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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:

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.
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.
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:

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.
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.
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.
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.
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.

Recombinant DNA technologies and genetically modified biological agents are being adapted for a wide scope of therapeutic applications, and their use is becoming increasingly common in clinical trials.

These types of investigational products (IPs) can present extraordinary hazards potentially unfamiliar to the clinical personnel responsible for handling these IPs.

The standard policies and procedures for safe handling of other types of hazards, such as antineoplastic drugs and infectious material, may not accommodate the specific risks posed by recombinant therapeutics.

This gap in hazard communication and safe handling practices training is bridged with an institutional biosafety committee (IBC) standard operating procedure (SOP) addressing specific risks. This blog describes why hazard communications are necessary and what an effective SOP should include.

Why Do You Need an SOP About IP Hazards?

When working with an unfamiliar IP, clinical personnel are likely looking for answers to three main questions:

What are the risks associated with this IP?
How can I protect myself from exposure?
What should I do if I’m exposed?

Genetically engineered products often require additional safety practices to ensure the infectious agents do not endanger participants, study staff, or the broader environment where such agents are administered. Because these therapies often use live viral vectors, there is the risk of accidental transmission that is not encountered with non-biological drugs and therapeutics.

Communicating the Specific Hazards of IPs Involving Genetic Engineering

The health consequences from an exposure depend primarily on the virulence of the biological agent (or organism) and whether the agent can replicate.

Bundling IPs of the same risk classification into one SOP version provides standardization and consistency for clinics participating in multiple clinical trials using recombinant therapeutics. For example, a site conducting only protocols involving mRNA may be able to leverage a generic SOP covering any mRNA protocol at that site.

This means site personnel do not have to review and sign a new SOP each time they submit a new mRNA protocol.

The following information includes common elements to consider in site hazard communications and use of this “bundling” approach to simplify things for stakeholders (this is the approach Advarra’s IBC has taken).

Replication-incompetent Agents

Many viral vectors used in clinical trials today are genetically engineered with safeguards to render them replication-incompetent.

Whether an mRNA therapeutic or a replication-incompetent viral vector, IPs in this class can be safely handled using similar risk mitigation strategies, and one SOP can be applicable to most, if not all.

These types of agents are classified as self-limiting, because the amount of agent potentially shedding or distributing systemically from the site of exposure cannot exceed, and is likely inferior to, the original amount exposed. Thus, the likelihood of transmitting (or spreading) the agent to others is highly unlikely.

Synthetic mRNA-based therapeutics used in clinical research today also fall into this self-limiting class of recombinant therapeutics. These IPs pose the lowest risk amongst all recombinant IPs. However, “replication-incompetent” does not mean these IPs are without risk altogether. Low-grade side effects are common for most mRNA-based IPs.

For a healthy individual, occupational exposure side effects would likely mimic, to a lesser degree, those experienced by study subjects receiving full doses of the IP. These side effects most commonly are low-grade reactions localized to the injection site.

However, some individuals may have pre-existing immune-related conditions, making them vulnerable to more severe reactions upon IP exposure, such as systemic allergic reactions requiring medical treatment.

Clinical personnel need to understand these risks and how risks are differentiated between healthy and vulnerable individuals.

Replication-competent Agents

On the other side of the risk spectrum, live replication-competent viruses are being developed as therapies for solid tumors. Known as oncolytic viruses, these are engineered to restrict replication and spread of the virus to within the tumor tissue, but the safeguards engineered for this purpose are not absolute (unlike those used to make viruses replication-incompetent).

Due to their unique complexities, oncolytic viruses normally require specific SOPs to communicate the risks and appropriate safe handling practices specific to oncolytic viruses, and also succinctly describe the nuances responsible for their exceptional risk.

Depending on the genetic modifications of the oncolytic virus, exposure may result in an infection or disease with symptoms mimicking those from an infection by the native parent virus. The SOP should list these symptoms and any available prophylaxis for post-exposure treatment.

This SOP should also advise persons who are immunocompromised or taking immune suppressive medications against handling the investigational product, as they could be particularly vulnerable to disease resulting from exposure. Since the risk posed to a pregnancy and unborn fetus is typically unknown, pregnant women may also be advised as such.

If a vaccine is available, clinical personnel working with the IP should consider vaccination status. That should be in the SOP as well.

The IBC’s Role in Developing Hazard Communications

In its review, the IBC derives these safe product handling answers using a risk assessment. The IBC’s risk assessment considers the biological properties inherent to the investigational product, as well as aspects specific to the clinical protocol (such as modes for preparation and administration).

In addition to these questions, the IBC also assesses the probability of the IP being shed into the environment, the risk such a release poses to the environment, the adequacy of the clinic’s facilities for working with the IP, and the competency and training of the principal investigator (PI) and clinical personnel who will work with the IP.

All this information is distilled into a concise hazard communication, which can be incorporated into a site’s standard SOP and training materials for the PI and clinical personnel. These communications and SOPs are typically specific to an investigational product (or class of investigational products) rather than a specific clinical trial protocol.

Benefits and Limitations of Bundling Common Hazard Communications

As mentioned above, in its risk assessment, the IBC considers aspects specific to the clinical protocol, which may be independent of the IP. The mode of administration to participants can significantly impact the protocol’s risk evaluation.

The one-size-fits-all approach mentioned above for SOPs covering self-limiting or replication-incompetent IPs applies for only the most common modes of administration, such as intramuscular or intravenous.

If, for example, a protocol requires the IP to be nebulized for administration into the lung, all persons in the room during administration will be at risk of exposure from inhalation. In this case, a protocol-specific SOP with exceptional exposure mitigation measures would be required. These measures could include use of respiratory protection for all persons in the room, restricting the room to only required personnel, and disinfecting all surfaces following administration.

The Importance of Hazard Communications in Clinical Trials

Recombinant therapeutics evaluated in humans are unlikely to be highly virulent because they are intentionally and carefully developed that way. However, some degree of virulence and risk is acceptable, depending on the disease and subject population being treated.

NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules require IBCs ensure hazards are appropriately communicated to those potentially impacted, and study staff receive training on appropriate safe handling practices. Most clinical research clinics do not have the type of administrative resources in place to maintain a registered IBC with the NIH. This is why using an externally administered IBC is paramount for the development of medical recombinant therapeutics.

The risk of these IPs to enrolled study subjects, who ostensibly receive full doses of the IP, are mitigated by the protocol’s defined exclusion criteria. Vulnerable individuals who may react adversely to the study treatment are not eligible to participate in the trial, which minimizes the possibility of adverse events occurring in these individuals.

Further, enrolled study subjects are informed of the known and anticipated risks of the IP in the informed consent form (ICF) they are required to review and sign prior to enrollment. Thus, mechanisms are already in place for hazard communication and training for enrolled study subjects.

However, no such formal communication or training requirement exists for clinical personnel with potential for exposure. A formal hazard communication or IBC SOP fills this gap by effectively providing the hazard communication and training clinical personnel deserve.

In recent years, the use of single institutional review board (sIRB) review has gained significant traction in the world of research ethics and compliance. sIRBs are intended to streamline the ethical review process for multisite research studies, ensuring research is conducted safely and efficiently.

However, implementing an sIRB reliance model involves important local considerations researchers and institutions must carefully address. In this blog, we explore these local considerations to help research teams navigate the complexities of sIRB implementation successfully.

What is an sIRB?

Before delving into the local considerations, it’s essential to understand what an sIRB is and why it’s used in research. An sIRB is a single ethics review board assuming responsibility for reviewing research protocols, and ensuring ongoing IRB oversight, across multiple institutions or sites engaged in human subjects research.

The primary goals of utilizing sIRBs are to simplify the ethical review process, reduce redundancy and administrative burden, and ensure the same ethical standards are applied consistently across all participating sites.

Local Considerations in sIRB Implementation

Local context, expertise, compliance, and collaboration are all critical factors to sIRB success. By carefully addressing these considerations, research institutions can effectively implement sIRB policies while respecting their local research environments’ unique characteristics and ensuring the highest ethical standards in their studies.

“Local context” is a concept mentioned in regulatory guidance but lacking an official definition. However, the research community generally agrees local context covers key site-level requirements and other local considerations an sIRB must include as part of its review.

Communication and Coordination

Effective communication and coordination are critical when implementing an sIRB policy. Additionally, the National Institutes of Health (NIH) requires grant applicants to provide a communication plan for sIRB reliance.

To ensure the review process runs smoothly, sites should work with the sIRB to establish clear lines of communication. This may involve establishing key contacts at both organizations, regular meetings, updates on protocol changes, and a transparent process for addressing questions or concerns. At the site, local communications should be organized to include the HRPP as well as the research team.

Consent Form Local Requirements

Many institutions have unique consent requirements related to the community they serve as well as state, local, or other organizational needs. This may include birth control language for institutions with religious affiliations or compensation for injury verbiage.

When developing your institution’s consent language for sIRB use, consider what is truly necessary and limit your requirements to just those protecting participants or meeting other local requirements. Establishing clear and reasonable local consent requirements helps ensure the sIRB appropriately addresses local needs while preserving sIRB efficiencies. Avoid the temptation to rewrite the entire informed consent or reword portions for editorial purposes, as this detracts from the purpose of sIRB and delays review timelines.

Local IRB Engagement/Transition Plan

Engage your local human research protections program (HRPP) in evolving the sIRB process. Even though the sIRB is responsible for IRB oversight of the overall protocol, the local HRPP staff will likely still have responsibilities, such as providing local informed consent requirements, reviewing sIRB applications, and ensuring local ancillary reviews (e.g., conflict of interest, feasibility, pharmacy, etc.) are completed as required.

Local HRPPs can provide valuable input in ensuring the sIRB understands local risk factors and respects community values and norms. The ceding institution (i.e., the institutional site giving up local IRB oversight and relying on an sIRB’s review) should be prepared to provide any relevant local context information to the reviewing IRB; for example, some communities may have long standing mistrust of researchers related to historical context not known to the reviewing IRB.

This essential information may inform the IRB review of the study and should be communicated as a part of the local context information. Institutions should consider developing a dedicated sIRB local context resource, perhaps a single document outlining the unique specifics that is shared with sIRBs periodically and whenever there is a revision.

Researcher Training

In developing institutional policies, ensure you include a process for training investigators and study teams on local requirements for ceding IRB review. Researchers and other stakeholders should be trained on the sIRB process, local considerations, and institutional expectations for sIRB research. This should include both initial requirements to cede review, and any requirements for ongoing updates and reporting to the local HRPP.

Researchers should also be aware of the unique ethical, cultural, and regulatory aspects of conducting research in their region so they can appropriately include such details in the sIRB submission process. They should also be familiar with the technology required for sIRB submission, including the sIRB’s platform and any local tools involved in the process.

Equip stakeholders with any special institutional sIRB submission requirements, process details for relying on an sIRB, and any other local elements potentially impacting sIRB review. For example, some institutions may require investigators to complete a reliance form prior to ceding review to an sIRB.

Finally, ensure stakeholders are made aware of and can easily find information regarding ongoing local requirements; for example, do researchers need local approval for a principal investigator (PI) change, and how is local approval obtained? Are study teams required to submit annual reports, or does the local HRPP only need updates if certain changes are made to the research? Are there local reporting requirements for unanticipated events that are in addition to and/or differ from sIRB requirements?

Institutional Culture and Policies

Each research institution has its own unique culture, policies, standards of care, and community expectations affecting how they approach research ethics. When relying on an sIRB, it is crucial to consider how the sIRB process aligns with the institution’s local culture and policies.

Consider what local processes and reviews (e.g., conflict of interest review, radiation safety committee review, etc.) must take place in conjunction with the sIRB review process. From there, think about how these local activities may impact sIRB review timelines. It may be valuable to assess which local processes have minimal impact on sIRB review. This proactive assessment then, can be done in parallel with the sIRB review, instead of waiting to submit until all ancillary reviews are completed.

Engaging an independent third party’s perspective could prove indispensable in assessing current processes and developing new approaches that capitalize on the efficiencies inherent to sIRB review.

Regulatory Compliance

Different communities and regions may have distinct regulatory requirements governing research ethics. Researchers and institutions must ensure the sIRB is aware of local requirements, state laws and statutes, and other regulations governing regulatory compliance.

This includes addressing any differences in informed consent procedures, reporting requirements, and other ethical considerations varying by location (e.g., reporting for-cause FDA or OHRP audits to the sIRB). For example, consent requirements for minors and the age of majority may vary by state. Additionally, it’s critical to notify the sIRB whether the institution has “checked the box” on its Federalwide Assurance (FWA).

Local Expertise

In some cases, local expertise may be required to provide insights into specific cultural or contextual nuances potentially impacting research ethics. Institutions should alert the sIRB regarding local researchers, ethicists, or community representatives whose perspectives may be necessary to the review process.

Data Privacy and Security

Local data privacy and security regulations may vary, and the institution should inform the sIRB of data handling compliance. This may involve encrypting data, obtaining specific permissions, or adhering to local data storage requirements.

Budget and Resource Allocation

Implementing an sIRB process may require additional resources, including financial support, administrative staff, and training. Institutions should carefully consider the budgetary and resource implications of sIRB implementation to ensure the process is sustainable.

Some institutional IRBs may decide to act as an sIRB in certain situations. While this might be easier for the local investigator, many operational considerations must also be made (e.g., local resources, technology, etc.). To do this sIRB work, institutional IRBs charge fees for their services, but many do so arbitrarily, without a clear understanding of their actual operating costs. This lack of cost clarity is a common shortcoming among many HRPPs . It may be valuable to assess this cost to help inform budget considerations for grant applications, to advocate for increased staffing, and other metrics.

Successfully Implementing an sIRB Process

While implementing an sIRB process can significantly streamline the ethical review process for multisite research studies, it’s essential to navigate the local considerations thoughtfully.

By acknowledging and addressing the unique cultural, regulatory, and logistical aspects of each participating institution, and establishing a consistent process for ceding IRB oversight, researchers and institutions can ensure the sIRB process is both efficient and ethically sound.

Effective communication, collaboration, and flexibility are key to successfully implementing an sIRB model designed to benefit all stakeholders involved in research.

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.

Evolving regulations, technological advancements, changing societal norms, and new research methodologies can cause an organization to pause and think, “Does our human research protection program (HRPP) have the proper expertise, policies, and procedures in place? Are we ready for increasing new single IRB (sIRB) mandates? Should we pursue accreditation?”

Maybe your organization has a vision for modernizing the HRPP. This may include implementing electronic management systems, creating new positions, or conducting intensive trainings to address identified gaps or new requirements. However, it’s hard to implement such changes or trainings without seriously impacting day-to-day operations. It’s difficult to know where to begin.

How Interim Staffing Can Help Evolve Your HRPP

External interim staff can help assess and revise an HRPP’s structure, policies, and procedures, ensuring they reflect the latest standards and best practices. Outside perspectives and experience are invaluable in identifying areas for improvement and ensuring policies and processes are both compliant and conducive to efficient operations. Benefits of external interim staff include:

Specialized expertise and experience: Interim staff bring targeted expertise and skills not necessarily available in-house. This option also provides access to experts with knowledge of and expertise in specific regulatory frameworks, emerging research technologies, specific therapeutic areas, or in nuances of regulatory processes or roles. They come with a wealth of experience garnered from working across different organizations and environments.
Objective evaluation and fresh perspectives: External interim staff can bring new eyes when evaluating an HRPP’s policies, procedures, and practices. It’s helpful they are removed from any internal dynamics, history, and implicit biases potentially existing within an institution. Because of this, they can identify gaps and previously unnoticed issues and offer unbiased assessments and fresh perspectives to the program.
Accelerated learning and knowledge transfer: Through targeted training and development initiatives, interim staff can quickly inform internal staff on the latest regulations, ethical considerations, and industry best practices. They can also provide training for staff with evolving roles or roles new to the HRPP. This direct infusion of knowledge and dedicated training can enhance research protection and compliance, as well as accelerate training and integrating new roles within the HRPP.
Filling the gaps: Special projects and big changes can be resource- and time-intensive. Even if the expertise needed is available in-house, the time needed might not be. Interim staffing can supply the necessary personnel for maintaining operations, and allow project completion without disrupting the HRPP’s ongoing, core responsibilities. In addition, if a recent change has resulted in accumulating reviews or “to dos,” interim staff can help your HRPP clear any backlogs.
Facilitating change and cultural shifts: At the institutional level, facilitating change requires a strategic approach to change management. Interim staff can serve as agents of change, guiding the institution through necessary transformations by leveraging proven strategies to minimize resistance and helping to ensure buy-in from key stakeholders. Their external status can also lend credibility to the change process, making it easier to implement new policies and practices.

When Accreditation is the Catalyst for Change

Of all the major changes an HRPP can make, the accreditation process is one of the more formidable and with high stakes consequences. It’s a lot to take on, especially for a team with little prior accreditation experience, and the process can place significant strain on current staff due to the time investment required. Interim staff can contribute to the accreditation process in several ways:

Streamlining the accreditation process: Professionals experienced with accreditation can demystify the process, serving as project managers, facilitating training and staff preparation as well as coordinating efforts across departments and ensuring milestones are met on time. Their experience can help the institutional team avoid common pitfalls and streamline efforts, making the path to accreditation smoother and more efficient.
Gap analysis and preparatory work: One of the first steps towards accreditation is conducting a thorough gap analysis to identify areas where the HRPP might not meet the standards established by the accreditation body. External interim staff, with their fresh perspectives and breadth of experience, can identify these gaps more efficiently and propose innovative solutions to address them. Their expertise is especially valuable in navigating the complex documentation requirements of the accreditation process.
Policy and procedure enhancement: Accreditation typically requires a comprehensive review, revision, and (often) policy and procedure creation to ensure they align with accreditation standards. Interim staff, particularly those with experience in accreditation processes, can lead these revisions and draft needed policies. With experience implementing new policies resulting from the accreditation process, they can ensure policies are compliant, meet the required standards, and are practical.
Addressing specific accreditation feedback: Following an accreditation review, HRPPs can receive specific feedback or directives about larger changes needed to meet accreditation standards, requiring additional resources and support to address. Interim staff can be engaged to help address various areas directly. Their targeted expertise allows for a focused approach to resolving these issues efficiently, ensuring the HRPP meets the expectations for accreditation.
Sustaining accreditation standards: Beyond achieving accreditation, maintaining those standards requires ongoing effort and vigilance. Interim staff can establish frameworks and continuous improvement processes to ensure the HRPP remains in compliance with accreditation standards. They can also help implement and/or staff a robust post-approval monitoring and quality improvement program that identifies potential issues before they become compliance risks, ensuring accreditation is both achieved and sustained.

By bringing objective evaluation, specialized expertise, and effective change management skills, interim staff can significantly improve an institution’s ability to identify issues and implement necessary changes.

External support can propel the institution towards accreditation success, facilitate a large project without impacting basic operations, or simply help build a stronger, more compliant HRPP designed to adapt to future challenges and changes in the research landscape. Engaging professionals from outside the institution is an important strategy for ensuring the ethical and responsible conduct of research involving human subjects.

In the realm of pharmaceutical development, ensuring the safety and efficacy of new treatments is paramount. One crucial aspect of this process involves establishing data safety monitoring boards (DSMBs) (also known as data monitoring committees [DMCs]) to oversee clinical trials.

Traditionally, pharmaceutical sponsors have formed a new DSMB for each individual trial. However, there’s a growing recognition of the benefits of utilizing the same DSMB members to oversee multiple trials within an entire therapeutic program.

This shift to a single DSMB for a therapeutic program not only ensures continuity of experience but also offers potential cost savings and efficiency gains.

Continuity of Experience

Imagine a pharmaceutical company is embarking on a series of clinical trials for a particular therapeutic area, such as oncology or neurology. By utilizing the same DSMB members across all trials in the series, the members develop a deep understanding of the drug, its mechanisms, and potential safety concerns specific to the therapeutic area.

This continuity of experience enables the DSMB to provide the pharmaceutical company with more nuanced and informed recommendations throughout the entire program.

Moreover, familiarity with the drug and its development process allows DSMB members to detect subtle changes or trends in safety data over time.

This long-term perspective is invaluable in assessing the overall risk-benefit profile of the drug, especially in cases where adverse events may manifest only after prolonged exposure or in specific patient populations.

Faster Setup

Establishing a new DSMB can take months for member identification, charter development, technology system setup, and other setup activities. (Though some independent providers can set up a DSMB in as little as six to eight weeks.)

Utilizing the same board members for multiple trials can substantially reduce the setup time required as members are already contracted, technology systems are already established, members are trained on those systems, prior charters can be leveraged, and many other advantages.

DSMBs retained to support every trial in a program can be set up and ready to cover the next trial within a couple of weeks.

Cost Savings

Forming a new DSMB for each individual trial demands time and resources. Setting up a DSMB involves identifying qualified experts, negotiating contracts, and ensuring compliance with regulatory requirements for each board.

By contrast, utilizing the same DSMB members across multiple trials streamlines this process and reduces administrative burdens.

Furthermore, ongoing engagement with the same DSMB members may lead to more efficient communication channels and decision-making processes. As the board becomes familiar with the company’s protocols and reporting mechanisms, discussions can be more focused, potentially accelerating the pace of clinical development.

Recent FDA Draft Guidance

The importance of continuity in data monitoring is underscored by the 2024 FDA draft guidance on DMCs. This draft guidance highlights and expands on the benefits the Food and Drug Administration (FDA) sees in having a single DMC oversee an entire therapeutic program, rather than focusing solely on individual trials.

The FDA’s added emphasis on program-level oversight reflects a broader recognition of the complexities involved in modern drug development.

Therapeutic programs often involve multiple trials conducted across different geographical regions and patient populations. In such scenarios, a single DSMB can provide consistent oversight and ensure harmonized safety monitoring practices across all trials in the program.

Utilizing the same DSMB members across therapeutic programs offers numerous advantages. Continuity of experience facilitates deeper insights into safety data, while potential cost savings and efficiency gains enhance overall trial management.

Moreover, recent FDA guidance on DMCs reinforces the importance of program-level oversight in ensuring the safety and efficacy of new treatments. Sponsors and contract research organizations (CROs) should thoughtfully consider leveraging these safety and efficiency advantages and engage a DSMB at the therapeutic program level.

Clinical trials are the cornerstone of medical advancements, but ensuring their integrity and safety requires meticulous oversight.

Data monitoring committees (DMCs, also known as data safety monitoring boards [DSMBs]) play a crucial role in this process, providing independent evaluation of unmasked trial data to safeguard patient welfare during the trial.

The Food and Drug Administration’s (FDA’s) February 2024 draft guidance Use of Data Monitoring Committees in Clinical Trials signals a significant shift in approach. Open for public comment until April 15, 2024, this draft seeks to modernize and clarify the agency’s expectations for DMC oversight. In this blog post, we dive into these latest updates regarding DMCs and the draft guidance’s implications for sponsors and contract research organizations (CROs).

DMCs and Their Importance to the Clinical Trial Ecosystem

Before discussing the FDA’s DMC draft guidance, let’s define the role of DMCs. These independent groups of experts review unmasked aggregate interim trial data, assessing safety concerns and making recommendations regarding trial continuation, modification, or termination.

The DMC’s independent viewpoint adds a layer of scrutiny crucial for maintaining trial integrity and protecting participants during the conduct of the trial – while sponsors, CROs, and investigators remain blinded to treatment arms or placebo controls.

Simply put: During the trial, someone needs to analyze the data to see:

If the drug/device is working or not
If there are safety signals in the unmasked data that would cause a need to stop early

What Does the FDA’s New Draft Guidance on DMCs Say?

The FDA periodically revises its guidance to align with evolving best practices and technological advancements. In its latest DMC draft guidance, the agency introduces several noteworthy updates and clarifications to its 2006 guidance.

Bear in mind: The February 2024 guidance is draft only, and not yet finalized. However, draft guidance from FDA typically signals the agency’s current thinking on a topic and therefore should be considered.

Clarifications and minor updates run throughout the new draft guidance. However, the following stand out as the most significant changes with an impact to sponsors and CROs:

Significant new emphasis on DMC independence: In section 6.1 of the FDA’s 2006 guidance, the agency indicated it would be “desirable” to have the DMC administered independent from those sponsoring, conducting, or regulating the trial. In the 2024 draft guidance, new section VI, the agency has replaced the “desirable” threshold with the following proposed language:

“Independence of the DMC from the sponsor is critical”

In the draft guidance, the agency discusses at length the need for the DMC to be separate from those sponsoring, organizing, conducting, or regulating a trial.

Many sponsors and CROs currently form and administer the DMCs overseeing the studies they conduct. The agency appears to be signaling in the draft guidance this is no longer an acceptable level of separation of oversight duties.

Expanded DMC scope: The draft guidance outlines a broader scope for DMC involvement, emphasizing their role beyond safety monitoring to also include efficacy assessments and overall trial conduct evaluation.
Emphasis on program-level DMCs: FDA expanded language supporting a common or continued DMC oversight for a series of protocols in a therapeutic program. Emphasis is placed on the advantages of continuity of DMC membership and familiarity with the therapeutic product as it continues its development. Familiarity with the drug and its development process allows DMC members to detect subtle changes or trends in safety data over time. This long-term perspective is invaluable in assessing the overall risk-benefit profile of the drug, especially in cases where adverse events may manifest only after prolonged exposure or in specific patient populations.
Enhanced communication protocols: Clearer communication channels between DMCs, sponsors, and other review committees have a new emphasis, ensuring timely dissemination of critical information and recommendations. This narrative also supports the agency’s signal that DMCs should be formed and administered by independent oversight organizations who can professionally manage the communications and separation of duties.
Adaptive trial design support: The agency recognizes the growing prevalence of adaptive trial designs, and the draft guidance offers suggestions on how to incorporate DMCs into these dynamic trial frameworks effectively.

With these important changes, FDA left the majority of the 2006 guidance language intact and instead focused largely on key trial advancements over the last 20 years.

The draft guidance preserves information from 2006 regarding the DMC’s organization and structure, the importance of a charter to describe the DMC’s operations, interactions between the DMC and the independent statistical center, and rationale for a DMC’s crucial role in the clinical trial ecosystem.

Impact of DMC Draft Guidance on Sponsors and CROs

The 2024 DMC draft guidance carries meaningful implications for trial sponsors:

Reinforced need for DMCs: After nearly 20 years, the FDA is doubling down on the utility and need for independent DMCs to oversee research. The FDA recognizes the utility of these independent oversight committees and, with this draft guidance, is reinforcing their importance within the continuum of research oversight.
Increased accountability and transparency: Sponsors and CROs are tasked with ensuring robust DMC establishment and operations, fostering transparency and accountability in trial oversight. This means sponsors and CROs will be expected to actively incorporate DMCs into their trials and engage trusted third parties to administer the DMCs independent of those who are sponsoring, conducting, or regulating the trial.
Adapting to changing trial landscapes: The draft guidance suggests sponsors must adapt trial management strategies to accommodate evolving methodologies. This includes incorporating DMCs into more areas of their adaptive trial designs. DMCs play a critical role in establishing an adequate data safety monitoring plan consistent with 21 CFR 56.111(a)(6); as trials change, where DMCs fit is also changing.
Resource allocation and expertise: Sponsors should allocate resources to engage independent DMC activities effectively. This includes using independent providers for the selection of qualified DMC members and provision of necessary data and resources. Sponsors should also consider engaging a single DMC for an entire therapeutic program to obtain operational efficiencies and continuity of oversight.

The FDA’s new draft guidance on DMCs reflects a proactive approach to enhancing clinical trial oversight and aligning with modern trial methodologies.

For sponsors and CROs, these updates necessitate a contemplative look at how they structure their DMCs and if those DMCs have the appropriate level of independence. FDA is emphasizing the need for separation of duties to uphold the highest standards of trial conduct and patient safety.

By embracing the FDA’s draft guidance and integrating independent DMCs into their trial management processes, sponsors can foster trust, integrity, and, ultimately, the success of their clinical trials.

As those familiar with medical device research are likely aware, there is some variation in the way medical device studies are regulated as compared to the regulations governing drug studies. When it comes to reporting to the institutional review board (IRB), however, the regulations are fairly similar.

According to the Food and Drug Administration’s (FDA’s) 2009 guidance document on adverse event reporting to IRBs, investigational device exemption (IDE) regulations “require sponsors to submit reports to IRBs in a manner consistent with the recommendations made…for the reporting of unanticipated problems under the IND regulations.”

However, unlike investigational new drug (IND) regulations, IDE regulations contain a unique term: unanticipated adverse device effect, or UADE.

Defining a UADE

A UADE is “any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects” (21 CFR 812.3[s]).

Reporting UADEs should occur as follows:

Investigators are required to submit a report of a UADE to the sponsor and the reviewing IRB as soon as possible, but in no event later than 10 working days after the investigator first learns of the event (21 CFR 812.150[a][1])
Sponsors must immediately conduct an evaluation of a UADE and must report the results of the evaluation to FDA, all reviewing IRBs, and participating investigators within 10 working days after the sponsor first receives notice of the effect (21 CFR 812.46[b], 21 CFR 812.150[b][1])

At Advarra, when a serious adverse event (SAEs) or safety report does not meet the UADE criteria and is submitted to the IRB, the submitting party will receive acknowledgement of receipt only. The IRB will not review the item. When these items are submitted by a sponsor or contract research organization (CRO), Advarra’s default process is to generate an acknowledgement of receipt to all open sites, though sponsors/CROs may opt out of this process.

Note: This article was originally published October 2, 2019, and has been updated to include new and clarifying information.

While the regulations governing clinical research refer to “noncompliance” several times, the term is not actually defined in the regulations. This leaves it up to individual institutional review boards (IRBs) to establish a definition, policies/procedures, and reporting requirements for sponsors, contract research organizations (CROs), and investigative sites to follow.

Understandably, this can cause confusion for researchers working with multiple IRBs. It’s important to make sure you’re familiar with your IRB’s reporting requirements—and if you’re not sure, it’s always appropriate to reach out to the IRB for clarification.

A Definition of Investigator Noncompliance

While no official regulatory definition is available, we wanted to provide some examples to assist the research community. Here are the definitions Advarra’s IRB has established:

Noncompliance is any action or activity associated with the conduct or oversight of research involving human subjects that fails to comply with applicable regulations, the IRB’s handbook, and/or the IRB’s determinations and requirements
- Noncompliance may range from minor to serious; be unintentional or willful; and may occur once, sporadically, or continuously
- The degree of noncompliance is evaluated on a case-by-case basis and takes into account whether subjects were harmed or placed at an increased risk of harm
Serious noncompliance is defined as any action or omission in the conduct or oversight of research involving human subjects that affects the rights and welfare of subjects, increases risk to subjects, or compromises the scientific integrity or validity of the research
Continuing noncompliance is defined as a pattern of repeatedly failing to comply with applicable regulations, the IRB’s handbook, and/or the determinations and requirements of the IRB that may affect subjects’ rights and welfare, increase risk to subjects, or may compromise the scientific integrity or validity of the research
- Continuing noncompliance also includes frequent instances of minor noncompliance or failure to respond to a request to resolve an episode of noncompliance

Consistent with other reportable events, Advarra expects noncompliance reports be submitted as soon as possible, no later than two weeks or 10 business days from the time of the event.

While these examples are unique to Advarra’s IRB, they were developed based on best practices and in consultation with other IRB professionals.

IRB Noncompliance Reporting Requirements

In addition to reporting the noncompliance event, some IRBs may require the report to also include information like:

The immediate action taken to ensure subjects were not harmed
A corrective and preventative action plan
Supporting information from other sources if applicable

Again, check with your IRB to understand the specific reporting requirements. When working with Advarra, your best source for this kind of information is the IRB Handbook, available in the Reference Materials section of the Advarra Center for IRB Intelligence (CIRBI) Platform.

Reports and allegations of noncompliance will be evaluated by the IRB and can result in an action up to and including suspension or termination of IRB approval. Any report of noncompliance determined by the IRB to be serious or continuing, or any determination to suspend or terminate IRB approval, will be reported to the appropriate regulatory agency.

When in doubt, it’s best to report noncompliance concerns to the IRB and allow it to make an appropriate determination to ensure the rights and welfare of research participants are adequately protected.

Note: This article was originally published December 4, 2019, and has been updated to include new and clarifying information.

The site-sponsor relationship continues to become more important day by day. With trial complexity increasing, site staff availability stretched thin, bespoke methods of interaction, and unique methods of engaging with patients administered by sites, the relationship is complicated.

While considering how to engage the global and very unique set of partners, we often silo down to the term “sites.” However, each site is different, and sponsors and contract research organization (CRO) study teams must continually evaluate how they engage uniquely with each sites and find ways to make collaboration and workflows more efficient. This is the root of reducing site burden – without adequate communication and understanding of site needs, sites will face unnecessary burden.

Examples of Where Burden Will Likely Occur, and How to Combat Them

Attempting to eliminate complexity and frustration throughout the entire trial can be an impossible task. However, focused small attempts to reduce redundancy and ease processes can have a big impact on the operational and regulatory success of your study.

Is Your Trial Designed to Leverage Site-provided Information?

Site Feasibility Questionnaires (SFQs)

To save time on their end, sponsor study team members often distribute generic SFQs to sites they may have already engaged or received responses from. This can create significant redundancies for sites. In a recent survey of 500 sites in North America, only 25% report sponsors and CROs met the goal of focusing feasibility on protocol-specific questions only and leveraging former responses to non-study specific questions.

Budget Negotiation and Contracting

The time investment in the legal process of contracting and very real limits of budgets will always be a factor. However, when writing out a budget, don’t start at ground zero. Take the time upfront to include previous clauses or rate cards the site has agreed to previously. If this is the first time working with a site, identify the country or state clauses to include in your country contract template and drive it as close to site specific as possible before sending. Additionally, find terms to apply across multiple programs. Similarly to feasibility questionnaires, this upfront investment will pull forward previous contractual and budget knowledge into your new trial, making the budgeting and contracting process go faster.

Is Your Trial Designed to Leverage Technology and Training Already in Place at Sites?

Document Exchange

If a site has an electronic investigator site file (eISF) or another document management system, consider interfacing rather than requiring an entirely new system. There are a myriad of hurdles sites face managing multiple systems, but one in particular is maintaining shadow systems, obfuscating a shared understanding of the source of truth. If one document is stored in multiple places due to a site aligning with their own SOPs or a sponsor’s desire to exchange documents via a second investigator site file technology, it can be nearly impossible to easily point to (or remember) which document is correct when a monitor or inspector arrives.

This has drastic implications, potentially leading to trial misinformation, using previously versioned documents, and providing risk to the trial and patient.

Training

Accepting training from your organization from one study to the next on general research requirements can go a long way. It’s not productive to force the same non-study specific training (for example, good clinical practice [GCP] training) on a site if they’ve already completed training through a different trial within your organization. Instead, verify the source of their training to ensure it meets reputable and regulatory standards.

Logins, Access, and Security

In a recent survey, sites reported using an average of four to six sponsor-provided technology logins per trial. When sites are supporting even just five studies, administrative headaches and security risks add up. In the same survey, 80% of sites rated using the site’s own credentials to access sponsor technology was rated at extremely or very valuable.

Does Your Trial Operations include Resources Sites Need for Success?

The investigators, nurses, and clinical research coordinators (CRCs) supporting a study likely have tight schedules with very little room for things to slip. This is especially true once they are engaging with patients – they don’t have extra time to focus on administrative tasks.

Visit Guidance and Protocol Text Search

Through these tools, sites can get up to speed on procedures and protocols quickly. Staff can also refresh their memory on what they have to do, who’s coming, and when, all while providing the relevant information to the patient to keep them informed as well.

Amendments

With protocol amendments, staff will need to update and resign documents. Additionally, they will need to modify training to reflect amendment changes. If there’s a significant amendment coming out, think about how sponsors can minimize the amount of touchpoints with their site while ensuring everything is compliant and on track. This could take the form of identifying a change log for each document to ensure the staff know the severity of the change. Sites could also implement training that can be incrementally changed and reviewed independently. This reduces the redundancy of all non-changed training while still maintaining the connection to the trial scope as a whole.

Audit Readiness

Before a study closes out, the Food and Drug Administration (FDA) may request an inspection. Sponsors must make sure the site is supported in documentation throughout the study. That way, if the FDA calls for an audit, everything is where it needs to be.

Centralizing, Connecting, and Simplifying the Process for Stakeholders

To enhance site efficiency, sponsors should focus on centralization, connecting stakeholder systems, and simplifying tasks. Centralizing study information streamlines processes, while integrating information flow ensures efficiency and seamless communication. Simplifying tasks by condensing requests and providing upfront resources alleviates organizational workloads, maintaining a smooth study process.

Addressing these areas of burden may vary across each unique type of site. However, it’s necessary to have these conversations with sites to minimize unnecessary burden and improve the clinical trial experience for all.

Sponsor and contract research organization (CRO) team members such as clinical research associates (CRAs), study managers, and startup specialists collaborate with research site teams to activate and execute clinical trials. Despite each stakeholders’ best efforts, there are persistent challenges regularly throwing studies off track and resulting in costly workarounds:

Failure to achieve recruitment goals: About 20 to 50% of clinical trials will require “rescue”, where new sites are added to cure patient enrollment shortfalls. Ensuring every selected site can achieve their recruitment targets is essential to meeting study timelines and eliminating unplanned costs.
Loss of patient data sets due to protocol non-compliance: The cost to recruit a new patient if one is lost due to non-compliance is an estimated $20,000. To maximize the investment in each activated site, it is important to not only monitor recruitment progress, but also site protocol adherence to retain adequate patient data.

When these challenges occur, it requires additional investment of unbudgeted resources and time. From the time a site is selected for your study, there is a critical window where study teams need to increase oversight to avoid these frequent study pitfalls.

Very often, study teams focus too heavily on recruitment progress, where it can take months for clear trends to emerge. However, there are other informative metrics which present themselves much sooner and allow you to take preventative action, versus costly reactive measures.

Key Risk Indicator #1: Have Site Staff Accessed Your Training System and Materials?

Just because you have distributed training materials does not mean your site teams have accessed or are familiarized with them. Leveraging an electronic system for training materials provides your team with more oversight into onboarding and training status of each site member and investigator. These systems are typically deployed at site activation and early adoption is a strong indicator of your site’s engagement.

Tip to reduce site burden: Consider how many systems you’re providing to sites on a particular trial (ex: electronic data capture [EDC], learning management system, etc.) and opt for ways to centralize access. In addition, providing all site training for your studies in a single location will reduce the challenge of finding and accessing essential training information for your sites.

Key Risk Indicator #2: Have Your Sites Completed Required Training, and are they Passing Training Evaluations?

In addition to overall training completion, knowledge retention and understanding is critical for an efficient and compliant trial. You should leverage systems designed to provide visibility into overall training completion, training documentation and certification routing, and ability to test for comprehension.

It’s also important to monitor site training beyond initial activation. With so many sites facing significant staff turnover, it is inevitable new site team members will need to get up to speed on your study. Continue to monitor training engagement and accuracy throughout the trial.

Tip to reduce site burden: Not all training materials are equal. Reduce site burden by providing engaging and concise materials beyond cumbersome brochures, like videos, to add to study-specific understanding. In addition, evaluate what training may be redundant, and explore ways to accept certain training completions across studies with the same sponsor to reduce duplicative burden on site teams.

Key Risk Indicator #3: Have Your Sites Acknowledged (Signed, Viewed, or Responded to) Essential Study Documents and Alerts?

This critical metric informs timelines and compliant conduct. Documents like signed informed consent forms (ICFs) indicate active recruitment activities. Additionally, acknowledgement of study communications, protocol amendments or safety letters are also an indication sites are working with the most up-to-date version of the protocol and are engaged with the trial.

If you’re using a system like email to facilitate document exchange or updates on amendments or safety notifications, you will likely lack visibility into the exact action of a site staff member. It is important to view status across delivery, opening, clicked, and acknowledged (or signed).

Tip to reduce site burden: We all experience notification fatigue. It is important to consolidate the number of notifications you’re sharing with sites, as well as centralizing them in a single system to provide them with an easy, actionable view of where their attention is most needed.

Key Risk Indicator #4: How Many Patients Were Prescreened? Is it an Appropriate Amount to Achieve Recruitment Goals?

Prescreening is an essential activity, laying the foundation for successful recruitment and is a reliable early indicator a site has commenced recruitment activity. We also know not every prescreened patient will be deemed eligible for your trial. Each trial has a conversion rate between the number of prescreened patients, those eligible, and those who enroll in the study as participants.

As study managers and CRAs, it is valuable to monitor both prescreening activities and associated conversion rates. This allows you to adapt targets based on real-time input, adjust efforts, and ensure you reach your desired recruitment targets. Technology reporting on common ineligibility criteria also enables sponsor teams to identify restrictive elements of their protocol.

Tip to reduce site burden: Prescreening is a numbers game – the more potentially eligible patients prescreened, the higher likelihood targets are achieved. Make prescreening simple and fast for sites with electronic checklists accessible via a variety of devices.

Efficient and compliant studies are a collaborative effort between study and site teams. Fit-for-purpose technology and proactive oversight of key risk indicators can support successful startup and execution of a trial, while minimizing administrative headaches for your sites.