How External Control Arms are Improving Clinical Trials: Q&A with Sujay Jadhav

Sujay Jadhav
CEO
Verana Health

Clinical trials are possibly the most vital access of the drug development process, and gathering the most accurate data possible during this process can vastly improve how a drug is commercialized. Sujay Jadhav, CEO of Verana Health, spoke with Pharmaceutical Executive about how external control arms (ECAs) are impacting clinical trials and improving the entire process.

Pharmaceutical Executive: Why are traditional clinical trials struggling? What solutions are there?
Sujay Jadhav: Clinical trials are the foundation of medical innovation, enabling life sciences companies to evaluate the safety and efficacy of new treatments. However, traditional study designs face increasing challenges, from recruitment barriers and ethical dilemmas to prolonged development timelines that delay patient access to life-saving therapies.

Patient recruitment is a significant challenge, particularly for diseases with small or highly specific patient populations, such as rare diseases, oncology, and ophthalmology. Enrolling patients in control groups can take months or even years, delaying the completion of studies and slowing the introduction of new treatments.

Ethical concerns further complicate trial design. In cases of life-threatening conditions where no clear standard of care exists, placing patients in placebo groups raises ethical concerns. Many individuals hesitate to participate in trials that do not guarantee access to potentially life-saving therapies.

Diversity in clinical trials is also an issue, as underrepresentation of racial and ethnic, and geographic groups in trials leads to gaps in treatment effectiveness.

Drug development is a brutally competitive industry, with the total capitalized cost of bringing a successful new drug to market now exceeding $2.6 billion. And despite significant increases in R&D expenditure, returns are diminishing with experimental drugs gaining regulatory approval falling to 7.9%.

Life sciences companies are in a race against time to reduce the innovation gap in drug development and costs. As the demand for more efficient and inclusive trials increases, alternative study models are emerging as powerful tools to optimize research without compromising scientific integrity. One such model is external control arms (ECAs), which leverage real-world data (RWD) to supplement or replace control groups in clinical trials, particularly when enrolling patients in placebo arms is impractical or ethically complex.

PE: How can real-world data (RWD) supplement or replace placebo arms?
Jadhav: Though randomized controlled trials (RCTs) remain the gold standard, there is a growing precedent for ECAs to play a substantial role in demonstrating comparative efficacy. Integrating real-world evidence (RWE) through ECAs presents an opportunity to accelerate drug development and improve trial feasibility without sacrificing scientific validity. The growing availability of high-quality RWD has made ECAs a viable alternative to traditional control groups, allowing life sciences companies to streamline studies, expand access to innovative therapies, and reduce patient burden.

While the promise of ECAs is compelling, their success hinges on rigorous planning and execution. ECAs are not expected to fully replace RCTs, but they can serve as valuable alternatives or augmentations in specific situations.

To ensure ECAs serve as scientifically valid alternatives to traditional control arms an assessment must be made of the availability and quality of RWD, the complexity of necessary analyses, and potential regulatory concerns. A clear articulation of the rationale - whether due to ethical concerns, recruitment challenges, or scientific necessity - helps align expectations and objectives from the outset. Choosing the right data source is foundational - researchers must conduct rigorous validation to confirm data integrity and alignment with study objectives. A robust ECA requires a well-defined protocol and statistical analysis plan. Life science companies should proactively engage regulatory agencies - this transparency builds credibility and fosters alignment with regulatory expectations. Detailed documentation of the ECA’s design, methods, and limitations will help to support regulatory review and peer evaluation.

When executed with precision and transparency, ECAs can enhance trial efficiency, expand patient access to active treatment, and support regulatory-grade evidence - all while maintaining scientific integrity.

PE: What are the regulatory considerations that could impact the future of ECAs?
Jadhav: As regulatory bodies are becoming more open to submissions that incorporate real-world evidence (RWE) the use of ECAs has been gaining momentum. In 2023, the FDA released guidance on the use of ECAs, recognizing the potential value of non-traditional control arms. As regulatory frameworks continue to evolve, ECAs will likely become an increasingly accepted component of clinical research.

ECAs can provide meaningful data to support regulatory decision-making and accelerate drug development. However, their success depends on the quality of RWD sources and analytical methodologies.

Regulatory agencies should be proactively engaged with on study design and methodologies to ensure alignment with regulatory expectations. Detailed documentation and transparency will help support regulatory review and peer evaluation.

PE: Are there any recent success stories involving the use of ECAs?
Jadhav: The benefits of ECAs have already been demonstrated in several high-profile clinical trials. For example, Kymriah’s Phase II trial for follicular lymphoma lacked a traditional control arm, but by using an ECA, leveraging matched, real-world oncology data, researchers demonstrated favorable outcomes with Kymriah compared to the real-world standard of care. This showcased the potential of an ECA to complement or replace control arms and overcome ethical and operational RCT challenges.

Blincyto (Blinatumomab), a bispecific T-cell engager, was granted accelerated approval for treating Relapsed/Refractory Acute Lymphoblastic Leukemia. Similarly to Kymriah, this decision was based on a single-arm trial, which was further contextualized by historical control group data extracted from chart review of patients who were treated with standard-of-care salvage chemotherapy. This approach demonstrates the potential of ECAs to help novel treatments reach patients faster while still allowing researchers to conduct robust studies. A Phase 3 trial was later used to support the full FDA approval.

In the CARTITUDE-1 clinical trial, patients from historic trials matching criteria for this study were used to generate an ECA to Carvykti MM (ciltacabtagene autoleucel, cilta-cel). Despite the lack of a traditional control arm and being an early-phase trial, the magnitude of benefit and safety profile made it suitable for regulatory consideration under accelerated approval pathways and provided a critical breakthrough for patients with Relapsed or Refractory Multiple Myeloma.

The FDA also granted accelerated approval to KEYTRUDA (pembrolizumab) in combination with lenvatinib (LENVINMA) for a subset of patients with advanced endometrial carcinoma (specifically, those without microsatellite instability high nor mismatch repair deficient disease and have disease progression following prior systemic therapy but are not candidates for curative surgery or radiation). This combination was studied in a single-arm trial. However, leveraging data from past monotherapy clinical trials to build an ECA, researchers were able to support the conclusion that this combination is more effective compared to KEYTRUDA or lenvatinib alone in this population.