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Breaking down barriers to participation in clinical research has long been a challenge, affecting every aspect of the industry. As the industry works toward a more cohesive, diverse, and inclusive environment for all, Advarra’s mission is to invest in understanding and educating the industry on this critical topic. Developing a more inclusive and equitable study and research environment will reap many benefits for the industry and establishes the precedent for future trials as we work toward a more inclusive environment for all.

However, figuring out where to address barriers and create a more inclusive environment is overwhelming. This blog aims to define diversity, equity, and inclusion (DEI), discuss exclusive trends in recruitment and trial design, and present actionable steps sites can take immediately.

Key Definitions

When researchers address the lack of diversity in clinical research and work to improve upon it in their current practice, a common mistake made is not understanding the nuances of DEI efforts, and looking at each concept as a separate entity, rather than understanding how they intertwine. While DEI is made up of individual concepts, every concept is needed to support one another, and it’s common for researchers to focus on one or two concepts, rather than all three simultaneously. To further understand how to achieve DEI in research, each concept needs to be defined as such:

Diversity: making sure everyone is represented
Equity: being fair to anyone involved
Inclusion: creating an appropriate environment for all involved

Many researchers attempt to solve the symptoms of the problem, when in reality, addressing the root cause – which is most often tied to a lack of equity – will allow research staff to address and work toward solving DEI-related challenges the industry faces today.

Effectively Recruiting Participants

Throughout the industry, recruitment proves to be a major roadblock at any stage of a protocol. Without the necessary amount of participants enrolled in any study, startup delays, ultimately costing researchers time and money. Each protocol must have appropriate inclusion and exclusion criteria; however, researchers still focus on populations most convenient to them and do not evaluate criteria critically for each study. This practice enables researchers to seek out populations they are familiar working with and neglects certain populations because of criteria denying them participation in a trial.

Actionable Steps to Take

Since racism is not individual, it must be addressed at a systemic and structural level. If researchers want to solve recruitment problems for their studies, they need to look at the system as a whole and improve and build upon the current infrastructure. If teams are unsure where to start, these common barriers may be the first place to look at and examine.

Enhance Communication

Communication is paramount for success, including the clinical research industry. If researchers are not effectively communicating their trials to seek out participants, whether that is through physicians, community leaders, or other forms of advertising, then they will lose out on obtaining a diverse participant population.

An easy way to ensure better communication is to create an action plan moving forward. Build workflows into patient visits so potential participants know there are trials available to them. Understand how staff communicates to participants during visits – both online and in person. Are researchers meeting their participants where they’re at in terms of the language they can understand? Are participants coming in for necessary visits, and participating in remote capabilities as well? Consider these as the action plan is formulated and built.

Build Trust

Oftentimes, people will choose to participate in a trial if they know they can trust the process. Building relationships with external stakeholders, such as community leaders, their own providers, or word-of-mouth referrals benefits everyone. It gives researchers an opportunity to spread awareness about a trial, it gives stakeholders the opportunity to help others seek treatment, and it helps potential participants feel reassured if it’s coming from a trusted source.

Building trust isn’t something research teams should rely on with just external stakeholders; trust needs to be maintained after a participant agrees to take part in the trial. For example, including a diverse staff team who may have a better understanding of participants’ backgrounds, allowing them to advocate for them. This effort will greatly aid in establishing trust, recruiting potential participants, and retaining them as the protocol moves throughout each phase.

Effectively Design a Trial

Many times, staff get into the “copy/paste” habit when designing a trial. This is normally done in an attempt to save time by transferring the same requirements from one protocol to the next, especially when dictating the trial’s inclusion and exclusion criteria. This method is a direct symptom of a staff’s heavy bandwidth, but in reality, every trial needs to be designed individually as each trial is unique from the rest.

Additionally, as humans design trials, we need to acknowledge our own implicit biases at work when creating one. As a trial is shaped, taking extra time to review and understand where an individual’s biases may have impacted the design can greatly minimize the risk of creating a non-inclusive trial. As we work together to create a more inclusive and equitable research environment, it’s important to understand this process will require intentional and continual learning and unlearning from everyone involved.

The investigator meeting and site initiation visit (SIV) are two critical milestones marking the beginning of a clinical trial for members of the site team.

Traditionally, investigator meetings involve the principal investigator and study coordinator traveling to large conference venues or hotels to view multiple presentations over the course of a few days. Often, the investigator meeting falls well in advance of the site’s target date to enroll a patient, and while these meetings are excellent networking and learning opportunities, learnings may be outdated by the time the site initiates. The SIV follows weeks or months later when the clinical research associate (CRA) arrives at the site. The CRA often arrives with a sizable amount of study-related information to disseminate to the site team. This challenging process is replicated by different CRAs across site teams in other regions or countries.

In some cases, PowerPoint is the best option to present information. When used effectively, it’s easy to use, easy to share, and cost-effective. Also, it is good for well-structured and concise presentations that are less than 10 minutes. If a presentation goes longer than 10 minutes, even the best speakers will start to lose impact.

In particular, SIVs do not lend themselves well to the PowerPoint approach because these meetings are lengthy and involve vast amounts of information. The challenge of presenting engaging and impactful information is compounded in a virtual setting.

Additionally, PowerPoint presentations vary widely between presenters and meetings, which potentially introduces misunderstandings and errors before the study begins. A CRA might present the material perfectly, and attendees may absorb all the information completely, but PowerPoint consistency is not likely.

Ensuring the Remote Investigator Meeting or SIV Meeting is Productive and Useful

Now more than ever, organizations prefer to virtually attend meetings rather than travel to a physical location. While some stakeholders may not view virtual formats as ideal, they still must ensure sites are well prepared and educated to enroll patients into clinical trials. Without gathering staff in person for a meeting or observe their engagement, it may be harder to gauge how much they have learned and how likely they will be to retain it. In this remote world, communicating in an uninteresting or disorganized manner can be disastrous.

To maintain an audience’s attention, look at an alternative approach. Try introducing variety to break up the training formats for the different SIV agenda items. For example, animated video is a well-recognized, impactful format and is very well suited in conveying study designs, disease overview, and IP mechanisms of action. Other sections may be better suited for simply reading and acknowledging a document similar to the narrative approach outlined above (e.g., a discussion around recruitment strategy). Additionally, a concise and well-delivered PowerPoint may suffice (e.g., a study introduction from your respected key opinion leader (KOL).

An added benefit of utilizing different training formats for different items means deploying information online through a site study portal for attendees to complete or view beforehand, allowing for shorter online meetings and more practical and audience-friendly interactions.

Since most informational meetings are currently conducted remotely, relying on a blend of video and other appropriate formats is a more productive way to disseminate information.

Using a site study portal to get information out to sites at the trial outset (as well as through the entire duration of study conduct) provides additional benefits. Deploying and tracking material through a validated 21 CFR Part 11 environment supports inspection readiness. And a portal can also provide analytics to assess engagement, and any presentations can be recorded and deployed as training modules for site staff who join the site team later in the study.

Advarra offers the solution to provide these benefits, reduce variability from presentation content, and offer sponsors and CROs the ability to know exactly how well site staff understands critical content and how prepared they are to operate a successful clinical trial.

Recently, we discussed the importance of connecting with advocacy groups in order to create more trial diversity. As a result of this connection, well-organized patient advocates are influencing the drug development industry, particularly in orphan diseases. Not-for-profit patient advocacy groups have demonstrated the power to affect significant change, even impacting therapeutic development and approval against expert recommendations.

A meaningful patient advocacy strategy is no longer a nice-to-have, fictional idea for pharma companies; it’s a must-have in order to increase diversity among their trials.

This blog tracks the origins and rise of patient advocacy groups and discusses milestones in the FDA’s acceptance of patient advocacy groups over the past 30 years.

Where it Started: AIDS Activists of the 1980s

After years of government inaction with regard to the AIDS epidemic, people living with HIV/AIDS and their advocates created local and global activist movements in an effort to change public perception and response to the disease. Activists fostered this movement through:

Adopting the practices of other social movements
Educating themselves to become their own researchers and lobbyists
Using fear and anger to impact public perception/action
Mobilizing, so the public viewed them as real people rather than statistics

Broader visibility and understanding of the disease forced pharmaceutical companies, the U.S. government, and regulatory agencies like the Food & Drug Administration (FDA) to open a dialogue with patient advocates, allocate funding, and expedite a response to the epidemic.

Highly successful, the AIDS activist movement provided a playbook for other patient advocacy groups in healthcare to use for years to come.

A Force to be Reckoned With

Within two years of two major AIDS activism events – a 1988 rally at both the Department of Health and Human Services in Washington, D.C., and the FDA headquarters in Maryland, and a 1989 protest at New York City’s St. Patrick’s Cathedral led by members of ACT Up – the FDA began recruiting patient advocates into its Patient Representative Program.

The Patient Representative Program recruits and trains patient representatives who have experience with diseases. Today, it has voting members sitting on FDA advisory committees and panels covering more than 300 diseases and conditions.

Patients now have a substantial role in the development and progress of potentially life-changing treatments. The FDA even celebrates collaborative milestones as part of its patient advocacy history.

Additional Milestones

The following list highlights major post-AIDS advocacy initiatives implemented by the FDA to allow patients to have a greater impact on a disease treatment’s regulatory process.

1993: The first FDA patient representative serves on an advisory committee.
1996: FDA patient representatives receive advisory committee voting rights.
2001: FDA begins seeking patient input during early development of medicinal products; FDA patient representative role expands to include consulting to scientific and regulatory reviewers.
2008: Patients and consumers are encouraged to report medical product problems using the existing FDA MedWatch system.
2012: Safety and Innovation Act is enacted, requiring the FDA to “develop and implement strategies to solicit the views of patients during the medical product development process and consider the perspectives of patients during regulatory discussions.” Multiple patient engagement programs launch as a result, including the FDA Patient Network, which facilitates patient engagement with agency decision-makers, educates people on the developmental process of new medications and promotes innovation.
2015: FDA issues treatment guidance for Duchenne muscular dystrophy based on recommendations composed by the disease community, marking the first time an external advocacy group (Parent Project Muscular Dystrophy) significantly impacted U.S. government drug policy.
2018: Patient Engagement Collaborative (PEC) launches with the Clinical Trials Transformation Initiative (CTTI).
2019: Patient Affairs Staff (PAS) online webform and Patients Ask FDA launches.

A New Culture of Drug Development

Today, patient advocacy groups are no longer serving only patients and caregivers – their most meaningful collaboration is now with the healthcare industry. Drug developers are also embracing these groups to increase patient engagement.

The mechanisms through which patient advocates create momentum continue to evolve but still center on social impact. Bloggers, YouTubers, and social media influencers are establishing their reputations and using their expertise not just to raise awareness but to sit on advisory boards, speak at disease-related events, and co-author research papers.

In a recent webinar, Advarra experts Emily Eldh and Ben Shankle provided insights and information in Remote Monitoring: Study Compliance in a Changing World. Due to time constraints, we were unable to answer all audience questions during the Q&A period, so our experts have responded to additional questions in this blog.

Q: When accessing an electronic health record (EHR) for remote monitoring, our privacy department expressed concern that the study monitor has access to the research participant’s entire medical record and not just to medical records related to the study. From an IRB perspective, do you have a concern or recommendation for additional protection/safeguards?

A: Monitors and auditors typically have access to all parts of the medical record available at the clinical site either in a hard copy or electronically. Sometimes certain parts of a medical record (e.g., psychiatric visit notes) may be separated out, and if those records are not relevant to the research, that access could be limited. It will largely depend on the type of research.

Q: Should we inform research subjects that we will review their data remotely via other systems and document sharing methods?

A: Generally, subjects should be informed that their data will be reviewed, but you do not need to specify how it will be done. If you do specify how that will be done in the protocol or consent, then you will need to follow that – and you will need to submit any changes as an amendment.

Q: Do you have any resources for learning more about remote monitoring?

A: The FDA recommends a risk-based approach to monitoring – using a combination of remote, centralized, and on-site techniques – since 2013. You could advise them of this guidance pre-dating the pandemic.

Q: Should the remote monitoring portal be a site-to-vendor agreement or a sponsor-to-vendor agreement?

A: It could be either or both, depending on the contractual relationship being established.

Q: Many sponsors have to re-write monitoring plans to accommodate for COVID-19. Does the IRB approve the updated plan every time? What is the investigator’s role in ensuring compliance?

A: The IRB does not need to review the revised monitoring plan unless the protocol changes and/or consent form documents previously approved by the IRB. The sponsor is responsible for monitoring the research.

A local/site investigator is responsible for developing a plan for the supervision and oversight of the clinical trial at the site. Provide supervision and oversight even for highly qualified and experienced individuals. As it applies, a plan may include routine meetings with the sponsor’s monitors.

Q: Do you know if there are discussions about moving monitoring back on-site in the future?

A: The FDA has recommended a risk-based approach to monitoring – using a combination of remote/centralized and on-site techniques – since 2013. I think a hybrid approach, including both on-site and remote methods, will become routine if it isn’t already.

Additionally, the American Society of Clinical Oncology (ASCO) Journal published an article last year outlining findings from a survey on COVID-19’s impact on oncology clinical trials.

Q: What should a vendor provide the site in order to document that they are HIPAA compliant? What other requirements should a site ask the vendor to ensure accuracy and security?

A: Vendors should provide institutions with an assertion that their product can be used in a HIPPA-compliant manner along with documentation on how their product achieves it.

Additionally, any vendor should provide a full explanation of how their product keeps data secure against unauthorized access.

From there, it will be up to your IT/Compliance team to determine if their measures are sufficient.

Developing an investigational new drug (IND) application is a big milestone for organizations, especially small companies bringing their first drug to market in the U.S. Too often, though, the chemistry, manufacturing, and controls (CMC) aspect of the IND are not fully considered until it is too late, resulting in a delayed IND submission or even a clinical hold letter from the Food & Drug Administration (FDA). To understand more about how these roadblocks may impact an IND, this blog outlines three common CMC pitfalls.

CMC Activities Did Not Start Soon Enough

Many times, small research-oriented companies moving toward their first IND do not adequately consider the requirements for manufacturing and testing clinical trial materials (CTM). To file an IND, an organization must produce batches of drug substance and drug product of the actual material to be used in the clinic study. Analytical development scientists can use analytic methods that are validated and fit-for-purpose to test the CTM. The batches of drug substance and drug product need to be placed on stability, and, at a minimum, one month of stability data must be included in the IND upon submission. Technical batches or data used for toxicology studies are not sufficient to satisfy this requirement. Generally speaking, the CTM supply strategy should be in place, and execution should start 9-12 months prior to filing an IND.

No Anticipation of Good Manufacturing Practices for the CTM

Manufacturing sites registered with the FDA to operate pharma GMP regulations can produce CTM for clinical studies. While manufacturers are located anywhere in the world, if the trial is in the U.S., they must be registered with the FDA in order to produce CTM. Sometimes, small companies will attempt to use material made in their own or others’ non-registered laboratories. Even though this material is suitable for nonclinical studies, it is not acceptable for use in human clinical trials.

Another pitfall observed is that the drug substance and drug product are manufactured under food grade or dietary supplement grade Good Manufacturing Practices (GMPs). The FDA may accept this concept in exceptional cases, not routinely. If this route is desired, it is recommended to obtain FDA acceptance of this practice be discussed in a pre-IND meeting rather than to propose this concept for the first time when the IND is submitted.

Good Laboratory Practice Toxicology Lots are Too Clean

Drug developers sometimes strive to make the best, most pure material possible for use in the good laboratory practice (GLP) toxicology studies. In the long term, this is not a good idea. The GLP toxicology studies not only support the safety of the active ingredient in animal and human settings but also the qualification of impurities up to the level that is seen in the toxicology material. To this end, “dirty is good” is an ideal to consider in order to qualify impurities. There is such a thing as “too dirty,” but some impurities are a good thing in a toxicology study.

Advarra’s Regulatory Center of Excellence CMC experts can plan and assist organizations to avoid these pitfalls and guide their new products through the IND approval process with minimum issues, beginning their clinical trial as soon as possible. Contact us today to get started.

At Advarra, we strive to provide sponsors, contract research organizations (CROs), and sites with the knowledge they need to perform adequate quality management as they work to advance safer, smarter, and faster research. Similarly, the Society of Quality Assurance (SQA)’s mission statement indicates the organization aims to “Promote and advance the ethics, principles, and knowledge of quality assurance essential to human, animal, and environmental health.”

Last month, at SQA’s annual meeting, Advarra’s VP of Research Services and Strategic Consulting, James Riddle presented Regulatory Fine Points: What Research Sites Need to Do for Part 11 Compliance. In his presentation, Riddle outlined how sponsors should consider 21 CFR Part 11 (Part 11) compliance at research sites and how that fits in with the overall quality management system they may administer, build, audit, or evaluate.

As the research industry is continually evolving and adapting, many institutions, health systems, and private research sites are adopting more electronic technologies to streamline operations. While oftentimes, sponsors or CROs provide sites with validated technology, many adopt these technologies themselves. For quality management professionals and site regulatory personnel in the position to evaluate a system’s effectiveness, quality, and compliance, they need to understand how Part 11 compliance fits into the quality management framework.

Understanding Compliance

According to the Food & Drug Administration (FDA), “Part 11 applies to records in electronic form that are created, modified, maintained, archived, retrieved, or transmitted under any records requirements set forth in Agency regulations.” Essentially, if a research site owns, controls, or operates its own systems with electronic FDA-regulated records, Part 11 applies. This is applicable for electronic records such as:

Signed consent forms
Source documentation
Institutional review board (IRB) records
Drug accountability logs
Delegation of authority logs
Other records required to be kept by the site per FDA regulation

As Sponsors/CROs evaluate sites, it’s important to inquire if there are computer systems in use at the site which store FDA-regulated records in an electronic format, as these will need to be evaluated to determine if the system housing those records has been validated per FDA guidelines. Validation is about objective evidence, consistency, and documentation of the processes put in place. Quality managers or individuals with an understanding of the Part 11 requirements need to make sure the site has appropriately validated any computer systems they’re controlling relative to Part 11 if they store FDA-regulated records within the system. For example, an eRegulatory binder system would apply to this situation because FDA-regulated records are stored electronically. A site’s accounting system, on the other hand, has financial data and would not be subject to Part 11.

To ensure compliance and validation, a site needs to have processes in place to provide objective evidence that they are using and providing good documentation of their records and that they have controls in place that do not allow unauthorized changes to the documentation. Sites must be able to produce evidence that their electronic records can be trusted in the same way as paper records.

Sponsors have utilized validated computer systems for decades and typically have well-established programs based on GAMP 5 with core documentation including installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ) documents and system development life cycle methods. Individual research sites may be less familiar with validation concepts and need some support from the quality management program or the software vendors to establish the necessary validation documentation.

What is risk-based validation?

According to Pharma Manufacturing, risk-based validation is “a validation philosophy in which qualification and validation processes are streamlined by an honest assessment of risks to product quality posed by an equipment feature, process step, or process capability.”

When coming up with their assessment of risk for systems, sites must be able to justify their definition of risk. Advarra advises most research sites to evaluate their computer systems in the context of risk to human health. For instance, the software used by a device manufacturer to run an implantable pacemaker is high risk. If the software does not work as designed the impact on human health can be immediate and severe. On the other hand, a site’s regulatory document management system storing electronic records such as consent forms, delegation logs, etc. has a low risk to human health if the system fails. Very similar to the concepts behind Risk-Based Monitoring; computer systems determined to be lower risk can have a less stringent level of validation testing as long as the level of testing is commensurate with the risk as outlined in the site’s risk-based validation SOPs.

Considerations for sites

If a site is collecting, maintaining, or storing essential records in electronic format, it is imperative to maintain Part 11 and validation statuses. Taking an inventory to see where these records are can help the site understand what systems may need to be validated. If sites are using electronic signatures on any of their essential records, Part 11 signature requirements also apply. Sites also need to remember to submit a certificate of intent to use electronic signatures to the FDA.

Additionally, if sites are using commercial, off-the-shelf software, they need to have procedures in place to ensure they are relying on software vendors who are able to attest their computer system complies with Part 11 and is built with computer validation processes in place. This is even easier with software as a service-based (SaaS) vendors, where there are no on-premises servers or other equipment for the site to install and validate in a hardware environment. For private research sites, it’s recommended to rely on a software vendor only if they have attestation about Part 11 – and most vendors will provide attestation.

Before site-level systems subject to Part 11 are set in place, sites need to implement a basic set of standard operating procedures (SOPs). These documentations need to outline policies or procedures on how sites are complying with validation and may include:

Policy on Part 11 Compliance and computer system validation
Conducting system inventories
Validation planning, testing, and summary documentation for covered systems
Conducting vendor assessments
Training and quality assurance
Business continuity plan

Sites can keep the records locally for systems they are maintaining and controlling, as well as the attestation from their vendor. Having this documentation ready for an FDA inspector, and more importantly, a quality manager will help keep research operations smooth and efficient.

A study opportunity is presented to your organization. How quickly and confidently could you take on the study? This is the concept of research readiness. Research readiness, when put into practice, ensures that your organization can accept, activate, and adapt to new studies and opportunities no matter the regulatory circumstances, be it decentralized structure, protocol complexity, or even a global pandemic.

To be research ready, your organization must have:

Visibility for all stakeholders into a central repository to keep regulatory processes moving
- Can your leadership team, whether on-site or remote, oversee study progress and identify bottlenecks?
- Are you able to support monitoring in-person and remotely?
- If you’re coordinating a multi-site study, do you have visibility and connection to their operations and required documents?
- Can you communicate with external stakeholders like monitors, sponsors, and IRBs quickly and compliantly?
Systems that communicate effectively and compliantly
- If you’re working within multiple technology systems, do they minimize duplicate data entry and support more efficient routing and storage of documents and signatures?
- Is each system appropriately 21 CFR Part 11 validated or secured for its intended use, regardless of in-person or remote workflows?
- Do you have a mobile-friendly signature process for investigators?
Easily accessible, documented, and scalable processes for research conduct
- Have you established compliant and optimized standard operating procedures (SOPs)?
- Where are your standard operating procedures stored? Are they accessible to all necessary staff?
Up-to-date training materials and systems to recognize training completion
- How do you manage and track staff training on study procedures and processes?
- How is training certification or acknowledgment routed to required locations?
- Once trained, how quickly and accurately can tasks be delegated across your portfolio?

No other system supports research readiness like an eRegulatory Management System. An eRegulatory management system can centralize your training, documentation, processes, and communication needed to efficiently and compliantly activate a trial. In collaboration with leading academic research institutions and cancer centers, Advarra eRegulatory Management System (eReg) has evolved to comprehensively support and ensure research readiness.

This past year has displayed firsthand that the definition and expectations of research readiness can change dramatically. When COVID-19 hit, many organizations found themselves without the necessary processes and infrastructure to conduct research or accept new studies, hurting their research goals and delaying activation timelines. That’s why we’re ensuring Advarra eReg is not only research ready today, but also built for the future.

Immediate Document Access from Anywhere

Access, route, store, and centralize staff credentials, standard operating procedures (SOPs), organization documents, and past performance documents to streamline regulatory workflows from any site location.

Integrated Processes

Leverage integrations with key regulatory systems within Advarra eReg including eIRB and local IRBs, OnCore Clinical Trial Management System (CTMS), and email correspondence to increase compliance and efficiency.

Community-Driven Workflows

Benefit from innovations by regulatory teams like yours. Utilize standardized workflows developed with community in mind including regulatory templates, digest notifications, and controlled and secured monitor access.

A Future-Proof eRegulatory System

Maintaining a research ready state requires a successful foundation for an ever-evolving industry. Advarra eRegulatory Management System is preparing for the future of clinical trials by expanding our solution to serve across the entire stakeholder spectrum, from sponsors to sites. We’re working closely with our customer community to maintain site-centricity as we expand integrations both inside and outside the Advarra ecosystem including connections with eConsent tools, OnCore CTMS documents, sponsor platforms, and more.

To explore recently released features in Advarra eReg and discuss how we’re building an eRegulatory management system that supports research readiness in the future, attend our Advarra eReg Open Demo.

The past year has been one of the most challenging ever for those working in healthcare and clinical research. The industry faces unprecedented obstacles as we navigated the dual challenge of developing a COVID-19 vaccine. At the same time, also keep research moving forward in other areas. As we begin to emerge from the pandemic, we see that the research landscape has fundamentally changed. The past year has shifted the focus of sponsors, CROs, and research sites to improve in critical areas, including:

Access to research for diverse and underserved communities
Education of the general public on the efficacy and safety of new treatments
Standardization of data and process across the industry
Adoption of enterprise technology

While some focus areas above are long-term challenges requiring joint effort across the industry, technology adoption can be a quick win for organizations looking to improve processes, cut costs, and adapt to remote workflows. At Advarra’s recent 2021 Spring Onsemble Conference, a longtime customer lamented his organization’s lack of an effective eRegulatory (eReg) solution as his team faced the pandemic. “We desperately need an electronic document management system,” he said. “There are things that we haven’t been able to do as efficiently or effectively as we needed to, and that’s something we need to address quickly.” His organization is not alone. As your site looks to address this fundamental need moving forward, here are four ways an eReg system can increase productivity, improve compliance, and ensure a solid return on your technology investment.

4 Ways an eReg System Ensures Regulatory Success

1. Enterprise Integrations

Staff productivity and data quality are critical priorities for any regulatory team. By integrating your eReg solution with enterprise technology such as your eIRB system, clinical trial management system, emails (and corresponding attachments), and even other eReg systems, you can ensure a more efficient and compliant trial.

Learn more: Utilizing eRegulatory Integrations to Expedite Regulatory Workflows

2. Remote Capabilities

With research staff forced to work from home and on-site monitoring halted, remote regulatory workflows have quickly become a necessity. As a centralized hub for regulatory documents and activities, a full-featured eReg system can be a vital resource to keep your team on track and provide visibility into the regulatory components of a trial. It can also facilitate remote monitoring by safely and securely granting access to monitors. A system such as Advarra eReg allows monitors to view only the essential documents they need to see on a site visit and only during the time specified by your site.

3. Master Delegation of Authority Workflows

For institutions managing a large volume of trials, a master delegation of authority can be a great solution to streamline the study activation process and minimize the burden on regulatory teams. However, standardizing staff delegation across multiple studies can be challenging without technology to manage the delegation process and electronic signatures. An eReg management system can help your organization manage an electronic master delegation of authority log, simplifying the delegation process and dramatically reducing the amount of time spent routing documents.

4. 21 CFR Part 11-compliant Routing, Signatures, and Document Management

At the foundation of any eReg management system is the management of your essential protocol documents. The ability to store protocol documents, efficiently route them for electronic signature, as well as track owners and expiration dates are critical components of an eReg solution.

The Advarra eRegulatory Management System provides all of the functionality above and has been developed through years of collaboration with dozens of leading academic medical centers, cancer centers, and health systems. This means it not only helps your institution become more efficient and compliant, but it also leverages the expertise of top organizations to help you build successful, centralized, and sustainable regulatory processes across all your trials.

To learn more about Advarra eReg, attend our two-part open demo series. Our first demo will focus on how eReg provides a comprehensive solution to boost productivity and compliance, taking a deep dive into many of the areas above. In the following demo, our team will discuss the future of eRegulatory management. Highlights will include:

Upcoming eReg functionality enabling additional remote workflows
Integrating across your technology ecosystem
Further centralizing your regulatory management and much more.

In a recent webinar, Advarra experts Constance Cullity and Michele Russell-Einhorn presented FDA Inspections of Clinical Investigators: Understanding the Process and What to Expect. Due to time constraints, we were unable to answer all audience questions during the Q&A period, so our experts have responded to additional questions in this blog Q&A.

Q: What is the likelihood an investigator-initiated Investigational New Drug application (IND) and non-IND study would undergo an FDA inspection at an academic center?

A: Investigator-initiated IND and non-IND studies at academic centers and elsewhere can be subject to an FDA audit. FDA may audit non-IND studies involving an FDA-regulated product.

Q: For multisite studies, does FDA inspect all sites, or might one specific site be selected to be monitored?

A: For routine inspections done in support of marketing applications, FDA generally inspects some of the sites in a multisite study but may also inspect all sites if warranted.

Q: Does the inspector directly access clinical site systems, like the electronic medical record (EMR)?

A: FDA may directly access clinical site systems and electronic medical records. How an FDA investigator handles review of EMRs during a clinical investigator (CI) inspection may vary depending on the person and any FDA policies that may affect that person’s permission to use on-site computers.

Q: Does the FDA evaluate systems (such as electronic consents) being part 11 compliant during a site inspection?

A: FDA may evaluate for compliance with relevant aspects of 21 CFR part 11 during a CI inspection.

Q: Is it required to de-identify records with protected health information (PHI) given to the inspector to go off-site?

A: The Health Insurance Portability and Accountability Act (HIPAA) permits covered entities to disclose PHI, without authorization, to public health authorities who are legally authorized to receive the PHI. FDA is authorized, under HIPAA, to receive PHI during FDA Bioresearch Monitoring (BIMO) inspections. FDA may review and copy relevant records that contain PHI, and FDA investigators may take copies of those records with them when they leave the inspection site.

Q: Can a fully executed paper or digital consent form be modified in any way? E.g., noting a file location, fixing a typo, etc.

A: For FDA-regulated clinical trials, FDA regulations are silent on whether minor modifications like those described may be made to a fully executed informed consent form (ICF). However, IRB approval could be needed to make such a change to a fully executed ICF. We suggest posing the question to the IRB of record overseeing any research in which you would want to modify a fully executed ICF.

Q: Are principal investigators (PIs) required to be listed on and delegated tasks in a delegation of authority (DOA) log?

A: DOA logs are not required by FDA regulations and are not discussed in FDA guidance documents for CIs. They are also not on the list of Essential Documents in the International Council for Harmonisation (ICH) Harmonised Guideline E6 (R2): Guideline for Good Clinical Practice. However, a sponsor may impose its own requirements for DOA logs and may require that PIs be listed on them.

Q: What about the role of study monitors in a CI inspection? Can they also participate? How can they support?

A: FDA inspects CIs as individuals. Generally, FDA cannot require third parties to participate in CI inspections. It is generally up to the CI whether to involve any other parties, including a study monitor, in the inspection.

Q: How do you suggest research staff/coordinators educate clinical investigators (CIs) that they need to pay attention to study oversight and the FDA will not hold coordinators responsible by FDA if things go awry in the study conduct?

A: Educational opportunities should be made available by the institution or entity where the investigator is located and/or the research is being conducted. Training requirements should be done on a regular basis and can be an ideal way to reinforce regulatory knowledge and responsibilities.

Q: Do you have any different or additional suggestions for sponsor-investigator inspections?

A: FDA’s sponsor-investigator inspections involve assessing compliance with FDA requirements for both sponsors and CIs. For more information on that type of inspection, please see FDA Compliance Program 7348.811 (Clinical Investigators and Sponsor-Investigators) and FDA Compliance Program 7348.810 (Sponsors, Contract Research Organizations, and Monitors).

Q: Is the establishment inspection report (EIR) only available after the inspection, or is there a draft sites can get at the closeout discussion?

A: The EIR is not prepared until after the inspection ends. Our recommendation during the webinar was meant to suggest requesting a copy of the EIR during the inspection, with the understanding that the EIR would not be available until a later date.

Q: If the FDA has no observations by the end of the inspection, is there any documentation provided confirming this?

A: The lack of a Form FDA 483 (Inspectional Observations) at the close of a CI inspection generally indicates that the FDA investigator did not have any significant observations during the inspection. Documentation confirming there were no significant findings would generally come later, in the form of post-inspectional correspondence from the FDA Center that issued the inspection assignment, if that FDA Center agreed the inspection did not uncover significant findings.

Q: In responding to a 483, does a corrective and preventive action (CAPA) need to be implemented by the CI who was inspected or is there an expectation that an entire facility/institution implement it across their research enterprise (especially when the CAPA is related to a process change)?

A: The FDA inspects CIs as individuals. Therefore, the CI should respond to any issued 483 to that person and should implement appropriate CAPAs to address the inspectional observations. Implementation of a CAPA across a facility or institution could be warranted depending upon the type of concern and issue that needs to be addressed.

Q: Do you anticipate inspections to pick back up as more people become vaccinated and COVID-19 cases decrease? Will the FDA catch up on missed investigations?

A: We anticipate that FDA inspections will probably pick back up once the pandemic subsides, but the extent to which that might occur is not clear. In March 2021, FDA stated, “As we look to the future, the FDA will continue to leverage and maximize every available tool and resource to meet our inspectional responsibilities while achieving optimal public health outcomes…. In concert with these efforts, we are pursuing agency-wide preparedness efforts for resuming a more normal state of operations, which will factor in how best to address inspectional activities that were paused due to the pandemic.”

A key element to successful study startup is identifying efficiencies to help meet critical milestones. Engaging with research compliance experts to partner with and seek advice throughout the clinical development process allows researchers to focus on what matters most: bringing therapeutics and devices to market safer and faster. This blog outlines five benefits of engaging with an expert partner for biopharmaceutical and medical technology companies.

Freeing Up Internal Resources

Many small to medium-size biopharmaceutical and medical device research teams have limited bandwidth, resources, and funding. It’s imperative for these organizations to find a partner to support them through the difficult and time-consuming components of the clinical development process. Partnering with an external organization to fill in staffing discrepancies, improve processes, and assist with site selection makes all the difference in streamlining study activation. Obtaining details on sites’ past performance and capabilities, such as therapeutic area, indication, location, and enrollment rates, helps you identify high-performing sites more easily. Seeking support in protocol design and feasibility can also free up internal resources and help speed the review process by ensuring regulatory and safety requirements are appropriately addressed, thus minimizing follow-up questions from the review committee. Utilizing these extra resources can increase research productivity, maximize your return on investment, reduce administrative burden, and ensure compliance.

Accelerating Timelines

Speeding clinical development timelines is always a priority, even for complex trials. For example, biopharmaceutical and medical technology companies are currently innovating cell and gene therapy research, which involves genetically engineered treatments and vaccines. Recent COVID-19 vaccines have brought attention to mRNA technologies in particular. This segment of the industry is growing rapidly and shows no sign of slowing. In many cases, studies involving cell and gene therapies require institutional review board (IRB) and institutional biosafety committee (IBC) review. While sites can receive approval from separate IRBs and IBCs, it is beneficial to consider a combined approach. Working with an integrated, central IRB and IBC can save weeks or even months off a study activation timeline, keeping the protocol on schedule and helping ensure safe, compliant research conduct.

Data Protection and Analysis

With technology being an increasingly integral element in research, being 21 CFR Part 11 compliant is equally critical to an organization. However, many are unaware of this requirement. Certain clinical trial management systems, mHealth mobile applications, and site and protocol training systems are subject to 21 CFR Part 11. Identifying a partner to rigorously inspect and reveal any gaps in compliance, proactively identifying and mitigating risks to help your organization avoid an FDA inspection citation or a possible halt in operations.

Additionally, you can further accelerate startup by finding a partner who can provide site identification and feasibility support with reliable and customizable performance metrics.

Compliance

The complexities involved in biopharmaceutical or medical device research require a diligent and comprehensive approach to quality assurance. As the national and international regulatory landscapes are ever-changing, it may be difficult to keep up with what is current and required. Partnering with research compliance experts helps sites and sponsors navigate the regulatory environment, ensuring compliant and high-quality clinical study conduct.

Increasing Site Engagement and Participant Retention

Participants who have a positive research experience are more likely to stay involved throughout the entire study. By engaging and supporting their sites, sponsors empower site staff to deliver that positive experience.

Biopharmaceutical and medical technology companies should embrace new technologies to build deeper engagement with participants and sites and make it easy to adapt to evolving regulatory demands. To ensure a successful trial, it is important to identify a clinical trial platform to keep your sites involved, identify risks, track communications, pre-screen participants, and engage patients.

Whether it’s for clinical development planning, study startup, site activation, or overall compliance, Advarra is the trusted partner for small- to mid-sized biotechnology, pharmaceutical, and medical technology/device companies as they work to achieve their development objectives. Contact us today.

Engaging participants and creating a positive experience throughout your clinical trial increases protocol compliance, participant retention, and future recruitment and referrals. It may seem difficult for large, international, multicenter trials to ensure a positive experience for each individual participant. However, organizations can succeed despite the distance, language, and trial complexity by focusing on three key aspects of engagement identified by participants:

Keeping participants informed
Ensuring they’re part of the team
Conducting smooth and seamless site visits

Strategy #1: Keeping Participants Informed

Participants want to feel completely up to speed and informed about their trials. To support comprehension and inclusion, how and what you communicate should incorporate your participant group’s unique needs. This includes consideration for diverse age ranges, ethnicities, and levels of health literacy. You should also consider participant preferences when it comes to communications, information-seeking behaviors, and what messages are most likely to resonate.

This may seem difficult to put into practice, but in reality, all you need are a few simple steps. Establishing a dialogue with your target population early on, delivering consistent communication throughout the trial, and seeking feedback from participants about their experience go a long way. In addition, extend engagement beyond the trial itself by informing participants of the potential trial outcomes.

Strategy #2: Making Participants Feel Part of the Team

Research shows there are highly significant benefits to feeling like you are part of a team working toward a common goal.¹ Tactics to harness team energy include generating buy-in for each team member’s role and responsibilities, communicating what the trial aims to achieve, and reiterating the importance of each team member’s active participation. To implement these strategies successfully, your organization must engage with and depend on the site.

Strategy #3: Establishing Smooth and Seamless Site Visits

To ensure site visits are smooth and seamless for participants, you need to first understand considerations influencing their experience. Ask the following:

Have you prepared participants for what procedures to expect during each visit?
Are participants aware of the time commitment of each visit?
Where can they access this information, and is it up to date?

For example, your site may need to conduct a procedure rendering the participant unable to operate a vehicle for a certain amount of time. Does your participant understand they will need to arrange appropriate transportation after the visit? To communicate expectations, utilize intuitive platforms like Longboat to guide your participants before, during, and after their visit.

As mentioned, engaged sites are critical to successfully engaging participants. It’s equally important to understand what factors affect the site team, as it is ultimately the participant’s interaction with site staff most significantly impacting the visit. A good trial experience relies on sponsors and CROs focusing on what really matters to both sites and patients. This means looking for ways to reduce site burden, allowing them to focus attention on participant engagement and care.

The Role of Trust in Engagement Strategies

The key to overall success is establishing trust between participants and trial staff. Each side needs to understand, acknowledge, and respect what is important to the other.

Participants are the single most important part of clinical research. To succeed, commit to giving the information and resources they need to be informed, empowered, and appreciated. Proven to increase retention and comprehension, the Longboat Platform supports and engages sites and participants. To learn how, reach out for a demo today.

Source:

https://news.stanford.edu/pr/2014/pr-motivation-walton-carr-091514.html

Over the course of seven weeks, Advarra conducted an anonymous survey to collect site-specific study activation data. This data covers a wide range of topics associated with clinical trial activation and startup. Topics include IRB/IBC, regulatory and compliance, and Medicare coverage analysis, to name a few. For the purpose of this blog, we analyzed the information associated with financial feasibility and budget negotiations.

It is important for sites to identify all potential costs associated with a clinical trial. This is needed to confirm all time and effort is accounted for and reimbursed by the clinical trial’s sponsor. Without the budget developed to show all research costs, sites risk unidentified or “hidden” costs going unaccounted for.

Additionally, the significance of obtaining reimbursement for these costs is even more vital. Research sites and sponsors continue to negotiate rates and payment terms, forever altering the definition of “fair market value.” Not only should sites obtain reimbursement for all applicable costs, but they should also do so in a timely manner to streamline their study activation process.

Advarra conducts budget development and negotiation tailored specifically to an institution’s guidelines and research rates. Learn more about how to streamline the budget development and negotiation process through Advarra’s Budget Negotiation Service.

Startup

Within the study activation survey, we asked sites how much they request for their study startup fees. This includes other one-time startup fees, such as the pharmacy startup, but exclusive of ongoing expenses, such as serious adverse event (SAE) reports or closeout costs. When asked how much a site would request in startup costs per the study, we found:

43% request under $10,000

29% request $10,000 to $15,000

6% request over $25,000

A piece of information believed to heavily influence startup rates was the disease setting of the clinical study. Early and late phase drug studies tend to yield higher startup costs. Settings like observational, behavioral, and device trials often have a lower startup rate in comparison. When comparing the site’s startup costs to the disease settings they participate in, sites participating in a higher percentage of early/late phase drug trials frequently have higher startup rates. However, these sites continued to request under $15,000 in total startup costs.

Demographics

Due to extensive regulatory processes, academic medical centers (AMCs) and universities typically take longer to develop and negotiate clinical trial budgets. Their private counterparts, such as health system-based sites and independent research centers, are more flexible in comparison. Nevertheless, we wanted to determine if these associations are true.

There was little to no difference in startup costs between AMCs and non-AMCs; yet, AMCs take notably longer to negotiate their budgets. AMCs most commonly reported their budgets take over 90 days to negotiate, while their non-AMC counterparts most commonly take between 30-90 days.

Turnarounds

Initially, we predicted the higher a site’s startup cost was, the longer negotiations would take. This is because of the back-and-forth needed between the site and sponsor to negotiate this high startup rate. However, our results did not support this theory. When comparing the turnaround timeline of budget negotiations to the site’s requested startup rate, our most common responses were:

<30 Days: Sites with the lowest startup costs (<$10,000)

30-90 Days: Sites with the highest startup costs ($15,000+)

90+ Days: Sites with the lowest startup costs (<$10,000)

The most notable takeaway is the split difference in answers from sites with the lowest startup costs (<$10,000). While many of these sites can reach an agreement in under a month, most sites taking 90+ days to negotiate a budget also are those requesting under $10,000 in startup costs.

One reason for this bell-shaped curve result is simply due to having a turnaround time goal. Of sites that complete negotiations between 30-60 days, 68% have a standard turnaround timeline goal with budget negotiations. On the other hand, only 45% of sites who complete negotiations in 90+ days stated they also have a standard goal turnaround timeline. Having a standard goal or deadline on budget negotiation timelines may result in more efficient processes without sacrificing funding expectations.

Challenges

When asked about internal pain points associated with budget development and negotiations, the top response was the number of available staffing. The second most common result was staff expertise, and the third was staff turnover. Building and then negotiating a clinical trial budget requires knowledge of both the site’s clinical and financial operations. Each institution operates in its own specific way, making the budget process that much more of a challenge.

Why do negotiations take so long?

In understanding why budget negotiations take so long, sites pointed to sponsor response times and negotiating the budget costs. These budget costs were itemized between startup, per patient, and other ongoing administrative costs, but respondents indicated all three selections were problematic when negotiating. Sponsor response time was a popular response as well, with many sites pointing out the budget review sits in the sponsor’s queue for an extended period of time.

Respondents also wrote in their answers for this question, more so than in other budget-related questions. Frequent responses included challenges surrounding new COVID requirements, internal staffing and turnover, and internal communications with the clinical team and/or a health system’s central office.

Conclusion

Obtaining site funding in a timely manner is critical to the success of a clinical trial. It is important for sites to calculate all costs associated with clinical trial participation, and to relay this information to the sponsor. While sponsor response times and the art of negotiating certain costs add to the study activation timeline, sites need to have specific timeline goals to ensure the success of their budget negotiations.

Download the Study Activation Industry Report

To better understand study activation roadblocks, Advarra asked sites to weigh in on their study activation experiences. Our latest industry report outlines these findings, providing sponsors and site suggestions and solutions, equipping them with information necessary to streamline and improve the overall study activation process. Access the Report