Identifying New Indications. One of the primary goals of drug repurposing is to discover novel therapeutic uses for drugs that are already approved for other conditions. TTE allows researchers to leverage RWD from electronic health records (EHRs), claim data, and registries to identify patterns where an existing drug may have shown benefits in treating off-label or unexpected conditions​. By designing a target trial that mimics the design of an RCT, researchers can test these observations rigorously.

Retrospective Analysis of Real-World Use. In clinical practice, many drugs are prescribed off-label, and RWD captures these real-world applications. TTE can analyze these off-label uses retrospectively, providing a structured way to assess the causal relationship between a drug and its new potential indication​.For instance, if a drug was commonly prescribed off-label for a condition and showed positive outcomes, TTE  can help confirm whether the observed effects are due to the drug itself or are confounded by other factors such as patient characteristics, co-treatments, or selection biases.

Overcoming the Limitations of Traditional RCTs. Conducting RCTs for drug repurposing can be costly and time-consuming, especially for drugs that are already off-patent or have limited commercial incentives for further investigation. TTE from RWD provides a cost-effective and timely alternative by leveraging existing clinical data to evaluate the potential of a drug for a new indication. This approach is particularly useful when the drug is considered for repurpose in urgent situations, such as during a pandemic or for rare diseases, where traditional trials may not be practical.

Reducing Bias in Observational Studies. Observational studies can suffer from biases, such as confounding and selection bias, which may obscure the true effects of a drug. TTE addresses these issues by applying rigorous trial design principles, such as defining eligibility criteria, treatment strategies, and follow-up periods, to real-world data​. This allows researchers to estimate treatment effects that are comparable to those from randomized trials, thereby enhancing the credibility of evidence for drug repurposing.

Evaluating Safety and Efficacy Across Diverse Populations. RWD encompasses a broader, more diverse population than traditional RCTs, which often have strict inclusion and exclusion criteria. TTE can evaluate a drug’s safety and efficacy in real-world patient populations, including those with comorbidities, different age groups, or those who are taking multiple medications​. This is particularly valuable for drug repurpose, as it allows for a more comprehensive understanding of the drug’s effects across various subgroups, which may not have been fully explored in the original trials.

Supporting Regulatory Submissions. Regulatory bodies, such as the FDA, EMA, and NICE, are increasingly open to the use of RWE to support drug approval and repurposing decisions. TTE generates evidence that is methodologically rigorous and comparable to RCTs, making it suitable for regulatory submissions​. This can accelerate the approval process for repurposed drugs, particularly when urgent health needs arise.

Causal Inference for New Treatment Strategies. By emulating a randomized trial using RWD, researchers can estimate causal effects of drugs in new therapeutic settings. This is crucial for drug repurpose, as it helps to establish whether the drug itself is responsible for the observed clinical benefit in a new condition, rather than confounding factors​. Target trial emulation can model treatment adherence, time to treatment initiation, and other key variables, providing robust evidence for repurposing strategies.