Industry groups call for better alignment between decentralized, centralized trials

US Food and Drug Administration (FDA) draft guidance on decentralized trials is a major step forward, but major clarifications are needed to make it workable, according to comments submitted by pharmaceutical and medical device trade groups.

Commenters said the draft guidance places a higher bar on decentralized trials than on centralized trials and that there should be more alignment between the two. They also called for more clarity with respect to investigator reporting and for virtual inspections for DCTs.

Comments were in response to FDA’s draft guidance on DCTs, which was released in May (Related: FDA issues draft guidance on decentralized clinical trials, Regulatory Focus 2 May 2023).

Many of their views also were raised by experts at an industry meeting in June (RELATED: DIA: Experts call for more clarity on reporting requirements in FDA’s DCT guidance, Regulatory Focus 30 June 2023).

The draft guidance fulfills a mandate of the Food and Drug Omnibus Reform Act (FDORA) to “issue or revise draft guidance that includes recommendations to clarify and advance the use of decentralized clinical studies to support the development of drugs and devices,” by late December 2023.

FDA defines decentralized trials as ones in which “some or all of the trial-related activities occur at locations other than traditional clinical trial sites.” These can include in the homes of trial participants or in local health care or laboratory facilities.

DCT guidance is a major step forward

Many of the respondents applauded the release of the guidance and said it represents a major step forward. The Pharmaceutical Research and Manufacturers of America (PhRMA)
“supports the recommendations put forth in this draft guidance and appreciates FDA’s work to provide guidance about an important area for the future of clinical trials,” according to their comments

The Decentralized Trials and Research Alliance (DTRA), a non-profit collaboration, concurred. “While decentralized research methodologies have been incorporated into drug development for over two decades … This guidance represents a seminal moment for the field as we focus on the future. Namely, this guidance enables sponsors, [clinical research organizations] and investigators alike to proceed with confidence with a regulatory framework to guide their incorporation of decentralized approaches into clinical trials.”

The Advanced Medical Technology Association (AdvaMed) noted that it “strongly supports FDA’s development of guidance for the conduct of decentralized medical device clinical trials. We believe such guidance can facilitate recruitment of diverse populations in clinical trials and may help expedite recruitment of human subjects to clinical trials to help accelerate patient access to innovative technologies.”

DCTs held to higher standard than centralized trials

One area of criticism was that the guidance assigns a higher bar to DCTs than centralized trials, and that the two should be better aligned.

PhRMA states that “there are instances in the draft guidance where DCTs appear to be held to a higher standard than traditional clinical trials.” For example, in the guidance, FDA recommends that investigators confirm the trial participant’s identity during each remote trial visit. “We are not aware of a similar recommendation to confirm patient identity at every visit for traditional clinical trials…. PhRMA recommends that a participant’s identity should only need to be confirmed during the first trial visit.”

Commenters also took issue with a statement in the draft guidance that “the variability and precision of the data obtained in a DCT may be different from the data in a traditional site-based trials.”

The Biotechnology Industry Organization (BIO) said FDA “appears to have more concerns regarding data quality in DCTs as compared to traditional site-based trials. While this concern may be warranted in some cases, we encourage the Agency to consider including the final guidance more balanced messaging and highlight some of the potential benefits of remote data collection such as continuous data acquisition and enhanced safety monitoring.”

DTRA concurred, and said this statement suggests that the agency may be more hesitant to accept data from DCTs and “may discourage drug developers from conducting a DCT.”

BIO added that the draft guidance imposes “numerous restrictions and requirements that are not required of sponsors in traditional clinical trials.”

More clarity on reporting and use of Form 1572

Respondents also called for more clarity on investigator reporting requirements on the Form FDA 1572. This form must be used by principal investigators (PIs) to record all locations where clinical trials take place.

DTRA stated that “a longstanding challenge both sponsors and investigators have grappled with in decentralized research is Principal Investigator (PI)-oversight expectations and associated documentation. While the FDA’s Form 1572 Statement of Investigator is well-suited for conventional, site-based clinical research (with centralized PI and associated institutions), it faces limitations in scenarios where remote assessments and delivery of care are a central feature.”

The American Society of Clinical Oncology (ASCO) said “there are several inconsistencies in the guidance regarding the use of Form FDA 1572.” The group added that “Our discussions with sponsors, CROs, sites, and FDA make it clear that some sponsors, CROs, and sites are requiring Form FDA 1572 reporting in more situations than FDA anticipated. This has a trickle-down effect on research sites and local HCPs [healthcare provider] that impacts workload and ultimately limits, rather than expands, access to clinical trials. We believe the draft guidance misses an opportunity to provide greater clarity for the use of Form FDA 1572.”

Eli Lilly concurred. “We urge FDA to expand upon the Draft Guidance by providing additional insight into the contours of when a “local HCP” or other third-party trial personnel should be listed on the Form 1572 as a sub- investigator. Even the most sophisticated clinical research sites cannot provide nationwide services for the entire range of medical care activities associated with clinical trials, e.g., registered dieticians or ophthalmology services.”

More allowance for remote inspections

Respondents also urged FDA to allow for the use of virtual inspections. The guidance states that “for inspectional purposes, there should be a physical location where all clinical trial-related records for participants under the investigator’s care are accessible and where trial personnel can be interviewed.”

DTRA stated that “the requirement to have a physical location associated with the clinical trial-related records would prevent implementation of a completely or largely virtual trial.”

AdaMed states that FDA should allow remote inspection for DCTs. “We propose rewording and removing ‘physical location’ to include the option of remote inspections.”

Broader definition of DCTs, rare diseases

In other areas, BIO said there needs to be a better definition for what constitutes a centralized trials versus a DCT, and that the current terms used to characterize these trials are “too limiting.”

Also, the National Association for Rare Diseases (NORD) said the guidance should address DCTs for rare diseases.

NORD states that “given the medical complexity of many rare diseases and the exceedingly small sample sizes, which magnify the impact of each minor data challenge, more guidance specific to rare diseases and small-population trials is needed to ensure the safety and quality of these trials for rare disease patients.”

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Industry groups call for better alignment between decentralized, centralized trials

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