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External Control Arms: The FDA Has Questions. Do You Have Answers?

  • 2 MIN READ
RWE
RWD
Clinical TRIALS

How do you ensure data quality when your External Control Arms / Synthetic Control Arms exists only in databases?

What’s the best way to mitigate bias when your comparator group comes from historical data? How can you convince regulators that your innovative trial design is robust and reliable?

These are just a few of the questions swirling around the use of synthetic control arms in clinical trials. And now, the FDA has weighed in. In a February 2023 draft guidance document, the agency outlined its current thinking on externally controlled trials, including those using synthetic control arms.

For drug developers navigating this evolving landscape, the guidance provides both clarity and new challenges. Let’s dive into what the FDA is saying and what it means for the future of clinical trial design.

What are External Control Arms?

Before we jump into the FDA’s guidance, let’s take a quick look at what external control arms (ECAs) and synthetic control arms (SCAs) actually are and why they’re gaining attention in the clinical research community.

Synthetic control arms, also known as external control arms, have gained attention in recent years as a potential alternative to traditional randomized controlled trials (RCTs) in certain situations. External control arms (ECAs) and synthetic control arms (SCAs) have emerged as promising solutions, especially in oncology and rare disease research1. By leveraging historical clinical trial data or real-world data (RWD), synthetic control arms aim to provide a comparator group without the need to recruit additional patients for a control arm.

This approach has shown promise in accelerating drug development timelines, reducing costs, and addressing ethical concerns in trials where randomization to a control group may be challenging. However, the use of synthetic control arms also raises important questions about data quality, potential biases, and regulatory acceptance.

A recent analysis of clinical trials registered on ClinicalTrials.gov found that the use of external control arms increased by 28% between 2015 and 2020, with oncology studies leading the trend2. This growing adoption reflects the potential of ECAs and SCAs to address some of the limitations of traditional RCTs.

In traditional randomized controlled trials (RCTs), participants are randomly assigned to either a treatment group or a control group. However, in some situations – particularly in rare diseases or oncology studies – this approach can be challenging. ECAs and SCAs offer an alternative by using historical clinical trial data or real-world data to create a comparator group1.

This approach can offer several benefits:

  1. Trial duration can be shortened by eliminating the need to recruit control group participants.
  2. Fewer patients and shorter timelines can lead to reduced trial costs.
  3. Fewer patients need to be recruited, and all trial participants can receive the experimental treatment.
  4. In cases of rare or severe diseases and situations where placebo control might be questionable
  5. , it may be more ethical to provide all participants with the experimental treatment.

However, these benefits come with their own set of challenges, which the FDA addresses in its recent guidance.

FDA Guidance on Externally Controlled Trials

In February 2023, the U.S. Food and Drug Administration (FDA) released a draft guidance document titled “Considerations for the Design and Conduct of Externally Controlled Trials for Drug and Biological Products”1. This guidance provides valuable insights into the FDA’s current thinking on externally controlled trials, including those using synthetic control arms. Here are key points from the guidance:

1. Study Design and Protocol Development

FDA Recommendation: Sponsors should finalize the study protocol, including the selection of the external control arm and analytic approach, before initiating the trial.

Impact: This emphasis on upfront planning necessitates a more comprehensive approach to protocol development. Sponsors may need to:

  1. Conduct extensive feasibility assessments of potential data sources
  2. Engage biostatisticians and data scientists earlier in the process
  3. Develop robust strategies for data integration and analysis

Technical Consideration: Sponsors might consider employing advanced simulation techniques, such as virtual trials, to evaluate different study designs and their potential outcomes before finalizing the protocol.

2. Data Quality and Comparability

FDA Recommendation: Ensure the quality and relevance of data used in external control arms, considering factors such as consistency in data collection methods, comparability of patient populations, and alignment of outcome definitions.

Impact: This focus on data quality may drive sponsors to:

  1. Invest in advanced data curation and validation technologies
  2. Develop standardized processes for assessing data quality across diverse sources
  3. Collaborate with specialized data providers or academic institutions to access high-quality, relevant datasets

Technical Consideration: Machine learning algorithms for data cleaning and harmonization could ensure data quality and comparability across different sources.

3. Bias Mitigation Strategies

FDA Recommendation: Address potential sources of bias, including selection bias, information bias, and confounding factors, through careful patient matching and appropriate statistical methods.

Impact: This emphasis on bias mitigation may lead sponsors to:

  1. Develop more sophisticated patient matching algorithms
  2. Implement advanced statistical techniques such as propensity score matching or inverse probability weighting
  3. Conduct comprehensive sensitivity analyses to assess the robustness of results

Technical Consideration: Causal inference methods, such as targeted maximum likelihood estimation (TMLE) or double robust estimation, could provide more robust approaches to addressing bias in externally controlled trials.

4. Regulatory Communication and Transparency

FDA Recommendation: Engage with the relevant FDA review division early in the drug development program to discuss the appropriateness of an externally controlled trial design.

Impact: This guidance on early engagement may result in:

  1. More frequent and detailed interactions between sponsors and regulators
  2. The need for sponsors to develop clear, compelling narratives about their trial design choices
  3. Increased transparency in reporting study methods and results

Technical Consideration: Sponsors might consider developing interactive data visualization tools to effectively communicate complex study designs and results to regulatory reviewers.

5. Endpoint Selection and Assessment

FDA Recommendation: Ensure that endpoints can be reliably and consistently measured across the external control arm and the treatment arm.

Impact: This focus on endpoint consistency may drive sponsors to:

  1. Prioritize objective, easily measurable endpoints in externally controlled trials
  2. Develop standardized approaches for endpoint assessment across different data sources
  3. Invest in technologies for remote or digital endpoint assessment

Technical Consideration: Wearable devices and digital biomarkers could ensure consistent endpoint assessment across trial arms.

The Road Ahead: Evolving Practices in Clinical Research

As the field of externally controlled trials continues to evolve, we can anticipate several trends:

  1. Increased use of real-world data: A recent study found that the use of real-world data in regulatory submissions increased by 47% between 2018 and 20204. This trend is likely to accelerate as data quality and analysis methods improve.
  2. Advancements in artificial intelligence: AI and machine learning algorithms may play a larger role in patient matching, data integration, and bias detection in externally controlled trials.
  3. Standardization of external control arm methodologies: As more experience is gained, we may see the development of standardized, validated approaches for creating and analyzing external control arms.
  4. Expansion to new therapeutic areas: While currently most common in oncology and rare diseases, external control arms may find applications in other areas as methodologies mature.

The Future of Synthetic Control Arms in Clinical Studies

The FDA’s guidance on externally controlled trials represents an important step in regulatory thinking about innovative trial designs. For drug developers, it offers both opportunities and challenges:

  1. Data infrastructure investments: Companies may need to enhance their capabilities in data management, curation, and analysis. This could include developing in-house expertise or partnering with specialized data providers.
  2. Interdisciplinary collaboration: Successfully designing and executing externally controlled trials requires close collaboration between clinical teams, biostatisticians, data scientists, and regulatory experts.
  3. Methodological innovation: The complexities highlighted in the guidance may spur further research into statistical methods for externally controlled trials. For example, recent work on “model-assisted” trial designs combines elements of randomized and externally controlled trials, potentially offering a middle ground between these approaches5.

The FDA sees the value in synthetic control arms, but these are not viewed as a universal replacement for randomized controlled trials. The guidance emphasizes that the suitability of an externally controlled trial design warrants a case-by-case assessment, taking into account factors such as disease heterogeneity, preliminary evidence, and the specific research question being addressed.

While the FDA’s guidance provides valuable insights, it also highlights the complexities involved in using external control arms and synthetic control arms in clinical trials. Moving forward, continuous dialogue among sponsors, regulators, and the scientific community will be required to refine best practices and realize the full potential of these innovative trial designs.

Sponsors considering the use of synthetic control arms should carefully evaluate whether their specific situation aligns with the FDA’s considerations. Early and frequent communication with the agency is crucial to ensure that the trial design meets regulatory expectations and can provide substantial evidence of effectiveness.

References

  1. Garg, M., Ye, Q., Bansal, A., & Halabe, E. (2021). Why external control arms should be in your clinical trial toolbox. ZS Associates.
  2. Thorlund, K., Dron, L., Park, J. J., & Mills, E. J. (2020). Synthetic and external controls in clinical trials – A primer for researchers. Clinical Epidemiology, 12, 457-467.
  3. U.S. Food and Drug Administration. (2023). Considerations for the Design and Conduct of Externally Controlled Trials for Drug and Biological Products: Draft Guidance for Industry.
  4. Mahendraratnam, N., Silcox, C., Mercon, K., et al. (2021). Determining Real-World Data’s Fitness for Use and the Role of Reliability. Duke Margolis Center for Health Policy.
  5. Schmidli, H., Häring, D. A., Thomas, M., et al. (2020). Beyond Randomized Clinical Trials: Use of External Controls. Clinical Pharmacology & Therapeutics, 107(4), 806-816.

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