or registries to allow a site to leverage those instead of creating its own from scratch.

Once your information is entered into the CTMS, you can segment it, create call lists and task lists for your staff, or manipulate it in other ways as needed.

Improve Team Member Satisfaction

Design matters in a CTMS – staff need to be able to confidently learn and use the CTMS system quickly. So, shop for an intuitive interface and easy-to-use workflows. User-focused design allows staff to focus on the clinical side of research rather than on the operational side, which most staff will appreciate.

Impress Sponsors

A CTMS can also help make a site more attractive to sponsors. By demonstrating efficiency, well-defined processes, and a track record of success in recruitment, you will set yourself apart from many other contenders for a sponsor’s business.

Elevate Your Site

To summarize, a comprehensive, site-friendly CTMS is the solution to multiple problems for busy sites wanting to successfully engage in clinical research. Since a CTMS offers an integrated workflow, everything can be centralized, streamlined, and simplified. When these centralized and simplified workflows extend to patient recruitment, you can ensure your site is ready for even the most complex trials.

The use of engineered genetic materials in clinical trials is rapidly expanding, with potential applications for genetic vaccines, gene-modified cellular therapies, and gene therapies.

This trend came to the forefront during the COVID-19 pandemic, as the three most popular vaccines developed in response to the coronavirus contained engineered genetic materials in the form of mRNA or a genetically engineered virus.

A similar phenomenon has taken place in oncology, as gene-modified chimeric antigen receptor (CAR) T cells have become popular for treating refractor or resistant B cell malignancies.

Among the various regulatory bodies providing oversight on clinical research, only the institutional biosafety committee (IBC) has a purview specific to research involving engineered genetic materials. IBC review ensures compliance with biosafety guidelines, issued by the National Institutes of Health (NIH) as well as the Centers for Disease Control and Prevention (CDC), intended to protect the health and safety of research personnel as well as the community and environment around the research site. A key part of the IBC’s evaluation is assessing the risks posed by the engineered genetic materials.

Why Does the IBC Need to do a Risk Assessment?

Any investigational product (IP) comprised of engineered genetic materials administered to a human subject, and whose development has received support from the NIH, must receive review and approval from an IBC registered with the NIH.

IBC review boils down to assessing the risks associated with engineered genetic materials. The committee is also charged with ensuring an appropriate risk mitigation plan is in place to protect research staff, the community, and the environment around the research site.

IPs containing engineered genetic materials may pose risks potentially not anticipated by the clinic’s standard infection control policies. With a membership comprised of subject matter experts in genetic engineering, microbiology, and biosafety, an IBC fills this gap with a comprehensive risk assessment tailored to the specific IP and the procedures performed as part of the clinical trial.

IBCs also include community members (who may or may not have a science background) to address the concerns of the general public and ensure representation is not purely scientific. These individuals provide a perspective that is equally important for consideration when evaluating the risks to the study participants and clinicians, as well as to the community where the study is conducted.

Gene Delivery Systems

Genetic material, in the form of DNA or RNA, does not easily enter cells without the aid of a delivery system. For example, the Pfizer and Moderna mRNA COVID vaccines utilize lipid nanoparticles, while other approaches utilize genetically engineered viruses. Either way, occupational exposure to these gene delivery systems bears potential risks to the research staff.

The diverse array of viruses capable of infecting humans leads to a menagerie of potential gene delivery vectors (also known as viral vectors) with diverse possibilities for uses, as well as potential toxicities or risks. To mitigate the latter, these viruses are typically genetically modified with built-in safety features to limit their ability to reproduce in human cells (while still delivering their genetic payload).

Although attenuated, these viral vectors can retain their potential to replicate under the right circumstances and cause disease in exposed individuals, which can also be transmitted to others. Further, the genetic modifications themselves, or the inserted potentially therapeutic transgene, have the potential to increase the virulence of the delivery system given the right context. In its risk assessment, the IBC considers all these aspects inherent to the recombinant IP.

Risk Assessment

The IBC also evaluates the research clinic’s policies and practices for handling the recombinant IP. These include the following:

  • Unpacking and storing the IP after receipt from the sponsor
  • Preparing and diluting the IP for administration
  • Administering the IP to subjects
  • Destruction or removal of contaminated waste and unused IP from the clinic
  • The clinic’s incident response plans in the event of a spill or release of the IP
  • The location where each of the above procedures will be conducted
  • Personal protective equipment (PPE) to be worn during each of the above procedures
  • The disinfectants to be used for decontaminating surfaces throughout the above procedures

At Advarra, this information is captured in the safety standard operating procedure (SOP) each clinic completes prior to IBC review and includes photos of the individual rooms. Every clinic receives a comprehensive facility inspection, which is normally performed remotely via live video, between one of Advarra’s biosafety experts and the clinic’s staff.

Then, at the convened IBC meeting when the clinic’s protocol is reviewed, the SOP and photos are presented to the committee by the biosafety experts who performed the inspection. This allows the IBC to assess whether the clinic has the facilities to safely handle the IP and prevent exposure or release at that site. Finally, the principal investigator (PI) of every protocol is evaluated for their competency to comply with the IBC’s recommended safety practices and to train the clinic’s staff on those practices.

For deficiencies identified with any of these practices, the IBC will typically recommend safety plan revisions to satisfy the committee’s concerns, rather than disapproving the protocol completely. The research clinic must satisfy these conditions of approval before the IBC releases full protocol approval.

The risk assessment is meant to be a collaborative process between the clinic/PI and the IBC, such that the risk mitigation procedures approved by the IBC are reasonable and practical for each clinic.

The Food and Drug Administration’s (FDA’s) proposed single institutional review board (sIRB) mandates are in part designed to support greater efficiencies and consistencies when conducting multisite research. This change has the potential for a substantial impact on sponsors and contract research organizations (CROs), as well as institutions conducting multisite research.

A Brief Overview of the Proposed FDA Single IRB Mandate

On September 28, 2022, FDA released two proposed new rules, also known as Notices of Proposed Rule Making (NPRM). Each of these proposed rules is intended to harmonize certain current regulations with the Department of Health and Human Services (HHS) regulations, also known as the Common Rule. Specifically, one NPRM identifies specific provisions regarding IRB review and the informed consent process; the other focuses on how cooperative research and the single IRB intersect.

Over the past decade, single IRB mandates were established for federally funded multisite research. Broadly speaking, most industry-sponsored trials haven’t needed to comply with these requirements, giving institutions flexibility to identify what their local IRB would review, versus what a single IRB would review centrally.

If the FDA’s proposed single IRB mandate becomes law, most multisite human research, with few exceptions, will require single IRB review. FDA oversight of clinical trials is typically determined by the type of research being conducted, rather than who is funding the study – with this in mind, it opens the door for more multisite studies requiring single IRB review.

Benefits to Using a Single IRB

How does this impact the industry as a whole? Industry sponsors have always had the option to require sites to rely on the study’s single IRB, but some sites have historically been able to opt out and rely on local review instead. Mandated single IRB review will help sponsors by removing local IRB review as an option in most cases and necessitating all sites rely on the same IRB for the study. There are many benefits to moving from a local IRB to a single IRB.

Consistent Study Conduct Across all Sites

In order for trials to get to their endpoints, it’s critical to conduct research the same way at every single site. One site can’t do something slightly different – they won’t get the consistent data to submit to the FDA for approval. By using a single IRB, this allows the same research to be conducted at every single site involved in the study. This also ensures the regulations are consistently applied for every single site.

During initial review, an IRB may request modifications to the protocol, informed consent form (ICF), and other materials to ensure participants’ rights and welfare are protected. With multiple IRBs reviewing a single study, that could mean multiple versions of the protocol, ICF, etc. in use with participants. This can lead to inconsistent participant protections as well as inconsistent study data. With a single IRB overseeing all sites, everything is much more consistent.

Streamlining Efforts

Additionally, required single IRB review would enable organizations to better streamline changes to the protocol. Say a particular study has 100 sites, and five or six of those sites’ local IRBs require specific changes to the protocol as a condition of approval. For sponsors and CROs, it’s burdensome and time-consuming to figure out which site materials to update and only update those. It’s also a task to keep track of who’s conducting which version of the protocol. Or, if the sponsor wants to simplify things and apply one IRB’s changes to the entire study, staff must go back through and communicate the changes to all those other various IRBs. With a central IRB, updates are streamlined since they are submitted just once centrally and apply for all sites at the same time, which leads to minimal disruption at the site level.

Working Together to Understand Processes

Working with a single IRB can enable sponsors to identify sites for a particular study, which also helps sites get studies up and running quickly and efficiently. The single IRB may also be able to help sponsor and CRO teams understand what needs to be in place (i.e., reliance agreement, items in the consent form) in order to move forward with a particular site. Even though the NPRM is not yet final, by communicating with your single IRB up front, it’ll help pave the way for an overall successful process.

Regulations for research involving devices, in vitro diagnostics (IVDs), and digital therapeutics differ from those governing pharmaceutical development. While drugs require Phase I-III clinical trials—and are also subject to post-approval tracking—digital therapeutics, devices, and IVDs may be able to leverage bench testing, animal studies, pilot studies, and training sets. These are usually followed by validation studies, pivotal trials, literature reviews, and even real-world evidence studies, depending on the individual product’s intended purpose and the risk level.  

Medical devices, IVDs, and digital therapeutics have the potential to bring significant health benefits to patients of every age group, including healthy populations and those with varying severity of health ailments and disease burdens. Interpreting evolving regulations for these devices is often a unique challenge for emerging biotech companies. Staying on top of evolving regulatory requirements for a complex medical device category can be overwhelming, even for well-established life science companies.  

How do you determine if clinical trials are needed for your device? Here are some ways to decide if clinical trials are necessary and navigate the compliance intricacies of a complex medical device category.  

Function Dictates Regulation 

It’s essential to understand how the product interacts with a patient, as well as what level of importance it holds to the patient’s health. In other words, what are the risks and benefits of the product? The greater the risk, the more likely a series of trials for market clearance or approval will be required. 

In the United States, a medical device, IVD, or digital therapeutic is categorized as one of the following: 

  • Class 1: Non-invasive, low risk to the patient, and subject only to “general controls” around registration, branding, and labeling. 
  • Class 2: Products posing a higher risk to the patient; most products in this category require a 501(k) premarket notification, meaning a detailed comparison to a device already in market.  
  • Class 3: Applied to products with the highest risk, or to Class 2 products that are the first in their category. These products will require clinical trial data to get to market, but with significantly fewer participants required as compared to a drug trial. 

Intended Use, Indication, and Mode of Action 

Intended use and indication for use are often confused or thought of as the same. Think of the intent or purpose for the intended use (e.g., what the device does) and the indication for use is the patient population, disease, condition, and duration of use. Additionally, consider intended users and the environment of use. These claims are those made on the product labeling, and they need to be successfully demonstrated in the clinical evidence. 

Consider three examples to determine your path: a tiny camera the patient swallows to take internal photos, a new blood test designed to indicate monkeypox, or a mobile device application monitoring a patient’s A1C levels.  

The indication follows the intended use, but it also places the product in the context of a disease/medical condition. It’s important to bear in mind the indication can change the product’s risk level. In the example above, the camera diagnoses intestinal disorders, the blood test diagnoses suspected infection, and the mobile medical app (MMA) supports patients with diabetes types 1 and 2.  

Finally, what is the product’s mechanism of action or mode of action (MoA), especially as it relates to patient interactions? Thinking about whether the product is invasive, non-invasive, significant, or non-significant risk, and how it operates inside or outside of the patient is crucial. This is how the product achieves its therapeutic effect. For instance, a harmonic scalpel vibrates as it cuts, a COVID-19 test detects SARS-CoV-2 antibodies by measuring antigens in a person’s saliva/mucus, and a digital therapeutic program electronically signals how or when a patient should adhere to best practices or adopt a positive-reinforced behavior.   

Gather and Publish the Evidence  

A comprehensive clinical evidence generation plan determines what critical data is needed as evidence indicating the product does what it is supposed to do safely. Some markets – specifically the EU – may require publication to obtain product approval. 

Most critical is understanding what kind of study to conduct. To find this answer, return to the type of product and its risk level to determine if a trial is required, and if so, what kind. Types of trials include:  

  • Pilot or feasibility: small study to collect safety results, proves a concept and can guide future study design 
  • Verification studies (training set): smaller studies designed to test a device or train an algorithm prior to design freeze 
  • Validation studies: larger studies designed to support the efficacy and safety – or sensitivity and specificity – of certain devices and/or algorithms claimed 
  • Demonstration of Equivalence: EU distinction for literature and other comparative evidence against an existing product’s performance 
  • In silico: Studies designed to simulate data without testing in humans 
  • Pivotal: Large, statistically driven study to confirm efficacy, safety, and risk-benefit 
  • Real-world evidence (RWE): Data is collected from real-world sources, including registries, electronic health records, administrative claims, etc. 
  • Post-market safety: usually in support of obligations after clearance or approval 
  • Human factors: to inform ease of use, features, labeling, and instructions by end users 

Stay focused on the future of the product after approval, when indications for other conditions may be added or the design of the product is adjusted. Approval may be the immediate goal, but it is likely not the product’s final goal.  

Maintaining regulatory compliance at research sites and institutions is no small feat – documents need to be updated and maintained in a consistent manner to ensure compliance. While regulatory management can take significant time and effort, utilizing an eRegulatory system can help staff increase productivity, improve compliance, and save money.

Advarra’s eRegulatory Management System (eReg) is designed to adapt to and streamline research site regulatory workflows. A 21 CFR Part 11 compliant system, eReg can benefit any type of organization, from the biggest academic medical centers (AMCs), down to individual research sites. This blog shows different eRegulatory use cases for different types of sites, as well as eRegulatory capabilities designed to serve all sites.

AMCs and Health Systems

Integrating a clinical trial management system (CTMS) enables the regulatory team to pull protocol details and place them into eReg. This saves organizations time while also ensuring consistency between information added in each platform. Once documents are filed and signed in eReg, they can be sent back and made available their CTMS.

For multi-site protocols, AMCs, cancer centers, and health systems can set up their protocol structure so it benefits them as the coordinating center. This allows staff to track their coordinating center documents, the participating sites, and documents the coordinating center files for each site. With document integration for multi-site protocols, coordinating centers can also send documents to every site simultaneously.

Utilizing an eReg system also allows for centrally managed credential and organization regulatory documents at AMCs and health systems. This ensures when an update is made for a staff member’s credential – or a document added for an organization – the new document automatically flows into any protocol the record is used on. This saves staff members time since they do not have to look up individual records to make sure credentials are present for each one.

Site Networks

Typically, site networks create and run a study as the coordinating center, and need to manage regulatory documents for participating sites on the study. Using an eRegulatory management system enables site networks to centrally manage their multi-site protocols while simultaneously connecting each site as they use the same system. This also lets documents flow between the multi-site protocol and sites, all within the same eReg instance.

Single Sites

As a single site participates on a protocol, they can connect to an eReg platform their coordinating center is using, and send their documents to the center from within their own eReg instance. If a site is using Advarra eReg, they can also receive documents from the coordinating center directly in the protocol inbox, making filing and organization easier as well.

Additionally, for sites using the Center for IRB Intelligence (CIRBI), they can integrate it with eReg. This allows studies to receive their IRB-approved documents directly into their protocol inbox from CIRBI. With this integration, staff won’t have to log into the IRB system, download the documents from that system, and re-upload them into eReg. This saves them time and reduces the chances of situations such as documents being uploaded twice or the wrong documents being updated into the system.

Similarly to AMCs, single sites have the ability to centrally manage credential and organization regulatory documents. When a staff member’s credentials are updated, or a document is added for an organization, this new document can automatically flow into any necessary protocol the record is used on.

All Types of Research Sites

While there are many organization type-specific benefits to using an eReg management system, there are plenty capabilities of the system designed to benefit every kind of organization. Additional benefits include:

  • 21 CFR Part 11-compliant electronic signatures: save users time to route for signatures, and ensures the organization remains compliant in their electronic signature usage.
  • Mobile signing: allow staff to sign documents from their phone, no matter where they are.
  • Electronic delegation of authority: a comprehensive and compliant delegation of authority log to be kept directly within the eReg system.
  • Regulatory templates: save time and eliminate redundant workflows by using predefined, templated builds for each new protocol.
  • Standard operating procedure (SOP) management: store SOPs in a central location, making it easy to find the latest SOP and share it as needed. eReg also can enable SOP-only review sessions, giving monitors access to SOPs during the site selection process.
  • Email integration: Input documents into the system easily, and have the ability to forward email correspondence or other documents received in email inboxes.
  • Investigational new drugs (INDs): Storage for INDs.
  • Review sessions: Enable organizations to grant limited eReg access to both internal and external monitors in order to more easily review documents.

As you work to streamline regulatory management, it’s important to understand all the ways an eReg platform can benefit your organization. Centralizing and integrating regulatory management processes and technologies is pivotal to successful operations at any site.

 

The implementation of the single institutional review board (sIRB) model has gained significant traction in recent years, particularly with mandates from federal regulatory agencies such as the National Institutes of Health (NIH) and the Office for Human Research Protections (OHRP). While this shift aims to streamline multi-site research, it has also introduced new complexities for institutions and IRBs.

A Brief History of Single IRB

Historically, IRB systems were decentralized, with each institution conducting its own ethics review for research involving human subjects. This system worked well when research was largely conducted within a single site. However, the rise of multi-site research in the 1990s and early 2000s highlighted inefficiencies in this model, as institutions conducting the same study were subjected to multiple, sometimes conflicting, IRB reviews.

In response, the NIH implemented a policy in 2018 mandating the use of an sIRB of record for all multi-site studies. This model was later incorporated into the revised Common Rule by OHRP in 2018. The goal was to reduce administrative burden, streamline study startup times, and enhance the efficiency of clinical trials without compromising ethical oversight.

How Single IRB Works

The single IRB model designates one IRB as the “IRB of record” responsible for overseeing the study for all participating institutions. This IRB is charged with ensuring compliance with federal regulations, while the other institutions, known as relying institutions, contribute through a local context review. This local review ensures site-specific policies, state laws, and community standards are considered.

The reliance process involves documentation between the IRB of record and the relying institutions, usually through reliance agreements like those provided by the SMART IRB platform. These agreements outline each institution’s responsibilities, reducing the need for negotiating individual agreements for each study. However, institutions must still undergo local reviews for issues such as radiation safety, pharmacy reviews, and other ancillary concerns.

Challenges in Implementation

While the sIRB model offers many potential efficiencies, institutions face several challenges during its implementation. One major challenge is navigating local context reviews. Although these reviews are not full IRB reviews, they still require the submission of materials to ensure site-specific policies and procedures are followed. This additional step can slow down the process, especially in institutions with less robust research infrastructures.

Moreover, establishing reliance agreements between the IRB of record and relying institutions can be time-consuming. Institutions may use agreements like SMART IRB, but not all sites are signed onto these platforms. In such cases, institutions need to draft and negotiate individualized agreements, which can further delay the process.

In addition to reliance agreements, many institutions are still learning how to effectively streamline the local context review process. The onboarding process for sIRB reliance can take longer than study teams expect, leading to frustration and delays in starting clinical trials.

Optimizing the sIRB Process

To make the sIRB model more efficient, institutions need to adopt established, clear reliance processes early. By using platforms like SMART IRB, which offer a master reliance agreement and other resources, institutions can streamline the reliance process and reduce time spent on negotiations. SMART IRB’s single sign-on approach allows institutions to bypass lengthy agreement reviews, as all parties agree to the same terms from the outset.

Institutions can also benefit from creating clear workflows for local context reviews. Using tools like two-part consent forms is key, which separate general study information from site-specific details such as HIPAA language and local contact information. This allows local institutions to review only the sections relevant to them, speeding up the process without compromising compliance or ethical review.

Another key to success is communication. Clear communication between the IRB of record and relying institutions is of utmost importance, particularly when managing expectations around timelines.

Regulatory Developments

The regulatory landscape for sIRB is continuing to evolve. In September 2023, the FDA published a draft rule proposing the expansion of the sIRB mandate to studies regulated by the FDA. Public comments are still being collected, but if the rule is implemented, it will mark a significant step toward harmonizing IRB requirements across federal agencies.

Moreover, OHRP’s recent draft guidance on sIRB addresses questions about local legal considerations, including how IRBs of record should handle state and local laws. Although the guidance is not yet finalized, it provides valuable insight into the role of sIRB in navigating local legal issues. A central resource or database of state laws can benefit institutions, helping them better understand legal requirements potentially impacting their IRB determinations.

While the sIRB model offers a more efficient framework for multi-site research, its implementation requires careful planning, clear communication, and a robust understanding of both local and federal regulations. Institutions investing in streamlined processes and leveraging tools like SMART IRB will be better positioned to overcome the challenges and fully realize the benefits of sIRB.

As federal mandates expand and guidance continues to evolve, institutions must remain flexible, adjusting their processes to ensure compliance while maintaining the highest standards of ethical review. By doing so, they can ensure the shift to single IRB not only reduces administrative burden but also enhances the integrity and efficiency of clinical research.

This February, Advarra’s “Honoring Clinical Trailblazers” video series paid tribute to the outstanding achievements of four pioneering African American physicians who defied the odds to make significant contributions to the field of medicine.

These physicians faced enormous challenges due to their race, gender, and societal barriers, but their passion for helping others and their unwavering commitment to advancing medical knowledge led to groundbreaking discoveries and changes, continuing to inspire and guide medical professionals today. We are incredibly grateful to the life science community for coming together to celebrate the legacies of these trailblazing physicians and their remarkable achievements.

Rebecca Lee Crumpler

Rebecca Lee Crumpler was one of the first African American women to graduate from medical school and to practice medicine. Crumpler’s focus on the care of women and children and her dedication to research led her to publish “A Book of Medical Discourses” in 1883. Her book covered a wide range of health topics, including the impact of poverty, lack of education, and discrimination on the health outcomes of African American women and children. Crumpler’s work helped to improve healthcare for the communities she served and advanced the field of medicine for future generations.

William Augustus Hinton

William Augustus Hinton was a clinical researcher and physician who made significant contributions to the understanding and treatment of syphilis. Despite facing racial prejudice and being denied opportunities in surgery, Hinton’s extensive knowledge of syphilis led him to develop a new method for diagnosing the disease, which was adopted by the U.S. Public Health Service. He also set up a laboratory technician program exclusively open to women, creating opportunities for women in laboratory medicine. Hinton’s remarkable contributions to clinical research continue to inspire and guide medical professionals today.

Charles Richard Drew

Charles Richard Drew was a pioneering African American physician and researcher who transformed the field of transfusion medicine. Drew’s work on long-term plasma storage and transfusions with plasma alone significantly broadened the scope and reach of those who could receive treatment. Despite facing obstacles such as racial segregation of blood donations and exclusion from the District of Columbia chapter of the American Medical Association, Drew’s impact on the field of medicine and social justice is still felt today.

Marilyn Hughes Gaston

Finally, Marilyn Hughes Gaston is a pioneer in the medical field for advocating for the improvement of health in underserved and minority families in the U.S. and abroad. Gaston’s groundbreaking research on long-term penicillin treatment for sickle cell disease led to nationwide newborn screening and prevention of complications through preliminary treatment. As the director of the U.S. Bureau of Primary Health Care, Gaston supplied healthcare for over 12 million disadvantaged people in the U.S., creating lasting change in the field of public health.

We are grateful for the opportunity to highlight the remarkable achievements of these trailblazing physicians. Additionally, we are honored to be part of a community taking the time to celebrate these physician’s contributions to the field of medicine. We hope their legacies continue to inspire and guide researchers for generations to come.

How do you know your experimental therapy is working? Sometimes, it can be as simple to determine as comparing drug A to placebo and measuring the physiological result with an approved assay. But what does “working” really mean when efficacy means something subjective, like quality of life, reduced psychiatric events, or less symptoms? 

In most cases, the results you are really looking for and trying to prove in a trial can be complex. How do you strategically plan your therapy and research objectives to improve the chances you will satisfy what the regulators are looking for and ultimately get your therapy approved for marketing? Can you use surrogate endpoints, multiple endpoints, what statistical power will you need, will diversity play a factor in planning your research strategy? All key questions to consider and address before the therapy even leaves the lab. 

One area receiving increased focus from the Food and Drug Administration (FDA) are trial designs incorporating multiple endpoints to support efficacy. FDA recently released guidance on how sponsors can approach multiple endpoints in their clinical trial design in a way which will likely satisfy the regulators when it comes time for marketing approval. This latest guidance also suggests and reenforces the need for an independent review of clinical events to establish unbiased verification of the endpoint, as outlined in the agency’s 2006 guidance. Similar guidance has been issued from the European Medicines Agency (EMA).   

Why Issue New Guidance?   

Therapies are increasingly complex – innovative cell and gene therapies, immunotherapies, and even traditional small molecule drugs are interacting with the human body in more advanced, multi-factored ways.  

When trying to demonstrate a therapy’s efficacy with potentially multiple complex modes of interacting with the human body’s cellular functions, sponsors naturally will include multiple endpoints to highlight and maximize the positive impacts of the therapy.  

In the new guidance, FDA alludes sponsors are increasingly including multiple endpoints in their trial designs presented to the agency. That the agency felt it was necessary to issue guidance on this specific topic implies there have been problems with multiple endpoint designs. These problems likely lead to delays in study startup and regulatory approval of innovative new therapies. 

When utilizing multiple endpoints to demonstrate potential efficacy of a new therapy, the recognized challenge is the trial designs require increasingly complex statistical methods to account for multi-variant and confounding variables. 

FDA is concerned these increased statistical complexities in a trial may increase the “likelihood of making false conclusions about a drug’s effects with respect to one or more of those endpoints … if there is no appropriate adjustment for multiplicity.” In short, FDA is acknowledging this is complex area, so make sure all clinical development and biostatistical experts are well-versed on how to design these types of trials to ensure startup and/or regulatory approval is not delayed. 

Approaching Multiple, Complex Endpoint Designs 

The task of developing protocols containing multiple endpoints is not impossible, but it needs to be appropriately thought out and integrated into the trial’s endpoint and statistical design.  

Determining the appropriate endpoints, and how best to measure them, is the first step. Sponsors need to carefully consider how they will prove safety and efficacy in a manner sufficient to satisfy the regulators. FDA is concerned that “failure to account for multiplicity when there are several endpoints evaluated in a study can increase the chance of false conclusions regarding the effects of the drug.” With that in mind, sponsors incorporating multiple endpoints in a trial must rigorously evaluate how to account for the array of endpoints potentially interacting or interfering with each other in such a way as to mask the true safety and efficacy of the therapy.  

In addition to having multiple primary endpoints, when evaluating the appropriate endpoint design for a trial, sponsors need to additionally consider the use of composite endpoints, co-primary endpoints, and multi-component endpoints. All of these depend on the nature of the disease condition and the modality of treatment interaction.  

Endpoint designs are as unique and varied as the disease conditions and therapies themselves. Developing the endpoint design and overall approach of a clinical trial program is mostly science, but there is a bit of art to it as well. 

Working with Statisticians  

FDA’s guidance highlights a number of statistical designs potentially suitable to account for multiplicity, including: 

  • The Bonferroni Method 
  • The Holm Procedure 
  • The Hochberg Procedure 
  • Prospective Alpha Allocation Scheme (PAAS) 
  • The Fixed-Sequence Method 

The sponsor’s biostatistical team and the independent data safety monitoring board (DSMB) statisticians should be well versed in these statistical methods. These groups are equipped to ensure the appropriate method is selected and detect safety issues within the data, so participants are appropriately protected. 

Engaging an Independent Endpoint Adjudication Committee (EAC) 

With complex and multivariant endpoints comes an increased need for medical experts to carefully scrutinize the clinical events and determine if the endpoint(s) have been met. Typically, an independently administered EAC handles this evaluation. Also known as a clinical event committee (CEC), EAC members evaluate a clinical event in the context of the protocol and the individual participant’s medical information. There are usually three or more reviewers who evaluate the dossier and determine whether the event meets the endpoint. 

An EAC’s determinations are incorporated into the overall trial data. As experience and data is accumulated, the statistical model begins to be satisfied. Eventually, an evaluation by the independent DSMB of accumulated data is completed to verify there are no emerging safety or futility issues. 

The Importance of an Independent EAC for Regulatory Approval 

The core role of an EAC is to have medical experts independently evaluate a clinical event to determine if a defined endpoint or clinical threshold has been met, or if the event should be categorized in some way (e.g., caused by the study drug or by an underlying condition). Such work requires medical judgment and a lot of associated information to make the determination. This is particularly important when untangling the complexities of multivariant endpoints.

Both FDA and EMA stress in their guidances the importance of the EAC evaluators being independent of those sponsoring or conducting the research. Using an independent EAC provides assurance to the regulators the endpoint determinations have been carefully evaluated by multiple experts without the impression of bias. 

What to do When Developing Clinical Trials  

FDA is clearly concerned about this topic – thus the need to issue guidance. Sponsors should take note and ensure their trials utilizing multiple endpoint designs have appropriate statistical designs to account for multiplicity.  

Study the statistical methods, plan the trials, and talk with experts and FDA early about trial design plans. Do not end up running a trial only to find the endpoint design, or the associated independent EAC/DSMB plans, are not adequate to satisfy the regulatory agency. 

Bottom line: Designing a clinical trial approach and program is complex. You can do a lot of things in a trial; it’s mostly science and part art. FDA is watching this area of trial design, so if you are planning a trial with multiple endpoints, be certain you have the right clinical and statistical experts as part of your team.   

Metrics in general are one of the ways we can gauge how well a program or service delivers. In the world of institutional review boards (IRBs), some measurements can be easily ascertained, such as review turnaround times and submission volumes, which help the human research protection program (HRPP) assess the IRB’s activities.

Measurements such as review timelines and volumes are typically easy to obtain and can inform the speed at which the IRB assesses proposed research and provides a determination back to the researcher. Measuring and seeking to improve upon such metrics can clearly benefit the research enterprise by facilitating scientific progress, offering faster study startup and subsequent participant enrollment.

However, there are other aspects of IRB quality and effectiveness that are more difficult to quantify but could provide equally useful insights. In this blog, we explore the challenges of defining and measuring “quality” IRB review and certain key efforts by research community stakeholders to overcome such obstacles.

Quality IRB Review Assessments

When attempting to identify the factors that define a quality IRB review, most stakeholders agree the goal is to determine whether the IRB’s actions truly improved protections for research participants.

The IRB’s primary mission is to protect the rights and welfare of participants in research. Thus, any measurement of IRB quality should assess how the IRB’s actions furthered (or distracted from) that primary responsibility. For example, questions that may be asked include, but are not limited to, the following:

  • Did the IRB’s changes mitigate or lessen the study’s potential risks for participants?
  • Did the IRB focus on what will truly make study participation safer?
  • Did the review focus on “need to have” regulatory issues vs “nice to have” preferences?
  • Does the review process help advance scientific progress with timely, informed ethical inputs?

Such measurements are not necessarily easy, but they can provide real insights into the IRB’s effectiveness in meeting its regulatory responsibilities. While other measurements may also be valuable, the primary focus in establishing IRB quality metrics should be on how the IRB is achieving its mission.

With that in mind, factors that may be indicative of a quality IRB review might include evaluating the types of changes an IRB may request or require prior to approving a research protocol. These changes can then be further categorized into “must have” versus “nice to have” as one way to measure if the changes led to improvement of participant protections.

It could also involve tracking how many times the IRB and submitting entity (e.g., study sponsor or principal investigator [PI]) go back and forth with questions or changes during the pre- and post-review process. Extending this back-and-forth may suggest the IRB’s instructions are unclear or incomplete. Alternatively, it may indicate the initial questions posed by the IRB reviewers led to protocol improvements, allowing the IRB to fully evaluate the criteria for approval – suggesting the extra time was well spent.

Once the metrics are defined, you can measure the data over time to drive improvement.

Current Initiatives to Measure IRB Quality

The Association for the Accreditation of Human Research Protection Programs (AAHRPP), the accrediting body for HRPPs, has recently provided accredited organizations with metrics to help “identify and support high-performing practices for HRPPs.” Their metrics focus on comparing information reported by academic organizations, hospitals, and a combination of all AAHRPP-accredited organizations.

The AAHRPP data includes elements like IRB review times, IRB staffing and budgets, the number of active studies the HRPP oversees, and applicable regulatory frameworks. HRPPs can potentially use the information from AAHRPP to, for example, help ensure appropriate staffing and budgets to support the review of research or compare review timelines with high-performing peers (assuming the metrics provide a fair comparison).

However, it’s unclear whether these quantitative metrics equate to the ultimate goal of protecting research subjects; rather, they help evaluate the quality of IRB operations. Evaluating quality IRB review is more difficult – consider:

  • How do you measure and compare ethical considerations?
  • How do you evaluate the consistent resolution of controverted issues?
  • How did the IRB ensure the protection of research subjects?

The Consortium to Advance Effective Research Ethics Oversight (AEREO) has studied and thought about this challenge since 2018. AEREO considers the outcomes of interest for measuring IRB and HRPP effectiveness to collectively be:

  • Protection of research participants
  • Promotion of justice
  • Creation of ethical research cultures
  • Public trust in the research enterprise
  • Socially valuable, scientifically valid, and ethical research

AEREO concedes these outcomes can be difficult to measure because they are in part not easily operationalized.

AEREO’s ongoing projects have led to a number of recommendations for IRBs and HRPPs assessment, such as:

  • IRBs can set up a process to evaluate the scope of meaningful discussion and debate about key ethical and regulatory issues during board meetings
  • HRPPs can implement survey assessments to gather research stakeholder feedback to help answer the question of what impact the IRB’s review had on the research conduct

Continuing research into how best to measure IRB quality or effectiveness will help move away from anecdotal beliefs. For example, if an IRB frequently uses outside experts, it might lead one to believe the membership composition was not appropriate. However, this could alternatively be an indication of a high-performing IRB. Recognizing the need for added expertise can help ensure knowledgeable review.

Projects such AEREO’s Institutional review board use of outside experts: What do we know? found the use of outside experts have important implications for IRB quality. A subsequent survey of IRB chairs confirmed appropriate expertise is critical to assess essential study elements.

Moving Forward

There are currently more questions than answers. But it’s important we continue to press on this to ensure the best possible participant protections and move the needle toward the development and adoption of specific, measurable goals.

Advarra believes in quality in everything we do, and we are committed to helping the research community develop IRB quality standards. As part of this commitment, we have collaborated with other stakeholders to review and to make sense of existing guidance and other research. We have also launched a working group focused on defining what makes a “quality IRB.”

We look forward to continuing to collaborate with our IRB colleagues and other stakeholders to better understand and apply what “quality” means for IRB review.

Medicare coverage analysis (MCA) is a systemic process of developing a billing plan for a clinical research study. Also known as coverage analysis, MCA provides an in-depth analysis of how all the items and services listed in the clinical research protocol are billed per guidelines provided by the federal agencies.

The Centers for Medicare and Medicaid Services (CMS) provides information and guidelines to determine whether billable items and services to be billed to the third party (insurance/patients) as routine cost or will be paid by the sponsor as a research-related procedure. Since 2000, Medicare has covered the cost of the routine care for the Medicare beneficiaries who are enrolled in qualifying clinical research studies. Effective January 2022, Clinical Treatment Act requires all U.S. states and territories to cover the cost of routine care for the Medicaid beneficiaries who are participating in a qualifying research study.

Advantages of Having an MCA

Developing a billing plan by performing MCA will help both the individual research site and sponsor estimate their expenses on protocol-required items and services. Clinical research studies enrolling human subjects also need to adhere to the approved MCA-generated billing plan if routine services are billed to the patient or their insurance. If not, sites enrolling the human subjects may face serious consequences, including federal lawsuits, financial penalties, and/or the ban of CMS coverage for the applicable institution or investigator. Additionally, by performing an MCA, research participants are assured of the financial liability (payments and copayments for the items and services) while participating in the clinical research.

Performing an MCA

The first step in considering what items and services are covered by insurance is first determining whether the clinical trial is eligible for coverage. The National Coverage Determination (NCD) 310.1 for Routine Costs in Clinical Trials outlines the requirements for clinical trials to be deemed eligible for coverage.

If the study is determined to be a qualifying clinical trial, each potentially billable item or service listed in the protocol should be analyzed to determine coverage. NCD 310.1 outlines coverage routes available for items or services provided in absence of a clinical trial (e.g., conventional care), performed to monitor known human side effects of an investigational agent, and/or considered reasonable and necessary for the management of the patient’s underlying condition. Further support can be obtained in referencing peer-reviewed treatment guidelines approved by Medicare.

Please note, service-specific NCDs and local coverage determinations (LCDs) may further affect coverage. Service-specific NCDs and LCDs should be prioritized when determining coverage, as any limitations noted will trump support found in peer-reviewed guidelines mentioned above.

It is also important to note coverage must remain consistent across the entire patient population. As per NCD 310.1 and ethical standards, no costs should differ between two patients entering the same clinical trial. If an assessment is determined to be routine care for one patient but solely research-related for another, the assessment in both patients should be covered by the sponsor conducting the clinical trial. This is yet another key benefit of performing an MCA, where potentially hidden costs are identified prior to budget execution.

A highly valuable tool for research staff, electronic consent (eConsent) can simplify the consenting process for both staff and participants. Used effectively, eConsent can increase consenting quality while reducing audit findings at sites. As the industry continues to shift from studies conducted exclusively in person to more convenient hybrid formats, eConsent can be very useful. 

When organizations begin to implement an eConsent platform, there are various things to consider to ensure a seamless implementation process. 

Understand Organizational Requirements 

Before implementing a specific eConsent tool, it may be helpful to understand how this can directly affect not only your organization, but other review committees as well. Specifically, you will need to consult your independent review board (IRB) as you use this platform for informed consent purposes. 

Depending on the individual IRB, processes may differ. For example, some IRBs may not require approval of a specific eConsent system, but rather, rely on an attestation stating the eConsent is aligned with the approved consent. In other cases, some IRBs may review the system one time, and any subsequent protocols on the same system are fine. However, other IRBs may want more detailed documentation and screenshots. 

In order to effectively understand your organization’s processes, the best thing you can do is speak directly with your IRB. They are there to help you and are willing to answer any questions you may have to ensure a seamless review. 

Consider Participant Population 

Equally important as organizational requirements, sites must consider their participant population and if the process they are using is effectively serving them. The right process will depend on the type of study conducted; a low risk study has a different process compared to a high risk study. There are also additional factors of the participant population staff need to consider, such as: 

  • Learning styles 
  • Access to email 
  • Access to a clinic 
  • Language 

Finding an eConsent platform to support multiple options in regard to language, location, or learning styles is key to ensuring a seamless user experience for participants. Thoughtfully implementing an eConsent platform tailored to your participant population can improve your organization’s patient centricity and help participant-study retention. 

Thoroughly Set up the eConsent Platform 

Before staff teams begin to use the eConsent system, it must be successfully implemented so they can effectively use it. Investing in the platform’s configuration setup up front will save staff headaches in the future. It gives staff a chance to become confident with the platform prior to a study, and when they work with participants to navigate the platform, it makes it easier for participants to understand what they are using. The more staff understand how to navigate the system, the easier it will be for them to teach participants, which also saves participants time as they use it. 

As staff are going through the setup process, it’s helpful to know the way they can configure the eConsent system to streamline the consenting process. eConsent allows staff to configure various requirements, such as signatures, initials, or checkboxes. Additionally, it allows staff to build “rules” or “required fields” around document signatures. This enables coordinators to complete their tasks and necessary signatures (and completing them themselves).  

Conduct a Mock Visit 

With everything set up in the consent platform, to test everything out, sites may want to consider conducting a mock visit. This is a great way to test the workflows for both participants and staff. Mock visits can be helpful for both remote and in person consenting processes.  

While a mock visit is helpful for many reasons, it’s particularly beneficial as research staff are getting ready to use it with trial participants. For many patients, this will be the first time they use a platform to consent, rather than setting up an appointment to go into a clinic to walk through it with a coordinator. They will only be confident using the system if staff are knowledgeable and thorough in explaining how it works. Conducting a mock visit will enable staff to see eConsent from the patient’s viewpoint, understand what they see as they use the platform, and this will help staff better explain the tool as patients navigate it.  

Mock visits are also beneficial for staff. Doing a test-run of the platform helps ensure everyone is on the same page and coordinated within the system. Encouraging staff to test out the system helps them see where sticking points could occur within the system. For example, going through a visit may help staff see if all required initials or signatures are marked, or if one particular section of consent needs to be explained in further detail. 

An eConsent platform has the ability to transform how participants understand the study they are a part of, and can make the process easier on sites’ behalf as well. Taking steps like these helps ensure your organization is set up for success well before the first patient successfully uses the platform.  

New privacy regulations seem to form every few months, especially with individual U.S. states adopting their own privacy regulations (e.g., the California Consumer Privacy Act or CCPA). Endpoint adjudication committees (EACs), also called clinical event committees (CECs), receive potentially identifiable research data from all over the world. Because of this, they need to stay abreast of these rapidly developing requirements and have systems in place to ensure data compliance and protection. This blog explores what it takes for an EAC/CEC to adequately support worldwide clinical trials.

The Global Reach of EACs and CECs

Pivotal research typically happens globally, from North America to Asia to Europe, and everywhere in between. While sponsors may have country- or region-specific regulatory support, there is typically just one EAC/CEC covering all worldwide data. Having one set of adjudicators across the entire trial aids consistency of determinations and allows for a central decision-making framework.

For the independent EAC/CEC administrators, this means information about events happening worldwide need to be adjudicated. And those pieces of medical records data, scans, electrocardiogram (EKG) results, digital imaging and communication in medicine (DICOM) materials, and other source materials typically have some form of privacy regulation attached to them from the source country.

Even if the materials are sufficiently redacted by the site or sponsor, most pieces of information in the adjudication dossier are coded with a participant number; in the world of international privacy regulations, the code number can mean the data or images for all intents and purposes might as well have the participant’s name on it. This means even if you code the data, the international privacy regulations apply – even if the Health Insurance Portability and Accountability Act (HIPAA) does not.

A Global Patchwork of Regulatory and Privacy Standards

The list of privacy regulations is as unique as the countries who make them:

A recent report from the United Nations Conference on Trade and Development (UNCTAD) indicated nearly 80% of the world’s countries either have or are developing privacy regulations. Almost all regulations impact the type of data for the EAC/CEC to complete its evaluation of individual clinical events occurring in a clinical trial.

Source: United Nations Conference on Trade and Development

EAC and CEC administrators also need to consider each of the 50 U.S. states and individual EU zone countries may also have privacy regulations which go beyond HIPAA or GDPR (e.g., California’s CCPA and Virginia’s Consumer Data Protection Act or VCPDA).

With this global patchwork comes the responsibility of the EAC/CEC administrator to address and adapt to each.

How do These Frameworks Apply to Information Sent to the EAC or CEC?

The core role of an EAC/CEC is to have medical experts independently evaluate a clinical event to determine if a defined endpoint or clinical threshold has been met, or if the event should be categorized in some way (e.g., was it caused by the study drug or an underlying condition). Such an activity certainly requires medical judgement and access to a lot of associated medical information to make the determination on the event.

Sponsor- or site-provided information is compiled by the EAC/CEC administrator into a dossier, which the adjudicators use to make their event assessments. Sites or sponsors almost always redact this information to remove and replace overtly identifiable information. It would be very rare an EAC/CEC would need to see identifiable information in order to make their adjudication determinations. Under the U.S. HIPAA privacy framework, this redacted and coded information would likely be considered a de-identified data set, thus not covered under HIPAA at all.

In contrast, for coded information coming from EU zone GDPR countries, or from other international privacy regulation regimes modeling GDPR’s framework, the coded information received by the EAC/CEC would likely be considered pseudo-anonymized data. Therefore, it would still be protected under the source country’s applicable privacy protections.

For coded information coming from EU zone GDPR countries, or from other international privacy regulation regimes modeling GDPR’s framework, the coded information received by the EAC/CEC would likely be considered pseudo-anonymized data.

Therefore, it would still be protected under the source country’s applicable privacy protections.

What do You Need to Keep in Mind?

An organization that understands the implications of worldwide privacy regulations and their impact on research will be more successful and reduce regulatory risk. The CEC/EAC administrator’s adjudication platform and associated company policies and procedures need to conform to all applicable privacy standards. Sponsors, contract research organizations (CROs), and sites need to work with a reputable partner for independent EAC/CEC administration.

Depending on the privacy regulation, the sponsor will typically consider the EAC/CEC administrator to be a data controller. Therefore, the sponsor organization would need to have appropriate policies and procedures in place, as the controller organization, to verify their associated data processors (e.g., the EAC/CEC administrator) conform with applicable regulatory standards.

With this in mind, it’s important to work with an EAC or CEC administrator who understands the diverse global data regulation landscape. A partner experienced in navigating this space likely has at least consulted with experienced international privacy experts to help ensure the EAC or CEC and associated enabling technology are properly set up to meet the necessary regulatory requirements.

What Else Should Sponsors Think About?

Sponsors need to think about more than just privacy regulations when considering who to work with for independent EAC/CEC administration. They also need to consider technical regulations applicable to the adjudication platform used by the administrator.

For worldwide clinical trials, the adjudication platform likely needs to comply at a minimum with U.S. FDA Part 11 and EU Annex 11, be operated in a SOC 2 compliant data center, and be developed following a GAMP 5 validation methodology.

An EAC/CEC administrator’s adjudication platform should conform with these basic international validation standards in order to compliantly provide adjudication services on a worldwide clinical trial.

Conclusion

Bottom line: Running a worldwide clinical trial is not easy. It takes discipline and a deep understanding of the rules. The independent EAC/CEC supporting the trial needs to be just as well versed in those rules, so working with an experienced partner who has a dedicated focus on these issues is key to the smooth operation of the trial and protection of the participant’s data.

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