Patient recruitment remains one of the most challenging and costly parts of clinical trials. One approach to tackle this has been partnering with healthcare providers to capture data gathered during routine clinical practice for use in clinical trials.

As part of the U.S. FDA’s Real-World Evidence (RWE) Program, the agency has issued a new draft guidance on the integration of randomized control trials (RCTs) into routine clinical practice.1 The draft is open to public comment until December 17, 2024.

Here we discuss what you need to know about the new draft guidance and the implications for the future of clinical trials.

Bringing together clinical research and clinical practice

Traditional randomized controlled trials gather a large amount of patient information, some of which is also collected during routine clinical care. Considering this overlap, data for a clinical trial could potentially also be gathered from patients in other clinical settings with health care providers.

Such integrated RCTs, often referred to as point-of-care or large simple trials, are designed to be more convenient and accessible for participants since they can reduce the need for trial sites, and thus can ultimately lead to more representative and generalizable results.

Additionally, there has been increasing interest in incorporating real-world data (RWD) similarly collected during routine clinical care into clinical studies.

While integrating clinical trials into routine clinical practice is not new — indeed efforts to do so have been going on for decades — recent tools, such as the use of electronic health records, have made such trials and the use of RWD far more feasible.

Integrating RCTs into routine clinical practice: What to know

The new draft guidance, “Integrating Randomized Controlled Trials for Drug and Biological Products into Routine Clinical Practice: Guidance for Industry,” aims to “support the conduct of randomized controlled drug trials (RCTs) with streamlined protocols and procedures that focus on essential data collection, allowing integration of research into routine clinical practice.”

The guidance emphasizes a few key points:

The role of established healthcare institutions and existing clinical expertise

The guidance highlights the importance of leveraging established healthcare institutions and existing clinical expertise, discussing the roles of sponsors, clinical investigators, and healthcare providers. This can reduce start-up times and speed up enrollment, making the trial process more efficient.

Streamlining RCTs to align with clinical practice

Here the guidance emphasizes that trials will be most successfully integrated with clinical practice when the data needed is collected routinely and does not require additional procedures or visits. Where this is not possible, a hybrid approach should be considered.

A quality by design approach

Successful integration will rely on designing trials that follow a set of principles that involves considering such aspects as eligibility criteria, choosing suitable investigational drugs, study endpoints, and so on.

Implications for the future of clinical trials

Enhanced accessibility and efficiency

By integrating RCTs into routine clinical practice, this guidance aims to make participation easier for patients, which could lead to higher enrollment rates and more diverse participant pools. This will be especially important for rare diseases, as the overall pool of patients is smaller, and trials compete for enrollment.

Furthermore, streamlined protocols and procedures are expected to reduce administrative burdens and costs, making trials more efficient and potentially accelerating the development of new therapies.

Improved generalizability of results

The use of RWD and the integration of trials into everyday clinical settings can produce findings that are more applicable to real-world patient care. This can enhance the external validity of trial results and improve their utility in clinical decision-making.

Faster innovation cycles

The ability to conduct trials more quickly and efficiently can shorten the time from discovery to market for new treatments. This can foster a more dynamic and responsive healthcare innovation ecosystem.

Integrating clinical trials with clinical practice: Challenges and perspectives

Although the emphasis has been put on the integration of clinical trials with clinical practice, such integration may face challenges in the short term. Over time, infrastructure and scientific advances could help us overcome them.

Quality, integrity, and accuracy of trial data

The guidance emphasizes that sponsors must ensure the quality, integrity, and accuracy of trial data. However, sponsors may encounter inconsistencies with how data is collected by healthcare providers and find that some study procedures cannot be performed within routine clinical practice without causing significant disruption.

Additionally, the lack of standardized formats and terminologies across different data sources can also make it difficult to integrate and analyze data uniformly. Although standards and common data models (CDM) are converging towards more standardization, the progress has been very slow.

Obtaining informed consent

When conducting a traditional clinical trial, sponsors must obtain consent from trial participants, but doing so within routine clinical practice may present additional hurdles. To overcome this when integrating an RCT into clinical practice, the guidance suggests that one solution can be to embed informed consent documents into EHRs.

However, when using RWD retrospectively, obtaining appropriate consent remains a significant challenge, and may need future changes in jurisdictions waiving such consent.

Controlling for bias

When incorporating a clinical trial into clinical practice, blinding may be difficult to ensure. According to the guidance, blinding may add complexity to trial implementation, require greater resources, increase costs, and require longer timelines. And when not possible to include blinding, identifying potential sources of bias and including measures to address them in the trial design will add additional challenges.

Data privacy and security

Ensuring the privacy and security of patient data is crucial. The use of RWD must comply with stringent data protection regulations, which can complicate data sharing and integration.

Facilitating secure and compliant data sharing between institutions and across borders also remains a significant hurdle.

Methodological challenges

Developing robust methodologies to analyze RWE and integrate it with traditional clinical trial data is essential to ensure the reliability and validity of the results.

RWD may also be subject to biases that can affect the validity and generalizability of findings. Ensuring that the data accurately represents the broader patient population is crucial.

Addressing these challenges requires collaboration among stakeholders, including researchers, healthcare providers, regulatory bodies, and technology developers. By overcoming these hurdles, the integration of RWD into clinical trials can enhance the relevance and efficiency of clinical research, ultimately leading to better patient outcomes.

Final takeaways

The FDA’s new draft guidance represents a significant step toward modernizing clinical trial methodologies, making them more patient-centric and reflective of real-world conditions. This evolution is poised to enhance the relevance, efficiency, and impact of clinical research in the coming years.

This approach is also consistent with the growing trend of considering the “entirety of evidence.” The conventional hierarchy of evidence, which opposes clinical trials with real-world evidence study designs, may also need to be revisited for a more complex and holistic consideration of evidence that includes a variety of needs on the one hand and a continuum of study designs and data sources on the other.

Notes

1 U.S. FDA. (September 2024).  Integrating Randomized Controlled Trials for Drug and Biological Products into Routine Clinical Practice: Draft Guidance for Industry.

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