Page 2 – Advarra

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.

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.

In clinical trials, time is both an ally and an adversary. Efficient site initiation can make or break the success of a trial. Centralized processes are essential in expediting these timelines, bringing together standardized workflows, advanced technology, and meticulous quality assurance.

There are many benefits of a centralized CTMS business operations team, which acts as a hub for resources, updates, and information related to clinical trial management. An intuitive intake form, data accuracy, custom reporting, and streamlined decision-making processes can collectively help reduce bottlenecks and enhance overall efficiency in clinical trial initiation.

Intuitive Intake Form: Developing Clinical Trial Submissions

The foundation of successful centralization lies in the implementation of an intuitive study intake form. This form empowers stakeholders to easily submit their clinical trials, optimizing the utilization of their CTMS. Here’s how this streamlined process enhances efficiency and collaboration:

Simplicity at its best: The intuitive intake form is designed to be user-friendly. There should be clear instructions and a straightforward layout to encourage active participation and guide stakeholders seamlessly through the submission process.
Unified data repository: The intake form consolidates all essential trial details, eliminating fragmented communication and preventing information gaps.
Catalyzing collaboration: Standardized data collection fosters seamless collaboration. With consistent and accessible information, stakeholders communicate more effectively. This can support better synergy in decision-making processes and insight into their clinical trial portfolio.
Accelerated review and approval: An optimized intake form expedites the review and approval process, contributing to quicker site initiation and trial commencement.

Harnessing the Power of Centralized Processes

Centralization lies at the core of an efficient process. This enables streamlined operations, enhances collaboration, and enables stakeholders to access vital information from a single source.

By developing standardized workflows, establishing clear working instructions, and leveraging advanced technology, clinical trial management can achieve new levels of efficiency.

A Complete Approach: The Clinical Trials Management Hub

A centralized CTMS business operations team that unites all aspects of clinical trial management is important. The clinical trials management hub creates a CTMS business operations website, providing stakeholders with a comprehensive repository of resources, updates, and essential process and timeline information.

This hub approach not only fosters cohesion but also simplifies the management of multiple trials, reducing complexity and promoting effective collaboration.

Precision and Quality Assurance in Data Management

A crucial benefit of centralization is maintaining data accuracy. To ensure information housed in the CTMS is accurate, sites should develop and implement quality assurance processes.

This meticulous approach guarantees that decisions are based on reliable data, enhancing the overall integrity of the trials. An important piece of good data is persistent documentation. This includes helping with documentation and developing training both on the new processes and the application.

Empowering Decision-making through Custom Reporting

Centralization not only simplifies data access but also allows for insightful analysis. Developing custom reports during the intake process delivers significant ongoing benefits, allowing stakeholders to extract specific data insights.

When reliable data comes out of a CTMS, institutions, leadership, and study teams have better insight into their clinical trials, their timelines, and the areas they need to improve upon. This data-driven approach empowers stakeholders to make informed choices that expedite trial initiation.

When executed as a consolidated business operations unit, centralization can identify and remove bottlenecks. By streamlining processes, this approach can significantly reduce delays, leading to an overall improvement in the efficiency of initiating clinical trials.

More than two decades ago, we created the OnCore clinical trial management system (CTMS) to serve as a comprehensive solution for a large academic medical center (AMC) to manage their research operations. Over the next decade, dozens of academic medical centers across the country adopted the CTMS. OnCore has since expanded to serve cancer centers as well, including many National Cancer Institutes (NCI)-designated centers.

As our customer community grew, so did the capabilities of the platform itself. Throughout the past two decades, OnCore has extended to track not just the protocol calendar, but aspects such as individual subject visits and details around financials. The ability to generate and create financial records, invoicing, and any number of tools allowing customers the ability to use the system to track almost every piece of the clinical research lifecycle – everything pertaining to a trial.

These changes have all been in collaboration with our users with the customer in mind. When OnCore was first developed, many, if not all research centers had their own processes in place with no sense of centralization. There was very little industry-wide standardization directing research site operations. Driven by input from our ever-expanding customer community, OnCore has sought to deliver standardized workflows for critical aspects of clinical trial management, including protocol and participant management, financial management and billing compliance, internal site communication and collaboration, and much more.

This customer-informed innovation, driven by our amazing community of more than 5,000 research professionals, has established OnCore as an invaluable tool for AMCs and cancer centers over the past 20 years. But how can we ensure the system continues to serve research professionals for the next 20?

Where we are Heading

As research has advanced, there’s a higher priority put on capturing data – not just through clinical research, but through all aspects of the medical industry. In order to accommodate to this, moving forward, we are focusing on how we can continue to help aggregate clinical research data in a meaningful way – not just from a reporting perspective. On top of this, we want to ensure we have the performance and data storage necessary for the amount of data captured, and the ability to make inferences about clinical research from that data.

The data collection process for a clinical trial has numerous steps. However, this is an opportunity to collaborate and understand how the research community can make the best use of modern technology to remove some of these manual steps. This not only saves time, but reduces duplicate data entry and processes within an individual trial and a research organization as a whole.

Cloud Storage

As we look to the future of our CTMS, we want to make sure it’s built in such a way it can support workflows for decades to come. Our goal is to build our system on the most modern framework that exists for hosting an application of this type. Our solution for this is utilizing Cloud storage.

Hosting OnCore on Advarra’s Cloud architecture is advantageous in more ways than one. It lets us utilize more modern tooling, enables the application’s performance and accessibility to be constantly available, and allows space and interconnectivity for hosting all Advarra solutions.

Analytics and Business Intelligence

Analytics and business intelligence have significantly evolved over the past two decades. Whereas these capabilities were a “nice to have” toolset in the early days of CTMS platforms, they are now vital to successfully managing a research portfolio.

OnCore already provides a wealth of comprehensive reporting capabilities. Moving forward, our vision is to evolve these businesses intelligence capabilities, while leveraging a much broader set of data sources for reports and dashboards. Imagine site staff having access to dashboards sourcing data not just from OnCore, but also from eReg, eIRB, eSource/EDC, and other platforms. This cross-platform reporting approach has the potential to significantly improve the way high-volume sites manage their operations.

Additionally, we aim to make this tool as user friendly as possible. Staff turnover and training continue to be pain points for the research community, and easy to use analytics, reporting and data aggregation is one of the ways we hope to ease the burden on research staff.

Single Sign-on (SSO)

Single sign-on (SSO) is a well-established authentication mechanism allowing users to leverage a single set of credentials across multiple applications. It’s already widely used by tens of thousands of organizations across the world, including research sites. Reducing site burden is a key focus area across the industry. As noted in Advarra’s 2023 Study Activation Report, sites continue to struggle with the wide array of they technology they are required to use to manage industry trials. By unifying the sign-on process across site technology, we can take a significant step towards reducing that burden.

Further, our vision is to expand on the unified user experience by creating a dynamic “home page” for site staff. This will allow users access to all relevant Advarra platforms (e.g. OnCore, Clinical Conductor, Advarra eReg, Longboat, and more) while also providing information most relevant to the user. Whether it’s quick links to assigned protocols, analytics driven by those protocols, the user role, or centralized task lists—just to name a few—this approach has the potential to significantly improve the way we enable sites to do groundbreaking research.

With all of our systems in Advarra Cloud and connected through Advarra SSO, it makes it easier to exchange data between systems. It also enables us to better pivot in the future. Whether we are working to expand to new partners, or adjust for industry needs, we will be ready.

A phased approach to quality management systems (QMS) ensures quality is embedded at every stage, from discovery to post study. A common misconception in the manufacturing and research development landscape is quality systems can be bought off the shelf and there are no significant differences among the proliferation of quality systems.

Clinical research is grounded in scientific integrity, participant safety, and data reliability. A robust QMS is an integral component of clinical research. A ReadyQMS approach to implementing QMS within the clinical research lifecycle ensures a structured and comprehensive methodology to maintain quality throughout the research process.

Discovery

Establishing a quality mindset at this phase sets the stage for effective enterprise quality planning. A key first step in a phased approach is risk assessment: Before conducting any clinical research, assess any potential risks to patient safety, data integrity, and regulatory compliance. This involves identifying all critical processes in the trial and any potential hazards or deviations potentially arising.

Pre-clinical

Building a quality framework at the pre-clinical stage is critical for setting the stage for timely and compliant study startup. An effective QMS must include standard operating procedure (SOP) development. These SOPs serve as the foundation for consistent execution and accountability for staff throughout the study. Procedures for every process in the trial, from patient recruitment to data management, are documented in SOPs.

Design Protocol and Planning

The trial design itself is meticulously planned to ensure the trial’s scientific rigor and relevant. This often includes:

Formulation of objectives
Endpoints
Patient populations
Statistical analyses

Identifying adequate resources, including qualified personnel, appropriate facilities, and necessary equipment, are characterized and allocated. The quality of these resources plays a pivotal role in the trial itself. At this stage, many sponsors are working with their strategic partners to supplement internal expertise to provide the most beneficial outcomes.

Training and Competency Assessment

In addition to identifying resources, training and competency assessments are built into a quality framework. Every member of the clinical trial team undergoes rigorous training on the trial protocol, SOPs, regulatory requirements, and other pertinent topics. Competency assessments are essential to ensure the team is qualified and prepared.

Study Startup

Study startup activity checklists are both extensive and exhaustive. A phased approach QMS means processes are finalized under an established quality framework. It also means everyone is following the same procedures to ensure both ethical and unbiased participant recruitment.

Study Conduct

Monitoring quality and compliance is the bedrock of a ready QMS during study conduct. Regular monitoring of trial sites ensures everyone is following the correct SOPs and protocols. Audits, which are independent evaluations, are periodically performed to verify compliance with regulatory standards and the trial protocol. Data collection and management and quality checks are set in place to ensure data accuracy, consistency, and integrity. Data management processes involve timely data entry, validation, and review.

Study Close

Once the trial is complete, data is statistically analyzed and findings are reported. This phase requires a stringent QMS to ensure the integrity of the results. All trial documents, including raw data, consent forms, communications, and reports, are archived as per regulatory requirements. This ensures any future queries or inspections can be adequately addressed. Post-trial, a comprehensive review is undertaken to evaluate the successes and areas of improvement. Lessons learned are used to enhance the QMS for future research.

The clinical research lifecycle’s phased approach to QMS ensures quality is embedded at every stage, from initiation to closure. By incorporating QMS at the discovery stage, regulatory agencies are assured that clinical trials are compliant and protect participants’ safety as well as ultimately leading to reliable results benefitting patients and advancing medical science.

Ensuring the safe and secure transport of investigational products (IP) is a core part of biosafety. This critical task requires meticulous planning and rigorous procedures to avoid any hazards potentially arising during the journey of an IP from the controlled environment of a pharmacy or preparation room to its destination.

Think about the familiar paths we traverse every day of our lives. I’m a runner, and there are sections of my neighborhood I’ve crossed numerous times. But a distracting thought (or a speeding squirrel) can change that familiar territory without warning, causing me to trip and fall.

It’s the same with the transport of an IP. Even if the environment is familiar, with or without hazards, the unknown or unlikely is a biosafety consideration.

Controlled Environment and IP Containment

The potential for a release, and the risk associated with a genetically engineered IP, are part of the IBC’s assessment purview under National Institutes of Health (NIH) Guidelines.

When the IP leaves the controlled environment of a pharmacy or preparation room, IP’s containment effectively becomes the controlled environment in itself. The containment must then prevent spills or leaks if the IP is dropped. This is a matter of protecting not just the IP’s integrity, but also the safety of employees, the community, and the environment from any adverse effects (AEs) potentially resulting from an accidental release.

Therefore, using the appropriate transport container is essential to prevent spills or releases. Even if you’re just traveling a familiar path across the hall, the unknown can still trip things up.

Requirements for Transport of Investigational Products

Accidents can happen. So, how do we ensure the transport container for an IP is up to this crucial task? Here are some fundamental guidelines:

The transport container should be sealed and leak-proof. Glass can easily shatter – plastic containers are the preferred choice. They’re sturdy, less likely to break, and can be easily decontaminated and cleaned after use.

A sealed container prevents leaks of any liquids or aerosols, so look for an O-ring or a sealing component in the lid. A secure latch is crucial to create a tight seal; it ensures the lid stays put and the contents remain safely inside, even if the container takes a tumble.
Size matters. Choose a container appropriately sized for its contents. And don’t forget to affix a biohazard sticker to the exterior for quick and clear identification.
Some institutions require additional specific paperwork, so be sure to review internal policies prior to transport of the investigational products.
If your IP is headed to a satellite location in a vehicle, you’ll need to follow the Department of Transportation (DOT) Hazardous Materials Regulation 49 CFR Parts 171-180, which allows for “in commerce” transport of materials or under the Materials of Trade (49 CFR 173.6)

Transport in a vehicle requires additional considerations such as:

Preventing the transport container from shifting enroute by securing an external container within the vehicle.
Maintaining the correct temperature for the IP, which may include using dry ice, wet ice, or heating packs.
Preparing for unforeseeable release with a small spill kit.
Maintaining the appropriate paperwork and labeling to identify the material’s hazards.

In conclusion, whether you’ve been conducting clinical trials involving recombinant nucleic acids for years or are just beginning to navigate the NIH Guidelines, your site should always assess transport procedures.

Using an appropriately sized, sealed, leak-proof container is best practice for transport from across the hall, within a building, or across a short distance to a satellite clinic. This is also the minimum requirement for transport under NIH Guidelines.

Safely and securely transporting an IP is a shared responsibility, requiring constant vigilance and a commitment to ongoing learning and adaptation.

Moving IP from a controlled environment means taking it to an area with increased risk of release and exposure. Remember, we’re not merely moving materials from point A to point B—we’re playing an essential role in the advancement of human health. Let’s ensure we do so safely and responsibly.

In the clinical research space, GxP is a set of quality regulations and guidelines designed to establish the safety, efficacy, and integrity of pharmaceuticals, medical devices, and clinical trials. This blog explores key concepts, regulations, and the importance of GxP in delivering successful clinical trials.

GxP: An Introduction

The term GxP represents a general abbreviation for “good practice” guidelines and regulations, with the “x” acting as a placeholder relevant to a particular field. Traditionally, based on the clinical research lifecycle, this includes:

Good clinical practice (GCP)
Good laboratory practice (GLP)
Good manufacturing practice (GMP)
Good pharmacovigilance practice (GPvP)
Good distribution practice (GDP)

Meeting good practice standards is paramount to the success of potentially lifechanging clinical research; strict adherence to GxP guidelines ensures patient safety and product quality while assisting research teams in meeting critical regulatory requirements for advancing study milestones.

GxP in Clinical Trials

To yield the best possible outcomes for clinical trials, GxP guidelines and compliance regulations assures regulatory agencies the safest and most productive research efforts are being delivered to the market.

Rigorously maintaining GxP compliance standards throughout each phase of the clinical trial process is essential to:

Protecting the safety and wellbeing of trial participants
Ensuring the quality and integrity of trial data
Facilitating the production of beneficial medicines and treatments

Failure to adhere to GxP guidelines and regulations can result in severe and even tragic consequences. Research teams can receive warnings from regulators, on the basis of which they may be required to enact corrective plans and/or to obtain FDA confirmation before resuming development. In more serious instances, sponsors might see their products recalled entirely.

GxP in Medical Devices

It’s no surprise: Developing and manufacturing medical devices is so highly regulated, and this regulatory approach extends to the recent proliferation of medical devices created using artificial intelligence and machine learning (AI/ML). Working together, the U.S. Food and Drug Administration (FDA), Health Canada, and the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) established a set of 10 principles to guide regulation of such AI/ML-developed devices. These principles serve as a foundation for the advancement of good machine learning practice (GMLP). They also aim to ensure medical devices created through the use of AI/ML are secure, efficient, and maintain a high level of quality.

Device manufacturers must adhere to GMP and GDP, both of which help to ensure:

Devices are consistently manufactured and stored
Distributed devices are consistent and of high quality
Minimized risks to end-user safety and well-being

Violating these GxPs requirements for device manufacturing could result in audit observations, product recalls, loss of revenue, government fines, and legal liability.

Compliance and Regulatory Bodies

Meeting critical study milestones is often dependent on compliance with relevant GxP requirements. Absent GxP guidelines and regulations compliance, clinical research stakeholders’ risk everything from product failure or recall to endangering the lives of trial participants. In the event of GxP noncompliance, stakeholders must absorb the consequences of ceasing operations until GxP violations are remedied.

GxP Challenges and Best Practices

Achieving and maintaining GxP compliance is not easy—it’s a multi-factorial responsibility requiring constant vigilance and assessment. A common challenge for many clinical trial stakeholders involves maintaining adequate GxP documentation – without this, it can result in fines and sanctions. FDA Observation Form 483 pertains to an absence of written procedures and may be used where corrective and preventive actions (CAPA) processes are not adequately defined or followed.

Clinical trial stakeholders should be able to demonstrate their compliance controls have been observed and conformed to, along with identifying and correcting potential non-conformance in end-products. In order to do so, this requires thorough implementation of several GxP best practices: documentation, communication, traceability, and accountability.

GDP is Key to Maintaining Compliance

Want to instill confidence in your GxP? Keep your data and documentation up to date and have controls in place to avoid tampering. GDP also informs regulators that, not only have required activities been undertaken, they’ve also been recorded at the right time.

Follow Record-keeping and Documentation Requirements

Doing so keeps processes trackable and makes it possible to hold companies fully accountable for their data integrity and quality of their end products.

Document Every Critical Action Across Development, Manufacture, and Delivery

For GxP compliance, it is essential to document every critical action made by every employee in the product’s development, manufacture, and delivery. Make sure this documentation is auditable and is comparable to the risk posed by non-conformance.

Quality Management Systems Support GxP Compliance

For several GxP categories, a key best practice for maintaining compliance is implementing a quality management system (QMS).

GLP ensures the quality and integrity of non-clinical laboratory studies that support research for products regulated by government agencies. A QMS ensures laboratory-run studies are planned, performed, monitored, recorded, archived, and reported under the right conditions and in a consistent and repeatable manner.
For GMP, the rules for regulation differ depending on the country. However, GMP requires products are consistently of high quality, are appropriate for intended use, and meet requirements for clinical trial authorization.
GPvP ensures companies continue to monitor the safety of the medicines they have developed after they have been launched in the market. GPvP best practices include maintaining a QMS capable of storing huge quantities of safety data used to monitor and report on the safety of potentially marketable drugs.
Finally, GDP governs the wholesale distribution of medicines, keeping products safe and in usable condition for consumers. GDP provides distributors with auditable systems to ensure safe storage and transport, contamination prevention, and recall management, while helping make certain only authorized products enter the distribution network. Using a QMS encourages greater accountability, traceability, and cooperation throughout the supply chain.

Future Trends and Innovations

The processes for achieving and maintaining compliance with GxP guidelines and regulations are increasingly subject to modernization. In clinical trials, for example, documentation processes can become streamlined through the use of eSolutions such as an electronic trial master file (eTMF). This allows all regulatory documents, whether originating with a sponsor or at a site, to be managed, signed, and securely exchanged to relevant stakeholders for long-term storage in an eTMF, while providing shared access amongst its users.

Similarly, clinical trial management systems (CTMS) have revolutionized the way researchers can conduct and manage clinical studies effectively. Because trials are becoming more complex, a CTMS is integral to maintaining a thorough and transparent process and facilitating GxP compliance efforts. Many CTMS platforms can optimize finances, assist with regulatory compliance, and streamline overall clinical research operations for all types of research sites, site networks, hospitals, and health systems.

Overall, the most impactful solutions will be those enhancing how researchers can maintain thorough organization of documentation, achieve quality data management, and keep robust oversight capabilities through each phase of clinical study. This all helps keep study teams on track towards producing impactful beneficial medical treatments and medical devices.

Making Clinical Research Safer, Smarter, and Faster

GxP programs can be complex and difficult to manage. GxP guidelines and regulations are in place to ensure the highest quality and most reliable end products are delivered to patients without compromising their wellbeing.

For life science organizations, prioritizing GxP regulations compliance can accelerate therapies to market, all while making your clinical research safer, smarter, and faster in the process.

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

Understanding the FDA Inspection Process

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

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

Best Practices to Becoming Inspection Ready

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

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

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

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

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

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

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

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

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

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

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

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

Identifying, Qualifying, and Selecting Sites

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

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

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

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

Budgeting, Contracting, and Managing Essential Documentation

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

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

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

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

Site Initiation, Training, Transparency, and Reporting

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

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

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

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

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

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

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

Unpacking why Groups are Historically Under-represented in Research

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

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

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

Ethical Concerns with Research Under-representation

There are at least two ethical concerns with these disparities.

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

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

Addressing Ethical Issues with Clinical Research Disparities

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

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

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

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

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

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

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

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

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

Establish the All-important Process

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

Consolidate Functionality in One Place

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

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

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

Improve Team Member Satisfaction

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

Impress Sponsors

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

Elevate Your Site

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