Understanding the importance of randomized clinical trials

The role of RCTs in drug development

An RCT is a prospective study in which participants are randomly assigned to receive either an experimental intervention or a control (placebo or standard of care). This randomization reduces selection bias and ensures that both known and unknown confounders are evenly distributed between groups.

RCTs continue to be the gold standard for establishing whether a drug causes an observed effect, making them indispensable during Phase 3 clinical development. At this critical stage, developers must provide evidence of statistically significant treatment benefits to obtain regulatory approval.

The FDA and European Medicines Agency consistently cite well-conducted RCTs as the primary basis for marketing authorizations. In 2022, the FDA alone approved 37 novel drugs supported by 413 studies, 227 (55%) of which were randomized clinical trials.

To meet regulatory and ethical standards, RCTs must also be registered in a public trials database, predefine primary outcomes and use methods such as allocation concealment and blinding to reduce bias. Analyses are often conducted using an intention-to-treat approach, which preserves the benefits of randomization even when participants deviate from the assigned treatment protocol.

Impact of RCTs on drug pricing strategies

Beyond regulatory approval, RCTs provide the foundation for health technology assessments, reimbursement negotiations and market positioning. Payers often prioritize randomized data when determining formulary access or deciding whether to enter value-based agreements. Without high-quality RCT results, securing premium pricing or demonstrating cost-effectiveness relative to standard treatments can be difficult.

The key reasons RCTs remain vital in market access include the following:

• Comparability. Randomization ensures clinical comparability between treatment and control groups, reducing confounding and selection bias.
• Statistical validity. Power calculations and predefined endpoints increase the reliability of efficacy estimates.
• Regulatory and payer credibility. RCTs are still the most universally accepted form of clinical evidence.

In critical therapeutic areas like oncology or rare diseases, a single robust RCT can have a significant commercial impact. A well-designed trial can validate a drug's list price, facilitate negotiations with payers and expedite its market entry.

Limitations

While RCTs are invaluable, they face several limitations, particularly in terms of cost and duration.

Depending on the therapeutic area, a full clinical trial can cost between $2 and $5 billion and may take up to 15 years to complete. Neurological products, for example, often require an average of 10 years to navigate all RCT phases before reaching market approval.

Additional barriers -- such as recruitment difficulties, lengthy follow-up periods and strict inclusion criteria -- further limit the applicability and external validity of RCTs.

Due to the highly restrictive eligibility criteria often employed by RCTs, study populations might fail to capture the full diversity of patients encountered in everyday clinical practice. Participants in RCTs are often younger, healthier and less diverse compared to real-world populations.

Consequently, the findings from RCTs might not accurately represent a drug's performance in routine clinical settings.

The complementary role of RWE

To address these gaps, developers are increasingly focused on using RWE and observational datasets to supplement clinical trial data. These sources, such as electronic health records, insurance claims and disease registries, offer insight into long-term outcomes, treatment adherence and real-world effectiveness.

When designed and analyzed properly, real-world studies can support regulatory filings and payer submissions. In fact, the FDA has already approved several therapies using real-world evidence either alongside or as a substitute for traditional trial data, including treatments for organ transplants, tuberculosis and spinal muscular atrophy, among others.

However, without randomization, these studies are vulnerable to confounding, selection bias and inconsistent outcome measurements. Their conclusions are most compelling when consistent with RCT results.

While RCTs are not perfect, they remain the gold standard in scientific research for determining cause and effect. For pharmaceutical companies navigating regulatory approval, randomized trials continue to serve as the most reliable tool for establishing therapeutic value. While real-world data can complement and contextualize these findings, it cannot replace the unique rigor of randomization.

Alivia Kaylor is a scientist and the senior site editor of Pharma Life Sciences.