New and Hybrid Clinical Trial Approaches Under Review

Companies and physicians planning and executing clinical trials have been challenged by the special circumstances and constraints brought about by the recent pandemic. The need to conduct the trials has accelerated the creation and adoption of new and hybrid clinical study designs, operational approaches, and data sources.

While these modern approaches have the potential to increase the speed and efficiency of drug development, FDA needs to ensure that the trials are conducted in such a manner that the data produced can be relied upon to make regulatory decisions.

[Related: Author Jerry Chapman discussed FDA inspection trends involving clinical investigators in a recent webinar. Click here to access a recording of the webinar including the slide presentation.]

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At the 2022 PDA/FDA Joint Regulatory Conference, FDA CDER Office of Compliance (OC) Director Donald Ashley explained that one of the roles of the Office of Scientific Investigations in CDER’s OC is to assess clinical study data quality, integrity, and acceptability, as well as human subject protection measures.

Ashley pointed to the need to understand and consider the impact that modern approaches to the design and the conduct of clinical trials have on the data that is submitted from those studies.

For example, data collected remotely in a point of care or decentralized clinical trial needs to be transferred securely as part of the record of the clinical investigation. And safety monitoring plans will need to ensure that abnormal measurements from patients that are collected outside of the clinical trial site are appropriately reviewed and managed.

The agency continues to gain experience from applications that are supported by data and trials using a variety of operational approaches, data sources, and trial designs. And this experience will inform development of future guidance policy.

In his presentation, Ashley covered terminology used in what he called the “clinical trial ecosystem,” what that system looks like, the use of quality-by-design principles in trial design and operation, and the critical importance of high-quality evidence needed to answer the questions posed by the trial being conducted.

What’s In a Name?

Ashley discussed several terms that are commonly used to describe various modern approaches to clinical trial design and conduct—for example:

  • Pragmatic Trial
  • Decentralized Clinical Trial
  • Point-of-Care Trial
  • Real-World Data/Real-World Evidence
  • Master Protocols—basket/umbrella/platform

These new approaches cover a spectrum of novel operational approaches, data sources, and trial designs, or some combination of these.

For example, a decentralized clinical trial may be designed as a traditional randomized, double-blind clinical trial, but some or all of the elements of the trial occur away from the clinical trial site. In other words, it is more about how the trial is operationalized.

A point-of-care trial integrates clinical research into routine healthcare delivery. Operationally, it is also occurring away from a traditional clinical trial site.

The data sources used for point-of-care trials will also be different than in a traditional clinical trial. Study data collection is accomplished by automatically extracting information from the electronic medical record. This is something that has become more feasible with the widespread adoption of electronic health record systems.

Real-world data and real-world evidence refer to the data source and can come from a variety of places, including electronic medical records, claims and billing activities, and product and disease registries.

Master Protocols

There are a variety of clinical trial designs being explored in an attempt to streamline and accelerate drug development. Master protocols are one such example.

In contrast to a traditional trial design where a single drug is tested in a single disease population in one clinical trial, master protocols use a single infrastructure trial design and protocol to simultaneously evaluate multiple drugs and or disease populations in multiple substudies, which allows for efficient and accelerated drug development. This approach continues to be used in COVID-19 studies.

…this experience will inform development of future guidance policy…

Basket and umbrella trials are both types of trials with master protocols.

“I want to note that when looking at these terms, this is really a continuum or a spectrum,” Ashley said. “A single trial may utilize some traditional approaches and some novel operational approaches, data sources and or trial design elements, and we see that reflected in the types of trials that are coming into the agency. There are going to be shades of gray, and we continue to gain experience on these different approaches.”

The Three Phase Trial Ecosystem

The CDER Compliance Director divided the “evolving trial ecosystem” into three sections. This representation creates a model to help “ensure that data from modern clinical trials can be relied on to make regulatory decisions,” (Figure 1).

Figure 1 Evolving Trial Ecosystem
FIGURE 1 | Evolving Trial Ecosystem
(Source: Donald Ashley presentation)

It begins with study design—ensuring that the study is properly designed and effectively uses principles of quality by design (more on that topic in the next section).

Next is study execution. An important question FDA asks is, “Was the trial operationalized effectively?’ This includes considerations for where data collection occurs—whether at the site or remote locations and how the study design choices play out in real-time during the conduct of a trial.

Third is study assessment. How can the agency ensure accurate and consistent assessments that are aligned with the unique needs of the application?

[Related: Last year, the top 2 most common FDA 483 clinical investigator observations involved: “General Responsibilities of Investigators Conducting Study” and “Investigator Recordkeeping and Record Retention > Case Histories.” Contact us today to learn about how Redica can help you access additional GCP enforcement insights.]

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Quality by Design in Clinical Studies

“I mentioned quality by design and I want to highlight it because it is so critically important as clinical trials continue to evolve,” Ashley stated.

He maintained that there is “absolutely no one size fits all approach in drug development,” and that it is important to apply a risk-based approach to the entire clinical trial lifecycle.

Quality in clinical trials is not the absence of error, he explained, “rather it is the absence of errors that matter.” That means identifying factors critical to the quality of the study and then working to reduce risk associated with those factors.

This needs to begin with study design—e.g., determining whether a trial or certain elements of a trial can or should be decentralized “has to begin in a thoughtful manner and through the conduct of a risk assessment.”

There are going to be shades of gray, and we continue to gain experience on these different approaches

Once a decision has been made to decentralize all or portions of a trial, specific risks associated with the decentralized trial need to be considered and managed. For example, if a trial is going to be using digital health technologies to monitor patients away from the clinical trial site, then one should consider how abnormal measurements related to patient safety are being reviewed and managed in the study.

The quality-by-design approach has been around for quite some time, Ashley pointed out, “but I wanted to include it here to reinforce the importance of the application of the quality-by-design approach to modern and evolving trial design and operational choices.”

High-Quality Evidence: A Touchstone

The need for high-quality evidence is without question. Beginning with this in mind, the trial design needs to be adequate to answer the scientific question. And if that trial is well conducted, the results should be credible and reliable.

“The best way to build quality into clinical research is using core principles of quality by design throughout the clinical trial lifecycle,” Ashley commented. “This is true for any clinical trial. But it is particularly important when considering novel approaches.”

The role of FDA in CDER’s Office of Compliance is to ensure that data produced in support of marketing applications are acceptable for regulatory decision-making and that the rights, safety, and welfare of trial participants have been adequately protected. This is true for traditional clinical trials conducted at a trial site as well as for trials using these novel designs, operations, and data sources.

“While the different study designs and operational approaches that I have touched on today are not all completely new, the COVID-19 pandemic really presented a set of unique challenges, certainly in amplitude at least, that we have never seen before. That has led to the increased adoption of these modern approaches out of necessity,” the CDER Compliance Director said.

“We are continuing to learn how to best use these approaches, but the fundamentals of utilizing a risk-based approach and the principles of quality by design throughout the clinical trial lifecycle will help to assure the data generated from studies are indeed acceptable for regulatory decision-making.”

Additional Resources

An FDA Perspective on Decentralized Clinical Trials: Part I
An FDA Perspective on Decentralized Clinical Trials: Part II
An FDA Perspective on Decentralized Clinical Trials: Part III
Data Integrity and Your Clinical Investigator: What the Data Shows
The Components of “Responsibilities of the Investigator” Observations
Extracting Specific Protocol Violations from Warning Letter Citations

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