As many research organizations are becoming more patient-centric and adapting to technological advancements and remote requirements, they are re-designing the way they conduct research. Accelerated by the COVID-19 pandemic, many trials have shifted from being exclusively conducted in a brick-and-mortar site to a decentralized clinical trial (DCT) model. This approach is typically more convenient for the participant, and it allows research to continue despite in-person limitations.

Within the DCT model, there are various labels and definitions to know. These definitions can change and evolve quickly, so it can be challenging to keep up with all the terminology. In this blog, we attempt to clarify the terminology, defining decentralized clinical trials and the various terms falling beneath the DCT umbrella. We also outline what this may mean for the clinical research industry.

What are Decentralized Trials? 

A decentralized clinical trial utilizes technology and processes to create options for participation beyond an exclusive physical presence at research sites. Unlike a traditional clinical trial where data collection and trial procedures are conducted entirely at a physical research site location, decentralized trials can enable telemedicine, remote collection devices, and mobile/local healthcare providers to provide additional options to participants for in-home visits.  

You may have also heard terms like “hybrid,” “virtual,” and “remote trials” used in conjunction with—or as quasi-synonyms for—the decentralized trial concept. What do these terms have to do with decentralized trials? What’s the difference?

Virtual and Remote Trials 

Catalyzed by the COVID-19 pandemic, virtual and remote trials incorporate data collection and participant interaction outside of physical site locations as much as possible. Participants provide informed consent remotely, researchers collect any samples remotely, and data is captured through wearables issued for the research or even through the participant’s own devices or apps. While study staff often remain centrally located, mobile medical providers may visit the participants’ home when the collection of specimens or data requires the presence of a trained medical professional.

Hybrid Trials 

A hybrid clinical trial incorporates a range of decentralized, virtual, and/or remote modalities of a clinical trial. It also integrates elements of a traditional randomized controlled trial, with strategic design elements to support real-world data collection. These design elements typically focus on randomization, can accelerate product development, and help lower the cost of data collection and participant follow-up.

Many organizations across the research community are learning the value of using new and innovative study designs to increase access to research, as well as increase the quality of data and quantity of information. As a result, industry stakeholders are now using the term “hybrid trials” and “decentralized trials” somewhat interchangeably. 

Telehealth Versus mHealth in Research 

Telehealth – also referred to as telemedicine – typically refers to patients receiving care from a healthcare professional without physically entering into a building to see them. There are multiple ways to conduct telehealth, including using video chat, communicating via text messaging or email, and utilizing other remote monitoring technologies (e.g., smart glasses) to conduct research-related interactions with the participant without an in-person visit.

Mobile health (mHealth), on the other hand, is typically used to refer to capturing health data via a smart device and may be useful in clinical research. Examples include electronic patient diaries, electronic patient-reported outcomes, monitoring apps, and devices to measure activity. While participants typically use mHealth to capture and track data about themselves, mHealth may also allow them to access clinical records and communicate with providers as needed.

What Does this Mean for Clinical Research? 

The relative explosion of DCT designs and technology brought on by necessity to deal with travel restrictions related to the pandemic will forever change the clinical research landscape. Sponsors and research sites who embrace these new modalities should see the quality and consistency of their data increase while capturing more data from participants where it really counts: in their natural environment. Eliminating logistical barriers to participation also enables an expansion in the diversity and the sheer number of participants in research. Participants who previously could not travel to the research clinic during weekday business hours are now able to participate through televisits, in-home measurements and specimen collection, and digital mHealth tools which are convenient to use both in terms of time and location.

Conclusion 

No matter the nuances or differences between each of these terms, each of them will continue to play an increasingly important role in clinical research, especially as we continue to adapt to the digital age. When designing a study, it’s important to utilize the best study designs and methodologies for the specific trial and participant population. Remaining as patient-centric as possible should continue to be the main goal for sites and sponsors as they work to advance clinical research safer, faster, and smarter.

As the clinical research industry continues to conduct more and more trials, sponsors and sites alike are faced with the task of expanding their budgets. They are faced with entertaining and requesting costs due to the growing need of bringing the posed drug or therapy through the phases and to market.

However, increased budgets leave room for increased billing compliance violations. In 2020 alone, $2.2 billion was recovered from the False Claims Act. How does this affect the study activation process? What are best practices to put in place to ensure proper billing compliance from the start? Perhaps the first steps are understanding why billing compliance issues occur, and where to start to mitigate risks.

Reasons for Billing Compliance Issues

Even with guidance and acts in place designed to prevent billing fraud, it still happens. The first case of billing fraud related to billing compliance happened in 2005, and we’re still seeing similar cases today. Some common reasons related to billing compliance issues includes:

  • Double billing
  • Inappropriately deeming clinical trials to be qualifying
  • Inappropriately billing items/services as routine costs
  • Falsely billing non-covered items/services as routine costs
  • Falsely billing study team’s time/effort when a participant hasn’t been seen

It may be helpful for institutions to conduct a coverage analysis to help with billing compliance. Designed to break down all items and services required in a clinical trial, a coverage analysis shows what is covered and what is not covered by Medicare.

Where to Start with Billing Compliance

Now that we understand reasons for billing compliance errors, it’s important to know how to start to become more compliant. When starting, it’s helpful to ask the following:

  • Are we compliant with billing practices?
  • Are these costs enough?
  • Are there any costs I’m missing?
  • How fast do I need to move on this trial?

In order to effectively ask these questions, we must dig deeper and ask more questions to get to the root.

Does this Study Meet Medicare’s Requirements for “Extended Coverage”?

Extended coverage is defined as costs that wouldn’t normally be needed outside a particular study. In order to understand if something is considered “extended coverage”, NCD 310.1 is a guide outlining routine costs in clinical trials.

In NCD 310.1, there are two portions to address. The first portion addresses whether the investigational product (IP) or the study falls under a Medicare benefit category, if there’s therapeutic intent, and whether the patient has a diagnosed disease. The second portion to address is more invasive, but it’s important to provide clarity. Staff must indicate if the study is funded by a government-funded center or agency, if the Food and Drug Administration (FDA) reviewed a 6-digit investigational new drug (IND), or if it’s exempt from IND status altogether.

What are the Routine Costs in the Study?

How do we define what a routine cost is in a study? First, you must know if an item or service is covered by the sponsor or if it’s a standard of care (SOC). Defining those upfront will help you understand if it’s routine or not.

Additionally, knowing if NCD 310.1 offers extended coverage, if Medicare policies apply, or if there are any site-specific preferences can help determine if an item or service is considered routine. Another way to look at this question is asking if any Medicare statues affect coverage.

How do I Determine What is a Reasonable Cost for Items or Services?

Determining a reasonable cost for items or services is another way to confirm expenses are met. To understand what cost is referenced, current procedural terminology (CPT) codes are often utilized. This is referred to as “language” between sites and sponsors and is used to determine cost references. These extensive codes are noted on insurance claims, showing specific items or services performed. In addition, Medicare has provided public reimbursement rates for each of these CPT codes.

Staff will likely have to provide input for time and effort costs as well. In these cases, it’s helpful to rely on study staff experience, and use time estimates as well. For any other costs, communicating with departmental teams is an effective way to gain insight as to what estimates should look like.

What Administrative Fees Should I Include?

Lastly, you will need to address any additional fees that may apply to an administration. To understand what types of fees these may be, it’s helpful to identify if it’s only incurred as a result of trial participation, if it’s a “cost of doing business”, if the sponsor is likely to accept the request, or if it’s a reasonable ask. An example of this are costs a hospital incurs to keep staff employed.

Knowing and understanding how to properly route costs and fees in a study will greatly benefit your study team when it comes to staying compliant and avoiding issues such as double billing. This will simultaneously keep your organization’s reputation intact, setting you up for future success.

In an effort to create safe, effective, and affordable ventilators to help combat the foreseeable shortages due to COVID-19, one nonprofit set out to fill this critical gap for hospitals across the U.S. However, they needed guidance as they moved through the Food and Drug Administration (FDA) Emergency Use Authorization (EUA) filing process. The EUA authority allows the FDA to help strengthen the nation’s public health protections against chemical, biological, radiological, and nuclear (CBRN) threats including infectious diseases, by facilitating the availability and use of medical countermeasures (MCMs) needed during public health emergencies.

Having never done this before, the nonprofit turned to Advarra’s global experts to guide them through this process. Together, both organizations collaborated through strategy to execution to successfully obtain an EUA from the FDA.

Process

As this nonprofit and Advarra began to work together, Advarra leveraged key members of its Regulatory and Quality Centers of Excellence (CoEs) to deliver strategic and tactical support across a wide range of skills. Team members included:

  • Regulatory experts to lead the FDA Authorization communication and filing process
  • Quality experts to help qualify and certify the nonprofit’s manufacturing facility
  • A packaging expert to help design and develop the device packaging

As a team, Advarra’s global experts worked together to help frame the nonprofit and their business model for advancing their medical device to various federal and state agencies. Advarra’s global reach connected the nonprofit to potential manufacturing partners and philanthropies. Through these connections, this nonprofit accelerated product development for production capacity up to 1,000 units per week.

Providing FDA Communication Expertise

To get this nonprofit ready for EUA submission, Advarra’s Regulatory CoE team prepared team members for the pre-investigational new drug (IND) meeting. Prior to this meeting with the FDA, Advarra regulatory experts also assisted the nonprofit as they submitted a letter to the FDA requesting this meeting. This letter included itemized questions designed for the FDA to review and discuss. After these questions were received, the FDA set up a meeting with the nonprofit 60 days after the initial request.

Thirty days prior to the meeting, the nonprofit submitted a briefing document with the same questions initially posed, but with scientific detail. The FDA met prior to the pre-IND meeting, and this became the basis for the meeting itself.

Additionally, Advarra’s regulatory experts provided guidance for the nonprofit to navigate the pre-new drug application (NDA) meeting. Scheduled four to six months ahead of a formal submission, this meeting discusses topics such as (but not limited to):

  • Program results
  • Location of results within the NDA
  • Addressing issues raised in the development program
  • Follow up on issues raised during the end of the Phase II meeting

Results

Within three weeks, the nonprofit had working units of its medical device in testing at a local hospital, and within five weeks, the FDA granted EUA to them.

Since receiving their EUA, the first batch of units were manufactured with a validated design. The nonprofit also scaled up to provide ventilators for rural and global needs with a production capacity of 1,000 units each week. This helped fill critical gaps in areas with the biggest shortages when organizations needed it most. Access the Case Study

The COVID-19 pandemic highlighted the need for organizations conducting research to have certain protocols in place, including robust emergency preparedness plans. Designed to guide communications and operations throughout an ongoing public health emergency, it’s important an organization has an emergency preparedness plan in place.

Identifying Potential Risks to Your Organization

There are many factors to consider when developing a Human Research Protection Program (HRPP)-focused emergency preparedness plan. Developing an HRPP-focused plan should begin by assessing potential emergencies affecting an organization’s HRPP and their impact on the HRPP’s operations.

When identifying potential emergencies, it’s helpful to understand risks involved. Types of risks may range from public health emergencies like the COVID-19 pandemic, to weather-related events (e.g., hurricanes, tornados). A risk is also anything likely to affect HRPP staff and research participants, such as cybersecurity incidents (e.g., data breaches) impacting electronic regulatory systems critical for conducting day-to-day operations.

Once potential risks are identified, organizational leadership should collaborate with HRPP leadership and staff. Together, they will consider any research operation modifications during an emergency to mitigate or manage risk based on the type of emergency. An HRPP’s emergency preparedness plan should clearly specify the actions an organization and its HRPP may take in response to an emergency, including what types of research may be suspended.

For example, during the COVID-19 pandemic, many HRPPs have shifted from working in an office-based setting to working remotely in order to mitigate the risk of staff spreading the virus to one another. Similarly, research teams have moved from conducting study visits in person to conducting them remotely when feasible in order to minimize risk to research participants.

Another risk management strategy institutions may want to consider is temporarily suspending non-interventional research – or research presenting no benefit to participants – during an emergency. Other examples of items to include in an emergency preparedness plan may include:

  • How research participants will receive a study drug/investigational product
  • How study teams will obtain informed consent from newly enrolled participants
  • How current participants will learn significant new information, possibly affecting their willingness to participate
  • How an IRB would respond if it no longer had access to records
  • Whether the organization might cede review of ongoing or newly proposed research if their IRB couldn’t operate due to an emergency
  • How the site will modify operational processes if it no longer has access to participants’ electronic records

Involving the Right Staff

Another critical component of an organization’s emergency preparedness plan is designating who is responsible for implementing the plan when an emergency arises and evaluating the plan on an ongoing basis. Organizations should consider designating an alternate or backup to assume responsibility, in case the individual primarily responsible is unavailable.

Once an organization has developed its HRPP’s emergency preparedness plan, educating its research community – including researchers, IRB members, HRPP staff and leadership – about the plan is critical to ensuring successful implementation.

Incorporating AAHRPP’s Element I.1.H

The Association for the Accreditation of Human Research Protection Programs (AAHRPP) recognizes the importance of having and executing an emergency preparedness plan to protect human research subjects during emergencies in its newest accreditation element: Element I.1.H.

AAHRPP’s Element I.1.H requires accredited organizations to have and follow “written policies and procedures specifically designed to protect the rights and welfare of research participants during an emergency.” [i] The Element includes four essential requirements:

  1. The HRPP has an emergency preparedness plan, appropriate to the size and complexity of the HRPP
  2. The plan is periodically evaluated and, when necessary, adjusted to ensure continuity of operations
  3. Organizations provide education about their emergency response plan for IRB members, staff, researchers, and other members of the HRPP
  4. Persons in the HRPP are knowledgeable about the organization’s expectations during emergencies [ii]

It’s important to recognize Element I.1.H is included in Domain I of AAHRPP’s Accreditation Standards, [iii] underscoring the responsibility of having an emergency preparedness plan to protect research participants rests with an organization, not just with its HRPP or institutional review board (IRB) office. AAHRPP’s guidance on Element I.1.H specifies emergency preparedness plans should be risk-based and tailored to the size and complexity of the organization’s HRPP—there is no one-size-fits-all emergency preparedness plan. [iv]

Organizations submitting initial applications for AAHRPP accreditation after January 1, 2022 must include an emergency preparedness plan in their written materials. Beginning in March 2022, AAHRPP-accredited organizations seeking reaccreditation must include plans for emergency preparedness in their reaccreditation applications. [v] Accredited and non-accredited HRPPs alike can benefit from having an emergency preparedness plan in place to guide human subjects research operations during an emergency and protect the rights, safety, and welfare of research participants.

[i] https://admin.aahrpp.org/Website%20Documents/Element%20I.1.H.%20(published)(2021-10-03).pdf

[ii] https://admin.aahrpp.org/Website%20Documents/Element%20I.1.H.%20(published)(2021-10-03).pdf

[iii] https://www.aahrpp.org/apply/process-overview/standards

[iv] https://www.aahrpp.org/apply/resources/procedures-and-standards, last accessed December 16, 2021.

[v] Id.

In the fast-paced clinical research industry, time is of the essence. Maximizing the time you have to efficiently meet with participants, collect data, and organize it is key to keeping your study on track.

Oftentimes, keeping paper records of study visits, participant data, and the like can cause significant delays during research. This may result in added labor hours, misplaced documents, or an increased risk of error. A solution for these roadblocks may be transitioning from paper source to an eSource solution. Knowing the benefits of using eSource, tips for implementing eSource, and maintaining compliance in your eSource solution may make all the difference in an efficient trial.

Benefits to Using eSource

As the research industry continues to move into a more decentralized, electronic age, there are many benefits to transitioning from paper to eSource. Top benefits include:

  • Saving time
  • Easier data interpretation
  • Increased organization

Saving Time

Switching to eSource can improve a study’s accuracy, compliance, quality, safety, and decrease deviations – all of which add up to significant time saved on protocol. Additionally, electronic source records decrease time and effort for source and electronic data capture (EDC) data entry verification. This leverages real world direct data entry and remote monitoring capabilities.

eSource also has the ability to leverage standardized research assessment templates, such as informed consent process documentation templates and clinical research assessment forms. In addition to standard healthcare outcome assessment forms and standard questionnaires utilized across all clinical trials, this also decreases time and effort recreating paper source documents per study.

Adapting standardized templates and forms, and implementing standard research questionnaires strengthens the site’s quality and safety outcomes. In turn, this will decrease protocol deviations and enhance the validity of source data collections.

Easier Data Interpretation

Switching from documents with hand-written notes to everything electronic standardizes writing, making it easier to read for everyone, since no time is spent trying to interpret what’s written out.

Additionally, eSource allows staff to put in order sets, which, due to the shift from paper to electronic workflows, will decrease deviations.

Increased Organization

With paper source, it’s easy to misplace necessary documents for a study, or to lose them altogether. Staples may come loose, or papers may get thrown out on accident. Not only would staff have to spend time retrieving documents if this happened, but it also accounts for the missing organization piece of paper source. Through eSource, everything is in one place, eliminating the risk of misplacing documents or not having everything you need as you collect data.

Additionally, using electronic patient reported outcomes (ePRO) with eSource further automates and improves data quality. Utilizing ePRO to its fullest extent also contributes to increased organization because it holds everything for a study subject, including standard forms they need. This not only keeps everything organized for study staff, but for participants as well, since everything is in one spot for them.

Tips for Switching Over to eSource

When transitioning source documents from paper to eSource, it can be helpful to implement standard templates across the organization for everyone to utilize. When looking for consistencies across studies, it’s helpful to use two buckets: research categories and therapeutic lines. Research categories include components such as serious adverse event (SAE) or adverse event (AE) logs, device tracking methods, or informed consent forms (ICFs). Therapeutic lines include head-to-toe assessments, vitals, or lab draws.

While there may be more consistencies than just the ones listed above, this provides a good basis for what goes into electronic source forms. By making short and simple form templates, you can reuse the templates from study to study, further saving time on repetitive tasks.

Think About the Assessment Flow

Keeping everything electronic eliminates the hassle of flipping through pages to find the correct documentation. Rather, you can set up a documentation flow, ensuring you fill out the correct documents in the correct order. eSource enables staff to set up requirements around documents – dictating which documents are essential to fill out, which are optional, or which ones to fill out in a specific order. Additionally, you can embed certain fields as “required”, ensuring critical information is collected, ultimately helping you avoid deviations.

Once everything is filled out, sending documents to the principal investigator (PI) is easier via eSource, because all you will have to do is send them a link, directing them to the specific documents they need to review and sign. This saves time on their end, and ensures everything needing their signature is filled out properly.

Maintaining Compliance in eSource

When transitioning to an eSource system, it’s imperative to remember the system needs 21 CFR Part 11 validation and conformance. If you are going to store and maintain a Food and Drug Administration-regulated (FDA) essential record, such as a delegation of authority log, a 1572, or a signed ICF that the FDA can ask for during an audit, the system needs to be validated. Incorporating electronic signatures on the signature process and program also need to meet 21 CFR Part 11 requirements per regulation guidelines.

Keep in mind, there are two parts to Part 11 regulation. The first part covers electronic records – if any FDA-regulated information is created, maintained, or stored in electronic format, Part 11 applies.

The second part entails the electronic and digital signatures piece. This second part outlines the FDA’s requirement for authentication, non-repudiation of the signature, meaning it has to be the legally binding equivalent to the manual signature. When transitioning to an eSource system, the institution employing the eSignatures needs to notify the FDA in their Part 11 regulation of their intent to use eSignatures in lieu of paper signatures.

While there are many parts to consider during the transition from paper source to eSource, the transition enables researchers to conduct their research more efficiently by allowing them to focus on tasks that matter most to them: interacting with participants and advancing science.

Ready to streamline your operational processes? Learn more

A clinical research trial can only be as strong as the participant population it’s actively reaching and serving. Additionally, the participant population should also match the population of those who need treatment. However, many research teams still struggle to improve access and retain participants in clinical trials. While there may be multiple factors involved in this challenge, location greatly affects a person’s ability to participate or not.

In fact, more than 70% of Americans live more than two hours away from a trial site. If someone were to live that far away and travel to a site on a weekly basis, that’s four hours each week they are giving up to participate – and that’s just on the commute.

Additionally, the industry is seeing a challenge in recruiting enough clinicians to participate in recruitment efforts. This is due to a high cost, low incentive ratio to participate in finding patients for trials. Since providers aren’t opting to participate in recruitment efforts, it’s increasing the challenge to find eligible patients, or even making patients aware of options available to them.

Addressing Common Challenges

The COVID-19 pandemic has given the research industry the workflows and infrastructure to address these challenges and change how research is conducted through decentralized clinical trials (DCTs). Defined as a non-traditional clinical trial model, DCTs utilize technology and processes to create options for participation beyond an exclusive physical presence at research sites. A decentralized model encompasses hybrid, agile, virtual, and remote study designs.

Shifting to a decentralized model can reap many benefits and help solve the industry’s biggest challenges. From a participation standpoint, we can remove the requirement to conduct all visits at a physical research site and allow patients from various parts of the country or world to participate. By doing so, we can allow ourselves to potentially condense the overall trial timeline, increase representation, and decrease trial costs.

Additionally, if we expand participation beyond just clinicians at sites, we can include more clinicians at various locations and organization types. This will also aid in broadening patient access by introducing clinical research to organizations normally without the option of providing a trial as a care option for their patients.

Designing an Adaptive Clinical Trial

When we move toward a decentralized model, we are moving away from limiting trials with labels. The key to success in a decentralized landscape is designing your trial to be adaptive and deployed in different ways depending on participant preference, technology, therapeutic area, and more. In this approach, patients and providers are in the middle, and surrounding them are various aspects going into a clinical trial, including:

  • Home
  • Site
  • Care Providers
  • Telemedicine
  • Sponsors

Bringing all of these components together allows the patient to participate how they want to and in manners that work best for their lifestyles. By enabling the most efficient modality for that specific intervention, everyone can participate, in turn strengthening representation across the industry.

Planning Ahead

It’s paramount to appropriately design and support a DCT on both a macro- and micro-level. Thinking of what the participant could expect, how the study may unfold, and what communication methods to deploy during a trial will help ensure it runs smoothly. Similarly, it’s important for the site or provider to understand what the trial could look like at their location, as well as what it will look like for in-home activities. Outlining these details will help everyone understand what options are available to them. Outlining these details will help all study stakeholders understand what options are available for them to provide, or participate in, connecting more patients to the care they need.

Dawn Wydner, former Food and Drug Administration (FDA) Consumer Safety Officer, LCDR, and current Managing Expert for Advarra’s Quality Center of Excellence, is a premier subject matter expert in FDA inspection readiness programs. Wydner has successfully collaborated with clients to improve their inspection procedures, documentation, and implementation of new regulations, emphasizing accountability is key for FDA inspection readiness. In this blog, Wydner provides insights for organizations preparing for an inspection by regulatory authorities.

What is the most common observation you have when helping companies become inspection ready? How would you advise them to tackle this issue?

Vendor oversight: Specifically, documentation demonstrating sponsors and contract research organizations (CROs) are actively participating in vendor oversight management. For example, issue escalation — identifying and resolving issues in a timely, standardized manner — is necessary, but documenting these steps is critical for inspection readiness investigators. Auditors and investigators look closely at the impact, the “so what is most important?” perspective, understanding what largely impacts participant safety and integrity. Having the right documentation ready is key, and implementing an inspection readiness mindset from the beginning can proactively mitigate risks at the end.

How has ICH E6 R2 changed the world of health authority inspections?

For FDA inspection readiness, accountability is key. Specifically, the execution of your responsibilities. This guidance clarified the accountability required for successful outcomes from health authority inspection readiness programs. Sponsors and contract research organizations (CROs) received clear preparation and inspection guidelines.

How have risk-based principles enhanced preparation activities for companies becoming inspection ready?

Well first, companies have to embrace them; it is the biggest challenge for most. A lot of companies are still working on adopting risk-based principles, but once implemented and integrated throughout the organization, additional time and resources are now free to build on efficiencies, focusing on impactful data and efficacy areas.

An important reminder for organizations is not to get discouraged by the volume of observations from agency investigators, as this approach was a new concept for the FDA as well.

How has sharing information between FDA and European Medicines Agency (EMA) health authorities changed the world of inspections?

It helps the industry by lessening the amount of inspections at any given stage. We’ve seen where the EMA will come to the US to inspect a company, and therefore, the FDA wouldn’t have to, even though it was on their list to inspect that sponsor or site. It’s a good method because sharing this information leverages responsibility for accountability between organizations.

For some companies, ensuring their preparation activities include requirements for both sides may be challenging. Although some aspects are very similar, there are distinct differences between the FDA and EMA.

Is there an optimal time when companies should start to think about being inspection ready?

Definitely — in the beginning. From the time you are selecting your site, building your protocol, and preparing for the inspection, you need to have this mindset. It’s necessary throughout the whole process.

It’s definitely a challenge though; having a preparedness mindset from the start can save a lot of time in the end.

Do you think companies do a good job on managing corrective and preventative action (CAPA) plans? If not, do you have any advice?

The biggest advice would be, really, to have specialized people at the ready who are fully trained in CAPAs and understand the concepts of building out a root cause analysis, etc. Otherwise, you may have to just give it to quality assurance (QA), but since they aren’t specifically trained for this, it may upset results. They may know the overall concepts of it, but subject experts really understand how to build it and get the right actions out of it.

Key Takeaways

A successful health authority inspection readiness program largely depends on a proactive and comprehensive approach. Companies embracing their responsibility for vendor oversight, adopting, and implementing updated regulations demonstrates their organization’s commitment to accountability, participant safety, and integrity.

The year 2021 brought many advancements in the clinical research industry. We’ve pushed for more diversity and inclusion in clinical trials, decentralized clinical trials have gained attention, among many more improvements. As the end of the year draws near, let’s take a look back at popular blog posts and webinars garnering the most interest from research community members like you.

Top Blog Posts

Q&A – Regulatory Fine Points: Exploring 21 CFR Part 11 Validation

James Riddle, Shannon Roznoski, and Stuart Cotter of Advarra presented Regulatory Fine Points: Exploring 21 CFR Part 11 Validation, reviewing how the partnerships between software vendors, research institutions, and other stakeholders work to support regulatory guidelines. They discussed in detail which parts each party is responsible for when building, implementing, and maintaining clinical trials software in a government-regulated process.

Defining Decentralized Clinical Trials and Understanding Their Nuances

It’s important to understand decentralized clinical trials are not one-size fits-all, and oftentimes, a hybrid approach is necessary. This blog offers considerations when rolling out decentralized clinical trials across multiple jurisdictions where laws, technological uptake, and populations will vary.

Informed Consent: When, Why, and How It’s Obtained

Aside from being a regulatory and ethical requirement, informed consent is a good way to ensure participant knowledge and develop a foundation of trust between the researcher and participant. This blog outlines the informed content process.

FDA Inspection Readiness: Preparing for an Inspection

A Food and Drug Administration (FDA) inspection of an investigational site can occur at any time, and preparation is critical to an efficient inspection. By understanding what the FDA typically looks for in its inspections, sites can make sure all documentation is ready for review and all staff are properly trained to interact with the inspector.

DMC vs IRB: What’s the Difference?

In this blog, we will take a look at the specific role data monitoring committees (DMCs) play in overseeing research, and how institutional review boards (IRBs) rely on the independent DMC’s oversight of interim trial data to ensure an adequate safety monitoring plan is in place.

Top Webinars

Budgeting and Billing Compliance in Study Activation

Wrongfully billing items and services to a participant’s insurance is an ever-growing risk in clinical research. Advarra’s Senior Business Operations Services Manager Jake Meyer discusses common strategies sites take to protect themselves from such financial risks. From making do with a tight budget to taking less conventional approaches, learn how you can ensure reliable and maintained timelines, even amid fluctuations in demand.

Leveraging Data to Lead and Manage the Research Mission: Data-Driven Decision Making at all Levels of the Organization

With data all around us and easier than ever to capture, we should use it at all levels of our organizations to drive strategy and manage operations. In this webinar, Teri Grieb, Associate Dean for Research Strategy and Senior Director for Research Administration, and Kate Huffman, Associate Director of Operations for the Clinical Trial Support Units at Michigan Medicine discuss how their organization uses data at all levels to lead and drive the research enterprise and day-to-day research operations.

Diversity and Inclusion: Who is Responsible – Site, CRO or Sponsor?

Attaining a diverse trial patient population is crucial to the success of any clinical trial. But who is truly responsible for maintaining a diverse and inclusive participant database? In this webinar, Judy Galindo, Monica Cuitiva, Ashley Margo, Dan Sfera, and Chris Sauber, the Co-Founders of Latinos in Clinical Research, outline why it’s important to recruit diverse patients of all backgrounds and why protocols should be more inclusive.

Do You Have Appropriate Oversight? Understanding the Role of DSMBs

Clinical trials are complex. Independent DMCs or data safety monitoring boards (DSMBs) provide necessary support to sponsors and contract research organizations (CROs) in the conduct of clinical trials. In this webinar James Riddle, Advarra Vice President of Research Services & Strategic Consulting, and Barbara Schneider, Advarra Executive Director of Biostatistical Services, take a look at the role and function of independent DMCs from charter creation through interim data analysis.

FWAs Part 2: Managing a Federalwide Assurance and IRB Registration

Join Advarra’s regulatory experts Lisa Rooney, Managing Director, Institutional Research Center of Excellence, and Lauren Hartsmith, Director of Regulatory Affairs, in another discussion of institutional responsibilities, digging deeper into the federalwide assurance (FWA) topic and adding IRB responsibilities to the mix. They answer questions such as:

  • How to obtain an FWA
  • When to update one
  • When an institution has to register an IRB
  • How an IRB registration fits in with the FWA process
  • What to do if an IRB no longer reviews research

For more content relevant to your research needs, visit Advarra’s Resource Library to explore blogs, white papers, case studies, webinars, and more. Joining our mailing list guarantees the latest Advarra content you want is delivered right to your inbox.  

Advarra experts Joan Versaggi and Leslie Paul answer questions from the first in the webinar series – FDA Updates: BIMO – What Sponsors Need to Know.

Q: How are inspections assigned domestically in the United States (US) versus outside the US?

A: The BIMO CPGM (Bioresearch Monitoring Compliance Program Guidance Manual) addresses in Part III (Inspectional), section V (International Data) what a Food and Drug Administration (FDA) investigator looks at during an inspection. Section B. 2. notes the Centers (e.g., CDER, CBER) issue sponsor inspection assignments. Domestic inspection assignments are issued through the ORA OBIMO headquarters to the appropriate ORA BIMO division. Foreign inspection assignments are issued to ORA OBIMO headquarters

Q: What are remote “assessments” and how do they differ from the “regular” inspection (i.e. no 482, no 483 etc.)?

A: This webinar covered the changes to the BIMO CPGM 7348.810 (Sponsors and CROs) and how the FDA conducts “regular” inspections. For details regarding the conduct of remote interactive evaluations of BIMO facilities, see FDA’s Guidance for Industry Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities During the COVID-19 Public Health Emergency.

Q: Where is the complete response letter in the chain of events?

A: After the FDA conducts their review of the sponsor-provided information, a complete response letter is issued indicating they will not approve the application at that time. This is outlined in 21 CFR 314.110.

Q: Can you give an example of a sponsor-investigator?

A: A sponsor-investigator is an individual who initiates as well as conducts the clinical investigation. A sponsor-investigator must comply with regulatory requirements applicable to both sponsors and clinical investigators.

Q: How transparent should a sponsor be with the FDA investigator during a pre-approval inspection (PAI) when there were issues in unblinding (e.g., mistake at sponsor)? Should the sponsor inform the FDA up front during the inspection? Or just be prepared to talk about it *if* the FDA investigator finds it?

A: Our advice is to be transparent with any quality issues, such as unintentional unblinding. While sponsors should have reported this in the clinical study report, they should be forthcoming with a serious issue and provide an explanation as to what happened, why it happened, and what was done or what controls are now in place to ensure the non-compliance does not occur in the future.

Q: Given that many sponsors are now working remotely due to COVID-19, can we expect that FDA would reach out in advance to schedule inspections, versus coming to a sponsor location unannounced?

A: Inspections under this program are generally pre-announced, unless otherwise instructed in the inspection assignment and at the discretion of the ORA BIMO division. Pre-announcements are generally no less than five calendar days in advance of the inspection.

Q: Can you please comment on FDA collecting more and more data on USB drives? Sponsors have started putting standard operating procedures (SOPs) in place restricting USB drive use due to security issues.

A: It’s best practice to have written procedures governing how electronic data is provided to a regulatory authority if they request it during an inspection. Chapter 5 of the Investigations Operation Manual (IOM) section 5.3.8.3.1 – Electronic Records, provides specific instructions to the FDA Investigators on the collection of electronic records. The IOM states in part, – If there are no mechanisms available for a firm to securely transmit the data electronically to the investigator, the data may be provided to FDA on a CD, DVD or a USB…The information obtained from the firm is commercial confidential information (CCI) and as such must be protected to the greatest extent possible. It is the responsibility of the investigator to make sure the physical data source remains secure. Likewise, data obtained from extra-governmental sources may contain viruses or malware that may be included with the information provided to the investigator either on purpose or accidentally. The transfer of electronic data must be evaluated along with concerns related to safeguarding the security of both FDA and firm information.

Q: What is the expectation of evidence for a sponsor to show oversight for a vendor’s subcontracted services as required by ICH E6 R2?

A: New Section F – Outsourced Services specifically states the following:

Review and evaluate the sponsor’s oversight of outsourced services as appropriate and as defined in contracts, written processes and procedures, and SOPs. Focus on the outsourced services playing a significant role in the clinical trial (e.g., management of primary efficacy endpoint or safety data) and/or were involved in any significant FDA regulation deviations. Determine if the sponsor has processes and procedures (e.g., SOPs, plans, or other work instructions) for selection of outsourced services and activities, and determine what criteria were used to select the CRO (and as applicable, other individuals or organizations providing outsourced services) and whether they meet those criteria.

Q: What documents are available to inspectors prior to the BIMO audit visit?

A: Centers will provide background materials when they issue sponsor inspection assignments, such as:

  • Study protocol
  • Case report forms (CRFs)
  • Data line listings
  • Complaint summary
  • Any additional information

Q: In providing the list of SOPs, should we provide only current SOPs or all versions in effect during study conduct?

A: The FDA investigator should receive SOPs in place during the conduct of the clinical trial(s). If you have updated SOPs addressing any deficiencies in the SOPs in place at the time of the study conduct, they can demonstrate the sponsor’s improvements.

Q: What’s the thought/guidance for providing a BIMO reviewer’s guide in a marketing authorization application (MAA)? Is it a best practice as it’s optional?

A: I have never provided this with an application, I suppose there may be a good reason to provide one. For example, if the drug has gone through several owners and the sponsor wishes to clearly outline who was responsible for what, when? Further I found the Bioresearch Monitoring Technical Conformance Guide, which is referenced by the Draft Guidance Document: Standardized Format for Electronic Submission of NDA and BLA Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for CDER Submissions.

To learn more about recent BIMO changes, watch the on-demand webinar FDA Update: BIMO – What Sponsors Need to Know.

Oncology research represents a significant percentage of all clinical research, reflecting the fact that cancer continues to be a leading cause of mortality and morbidity worldwide. At the same time, we’ve made significant treatment advances for different types of cancers in the past decade, and the death rate from cancer is declining in the United States.

Phase I oncology trials play an essential role in assessing investigational therapeutic safety and determining whether they are promising candidates for further exploration. They also raise unique ethical challenges that sponsors, investigators, and institutional review boards (IRBs) should anticipate and ensure are adequately addressed.

Vulnerability in Phase I Oncology Research

Participants in Phase I oncology trials are typically sick and suffering from the cancer being studied. This is unlike Phase I research in other disease areas, which typically enrolls healthy volunteers. Phase I oncology protocols usually require individuals to have advanced disease and/or to have failed available treatments in order to be eligible. As a result, individuals eligible for Phase I oncology studies are often in very difficult and vulnerable situations, which itself merits additional sensitivity, and the possibility for additional safeguards, from researchers and IRBs.

Therapeutic Misconception

Phase I oncology studies give very sick individuals with few or no other options an opportunity to access investigational therapies. Nonetheless, they are often first-in-human studies to evaluate for safety, not primarily for efficacy. Because of this, care is needed to ensure “therapeutic misconception” avoidance in participants, which involves assuming research is more similar to clinical care than it actually is, and (as a result) a tendency to overestimate the benefits of research participation.

Participants in Phase I oncology trials should have a realistic understanding of the risks and benefits and understand the investigational therapies evaluated have not been shown to be effective. Design consent forms (including recruitment materials) with this aim in mind, avoiding overly promissory statements about personal benefit. While consent forms often state, “you may or may not benefit,” the likelihood of sustained personal benefit on a novel Phase I study is vanishingly small.

Study Design and Monitoring

Phase I oncology studies are typically designed to assess for safety, which they do by monitoring adverse event (AE) occurrence and frequency. They also pursue aims relevant for future studies, such as determining the maximum tolerated dosage of an investigational drug. Phase I oncology trials often have distinctive designs allowing them to accomplish both of these aims efficiently, with the fewest number of participants possible and in relatively short time frames.

For example, in a standard 3+3 dose escalation study with an objective of identifying the maximum tolerated dose (MTD), cohorts of three participants are given a starting dosage of an investigational drug. If none of the initial three participants experience toxicity, the dose is escalated to the next level. If, by contrast, two or three participants experience toxicity, no further dose escalations take place and this is considered the MTD. If only one participant experiences a toxicity, three additional participants are dosed at that level. If any of those additional three (i.e., more than one participant out of six) experience toxicity, no additional dose escalations take place and this is considered the MTD; if not (i.e., if only one out of six experiences toxicity), the dose is escalated. This process continues for each subsequent dose until an MTD is reached.

In first-in-human oncology studies, where the drug has not been previously tested in humans, some form of staggered or sentinel dosing is usually ethically advisable. This will involve dosing one or two participants, followed by a time delay and observational period before additional participants are dosed. Sentinel dosing can be limited to the first participants dosed in the entire study, or employed within each dose cohort; which approach is best will depend on the nature of the study and therapy being evaluated. By limiting the number of participants simultaneously exposed to a drug with unknown risks, sentinel dosing minimizes damages in worst-case scenarios, which unfortunately do occur, if rarely, in first-in-human studies. Sentinel dosing can be difficult for studies with novel antibodies, which may have long half-lives, and careful assessment is needed in these studies to arrive at reasonable dosing windows and timelines.

Due to participants in Phase I oncology trials being sick, and the potential for toxicity and unknown risks, robust safety monitoring plans are needed. These will typically include both routine assessments and blood labs, the details of which will vary depending on the study. Take care when balancing the need for monitoring assessments and data collection requiring blood samples against the fact that certain oncology populations may have low hemoglobin or platelet counts, potentially resulting in a need for transfusions. Sponsors and investigators should consider these factors, with efforts made to accomplish study objectives with the least amount of blood collection possible in these populations.

Whereas many Phase I non-oncology studies will mandate a pause for a subject death, that may not be the case for Phase I oncology studies, even first-in-human Phase I oncology studies. This may reflect the precarious nature of participants’ health, the likelihood a terminal event is unrelated to study procedures, and other factors. The IRB should read the definition of serious adverse events (SAEs) carefully when reviewing these studies.

Conclusion

Phase I oncology studies are designed to yield basic data about safety and other parameters in people suffering the condition under study. Increasingly, these studies leverage complex designs in an attempt to accomplish their objectives efficiently and on tight timelines; for example, by moving seamlessly from Phase I to Phase II or allowing for greater flexibility in adjustments to dosage, sample size, and other features.

Everyone can agree speeding therapeutic advances in oncology is a worthy goal. At the same time, care is needed to ensure such advances do not happen at the expense of the rights or interests of participants in these studies. The research community can ensure this does not happen by recognizing the vulnerability of Phase I oncology participants, being forthright and realistic about the risks and expected personal benefits of these studies, and taking care to ensure they are well-designed with robust mechanisms for promoting participant safety and minimizing risks.

As March 2020 completely disrupted any sense of normalcy, including in the workplace, many were forced to adapt rather quickly. As we begin to enter into a “next normal”, we surveyed the industry to get their take on what they think the industry will look like moving forward. The report includes analysis from those at sponsor organizations and sites alike, and this blog focuses on important shifts we will see industry-wide as we continue to navigate the pandemic: staffing, budgeting, and time allocation.

Shifts in Staffing Across the Industry

Survey results found 48% of respondents indicated research staffing will change at their organization – 73% of those respondents anticipated research staffing would worsen over the next 12 months at their organization. While that may indicate people are leaving the industry altogether, we’re seeing a shift in staff leaving sites and moving over into the sponsor realm. What are some contributing factors to this shift?

In order to understand future trends, we must understand how we got to this point. When the pandemic set in around March 2020, and regular research operations weren’t able to continue for the foreseeable future, many clinical research sites experienced furloughs or layoffs. As staff were laid off, many moved into other forms of the industry instead of exiting it altogether.

This shift caused a wide influx of staff coming into sponsor organizations, and many are staying even as research operations resume. Currently, sponsors are providing a more flexible work style for most, including remote modalities, and allowing staff to work from home instead of coming into an office.

With this in mind, sites will need to rethink how to navigate a research study if the staff shortage continues. Sites will need to consider how they can work with sponsor organizations and contract research organizations (CROs) on what parts of their clinical trials they can outsource, such as to a home health care organization. This can minimize the need for in-house staffing due to staff shortages.

Resuming On-site Activities

As research continues to open back up and activities resume, there are still differences in what in-office work looks like now versus early 2020. For research sites, operations look different in every organization, and many coordinators are still facing restrictions, especially in clinics with higher-risk patients or in locations still facing high COVID-19 infection rates. It’s important to remember we are still in a pandemic state, and most organizations are still adapting to rapidly changing situations.

Shifts in Budgeting and Time Allocation

Since the industry is seeing a shift in staffing, many sponsors are noticing sites are having a hard time staffing sites for various tasks, such as database logs, training, monitoring, and more. Because of this, it affects the sponsor’s timeline across the board, and they must make updates to accommodate, including extending timelines. This also impacts study startup timelines, as clinical trial agreements (CTAs) and budget approvals take longer. Study conduct time increases due to minimal staff having the time to recruit and screen study participants, perform data entry, and have monitoring visit availability.

Adjusting a trial’s timeline ultimately costs sites and sponsors money as well, affecting budgets and money allocations. A notable area where budgets are expanding is in the realm of remote monitoring. At the site level, it’s costing more for sponsors to monitor trials remotely. Instead of a study coordinator being available at set times and intermittently throughout the day, they need to be available for the entire day. They also must make additional system access requests and privileges for the various systems a sponsor monitor needs to review. This requires giving site personnel time to complete the tasks as well as procedures to ensure privacy and access rules compliance.

Key Takeaways for Sponsors and Sites

While remote monitoring can benefit sites and sponsors in the long run, they are currently costing about twice as much since personnel are taking twice as long to complete tasks. This also drains the staff because it’s taking time away from them for tasks they also need to get done or could do instead of tending to remote monitoring needs. Over time, however, we anticipate timelines and budgets will tighten up as staff continue to adapt to remote modalities.

Special thank you to Wendy Tate and Adam Ruskin for providing insight into this blog.

To learn more about how the COVID-19 pandemic impacted the future of the clinical research workforce, read our trend report.

Since early 2020, clinical research sites – like many industries – experienced profound COVID-19 impacts. Specifically, sites had to maneuver restricted access, pivot their research priorities, and move procedures they’ve traditionally performed on-site to a virtual or remote format. Curious to further understand these impacts, Advarra conducted The Future of the Clinical Research Workforce survey in Summer 2021. Our survey found while sites tended to have similar habits prior to the pandemic, individual organizations are approaching the “next normal” differently.

In order to effectively analyze survey results, it’s helpful to know the demographic we are talking about further. Representing 70% of survey respondents, we found research site staff worked for the following types of organizations:

  • Independent research sites: 41%
  • Academic medical centers (AMCs): 28%
  • Hospital/health systems: 23%
  • Cancer centers: 9%

We also asked respondents how many protocols they work on each year. AMCs had larger clinical research portfolios, with 34% stating their organization managed 500 or more protocols. The majority of independent research sites – 83% – reported working on fewer than 50 trials yearly. Cancer centers and hospital/health systems varied across all portfolio sizes. We found 95% of cancer centers had portfolios of at least 10 protocols, while hospitals and health systems were distributed across all sized portfolios.

Sites are Facing Staffing Shortages

Survey results showed us staff shortages are occurring industry-wide. Overall, 28% of our site respondents indicated they anticipate staffing shortages in “numerous areas” of their organization or “widespread” staffing shortages, as opposed to having “enough” staffing, or shortages in a few areas in their organization.

However, this varied by site type. About 49% of independent research sites indicated they had “enough research site staff” and only 3% said they would experience a widespread shortage. Over 10% of respondents from other site types reported there would be widespread shortages. Conversely, AMCs were the least confident, with only 15% stating there would be enough research staff over the next 12 months and 19% respondents indicating they will experience “widespread” shortages.

When adding shortages in “numerous” areas to the respondents anticipating widespread shortages, the gap widens with only 12% of independent research sites giving one of those two responses versus 51% of respondents from AMCs (31% for cancer centers and 28% for hospitals/health systems).

Work Locations are Changing

Due to the frequency of interacting with participants through visits, research site staff have traditionally worked on-site almost exclusively. In fact, prior to the pandemic, 85% of site survey respondents indicated they worked fully on-site, as opposed to working a hybrid format, or a remote schedule including travel. Of the 85% working fully on-site, 45% indicated their organization will not bring them back fully on-site. This will force many to work remotely with some time each week on-site.

However, this seems to be in line with how staff would like to work moving forward. Many respondents who previously worked fully on-site would like to move to a hybrid or fully remote work scenario (63%). The remaining 37% of staff who worked fully on-site prior to the pandemic would like to remain fully on-site.

No matter where someone wants to work, all organization types are expecting a change in how their employees work. At AMCs, 66% of respondents expect their work location to become more remote or more on-site. Independent research sites were the least likely to report a difference in their work locations, with only 27% reporting a change from pre-pandemic. Cancer centers and hospital/health systems reported they’re expecting a shift in their work location at 47% and 58%, respectively.

Independent research sites showed the smallest change in work location scenarios pre-pandemic to the next stage. Of those respondents, 69% expect to return fully on-site, compared to the 84% working on-site pre-pandemic. Other site types are shifting many employees to hybrid weekly on-site/remote locations, including:

  • 51% of AMC respondents
  • 41% of cancer center respondents
  • 44% of hospital/health system respondents

This shift is gaining traction because it’s shown the clinical research industry it is possible to effectively conduct remote research. However, a key component to productive remote workflows is communication. While important to facilitate successful in-person interactions, communication is crucial to ensure safe and compliant research.

In our survey, we asked people where they thought they would primarily work versus where they would like to work. About 25% of respondents from independent research sites wished for a different work scenario than what their organization wants. For the remaining organizations, between 40%-50% of respondents indicated they wanted a different work scenario than the one they think their organization wants.

Communication is Key

Even though many organizations are still in the midst of figuring out what the “next normal” will look like, remote work is here to stay. Many site types are finding ways to incorporate non-traditional work locations to meet the needs for their site, participants, and staff members. With a lot of unknowns still in the air, it’s more important than ever to keep open communication. Leadership as well as independent contributors need to initiate communication sooner rather than later to ensure a satisfying and efficient workplace. The more visibility staff have into future changes – no matter how small or seemingly insignificant – the more they will feel valued and included. This also will contribute to a higher work morale and greater buy-in from staff as everyone navigates the unknowns.

To learn more about Advarra’s findings about the “next normal”, download the Advarra Trend Report: The Future of Work in Clinical Research.

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