Clinical research is a vital driver of medical progress. Yet, many people are unaware of the essential role of institutional review boards (IRBs) in protecting clinical trial participants by ensuring compliance with human subject protection requirements. With more than three decades of experience, Advarra is dedicated to advancing clinical research by providing expert oversight. As a trusted partner in supporting the advancement of life-changing therapies, Advarra prioritizes transparency, compliance with regulatory requirements and guidance, integrity, and participant safety in every trial. The company’s rigorous review process, conducted by professionals—physicians, clinicians, therapeutic area experts, pharmacologists, and others—with deep expertise across various scientific disciplines, as well as non-scientists who provide ethical balance and participant advocacy, ensures that trials meet regulatory requirements and the highest ethical standards and minimize risks to study participants

What is Clinical Research? 

Clinical research tests new treatments and therapies to determine their safety, effectiveness, and potential to improve health outcomes. It is the foundation of medical innovation. Advancement in treatment of diseases—from cancer to diabetes to rare diseases—have all come about because of clinical trials.  Clinical trials progress through several phases:

  • In Phase I, the focus is on testing the safety, dosage, and side effects, rather than effectiveness of a new treatment in a small group of participants.
  • Phase II further assesses safety, investigates whether the new treatment is effective, and determines the optimal dose.
  • Phase III involves more significant groups of participants to confirm the new treatment’s effectiveness, monitoring long-term safety, and comparing it to existing therapies. 

Participants in clinical trials bravely volunteer to help test new treatments, contributing to scientific advances that ultimately stand to benefit society. This process ensures that new therapies meet the U.S. Food & Drug Administration’s standard for safety and efficacy. A critical part of clinical trials is to learn and confirm scientific assumptions, and to incorporate learnings to enhance the study protocols for the sake of safety, efficacy and efficiency to introduce products to patients in need.

The Vital Role of Institutional Review Boards (IRBs) 

As set forth in the federal regulations that govern the conduct of clinical trials, an IRB is an independent group of experts, including scientists and non-scientists, that reviews clinical trial proposals to ensure they meet ethical standards that are designed to protect participants’ rights. The role of the IRB is crucial in examining clinical trial designs to make sure the research complies with regulatory requirements and is ethically appropriate, informed consent procedures are thorough, clear, and transparent and that patient recruitment materials are accurate and not misleading. The IRB achieves its mission through a comprehensive and thoughtful review of study-related information/documentation (e.g., protocol, investigational product information, informed consent form(s), other participant facing materials).  This process better enables investigators and participants to engage in a discussion that empowers participants to fully understand the nature and potential risks and benefits of the trial, before agreeing to participate.  The role of the IRB is to review the study documentation and Investigator qualifications, collect safety reports, and evaluate requests for modifications to the study. The IRB does not monitor patients nor advise the sponsor on the design of the study.  Moreover, the IRB does not evaluate patients for inclusion or exclusion in a given clinical trial; such determinations are made by the investigators responsible for the conduct of each study. Advarra’s IRB is highly experienced and works diligently to provide expert oversight, ensuring that every clinical trial adheres to the highest ethical standards and is compliant with applicable regulations. 

The Impact of Clinical Research: Empowering Participants and Advancing Medicine

The existence of clinical trials is the reason why many life-saving treatment options are available today. For example, these trials may help to advance cancer treatments and chronic disease management medicines and potentially offer patients access to cutting-edge therapies that may not yet be available through conventional medical channels. 

The Future of Clinical Research

Advarra recognizes that clinical research is an essential component of medical progress, and we remain dedicated to upholding the highest standards of ethics, integrity, and regulatory compliance. 

Through expert oversight, Advarra works hand-in-glove with the most experienced researchers in the United States and Canada to advance new scientific discoveries. By remaining at the forefront of clinical research, Advarra is helping scientists and industry leaders bring new treatments to market and into the hands of patients who need them.

Institutional review boards (IRBs) play a crucial role in the ever-evolving field of clinical research. For more than 35 years, Advarra has been committed to protecting the rights and welfare of clinical trial participants while helping to improve healthcare outcomes, advancing medical knowledge, and bringing innovative, life-extending treatments to market that benefit millions of patients worldwide.

The Value of Clinical Research

Clinical research is the engine that drives medical innovation, leading to the discovery of new drugs, treatments and medical devices that enhance patients’ access to treatment options, improve patient care and outcomes, and transform the healthcare landscape. Innovations in fields such as immunotherapy, cancer and chronic diseases owe their existence to clinical trials, which judiciously test and evaluate safety and efficacy. Without clinical research, these medical breakthroughs would remain out of reach for patients. Over the years, Advarra has reviewed a wide range of clinical research studies and worked every day alongside leading pharmaceutical manufacturers, medical researchers, and healthcare institutions. Advarra ensures that clinical trials comply with the U.S. Food and Drug Administration’s (FDA)  regulations on good clinical practice, which are based on ethical standards outlined in frameworks such as the Belmont Report and the Declaration of Helsinki.

Protecting Trial Participants

Trial participants are courageous volunteers, and every step must be taken to ensure their rights and welfare are protected. That is not to say that they do not face potential risks. This is why IRBs are tasked with conducting an ethical review of clinical trial proposals to ensure participants are  informed of risks before and during their participation in any trial.

Advarra prides itself on not only providing ethical review services but also performing this critical work in a manner that fulfills regulatory requirements.  For example, Advarra’s IRB is composed of approximately 200 experts, including scientists with diverse and extensive therapeutic area expertise, allowing for specialized and highly knowledgeable reviews, as well as non-scientists such as legal experts, ethicists, and members with expertise in vulnerable populations offering a different perspective than members with scientific/medical backgrounds.   

Expertise and Experience

Advarra’s value to clinical research is driven by its team of dedicated professionals and collaborations with highly qualified research experts. Advarra draws members from leading academic institutions, government agencies, and clinical research organizations. This includes researchers, ethicists, and compliance professionals with decades of experience, many of whom have worked with prominent institutions and top academic medical centers. The team also receives ongoing training and professional development to stay at the top of current clinical research practices.  

Furthermore, Advarra’s IRB includes hundreds of expert members, many of whom bring expertise and experience in several therapeutic areas and disciplines, including oncology, bioethics, investigational pharmacy, internal medicine, psychology, physiology, radiology, public health, pediatrics, nursing, and social and behavioral science. Many individuals that belong to Advarra’s extended network of experts are active or recently retired clinicians from academic and large network clinical and hospital entities such as Harvard University, Mayo Clinic, Vanderbilt University, and several National Institutes of Health designated Comprehensive Care Centers.

This unique depth of expertise allows Advarra to maintain the highest standards in clinical trial reviews.

Industry-Leading Ethical Standards

Advarra is organized and operates in compliance with U.S. and Canadian regulations and policies governing research with human subjects, as applicable, and is fully accredited by the Association for the Accreditation of Human Research Protection Programs (AAHRPP).  Advarra’s commitment to quality and ethical conduct is apparent in our internal policies and operational procedures, which often exceed federal regulations and set a benchmark for the industry.  One such area that has always remained a focus for Advarra is our commitment to a robust set of policies that govern potential conflicts of interest.

Moreover, Advarra separates client services and IRB review teams to guarantee each clinical trial we review is unbiased.  This firewall ensures that clinical trial reviews focus solely on ethics and scientific integrity.  

Investing in Improvements

At Advarra, we understand that to maintain our position as a trusted partner to the clinical trials ecosystem, we need to invest in our people, processes, and technology.  While other companies in the clinical trial industry are reducing staff and investments in technology, Advarra is committed to fostering continued innovation. One significant investment in this area is the Center for IRB Intelligence (CIRBI) platform, which streamlines the review process, improving the speed and quality of clinical trial evaluations. Over $25 million has been invested in this platform to enhance the effectiveness of the IRB process without compromising its thoroughness. Advarra has continuously hired additional staff to manage the increasing workload, demonstrating our commitment to continuous improvement and ensuring our standards align with Advarra’s best-in-class practices.

Looking to the Future

Advarra’s work benefits clinical trial participants and the entire healthcare ecosystem. By ensuring clinical trials are ethical and are held to rigorous standards of scientific integrity, Advarra helps advance the development of new therapies and treatments. Advarra’s commitment to quality, transparency, and continuous improvement sets a high standard for clinical research, ultimately advancing medical science and improving patient outcomes worldwide.

2024 has been a year of growth and evolution in clinical research. The coming year is expected to be no different. As we look to 2025, Advarra thought leaders have compiled predictions and perspectives on key topics shaping the industry. These topics include perspectives on how artificial intelligence (AI) will be leveraged in clinical research, key regulatory trends shaping the industry, the movements of site consolidation, the continued challenges (and potential solutions) of study startup, and more.

2024 has been a year of growth and evolution in clinical research. The coming year is expected to be no different. As we look to 2025, Advarra thought leaders have compiled predictions and perspectives on key topics shaping the industry. These topics include perspectives on how artificial intelligence (AI) will be leveraged in clinical research, key regulatory trends shaping the industry, the movements of site consolidation, the continued challenges (and potential solutions) of study startup, and more.

Prediction Area: Artificial Intelligence

Advarra Thought Leader: Jeff Sidell, CTO

AI in clinical research is poised for significant evolution, driven by advances from organizations like OpenAI and Anthropic. These companies are laying the groundwork for more sophisticated AI applications designed to transform clinical operations, improving both efficiency and productivity. In addition to generative AI, there is promise in predictive analytics, which can leverage historical and real-time clinical operations data to forecast outcomes, optimize resource allocation, and streamline timelines.

AI can also automate labor-intensive tasks, such as extracting key information from protocol documents to populate downstream systems. For example, AI tools can pull data from protocols and automatically update clinical trial management systems (CTMS), reducing manual entry errors and increasing workflow speed. This same data could be used to auto-generate study calendars based on the schedule of assessments, streamlining trial planning.

Moreover, AI can enhance study design by analyzing past trials and recommending improvements based on data patterns. Site selection will also benefit from AI by identifying optimal sites with a high likelihood of recruitment success, considering factors like demographics, past performance, and patient availability. As AI continues to evolve, its ability to transform the efficiency, quality, and scalability of clinical research will grow exponentially.

Prediction Area: Study Startup

Advarra Thought Leader: Ashley Davidson, VP Product – Sponsor Technology

Clinical research study startup will continue to pose challenges for sponsors as the industry’s tendency to address individual process pain points with focused, siloed solutions persists. While these targeted technologies may offer immediate relief in specific areas – such as site identification, contract management, or regulatory document collection – they often fail to integrate seamlessly with other aspects of the startup process.

This fragmented approach results in inefficiencies and data silos, slowing down study initiation rather than accelerating it.

Sponsors, in pursuit of solving these isolated issues, may overlook the broader need for a more connected and streamlined workflow across the entire study startup process. To truly address the complexity of study startup, a more holistic strategy is needed – one prioritizing system integration and data connectivity. By linking key steps, such as site selection, regulatory submissions, and contract negotiations, sponsors could improve transparency and reduce redundancies.

The future of study startup will likely involve an increasing recognition of the value of connected systems enabling real-time data sharing and decision making. However, achieving this vision will require a shift from focusing solely on fixing individual pain points to building a unified, interoperable framework to bring together data and processes across the study startup ecosystem.

Prediction Area: Regulatory

Advarra Thought Leader: Julie Ozier, SVP Global Review Regulatory

Regulatory bodies, particularly the U.S. Department of Health and Human Services (HHS) and the Food and Drug Administration (FDA), will continue to drive harmonization in the clinical research industry. Over the years, these agencies have made significant strides in aligning their rules and guidance, as seen with the harmonized definition of an institutional review board (IRB), informed consent, and the recent implementation of the single IRB (sIRB) model. This push for consistency aims to streamline regulatory processes and reduce administrative burdens for sponsors and researchers.

As the harmonization effort advances, the focus will likely shift toward refining guidelines and regulations for vulnerable populations, including children, pregnant women, and prisoners. These groups require special protections in clinical trials, and aligning regulations across agencies will simplify the ethical review and approval process for studies involving these populations. This consistency will enable more efficient trial oversight while ensuring the highest standards of protection for vulnerable participants.

Continued harmonization will not only ease the regulatory burden but also facilitate faster study initiation and improve compliance. It will foster a clearer, more unified regulatory framework, reducing confusion for sponsors and researchers, ultimately enhancing the inclusivity and efficiency of clinical research involving vulnerable groups.

Prediction Area: Increased Site Consolidation

Advarra Thought Leader: Christine Senn, SVP Site/Sponsor Innovation

After a year of site consolidation slowing down due to difficult times for most independent sites from Q3 2023 to present, 2025 will see an upsurge in consolidation.

There are varied opinions about site consolidation, but I would like to add some perspective: Pharmaceutical companies routinely buy up small pharmaceutical and biotech companies and add them to their portfolio. Contract research organizations (CROs) only came into existence in the 1980s and were, by default, all small when they started; consolidation brought us the large CROs we know of today and are used for global trials. Hospital systems built up smaller, independent hospitals and independent regional clinics, all in the hopes of improving profit margins by consolidating centralized operations – which has the goal of keeping these clinics and hospitals in business in order to reach more patients.

Site consolidation is much the same. It has its pros and cons, but I will speak to the positives of such consolidation. They are, of course, similar to the reasons all the businesses just mentioned aim to consolidate. First, in nearly any business in any industry, staying afloat financially is difficult. Consolidating resources and streamlining processes can improve profit margins, which can keep businesses afloat longer.

Second, there will always be some locations or business arms not doing well financially. In the case of clinical research sites, no sponsor wants to see a site close while they are in the middle of a trial. Being part of a larger network, the network is able to provide resources to stay afloat and continue doing research even while losing money. This is also true of academic medical centers, which often see their research activities losing money while the other business lines are able to keep this important endeavor afloat. It is often critical to conduct research without much, if any, profit.

Third is a related topic. As we approach a crisis of a lack of principal investigators and have become increasingly acutely aware of inadequate diversity and clinical trial enrollment, opening new sites is paramount to helping the industry as a whole. Again, a site network has the ability to help keep a new site bankrolled. In my experience, a new site is likely to lose money for up to a year.

Fourth, consolidation at a global level can improve trial enrollment and efficiency. There are many ways in which being a small biotech company, small CRO, or individual site is absolutely wonderful for this industry. At the same time, we know global sponsor companies and global CROs offer unique benefits in reach, understanding country-specific regulations, having staffing already onsite in various locations, etc. Global site networks offer a similar benefit.

Prediction Area: Industry Standards

Advarra Thought Leader: Elisa Cascade, Chief Product Officer

The increasing complexity of clinical research studies will continue to have far-reaching implications, particularly in terms of cost and efficiency. As protocols grow more complex, the associated cost to operate these studies rises at a time when sponsors are under pressure to manage expenses while also accelerating the pace of research. This tension between cost containment and speed to market highlights the need for innovative solutions to streamline processes and consolidate technology systems all without sacrificing quality.

One promising approach is the adoption of industry-wide standards which open the door towards greater connectivity and a digitized data flow. For example, use of a common protocol template can drive consistency and efficiency, reducing the time and effort needed for study design and technology setup. Standardization also simplifies integration between site and sponsor technology systems, enabling all users to operate in their system of choice and data and documents to flow throughout the connected ecosystem.

While the industry will continue to identify opportunities for standardization, implementing these standards will remain a challenge. Diverse stakeholders, competing priorities, the need for change management in large, conservative, process-driven organizations, and in some cases, older, monolithic technology can all slow down progress. To realize the full benefits of standardization, the industry must work collaboratively, overcoming hurdles in adoption and ensuring new standards are embraced and applied consistently across all phases of clinical research.

Selecting an electronic institutional review board (eIRB) system is a critical decision for institutions looking to streamline their research compliance processes. Navigating the eIRB landscape can be overwhelming for researchers, human research protection program (HRPP) team members, and institutions alike.

The responsibility to manage submissions, track approvals, and ensure compliance with increasingly complex regulatory standards is a top priority for the research community. Transitioning from a paper-based approach or an existing eIRB system can introduce both opportunities and challenges, making it essential for impacted teams to understand an eIRB system’s intricacies.

Research integrity is paramount, and selecting the best eIRB system for your institution is crucial. An effective eIRB system should streamline and enhance the review process while ensuring adherence to regulatory requirements.

Choosing a system that does not meet an institution’s expectations can lead to administrative burdens, inefficient workflows, delays in the review and approval of research proposals, and can lead to noncompliance with regulatory requirements.

Assess Your Needs

Each institution has unique policies (or local laws), workflows, and user expectations to consider when evaluating an eIRB system. Identifying your specific needs for an eIRB solution is crucial to ensuring the selected system effectively supports your institution’s research compliance requirements and goals. Some steps to take are:

  • Assess current processes: Begin by evaluating your current IRB processes and identifying pain points; as appropriate, this can also be completed for conflict of interest (COI), institutional animal care and use committee (IACUC), and institutional biosafety committee (IBC), especially if there are communication gaps between these offices. What are the major inefficiencies? Does the current process include burdensome workarounds and impacts your ability to efficiently complete reviews? What specific features are necessary for your institution? Would your institution benefit from a system with integration capabilities, the ability for customized reviews and process, or standardized templates and checklists?
  • Assess current eIRB system: Evaluate your current eIRB system and identify if it meets your institution’s expectations. Does the current system include upgrades, enhancing its features and functionality? Will the system upgrades impact research processes beneficial to the institution, such as increased efficiency and improved compliance?
  • Evaluate data migration: What historical protocol information will need to be transferred to a new eIRB system? Will the vendor assist with data migration efforts, or is the institution responsible for inputting historical data manually into the new system?
  • Review current research portfolio: What is the volume of your research portfolio and what type of research is conducted? What are the current turnaround times for the existing portfolio and what improvements need to be made to minimize future review delays?
  • Evaluate your ancillary review process: Does your research portfolio require ancillary reviews, such as radiation safety, COI, IBC, or scientific? Consider a system to help improve the efficiency and effectiveness of your institution’s ancillary reviews.
  • Analyze institutional research strategy: Is your institution looking to grow research? Will your institution be expanding support for the types of research conducted – i.e., sponsor-investigator research? Will the new eIRB system have the capability to support the institution’s research strategy?
  • Obtain stakeholder input: Engage with IRB members, researchers, and HRPP team members to gather insights into their needs and preferences. This will help in identifying must-have features and potential pitfalls. For example, what other systems (e.g., a clinical trial management system [CTMS], HR systems, learning management systems [LMS]) are stakeholders using? Is it beneficial to look for an eIRB system integrating with them?

Taking the time to identify and prioritize the needs of those who will utilize the eIRB system will not only facilitate a smoother implementation but will also contribute to a successful research program and goals.

Key Features to Look For

Each eIRB system has its own selling points; however, it’s important to focus on the system supporting the ethical oversight of research, the complexity of managing submissions, keeping track of approvals, and ensuring compliance with regulatory standards. Additionally, a system should enhance the overall user experience when submitting to the IRB. Some key features to consider include:

  • Compliance and regulatory oversight: If appropriate, ensure the system adheres to regulatory requirements such as 21 CFR Part 11 and is compliant with protocol and IRB policies. The system should also include the ability to capture regulations applied to a research project such as Common Rule, Food and Drug Administration (FDA) regulations, and expedited and exempt regulations.
  • User-friendly interface: A system should be intuitive. It is important for users to be comfortable using the system and complete tasks when needed.
  • Customizable workflows: Look for a system allowing you to create unique workflows to fit your institution’s specific needs. For example, if a study includes radiation, will the system allow for automatic routing to the radiation safety committee? Also, consider if the workflows include automation to help streamline processes and minimize “clicks” (or manual work by a user) required to complete a specific task in the system. For example, can the system be set up to send out continuing review reminder notifications for protocols with an upcoming expiration date or annual check-ins for minimal risk research?
  • Smart form creation: To help streamline the submission process, an eIRB system should include the ability to create and maintain smart forms. Smart forms are built with customizable digital elements or logic and are intended to capture protocol information. Creating customizable forms provides a standardized format for researchers to present their study protocols and supporting study documentation. In addition, this helps create consistency across various studies submitted to the IRB and drives higher quality applications.
  • Study documentation: The system should be able to store historical study information that is easy to access, view, and download.
  • Reporting: Metrics are essential for evaluating a system’s effectiveness, efficiency, and overall performance of the submission process. Look for a system with the ability to create and download customized reports on approval turnaround times, submission volume during a specific period, or types of studies submitted (e.g., studies involving children).
  • Passive education: To help with user experience, look for a system including the ability to build in frequently asked questions (FAQs); help text; and quick links to regulations, guidelines, and internal policies.
  • Integration capabilities: Check if the system integrates well with other institutional systems such as the COI program, grants management, research compliance, and ancillary reviews. Consider other areas outside of research such as reporting and analytics systems, as well as CTMS. An eIRB system with integration capabilities improves operational efficiencies, enhances compliance, and supports a more collaborative research environment.

Comparing eIRB Systems

Comparing the different eIRB systems available is a crucial, yet daunting, step. With so many different systems available, it’s challenging to pick a system best for your institution’s needs. With any new system, the intent is to have one to utilize over time, so finding a good fit will take time. Some key areas to consider when selecting a new system are:

  • Vendor research: Compile a list of potential vendors and evaluate them based on features, functionality, customer support, and cost. Each vendor will have unique offerings, so it is important to evaluate systems with one another and with your current needs.
  • Experience: Look for venders with a solid footprint in the eIRB space and consider their experience in working with institutions of your size. It is also important to know if a vendor can adapt to your growing research needs, such as the ability to accommodate an increase in research portfolio size.
  • eIRB system upgrades: As technology evolves and the research landscape changes, a system should update to stay relevant. It is important to inquire about future system updates and how they support the ever-changing research environment.
  • Demo requests: Schedule demonstrations with each potential vendor for a more hands-on experience. This will allow you to see the system in action and ask questions specific to your needs.

eIRB systems are not software solutions that will fix every broken process at your institution. Selecting an eIRB system requires deciding on which features you can and cannot live without.

Selecting an eIRB system is a significant investment for an institution’s research program. Seeking external expertise and guidance can be beneficial when looking into a new eIRB system. By following a structured approach and carefully considering the needs of your institution, you can ensure a successful transition to an efficient and compliant eIRB system.

In the complex landscape of clinical trials, the data monitoring committee (DMC) serves as the cornerstone at the intersection of participant safety and data integrity. A pivotal aspect of a DMC\’s effectiveness is its member composition, particularly key opinion leaders (KOLs).

The Role of KOLs in DMCs

KOLs are highly respected experts in their individual fields, often with extensive research experience and deep clinical insights into specific therapeutic areas and indications. Their involvement in DMCs brings several benefits:

  • Expertise and insight: KOLs provide advanced scientific and clinical insights crucial for interpreting complex data and making informed decisions
  • Credibility: The presence of recognized experts enhances the DMC\’s recommendations, fostering trust among stakeholders
  • Network influence: KOLs can leverage their professional networks to facilitate better communication and collaboration across the clinical trial ecosystem

The Importance of a Large KOL Network and Independent Third-party Support

A large KOL network greatly benefits DMCs and clinical trial sponsors. When leveraging such a network, it’s critical to have the right administration tools to support diverse reviewers.

Diverse Perspectives

A large network of KOLs is essential for comprehensive and balanced decision-making. Different experts bring varied viewpoints and experiences, which can lead to more thorough assessments of trial data and better strategies for addressing potential issues.

A geographically diverse membership also brings varied viewpoints on local treatments, access, and therapeutic questions. An experienced third party should have an extensive network of KOLs across numerous therapeutic areas. This vast network allows the company to match the right experts with a clinical trial’s specific needs, ensuring DMCs are composed of the most qualified and relevant professionals.

Access to Specialized Knowledge

A clinical trial can often span multiple disciplines and therapeutic areas. A broad network of KOLs provides access to specialized knowledge critical for evaluating the nuances of trial data. This is particularly important in complex global trials where it’s required to have expertise in multiple fields.

With a diverse DMC, it is important to have a rigorous selection process to ensure only the most qualified and independent KOLs serve on DMCs. This process includes thorough vetting for both financial and contractual conflicts of interest, ensuring the committee’s decisions are unbiased and focused solely on participant safety and data integrity.

Enhanced Problem Solving

With a larger pool of experts, DMCs can more effectively address unexpected challenges during clinical trials. The collective problem-solving capabilities of a diverse group of KOLs can lead to more innovative and effective solutions.

It’s necessary to provide comprehensive support and infrastructure with geographically diverse committees, since these are critical to a DMC functioning effectively. Considerations include logistical support, data analysis tools, and regulatory guidance, as well as ensuring KOLs can focus on their critical oversight responsibilities without administrative burdens.

Strengthened Regulatory Compliance

Global regulatory bodies highly value KOLs in DMCs due to what they bring to the oversight process. A large network of KOLs can help ensure trials meet international regulatory standards and any issues are promptly and appropriately addressed.

It’s crucial for a DMC administrator to provide global support. That administrator must be committed to continuous improvement and innovation, including regular updates to processes and tools to incorporate the latest advancements in clinical trial oversight. This commitment ensures DMCs benefit from cutting-edge methodologies and best practices, so members can focus on their review responsibilities with minimal administrative burden.

The Importance of Independent DMC Administration in Managing a Large KOL Network

A DMC’s effectiveness is undoubtedly hinged on having a large KOL network. Their expertise, diverse perspectives, and problem-solving capabilities are invaluable for maintaining clinical trial integrity and success. An independent third-party DMC administrator with an extensive KOL network, rigorous selection process, and robust support infrastructure is the ideal choice for leveraging the power of KOLs in DMCs.

For sponsors seeking to ensure the highest standards of safety and efficacy in their clinical trials, partnering with independent third-party DMC administrators offers unparalleled advantages. Having a large, independent, and diverse KOL network enhances the oversight process, ultimately contributing to the advancement of safe and effective medical therapies.

In an era where clinical trials are increasingly global, it’s more imperative than ever to leverage international expertise.

Data and safety monitoring boards (DSMBs), also known as data monitoring committees (DMCs), play a critical role in overseeing a clinical trial’s safety and efficacy. These independent committees are entrusted with the task of safeguarding study participant’s interests while ensuring the trial’s scientific integrity.

The February 2024 FDA draft guidance on DMCs highlights the necessity of incorporating diverse, global expertise into these critical oversight functions.

The Role of DSMBs in Clinical Trials

DSMBs are integral to clinical trial conduct, particularly those involving high-risk interventions or vulnerable populations. In a trial taking place in multiple countries, there is an increased need to understand any regional nuances. This may include differences in standard of care, acceptable practices, and the like.

The DSMB’s primary responsibilities include:

  • Monitoring patient safety: Ensuring participants are not exposed to undue risk and adverse events are promptly identified and addressed.
  • Evaluating interim data: Analyzing data at predefined intervals to determine if the study should continue, be modified, or be terminated early.
  • Ensuring study integrity: Protecting the trial’s integrity and credibility by preventing biases and maintaining confidentiality of interim results.

The 2024 FDA Draft Guidance: A Focus on Global Expertise

The latest FDA draft guidance emphasizes the importance of a diversified DMC composition, advocating for including key opinion leaders (KOLs) from around the world. The preamble makes clear the agency’s belief in the DMC’s role progressing alongside evolving trial conduct and design approaches.

The draft guidance highlights several key points pertinent to international trials:

  • Diversity of expertise: KOLs with varied backgrounds and expertise enhances the DMC\’s ability to address complex clinical and safety issues, and is crucial for interpreting data accurately and making informed decisions.
  • Global representation: Having DMC members who understand regional medical practices and regulatory environments is vital and ensures the DMC can provide culturally and contextually relevant oversight (e.g., local standards of care).
  • Enhanced objectivity: A DMC composed of diverse international experts can mitigate potential biases arising from local or regional perspectives. Consider the differences between supporting (concomitant) medications used in different countries or the differences generally in how a disease state is considered or treated. A multi-national DMC enhances the objectivity and credibility of the committee\’s recommendations.

These are important considerations no matter where a trial takes place; they are especially important when considering disparate cultural standards and other international differences.

Benefits of a DMC Leveraging a Worldwide Network of Key Opinion Leaders

Having a DMC whose members represent the regions included in a clinical trial allows for expertise and understanding both the culture and common medical practices. Consider the following:

  • Comprehensive expertise: A global network of KOLs brings together experts from diverse medical, scientific, and regulatory backgrounds. This allows DMCs to tackle complex issues from multiple angles – ensuring robust, well-rounded, and consistent decision-making processes.
  • Cultural competence and sensitivity: In multinational trials, cultural competence is critical. KOLs from different regions can provide insights into local healthcare practices, patient behaviors, and regulatory expectations. This cultural sensitivity enhances the DMC\’s ability to interpret data accurately and make decisions respectful of regional nuances.
  • Rapid access to specialized knowledge: In the event of an emerging safety concern or unexpected data trend, having KOLs with specific expertise readily available ensures timely and informed responses – thereby protecting participant safety and trial integrity.
  • Strengthened regulatory compliance: Different countries have varying regulatory requirements and expectations. A globally diverse DMC ensures the trial adheres to local regulations while maintaining high ethical standards. This compliance is crucial for the successful regulatory approval and dissemination of trial results.
  • Enhanced credibility and trust: Having respected KOLs enhances the credibility and trustworthiness of the DMC\’s recommendations. This is particularly important in high-stakes trials where public and stakeholder trust is paramount. For example, consider a global Phase III, double-blind study, in a novel new therapy. By having a trusted KOL on the DMC, physician investigators can feel confident their patient’s safety and welfare is independently supervised.
  • Fostering innovation and collaboration: Global collaboration fosters innovation by bringing together diverse perspectives and approaches. This collaborative spirit can lead to developing novel methodologies and strategies for monitoring and evaluating clinical trials, ultimately advancing the field of clinical research.

Global Perspectives Necessary for Clinical Trial Success

The FDA\’s February 2024 draft guidance on DMCs underscores the importance of incorporating global expertise and leveraging worldwide networks of KOLs. In an increasingly interconnected world, this approach is essential for ensuring a trial’s safety and efficacy.

By embracing diversity and fostering international collaboration, DMCs can enhance their oversight capabilities, protect participant safety, and uphold the highest standards of scientific integrity.

As we move forward, the integration of global expertise will continue to play a pivotal role in successful and credible clinical research endeavors.

Embracing the power of global expertise and fostering a worldwide network of KOLs not only aligns with regulatory expectations, it also represents a proactive approach to addressing modern clinical trial complexities. This strategy is indispensable for advancing the clinical research field and ultimately improving patient outcomes across the globe.

The International Council for Harmonisation (ICH) good clinical practice (GCP) guidelines are critical in ensuring the safety and rights of clinical trial participants. The guidelines also facilitated international harmonization of clinical research making it easier to conduct multi-national trials and bring new therapies to market more efficiently.

The Council was first formed in 1990 with the goal of harmonizing regulatory requirements across Europe, Japan, and the United States. The first guidelines published in 1996 and known as ICH GCP E6 provided guidance on the design, conduct, and reporting of clinical trials. ICH GCP R2 was subsequently published in 2016 and expanded on steps to ensure data integrity, encourage risk-based monitoring, and address the use of electronic records and signatures.

Updates to R3

Now, ICH GCP E6 R3 introduces quality by design, further refines risk management, and establishes clearer roles and responsibilities. The transition from R2 to R3 represents a significant evolution in the ICH guidelines – there are some key elements for sponsor organizations to focus on as they optimize clinical quality.

Quality by Design

R3 builds on the quality by design framework, introduced in ICH GCP R8. This framework encourages the implementation of quality assurance throughout the clinical trial lifecycle. Principle 6 of R3 expands on the identification and implementation of critical to quality (CtQ) factors – attributes vital to the protection of subjects and the integrity of the data collected. The guidelines encourage the strategic use of CtQ factors to detect and address deviations from GCP, as well as the protocol and regulatory requirements so that recurrence is prevented. Ultimately trial participant safety and data integrity is maintained.

Risk Proportionality

Risk management is further streamlined in R3, focusing on tailoring trial processes proportional to the risks they pose to subjects as well as critical data. Risks to CtQs factors should be proactively managed and risk language/monitoring adjusted according to new and changing information during the clinical trial. Furthermore, systems and processes capturing, managing, and analyzing data need to be fit for purpose, capturing data required by the protocol and should address key risks to subjects and data integrity.

Trial Design

The importance of robust and risk-based trial design is a key element of R3. Emphasis should be placed on creating operationally sound processes and avoiding unnecessary complexity, procedures, and data collection. This all starts with a well-designed clinical protocol, in addition to trial plans and documents aiding in protocol execution. Trial processes should also be optimized to focus on the key objectives and quality and risk management elements should be put in place. Sponsors should ensure a diverse multidisciplinary team of stakeholders supports the design of the study and the clinical development plan. Lastly, computerized systems used in the capture of data should be fit for purpose and support the CtQ factors.

As trial designs and clinical technologies become increasingly complex, sponsors must prioritize patient safety and data integrity more than ever. R3 acknowledges no clinical trial can be flawless, but it encourages organizations to adapt their processes and systems to address the most critical risks effectively. By embracing this proactive approach, organizations can continue to drive innovation while upholding the highest standards of clinical research and patient care and can more effectively bring world-class treatments to market.

Managing clinical trial budgets efficiently is necessary for the success and sustainability of clinical research sites. Effective budget management not only ensures trials are financially viable but also maximizes return on investment (ROI). This enables sites to allocate resources strategically, attract more studies, and maintain long-term financial health.

Understanding ROI in Clinical Trials

Calculating ROI for clinical trials involves measuring the cost of collecting and analyzing data against the trial’s productivity (i.e., the impact and value of the data produced). The higher the ROI, the greater the financial return and the better use of resources.

It\’s difficult to calculate a clinical trial’s ROI if the potential research outcomes are unknown. However, a strong focus on cost-effective budget management can help research sites maximize their ROI.

Calculating the ROI of studies is essential for a research site’s success. It allows them to assess the financial viability of trials and ensure funding is allocated to the most profitable projects. By maximizing ROI, research sites can ensure sustainable growth and success in their research endeavors.

Strategies For Cost-effective Budget Allocation

Cost-effective budget allocation is the key to ensuring optimal use of resources in clinical trials. Prioritizing high-impact budget items, negotiating for better rates from vendors, making use of budget management technology, and using historical data to predict costs can all allow for more efficient use of funds.

Prioritizing Budget Items

High-impact items are those most likely to contribute to a trial’s overall success, efficiency, and quality. Identifying and prioritizing spending for these items is a central aspect of effective resource allocation, which is key to maximizing ROI. Examples of high-impact budget items include:

  • Patient recruitment and retention
  • Staff salaries
  • Patient care
  • Laboratory and medical procedures
  • Data management and analysis
  • Regulatory compliance
  • Staff training
  • Supplies and materials
  • Technology and equipment

Utilizing Technology

Budget management tools and software, like clinical trial management systems (CTMS), can streamline trial processes and reduce costs in several ways.

For example, these tools can automate the recording and tracking of financial data, reducing the risk of human error and ensuring greater data accuracy. It also records data on a centralized system available to both the research site and sponsor, so all parties have access to up-to-date information. In doing so, budget management tools allow for faster identification and mitigation of financial risks.

Software tools can also help to maintain a budget by accurately tracking expenses and keeping records of the budget list, budget summary, and any budget adjustments.

Leveraging Data

Historical data is very useful for accurately predicting costs in clinical trials and can help prevent overspending. It provides valuable insights into costs associated with:

  • Site payments
  • Vendor costs of supplies and services
  • Patient recruitment and retention
  • Effect of protocol complexity on costs
  • Staffing costs
  • Cost-effectiveness of research sites
  • Costs associated with different study durations
  • Cost of regulatory approval

The information gleaned from historical data analysis can allow for more effective optimization of a clinical trial budget and, therefore, resource allocation.

Detailed Cost Breakdown

When budgeting, consider all necessary activities and the costs associated with each activity. Research sites usually budget for staff salaries and training, but frequently overlook the costs of other essentials. Some examples of often-forgotten research costs include:

  • Costs associated with trial participants: These include the costs of recruiting participants, screen failures, and screening activities. They may also include costs relating to data entry, preparing institutional review board (IRB) documents, and scheduling assessments of participants.
  • Site costs: Charges for the study site include a start-up fee, payments for site personnel, and IRBs on site. Other potential costs include those for additional sites (or removal of sites), administrative fees, storage fees, and site closeout.
  • Safety costs: Safety costs include the cost of evaluating, addressing, and reporting adverse events. They may also include payments to safety oversight committees (e.g., for generating reports) and independent consultants.
  • Quality management costs: Quality management expenses are associated with clinical monitoring (including site monitoring and closeout visits), data management, and project management.
  • Regulatory costs: Regulatory costs may include submissions to regulatory authorities, such as applications for new investigational drug or device exemptions, annual reports, and final reports. They may also include the cost of registration to clinicaltrials.gov and those associated with posting results.
  • Other costs: Other costs commonly overlooked when budgeting for clinical trials are those of laboratory work, medical monitors, staff training, meeting, travel, translators, advertising, and shipping and storing investigational products.

Specific Cost Categories for Federally Funded Trials

The major cost categories for federally funded clinical trials are as follows:

  • Personnel costs: These include staff salaries and expenses and fringe benefits, such as health insurance and pension contributions.
  • Patient care costs: These are costs associated with the routine care covered by the trial.
  • Data management: Data management and monitoring in federally funded trials must meet federal standards. This often requires using specific electronic data capture systems and adhering to strict protocols.
  • Supplies and materials: These include costs for medical supplies (like drugs, medical devices, and other trial-related materials) and laboratory supplies (such as reagents, kits, and other materials for laboratory activities).
  • Patient reimbursement: Patients may be reimbursed for their time, travel, and other expenses.
  • Consultant fees: These are fees for medical or scientific experts providing consulting services to the clinical trial. In federally funded trials, these services must be justified and approved, and fees are capped according to federal guidelines.

Negotiating Better Contracts With Sponsors

Negotiating for a better contract with sponsors is a foundational aspect of cost-effective clinical trial budget management. Successful negotiation is a product of thorough preparation and effective communication, with careful consideration of factors such as:

  • Building relationships: A strong relationship with a sponsor can give you leverage in contract negotiations. Understanding your sponsor’s budget limitations can allow you to identify fair goals and requests. It is also helpful to identify your mutual goals so you can take a collaborative approach to negotiations.
  • Transparent communication: Open communication is at the heart of every successful professional relationship. When entering budget talks with a sponsor, clearly communicate the trial costs and maintain a firm-but-flexible attitude throughout negotiations. Clear itemization of costs can prevent misunderstandings and ensure coverage of all expenses.
  • Fair market value: Do some research prior to negotiations to establish the standard pricing for supplies and services, and make sure the budget reflects fair market value.
  • Redlining budgets: Identify which of your terms are non-negotiable (like site costs) and ensure your sponsor’s proposed budget aligns with these terms.
  • Avoiding double billing: Avoid duplicate charges for budget items by ensuring compliance with the research billing plan.
  • Gathering evidence: Leverage historical cost data from similar trials to support your budget requests, and gather well-documented evidence to support any requests for additional funding.
  • Escalation plans: Use internal and sponsor escalation plans to navigate any challenges arising during the negotiation process.
  • Long-term partnerships: Establishing a long-term, mutually beneficial partnership can help secure a more favorable budget from a sponsor.

Strong negotiation skills are central to the success and cost-efficiency of research institutions. Therefore, learning new strategies for budget negotiation can equip researchers with the tools to optimize their site’s use of resources and, therefore, the success of their research endeavors.

Identifying and Eliminating Budget Inefficiencies

Budget inefficiencies can bleed resources from a clinical trial, to the serious detriment of its overall ROI. Therefore, identifying and eliminating financial inefficiencies is vital for a research site’s success. Regular budget reviews and close budget monitoring, cost-benefit analysis, process improvement, budget management skills training, and strict regulatory compliance are vital for mitigating financial risks in clinical research.

Regular Budget Reviews

Conducting regular budget reviews can identify and address financial inefficiencies in a clinical trial. Unforeseen expenses can contribute to the failure of a clinical trial, and may include:

  • Inefficient use of research sites
  • Unnecessary protocol amendments
  • Unnecessary data collection and procedures
  • Inefficient monitoring strategies
  • Failure to leverage technology effectively
  • High participant dropout rates
  • Ineffective negotiation with vendors

Financial inefficiencies can be mitigated with careful planning and resource allocation, along with frequent budget reviews. Budget management tools, which allow for closely monitoring financial data, can make it easier to detect and address financial inefficiencies and improve a trial’s economic viability.

Cost-benefit Analysis

A cost-benefit analysis measures the financial costs of specific budget items against their potential benefits. This ensures each item adds value to the trial and each resource is used to its greatest benefit. It can also help researchers decide where to allocate resources to maximize a clinical trial’s ROI.

Process Improvement

Process improvements can enhance a trial’s speed, accuracy, and reliability while improving patient safety and clinical outcomes. This is essential for streamlining clinical trial processes to reduce waste and enhance cost efficiency. Examples of process improvements include:

  • Using adaptive trial designs allowing for real-time modifications and adjustments.
  • Optimizing patient recruitment and retention by utilizing data analytics to more effectively identify and target patient populations, more efficient screening processes, and patient-centric approaches to recruitment.
  • Leveraging technology like electronic data capture (EDC) systems and wearable medical devices to improve the speed and accuracy of data collection.
  • Optimizing data management and analysis using a centralized clinical data management system (CDMS) and standardizing data collection methods.
  • Reducing delays in obtaining regulatory approvals through standardization of contracts.

Training and Development

Training and development programs can improve the budget management skills of clinical staff and are, therefore, a solid investment in the long-term financial efficiency of a research site. These training programs can teach staff to:

  • Perform comprehensive budget planning and allocate resources effectively
  • Identify and plan for the costs of patient recruitment and retention
  • Consider effort costs associated with various recruitment strategies
  • Use budget management software tools to track and monitor a budget
  • Identify and mitigate financial risks
  • Negotiate effectively with vendors

Regulatory Considerations and Compliance

Clinical trial regulations are the laws and guidelines governing clinical research and ensuring participant safety, rights, and wellbeing. They include:

  • Good clinical practice (GCP)
  • Informed consent
  • Ethical approval from an IRB
  • Ongoing monitoring and reviews from the IRB
  • Regulatory authority approval (e.g., from the Food and Drug Administration [FDA])
  • Safety reporting (e.g., of adverse events)
  • Data management and privacy
  • Good manufacturing practice (GMP)

Compliance with these regulations is essential for protecting patient’s rights and safety, ensuring the integrity and validity of research, and securing regulatory approval for the marketing of new medical treatments. Therefore, researchers must carefully consider regulatory costs when budgeting for clinical trials, such as:

  • IRB approvals
  • Regulatory authority submissions
  • GCP compliance
  • Safety monitoring and reporting
  • Data management and privacy

Costs associated with regulatory compliance are divided into direct and indirect costs. Direct costs are those directly attributed to a particular aspect of regulatory compliance (such as GCP training costs). Indirect costs cannot be directly assigned to regulatory compliance, but are necessary for supporting regulatory activities. These may include staff salaries and infrastructure costs. The budget must factor in both direct and indirect costs, and resources must be allocated accordingly.

The budget must also account for both study-related and standard care costs. Study-related costs are expenses directly associated with the clinical trial, and may include:

  • Staff salary
  • Training
  • Fees for ethical or regulatory authorities
  • Data collection and monitoring costs
  • Laboratory costs
  • Insurance
  • Study-specific medical procedures
  • Participant reimbursements

Standard care costs are expenses that would be incurred regardless of whether a patient is participating in a clinical trial. These are routine medical care costs usually reimbursed by healthcare insurance providers, such as:

  • Diagnostic tests
  • Standard medications
  • Hospital treatment

Efficient budget management is essential for maximizing ROI in clinical trials. By prioritizing budget items, negotiating better contracts, leveraging technology, and conducting regular reviews, clinical research sites can optimize their financial resources and ensure sustainability. Implementing these strategies will not only improve financial outcomes, but also enhance operational efficiency and competitive positioning.

Artificial intelligence (AI) has taken the world by storm – and regulators are paying attention. The European Parliament recently adopted the Artificial Intelligence Act (AI Act), marking a significant regulatory step in the oversight of AI technologies.

This landmark legislation aims to create a comprehensive framework for AI development and deployment, ensuring ethical use, safety, and transparency for European Union (EU) residents.

The EU AI Act’s implications extend into clinical research, where AI is increasingly utilized for tasks like medical image analysis, natural language process for endpoint analysis, and generating/analyzing data for synthetic control arms.

This article explores the likely impact of the AI Act on software and systems used in clinical research and how it affects entities outside the EU. We also summarize the key information pharmaceutical companies and contract research organizations (CROs) need to know to prepare for compliance.

An Overview of the AI Act

The new Act categorizes AI applications based on these risk levels: unacceptable, high, limited, and minimal.

An example of limited and minimal risk systems include AI in benign gaming apps and language generators. These risks face fewer regulations but must meet certain standards to ensure ethical use.

Unacceptable risk AI systems are banned outright, while high-risk systems must comply with stringent requirements, including transparency, data governance, registration with the central competent authorities, and human oversight.

While some of the AI Act’s compliance dates are set for August 2024, the full Act will be enforced in March 2026.

High Risk AI-powered Systems: Key Requirements

The AI Act will likely consider many AI-based systems used in clinical trials today as “high risk.” This includes drug discovery software, study feasibility solutions, patient recruitment tools, and others.

Here are some key requirements for “high risk” AI systems as they relate to clinical trials. (This is not an exhaustive list; reference the AI Act for complete details.):

  • Transparency and explainability: AI systems must be transparent, meaning their decision-making processes should be explainable to healthcare professionals and patients. The AI Act requires healthcare professionals and patients to understand and trust AI-driven determinations.
  • Data governance: High-risk AI systems must implement robust data governance measures – including data quality management – to ensure the data used for training and operating these systems is accurate, representative, and free from biases.
  • Human oversight: The AI Act indicates human oversight is essential to deploying high-risk AI systems. In clinical settings, healthcare professionals must be involved to ensure human experts have reviewed and validated AI recommendations.
  • Accuracy and reliability: The Act requires rigorous validation and documentation processes to verify AI models are accurately and consistently simulating control group outcomes, endpoint analysis, etc.
  • Ethical considerations: AI must consider ethical implications, particularly regarding data privacy and consent. This requirement is especially relevant to participant recruitment. The Act emphasizes AI systems should be designed and used in ways to respect fundamental rights and values.
  • Continuous monitoring: AI systems must be continuously monitored to ensure they remain accurate and effective. As new data becomes available, researchers must conduct ongoing assessments and recalibration of AI models.

Potential Impact on Clinical Research

Software vendors, sponsors, CROs, and clinical sites are all increasingly using AI components in their processes, programs, and systems. Here are the three key areas in clinical research the AI Act might impact:

Medical Image and Medical History Analysis

One of the most transformative AI applications in clinical research is in medical image and history analysis. AI algorithms can process vast amounts of imaging and medical chart history data to detect anomalies, identify disease markers, and assist in diagnosis and endpoint identification with remarkable accuracy and speed.

Medical image and history analysis systems likely fall under the AI Act’s high-risk category, due to their significant potential impact on health and safety in clinical care delivery. This categorization also considers AI’s impact on endpoint adjudication analysis, which ultimately drives drug and device regulatory approval determinations.

Synthetic Control Arms

The use of AI-powered software to generate data for synthetic control arms in clinical trials is another likely “high risk” area poised for significant impact. Synthetic control arms use historical clinical trial data and real-world evidence to simulate a control group, reducing the need for placebo groups and accelerating the trial process.

Regulatory agencies are pushing for the use of real-world evidence (RWE) to accelerate approvals and reduce clinical trial cost and complexity. What happens, though, when AI technology ingests large datasets of real-world data (RWD) and extrapolates what a hypothetical control arm of hypothetical patients would look like giving aggregated massive datasets (i.e., a synthetic control arm)?

While the synthetic control arm described above is based on real data, the challenge lies in how to trust the AI’s assumptions. Regulators must consider how to verify the data provenance and what the AI determined and assumed to generate the control data, as well as the implications those assumptions have on the end result – drug or device approval.

Patient Identification

AI is also revolutionizing patient identification for clinical trials, a challenging process crucial for research success. AI algorithms can analyze vast datasets, including electronic health records (EHRs) and genomic data, to identify suitable candidates for clinical trials with greater precision and efficiency. This can be particularly valuable for the growing number of trials analyzing biomarkers, which can make it more challenging to find participants meeting narrow criteria and require more data collection before and during the study.

Under the EU AI Act, patient identification systems are likely considered high-risk due to their potential impact on patient health and privacy.

Impact of AI Act on Companies Outside the EU

Similar to the EU General Data Privacy Regulation (GDPR), the AI Act extends enforcement outside the EU Economic Zone. It has potentially significant implications for any company doing business within the EU, particularly those marketing AI-driven clinical research products and services within the region.

Non-EU companies must comply with the AI Act if their AI systems are used in the EU market. For those non-EU based organizations conducting clinical trials, consider the following:

  1. Understand the regulatory landscape: Non-EU companies need to thoroughly understand the AI Act\’s requirements and its application to products, services, and actions. This includes staying informed about regulatory updates and any clarifying guidance issued by EU authorities.
  2. Establish an EU representative: Similar to GDPR, companies outside the EU may need to appoint an EU-based representative to ensure AI Act compliance and liaise with EU regulatory bodies.
  3. Adapt products and services for compliance: Non-EU companies must ensure their AI-enabled systems meet the Act\’s standards for transparency, data governance, human oversight, and other requirements. This may require modifying existing offerings and potentially developing new ones specifically for the EU market.

How Clinical Trial Stakeholders Doing Business in the EU Should Prepare for AI Act Compliance

Sponsors, CROs, and others in the research industry should consider the following actions:

  1. Conduct an inventory and compliance assessment: List all current AI enhanced or supported systems and determine each system’s risk classification under the AI Act. Then, identify areas requiring upgrade or modification to meet new regulatory requirements.
  2. Implement data governance protocols: Establish or enhance data governance frameworks to ensure the quality, representativeness, and security of data AI systems use – including processes for regular data audits and updates.
  3. Enhance transparency and explainability: Develop mechanisms to ensure AI systems are transparent and their decisions explainable, like user-friendly interfaces allowing healthcare professionals to understand and interpret AI outputs.
  4. Strengthen human oversight: Ensure AI systems are designed with robust human oversight mechanisms, such as training healthcare professionals and researchers on how to effectively supervise and validate AI decisions.
  5. Ethical and legal training: Train staff on the ethical and legal implications of using AI in clinical research to help ensure all team members are aware of their responsibilities in AI Act compliance.

The European Parliament’s adoption of the AI Act represents a pivotal moment in AI technology regulation, particularly in high-stakes fields like clinical research.

It’s likely this is just the beginning of AI regulation; even companies not involved in EU business should still take notice and consider the Act’s impact, as it may foreshadow future domestic policies. The Act’s emphasis on transparency, data governance, and human oversight aims to ensure the safe and ethical use of AI, ultimately fostering greater trust and reliability in AI-driven clinical research.

A version of this article originally appeared in PharmaPhorum in July 2024.

When developing a new drug, clinical project teams often struggle to know when current good manufacturing practices (cGMP) regulations apply. In this article, we will discuss the U.S. Food and Drug Administration’s (FDA) expectations for applying cGMP to investigational drugs.

FDA Regulations and Guidance

GMP is a system for ensuring drug products are safe, consistently produced, and controlled according to quality standards. It’s designed to minimize the risks involved in any pharmaceutical production that cannot be eliminated through testing the final product. The FDA cGMP regulations for drugs are published in 21 CFR 210/211. Generally, U.S. law exempts drugs used for Phase I studies from compliance with 21 CFR 210/211; however, it does not exempt:

  • An investigational drug for use in a Phase I study once it is available for use in a Phase II or Phase III study
  • A drug lawfully marketed as a monograph drug or by an FDA-approved market application

There is additional FDA guidance for Phase I clinical trials using cGMP for investigational drugs. According to 21 CFR 210.2(c), the cGMP regulations formally apply for drugs used in Phase II/III studies.

cGMP Implementation

There are many benefits to implementing cGMP as early as possible in drug development. Beyond protecting participant safety, cGMP provides a foundation for a sound quality management system (QMS). Adopting a QMS early allows processes to gradually integrate, which benefits research staff.

Additionally, early adoption ensures tighter controls, builds organization-wide quality, and minimizes noncompliance risks. For organizations moving toward commercialization, this helps assure a successful pre-approval inspection.

However, cGMP requirements can be difficult to understand. In an effort to clarify, FDA adopted the International Council for Harmonization (ICH) of Technical Requirements for Pharmaceuticals for Human Use:

These guidelines assist sponsors when developing a QMS. For sponsors who are also manufacturers, their QMS should address all the cGMP’s requirements. Other sponsors may want to outsource their investigational drug manufacturing. In doing so, their contracted vendors must prove their QMS is complete with appropriate facilities, systems, and fit-for-purpose processes.

In this scenario, the sponsor’s QMS should:

  • Address management commitment to quality
  • Include a quality policy
  • Have defined processes for:
    • Resource management, including employee role based and GMP training
    • Internal communication
    • Management review
    • Document, data, and records management
    • Vendor lifecycle management
    • Product lifecycle management

Complying with cGMP throughout the drug development process helps ensure quality investigational products. This also helps protect clinical trial participant safety and reduces variability due to poor quality. Even with outsourced manufacturing processing, sponsors are still responsible for meeting cGMP requirements.

Note: This article was originally published July 15, 2020, and has been updated to include new and clarifying information.

A regulatory binder is essential for managing clinical trial documents, ensuring regulatory compliance, and facilitating audits. It organizes critical documents; provides easy access for trial monitors, auditors, and regulatory authorities; and serves as a reference for the research team. Though not legally binding, maintaining a regulatory binder is highly recommended for all intervention trials. This checklist offers a comprehensive framework for managing all necessary documents efficiently.

Download a Printable Version of this Checklist

Notes

Terms Used Synonymously

  • Study binder
  • Investigator binder
  • Administrative binder
  • Regulatory files
  • Investigator’s study files

Guidance Documents

  • ICH GCP E6 Section 8: Specifies essential documents and their purposes
  • ICH GCP E6 4.9.4: Guidelines for maintaining trial documents to prevent accidental or premature destruction

For more information, you can download our eBook detailing good clinical practice (GCP) and its role in the clinical research ecosystem.

Centralization of Documents

When multiple studies share regulatory documents, it is most efficient to centralize them, often done electronically in an eRegulatory management system (eReg).

  • Laboratory certifications and normal ranges
  • Institutional review board (IRB) membership lists
  • CVs
  • CTEP 1572s

Essential Documents of a Regulatory Binder

These documents demonstrate the investigator’s, sponsor’s, and monitor’s compliance with GCP and regulatory requirements.

  • Protocol and amendments
    • Purpose: To document revisions of trial-related documents during the trial
    • Documents: Log of protocol changes, IRB-approved protocol with principal investigator (PI) signature page, IRB-approved case report forms, IRB-approved advertisements and participant information sheets, protocol amendments
  • Informed consent documents
    • Purpose: To document the informed consent
    • Documents: Log of informed consent versions, IRB-approved informed consents
  • IRB documentation
    • Purpose: To document the trial has been subject to IRB review and approval
    • Documents: IRB federal assurance number, updated IRB roster, IRB approval letters, submissions, and correspondence including initial review, continuing review, advertisements, subject compensation, and other reporting requirements
  • Investigator qualification documentation
    • Purpose: To document qualifications and eligibility to conduct the trial
    • Documents: Updated investigator CVs (signed/dated within two years), clinical licenses for PI and co-investigators, training certificates
  • Clinical investigator’s brochure
    • Purpose: To document relevant and current scientific information for the investigational product has been provided
    • Documents: Investigator’s brochure or package insert for approved medications
  • FDA documents (if applicable)
    • Purpose: To document the investigator’s agreement to conduct the study according to the protocol and GCP
    • Documents: FDA Forms 1571 and 1572, sample labels for investigational products, regulatory approval or authorization, FDA correspondence log
  • Financial disclosure forms
    • Purpose: To document compliance with FDA regulations regarding financial interests
    • Documents: Signed forms for PI and co-investigators
  • Study communication
    • Purpose: To document important decisions and agreements
    • Documents: Confidentiality agreement, data sharing agreement, material transfer agreement, signed agreements between sponsors and investigators, important decisions or notes to the study file
  • Delegation of authority log
    • Purpose: To document which study-related tasks the PI has delegated to others
    • Documents: Delegation of authority log, signature form
  • Clinical research and study training
    • Purpose: To document adequate training for all staff participating in the study
    • Documents: Documentation of training (e.g., human subject protection, GCP)
  • Screening/Enrollment log
    • Purpose: To document identification of subjects who entered pre-trial screening and those who were enrolled
    • Documents: Log of screened subjects without identifying information, subject identification code list (kept separately)
  • Signed consent documents
    • Purpose: To document informed consent
    • Documents: Signed informed consent documents
  • Study product records
    • Purpose: To document the disposition and accountability of study products
    • Documents: Documentation of study product disposition and accountability
  • Laboratory certification
    • Purpose: To document the competence of the facility performing protocol-specific tests
    • Documents: CLIA, CAP, or other certifications, updated normal-range values for reference labs
  • Specimen Tracking Log
    • Purpose: To document the tracking and handling of specimens
    • Documents: Specimen tracking logs
  • Serious adverse events (SAEs)/Unanticipated problem documents
    • Purpose: To document the sponsor was notified of all SAEs and related reports
    • Documents: SAE report forms, unanticipated problem forms, investigational new drug (IND) safety reports
  • Protocol deviation form or memo
    • Purpose: To document any deviations from the protocol
    • Documents: Protocol deviation forms or memos
  • Clinical site monitoring visits
    • Purpose: To document site visits and monitor findings
    • Documents: Site visit log, reports, and correspondence
  • Sponsor correspondence
    • Purpose: To document agreements or significant discussions regarding trial administration
    • Documents: Sponsor correspondence
  • Data and safety monitoring documents
    • Purpose: To document compliance and actions related to safety monitoring
    • Documents: Data and safety monitoring plan, reports generated for independent safety monitor(s), safety monitor meeting minutes
  • Other documents
    • Purpose: To document additional relevant information and procedures
    • Documents: Unmasking procedures for blinded trials, certificate(s) of confidentiality

Streamline Regulatory Compliance with Advarra eReg

Advarra eReg simplifies the management of essential documents, ensuring your clinical trials remain compliant and organized. This system provides key benefits to binder management such as:

  • 21 CFR Part 11-compliant electronic signatures: Save time routing for signatures while ensuring compliance
  • Mobile signing: Staff can sign documents from their phones, no matter where they are
  • Electronic delegation of authority: Maintain a comprehensive and compliant delegation of authority log within eReg
  • Regulatory templates: Save time and eliminate redundant workflows with predefined templates for each new protocol
  • Standard operating procedure (SOP) management: Store and easily access SOPs in a central location
  • Email integration: Input documents easily and forward email correspondence directly into the system
  • IND storage: Manage IND documentation efficiently
  • Review sessions: Grant limited eReg access for internal and external monitors for easier document review

Download a Printable Version of this Checklist

A well-designed GxP audit program, in addition to satisfying the regulatory requirement of sponsor oversight, allows for early detection of potential issues, development of key performance indicators (KPIs), and development of best practices for an organization. GxP audits are a critical component of ensuring compliance and quality in clinical trials.

By following this step-by-step guide, sponsors and sites can prepare for and navigate the several types of audits needed at each stage of the clinical trial journey. A clinical quality assurance (CQA) audit program ideally would comprise of three prongs: investigator site audits, vendor (supplier) audits, and internal audits (process, system, or individual departments).

This is unlike current good manufacturing practices (cGMP), which has detailed regulations under the U.S. Code of Federal Regulations (CFR) under 21 CFR parts 210 and 211. Clinical trials encompass several areas of GxP under the CFR: good laboratory practices (GLP) 21 CFR part 58, good pharmacovigilance practices (GVP) 21 CFR parts 314 and 600, and good clinical practice (GCP) CFR parts 50, 54, and 56. All of which must be reviewed during the clinical trials process to ensure compliance with regulations.

Developing a Robust GxP Audit Program

In tandem with protocol finalization, the sponsor should select vendors for the clinical trial. Vendor management procedures should align the risk of the vendor with the industry standardized audit observation classification system. This is where critical vendors (contract research organization [CRO], central labs) would have a higher frequency of audits than lower risk vendors (institutional review boards [IRBs], translation services), which depending on local procedures, may be qualified and re-qualified by robust questionnaires.

Key areas for review during vendor qualification audits should include:

  • Quality management system (QMS)
  • Experience in therapeutic area
  • Length of time in business and experience with regulatory inspections
  • Communication and escalation paths (i.e., are these items formalized or based on individual contracts?)
  • Experience in region(s) where services will be performed
  • Expansiveness of IT security, data privacy and data protection systems and awareness

In-process audits, or audits conducted once the vendor has begun trial participation, would review vendor execution to regulatory requirements, their QMS, and sponsor agreements. Often, corporate audit standard operating procedures (SOPs) allow for a three-to-five-year window for in-process audits. While this is understandable for long-standing relationships, a better practice would be to consider a qualification audit, an in-process audit between years two and three, and then after, a satisfactory audit. This allows for greater length of time between audits with a robust vendor management plan. When performing an in-process audit, the auditor should examine:

  • If the vendor performed requirements to regulations and internal procedures
  • If the vendor communicated issues to the sponsor in a timely manner
  • If the vendor’s KPIs are in alignment with sponsor expectations
  • If project milestones are being kept
  • The trial master file (TMF) status

Investigator Site Audit (ISA)

The ISA program audits clinical sites are based on identified risk factors and is ongoing during the life of the study. Ideally, the number of sites audited are determined during protocol development once the number of sites has been determined by taking a representative sample using the √n +1. Across the study, 25% of the identified sites should be audited early in the trial. Early trial auditing will help to determine if there are points of clarification required, which may necessitate re-training or a protocol amendment. In the middle phase of the study, 50% percent of the identified sites should be audited.

Identifying Vendor, Investigator Sites, and Sponsor Audits

Middle- and late-stage audits provides the sponsor with a secondary review of critical vendors (Pharmacovigilance [PV], CRO, and central labs), as well as verify data which has been captured for the clinical trial. The final group of identified sites, also 25% of the total, should be audited as close to data lock as possible, allowing time for necessary corrections or remediation.  In addition, the last group of sites should include sites the sponsor feels may be audited during a regulatory filing.

During the ISA, the auditor reviews protocol adherence, and regulatory standards (protection of subject rights and welfare), data integrity, and GCP compliance. The ISA will provide feedback to the sponsor of the study as well as the CRO, vendors, and sponsor team. The ISA is a snapshot of how well the trial is executed to expectations from both a regulatory and sponsor perspective. Key areas of focus include:

  • The consenting process to include inclusion/exclusion criteria, reconsent, consenting in non-local languages, consent of minors
  • Investigator site files (ISF) and TMF document review for, as well as against completeness of filing and ALCOA standards
  • Protocol adherence and protocol deviations
  • A pharmacy’s storage, dispensing, and blind maintenance of the investigational product
  • Adverse event (AE), serious adverse event (SAE), and adverse event of special interest (AESI) capture and reporting
  • CRO oversight at the site

Overall, site selection should be determined between quality groups (research and development [R&D], compliance) with input from clinical operations, pharmacovigilance, and potentially supply chain. Finally, the sponsor should conduct at least one audit in every regulatory jurisdiction (Food and Drug Administration [FDA], Health Canada, Medicines and Healthcare products Regulatory Agency [MHRA], etc.) to ensure regional nuances are met.

Identification of sites for an ISA is risk-based and should be evaluated yearly. Key areas to review for outliers which may have a site identified for audit include:

  • High-enrolling site
  • Significantly high or low number of screen failures to protocol expectations
  • Principal investigator (PI) with recent regulatory findings
  • Disproportionate number (high or low) of SAE/AESI findings and/or protocol deviations
  • Change in PI or change in location
  • Research-naïve PI or site
  • High site turnover (site staff turnover or clinical research associate [CRA] turnover)

While sites will answer many of the ISA findings with CRO assistance, the sponsor should review the findings against their wider portfolio to look at areas for improvement which include:

  • Are several sites missing a specific endpoint or lab test?
  • What are common issues in the findings, potentially indicating a communication issue between the sponsor and CRO? CRO and site?
  • Are different studies experiencing similar issues?

Internal Audits Essentials

The last area for discussion is the sponsor’s internal audit program. The internal audits should be conducted as part of the ongoing audit program to ensure the sponsor is also in an inspection-ready state and compliant with regulatory expectations for all countries where the sponsor conducts business. Common areas of focus on the internal audit program include:

  • Pharmacovigilance and safety
  • Clinical project management
  • Vendor management and governance
  • TMF

For the first three areas, the audit reports from the vendor and sites provide valuable input to the audit plan development. The findings should be reviewed as part of the audit preparation to examine the internal process for points of failure may have contributed to findings at the vendor or site level. Aside from the standard audit areas, the internal audits should review the following:

  • Common findings among similar vendors
  • Meeting minutes for relevant meetings with sites, vendors, and internal teams
  • Project plans for vendor transition(s)

All three common audit areas – vendor, investigator site, and the sponsor’s internal audit program – are part of a robust GxP audit system for sponsors. While each segment focuses on different aspects of the regulations governing clinical trials, the comprehensive review of audit reports and findings will assist the sponsor in developing a comprehensive inspection readiness plan.

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