Questions remain on PI oversight of participant safety, protocols, and data handling.
Clinical research professionals are on the front lines of decentralized clinical trial (DCT) implementation – an evolution that is transforming clinical research. ACRP began outreach efforts on DCTs in 2022, with a survey, a report, a think tank, several papers, and multiple new working groups designed to understand and address impacts at site level (Sidebar 1). DCTs were also the subject of a poll at the recent ACRP 2023 annual meeting in Dallas (Sidebar 2).
ACRP welcomes newly published U.S. Food and Drug Administration (FDA) draft guidance on decentralized clinical trials. This is a key step forward in providing much-needed regulatory clarity – yet questions remain. Examples center around:
- Principal Investigator (PI) oversight, especially of home health visits by local healthcare practitioners, which involve potential risks to participant safety
- Addition of new elements to the protocol, which may reduce PI and site flexibility and increase the chance of protocol amendments and violations
- Lack of clarity around what an FDA audit will look like for a DCT, specifically how these would differ from an audit for a traditional, site-based study
- Data handling for hybrid and remote studies, including whether data gathered remotely and onsite will be handled differently for regulatory purposes
- Training, including when this is required for local healthcare providers, and when patients need to be trained to enable remote data gathering, including the use of remote technologies
This blog provides viewpoints from senior ACRP members on the FDA document, titled Decentralized Clinical Trials for Drugs, Biological Products, and Devices: Guidance for Industry, Investigators, and Other Stakeholders, published on May 2, 2023.
Sidebar 1: Recent ACRP Efforts to Advance DCTs
Due to the vital importance of clinical research professionals in DCTs, ACRP is active in resolving challenges to advancing these types of trials. Recent efforts include:
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- An ACRP 2023 annual meeting session to Sound off on DCTs, held on April 30 in Dallas, Texas.
- A first-of-its-kind survey to understand site viewpoints on DCTs and a report on Delivering on the Promise of Decentralized Trials: Unexpected Perspectives from Clinical Research Professionals.
- A think-tank on DCTs titled From Trepidation to Trust: Documenting the Realities of Hybrid and Decentralized Clinical Trials Adoption.
- Setting up three new ACRP working groups based on priorities identified at the think-tank: regulatory requirements and PI oversight; process mapping and change management; and new budget models, designed to fully reflect DCT-related activities and change management efforts. These working groups are capturing the real-world experience of study teams at site level, including a focus on areas of FDA guidances that require clarification.
- A white paper by members of the ACRP Fellows Advisory Panel on Decentralized Clinical Trials: Perspectives for Clinical Research Professionals.
- A peer-reviewed paper on FDA draft guidance on clinical trial diversity, emphasizing the role of DCTs in improving diversity, equity, and inclusion.
Sidebar 2: Informal Poll at ACRP 2023 Finds Regulations to be “Clear as Mud!”
In an informal poll carried out on April 30, just before publication of the new FDA draft guidance, nearly all of the hundreds of attendees at the ACRP 2023 Sound Off on DCTs session agreed that regulatory requirements were not really helping them guide implementation of DCTs. Nearly 50% said the regulations were “clear as mud” and nearly 50% wished “someone would send help” for dealing with the challenges faced. Two-thirds of respondents said they were “not sure” whether DCTs saved study teams time, and 32% said there was “no way” DCTs saved time. Asked if study budgets at their sites accurately reflected the time and effort involved with DCTs, 83% of respondents said, “not even close” and 17% said, “it’s not so bad – we can live with it.” Finally, half of respondents said they are “still unsure” whether they believe that DCTs are good for patients, 42% said “yes” and 8% said “no.”
Catherine Gregor of Florence Healthcare: Gaps in guidance on PI oversight remain
“As ACRP has pointed out in the past, there has been a gap in the regulatory guidance on principal investigator oversight of DCTs, particularly for home health visits,” says Catherine Gregor, MBA, CCRP, CCRC, Chief Clinical Trial Officer at Florence Healthcare. “Staff carrying out such visits tend to be under contract with the sponsor, rather than being selected and trained by the PI. The latest draft guidance notes that FDA’s regulatory requirements are the same for traditional trials and DCTs – doing little to resolve the issue of PI oversight of home health visits.
“Local healthcare providers who offer routine, standard-of-care procedures to study participants have not typically needed a delegation of authority,” notes Gregor. “The draft guidance offers welcome clarity that this is still the case for DCTs. However, home health nurses carrying out research-specific procedures for study endpoints would still require a delegation of authority. The document also notes that local healthcare providers offering routine procedures should be included in the task log. This is a new requirement, and will add to the PI’s record-keeping burden.”
Gregor points out that, “the draft guidance specifies that ‘sponsors should describe in the trial protocol how operational aspects of the DCT will be implemented.’ This seems like an over-correction from previous, minimal requirements to describe DCT elements within the protocol. The result would be a reduction in flexibility and autonomy for the PI and site staff to make changes to operational aspects of the study – for example, determining whether telehealth or home health visits are acceptable for a particular patient.
“Interestingly, the draft guidance confirms the need for a physical site that can be inspected by FDA, even for fully remote trials with no site visits,” concludes Gregor.
Christina Brennan of Northwell Health: Potential for patient safety to be compromised
“Clarity on PI oversight is the most critical element from my perspective,” says Christina M. Brennan, MD, MBA, Senior Vice President, Clinical Research, at Northwell Health. “There are still a lot of unknowns around PI responsibilities, including delegation of research tasks, documentation, and training of personnel.
“There are contradictions in the draft guidance about whether local healthcare providers giving routine care to the patient – such as a physical exam – need to be included in study documentation or not,” states Brennan. “Clarity is needed to ensure that research participant safety is fully protected in those receiving home healthcare visits, including how any adverse events are reviewed, and who enters these into the case report form. There is a risk that patient safety may be compromised by home health visits, since the PI may be asked to sign off without knowing who the local providers are. In addition, questions remain about who will vet and train these local healthcare providers, and how to assess the level of risk involved with any procedures carried out. There is also ambiguity about PIs delegating tasks and when a delegation of authority is needed.”
Brennan asks, “Who is responsible for vetting contractor conflicts of interest when these contractors have been hired by the sponsor or contract research organization?” She notes that this is an important step in complying with FDA and institutional requirements to promote objectivity. “Also, for telehealth, there is not enough detail of which platforms and software are acceptable. There may be a security risk if devices are not adequately vetted for cybersecurity risks and Health Insurance Portability and Accountability Act compliance.
“The option of patients going to clinical laboratories close to their homes is mentioned, yet it is not clear how the PI and site would be able to verify that these laboratories meet certain standards and are certified under the Clinical Laboratory Improvement Amendments and accredited by the College of American Pathologists,” adds Brennan. “Also, in a multicenter trial, patients may be in many locations to encourage broader and more equitable recruitment. This means that many local laboratories near participants homes might be involved, making it impractical to include them all on the Form FDA 1572 (Statement of Investigator), which was mentioned in the guidance document. There is also a mention of biospecimens being taken at these laboratories and then sent to the study site for processing, raising concerns about the chain of custody for these biospecimens and the need to follow standard operating procedures for this process. This approach seems unrealistic.
“The draft guidance says that FDA recommends the use of a central institutional review board (IRB) for efficient protocol review,” notes Brennan. “This also needs clarification, since many clinical sites currently use local IRBs. If central IRBs become a requirement, this may eliminate some sites from consideration for studies. The document mentions the possibility of using a central distribution service to ship investigational product direct to study participants, stating that PI must control release of IP and monitor its receipt and use by participants – all of which could be complex and impractical.”
Caroline Redeker, Advanced Clinical: Clarity needed around use of local healthcare professionals
“Details around using local healthcare professionals needed to be addressed, but the responsibility for patient safety remains with the PI,” says Caroline Redeker, Senior Vice President, Corporate Development, Advanced Clinical. “This puts the related Good Clinical Practice accountability on the PI to create qualification, onboarding, oversight, and documentation processes for home health visits. An industry cannot change the way patients are seen and introduce new players without aligning on roles, responsibilities, and new processes for the PI who is held accountable. Sites have not been set up to operate this way, so they will need to align their processes, re-determine their resourcing needs, and adjust PI grants to accommodate this work effort.”
Redeker points out that, “The draft guidance states that the DCT procedures should be described in the protocol, including scheduled vs. unscheduled visits, remote vs. in-person activities, and what procedures will happen at different locations. During protocol design, sponsors will have to be clear whether some of these things can be chosen by the patient or whether everyone needs to be seen in the same environment (by visit). This will be an important factor to understand as we design protocols that strive for diversity and inclusiveness in trial populations, which is also one of the items suggested in the DCT guidance.
“I was happy to see that the draft guidance accommodates the inclusion of more patients by requiring devices to be provided to patients that otherwise may not be able to participate in the trial,” says Redeker. “This is a step in the right direction for accomplishing the inclusion of diverse populations.”
Leigh Burgess of Bold Industries Group: Inspection-related concerns not yet addressed
“We need more clarity on the ‘bumpers’ around DCTs, to support everyday decision-making by clinical trial stakeholders,” says Leigh Burgess, CEO, Bold industries Group. “More precise definitions of roles and responsibilities for each stakeholder will be essential to help address uncertainty about who is responsible for various regulatory components. Home health is a great example – with many PIs and sites preferring to send site employees to visit their patients at home. Home health visits pose risks, and many sites would prefer to have a role in selecting these and other vendors, since PIs and sites are responsible for the vendor deliverables.”
Burgess explains that PI responsibilities are outlined in existing guidance that has not been updated since 2009. “This needs to be updated in the era of remote trial elements and DCTs,” she says. “Also, there is a lack of clarity around what an FDA audit will look like for a DCT, specifically how these would look different from an audit for a traditional, site-based study. Inspection-related concerns may deter sponsors from implementing DCTs, while patient safety-related issues linked to home health visits may have a similar effect on PIs.
“DCTs were extremely useful during the COVID-19 pandemic, but my fear is that we are now back-tracking toward doing more onsite studies,” states Burgess. “At ACRP we are working to help sites become ‘research-ready’ and ‘DCT-ready.’ This should help during audits, although requirements for these are unclear at present.
“The draft guidance says FDA’s regulatory requirements are the same for DCTs as for traditional site-based clinical trials,” adds Burgess. “This may be true at a high level, but different approaches used in DCTs – for example, gaining informed consent remotely via a device rather than in person and on paper – mean that differences in how these elements will be reviewed are inevitable.
“In addition to ACRP, several trial-related groups, including Decentralized Trials and Research Alliance and Society for Clinical Research Sites, have been working on ways to support implementation of DCTs,” notes Burgess. “Further building collaboration between these groups and FDA will help inform the next iteration of this draft guidance. Regulatory clarity – especially around roles and responsibilities – will help ensure that the benefits of DCTs continue to be realized in future, improving recruitment and diversity, and bringing more people into clinical research.”
Author: Jill Dawson
