In the realm of pharmaceutical development, the pursuit of safe and effective treatments is paramount. To achieve this, rigorous clinical trials are conducted to evaluate the efficacy and safety of new interventions. However, the traditional randomized controlled trial (RCT) framework, while invaluable, is not always feasible or ethical. In such cases, External Control Arms (ECAs) have emerged as a potential solution.(1)
ECA refers to a trial design strategy where an experimental treatment arm is compared to a control group using external data rather than traditional randomization. This approach is particularly useful when randomization is impractical, such as in rare diseases or when the experimental treatment is intended for patients with no other viable options. ECAs utilize historical, observational, or real-world data to construct an appropriate control arm against which the experimental treatment can be evaluated. (2,3)
Creating an ECA involves several steps. First, a suitable data source is identified, which could include medical registries, electronic health records, or administrative databases. The control group is then defined using patient-level data from the chosen source. Statistical methods, such as propensity score matching or weighting, are often employed to balance the characteristics of the treatment and control groups, reducing bias and ensuring comparability.(4)
ECAs offer several advantages over traditional RCTs. They can expedite the evaluation process by providing more timely results, potentially accelerating patient access to promising therapies. ECAs can also be more cost-effective, as they utilize existing data rather than requiring the recruitment and monitoring of additional participants. Furthermore, they can fill the evidence gap in rare diseases, where conducting RCTs may be challenging due to limited patient populations. ECAs offer an opportunity to evaluate interventions in such cases, providing valuable insights for patients and healthcare providers.(1, 3)
However, ECAs also have their limitations. As they rely on non-randomized data, there is an inherent risk of confounding and bias. While statistical methods can mitigate some of these concerns, residual confounding remains a potential issue. Additionally, the use of ECAs requires careful consideration and discussion with regulatory bodies, as there may be skepticism regarding the reliability and generalizability of the external data. Striking a balance between the benefits and limitations of ECAs is crucial to ensure their appropriate and ethical application.(2)
Optimizing ECAs for submission to HTA agencies involves careful planning and execution. First and foremost, robust data sources with high-quality information are essential. This may involve collaborations with data custodians, healthcare institutions, or research networks to access relevant datasets. Additionally, comprehensive data analysis plans should be developed, specifying the statistical methods to be employed, addressing potential biases, and ensuring transparency in reporting results.(1, 2)
Collaboration and engagement with HTA agencies throughout the ECA process is crucial. Early dialogue can help align expectations, address methodological concerns, and understand the specific requirements of the agency. Transparent reporting of data sources, study limitations, and potential biases is essential for successful submission. It is imperative to demonstrate the validity and reliability of the ECA results and their relevance to the target population.(5)
In the current landscape, regulations and guidelines regarding ECAs for HTA submissions are still evolving. HTA agencies are increasingly recognizing the value of ECAs as an alternative to traditional RCTs, particularly in situations where randomization is not feasible. As the field progresses, it is expected that guidelines and frameworks will continue to be refined to ensure standardized and rigorous evaluation of ECAs.(2, 5)
In conclusion, External Control Arms (ECAs) provide a valuable alternative to traditional randomized controlled trials, particularly in cases where randomization is not feasible or ethical. Their ability to expedite the evaluation process, fill evidence gaps in rare diseases, and potentially reduce costs make them an appealing option. However, careful consideration of potential biases and engagement with HTA agencies are crucial to ensure the appropriate use and optimization of ECAs for submissions. As the field continues to evolve, collaboration and transparent reporting will be key to harnessing the full potential of ECAs in advancing pharmaceutical research and development.
Become A Certified HEOR Professional – Enrol yourself here!
Reference
- Davi R, Mahendraratnam N, Chatterjee A, et al. Informing single-arm clinical trials with external controls. Nat Rev Drug Discov. 2020 Dec;19(12):821-822.
- Burcu M, Dreyer NA, Franklin JM, et al. Real-world evidence to support regulatory decision-making for medicines: Considerations for external control arms. Pharmacoepidemiol Drug Saf. 2020 Oct;29(10):1228-1235.
- Ventz S, Lai A, Cloughesy TF, et al. Design and Evaluation of an External Control Arm Using Prior Clinical Trials and Real-World Data. Clin Cancer Res. 2019 Aug 15;25(16):4993-5001.
- Seeger JD, Davis KJ, Iannacone MR, et al. Methods for external control groups for single arm trials or long-term uncontrolled extensions to randomized clinical trials. Pharmacoepidemiol Drug Saf. 2020 Nov;29(11):1382-1392.
- Curtis LH, Sola-Morales O, Heidt J, et al. Regulatory and HTA Considerations for Development of Real-World Data Derived External Controls. Clin Pharmacol Ther. 2023 Apr 20.