Reimagining Clinical Trials: Bridging Randomized Controlled Trials with Real-World Evidence

What if the next breakthrough cancer therapy could be approved in half the time, without compromising safety?
Clinical research is undergoing a transformative shift, one that’s redefining how trials are designed, conducted, and evaluated. For decades, randomized controlled trials (RCTs) have been the gold standard for evaluating the safety and efficacy of new therapies. Their rigor and structure have delivered countless medical breakthroughs. Yet, as the healthcare ecosystem evolves, so do the expectations from clinical trials. Today, the industry faces mounting pressure to accelerate drug development, reduce costs, and ensure that studies reflect the diversity and complexity of real-world patient populations.

Why Traditional Trials Don’t Meet Modern Healthcare Needs

Traditional RCTs, while scientifically robust, are increasingly challenged by practical realities. They are expensive, time-consuming, and often exclude large segments of the patient population due to restrictive eligibility criteria. This not only delays access to promising therapies but also limits the generalizability of trial results. In an era where patient-centricity and value-driven outcomes are paramount, the limitations of RCTs have become more pronounced.

Regulators, notably the FDA, have recognized these challenges and are actively promoting innovation in trial design. Through initiatives such as the 21st Century Cures Act and the Real-World Evidence Program, the FDA is encouraging the use of real-world data (RWD) and external control arms. This marks a significant shift, enabling data from electronic health records, insurance claims, and patient registries to inform regulatory decisions and supplement, or even replace, traditional control groups.

To address these limitations, researchers are exploring new trial designs that blend rigor with real-world relevance.

Innovative Trial Designs: Merging Science with Real-World Relevance

Leading organizations are reimagining how trials are designed and conducted. Several innovative approaches are gaining traction:

1. Hybrid Trials

Hybrid models combine randomized and non-randomized methods, leveraging RWD to supplement internal trial results. This approach accelerates processes, increases statistical power, and can reduce the number of participants needed for conventional control groups. By integrating real-world cohorts, hybrid trials also enhance the representativeness of study populations, making findings more applicable to everyday clinical practice.

2. External Control Arms

External control arms use historical datasets or contemporary real-world cohorts as comparators. This is particularly valuable in rare diseases or situations where placebo use is impractical or unethical. By drawing on existing data, these trials can proceed more quickly and with fewer logistical hurdles, while still maintaining scientific integrity.

3. Decentralized Clinical Trials (DCTs)

DCTs are transforming the clinical trial landscape by enabling remote participation and data collection through digital platforms, wearables, and telemedicine. These approaches break down geographical and logistical barriers, increase patient access, and foster more representative study populations. DCTs also reduce the burden on participants, making it easier for diverse groups to enroll and remain engaged throughout the study.

4. Digital Twin Technologies

Digital twins, virtual models of individual patients built from real-world data, are emerging as powerful tools for simulating clinical scenarios, optimizing trial protocols, and personalizing interventions. By integrating digital twins into trial design, researchers can predict outcomes, refine study parameters, and improve the efficiency and reliability of clinical research.

Navigating Complexities in Next-Gen Clinical Trials

While these innovations promise greater efficiency and inclusivity, they introduce new complexities that must be addressed head-on. The journey toward advanced trial designs requires careful attention to several critical factors:

• Data Quality and Bias
  Ensuring the quality and completeness of real-world data is paramount. Inconsistencies or gaps can introduce bias and compromise the integrity of trial findings. Advanced analytics and rigorous data curation are essential to manage confounding variables and selection bias.
• Regulatory Acceptance
  Regulatory bodies are increasingly open to innovative trial designs, but acceptance requires transparent methodologies and early engagement. Sponsors must provide thorough justification for employing RWD and external control groups, demonstrating that these approaches meet the standards of scientific rigor and patient safety.
• Ethical Considerations
  The use of patient data outside conventional trial frameworks raises important ethical questions, particularly around informed consent and privacy. Robust consent processes and data governance are essential to uphold patient rights and maintain public trust.

Real-World Applications of Next-Gen Trial Designs

Recent examples in oncology and rare disease research highlight the transformative potential of innovative trial designs. In oncology, external control arms constructed from patient registries have supported accelerated approvals for therapies targeting rare cancers. In rare disease research, hybrid trials have enabled meaningful efficacy assessments where randomized controls would be impractical or unethical.

Beyond oncology and rare diseases, several other therapeutic areas have successfully leveraged real-world data (RWD), external control arms, decentralized clinical trials (DCTs), and digital twin technologies to advance clinical research:

• Cardiology: Researchers have utilized electronic health records and insurance claims data to form synthetic control groups, enabling evaluation of heart failure and arrhythmia treatments without relying solely on conventional randomized trials. This aligns with the external control arm approach, enhancing trial efficiency and relevance.
• Neurology: In multiple sclerosis research, external controls using patient registry data have facilitated the assessment of new therapies, particularly for underrepresented subgroups. This supports the use of real-world cohorts to improve inclusivity and scientific rigor.
• Diabetes Management: Hybrid trials incorporating decentralized data collection through wearable devices and patient-reported outcomes have accelerated the evaluation of innovative insulin delivery systems and digital therapeutics. These trials exemplify the integration of DCTs and hybrid models to enhance patient engagement and trial agility.
• Pediatric Research: For rare pediatric conditions, digital twins and external controls have enabled trial designs that minimize the burden on young participants while maintaining robust evidence generation. This demonstrates the ethical and scientific advantages of virtual modeling and real-world comparators.

These industry examples highlight the role of transparent methodology, thorough data curation, and early regulatory engagement in supporting innovative trial design that produce reliable and ethical outcomes across various clinical settings.

What’s Next: Building the Future of Clinical Research

Clinical research is experiencing significant advancements through the adoption of real-world data (RWD), external controls, decentralized trials, and digital twins. Realizing the full benefits of these approaches requires stakeholders to focus on standardizing data, establishing robust infrastructure to support RWD and digital technologies, implementing advanced statistical techniques to address bias and confounding factors, upholding ethical standards like informed consent and data privacy, and engaging collaboratively with regulatory authorities.

This evolution necessitates sustained collaboration, innovation, and adherence to scientific excellence and patient-centered practices. By adapting to these developments, the industry stands to generate faster, more inclusive, and pertinent insights, thereby enhancing patient outcomes. In this context, innovation has become an imperative for progress.

About the Authors

Sanjay Martis
Senior Partner and Head of Life Sciences, North America, Wipro Consulting

Sanjay brings over 30 years of experience in commercial life sciences, both as a practitioner and as a consultant. A seasoned senior executive, Sanjay has extensive expertise across the international life sciences sector, including information technology, pharmaceuticals, biotechnology, and medical devices.

Yachna Jatwani
Domain Consulting Partner, Life Sciences, North America, Wipro Consulting

Yachna brings deep expertise in life sciences consulting, with a strong focus on clinical trial optimization, regulatory strategy, and digital transformation. She partners with pharmaceutical, biotechnology, and medical device organizations to accelerate development timelines, enhance patient engagement, and ensure GxP compliance. Her experience spans integrating platforms like Medidata and Veeva, leveraging AI and real-world evidence, and designing impactful Patient Support Programs to deliver safe, effective therapies to market faster.