Real-World Evidence Should Be Part of Clinical Trials in Oncology

Sarah Alwardt, PhD

As cancer treatment shifts from broad chemotherapy to highly personalized therapies, drug development in oncology is also evolving. There are currently some 71,000 oncology trials listed on ClinicalTrials.gov, with new studies being added every day. Although the trials may involve varied forms of disease or new modalities such as cell and gene therapies, all share 1 thing in common: They are competing with one another to recruit patients.

In the United States, fewer than 5% of adult patients with cancer enroll in clinical trials. This makes every patient extremely valuable.¹ Sufficient enrollment is essential for successful completion of randomized controlled trials (RCTs) and for bringing new oncology drugs to patients sooner. However, we are unlikely to be able to recruit enough participants for many of these trials. In the oncology community, we must rethink how we populate trials and gather data for regulatory decisions.

RCTs remain the gold standard for evaluating the safety and efficacy of drugs, but the industry must identify alternative methods of gaining insight into treatment patterns and drug performance. The growth of personalized medicine and the complexity of the oncology treatment landscape offer an opportunity for the industry to expand the use of real-world evidence (RWE). We must consider expanding RCT eligibility to utilize RWE differently. This shouldn't occur for the purposes of trial rescue, when recruitment and data capture have been inadequate. This use of RWE should involve planned studies with methodologies designed to capture data on the day-to-day usefulness of drugs. Examples of how RWE can be used in trials are below.

Real-world cohorts as part of RCTs

The use of pragmatic clinical trials, focusing on the correlation between treatments and outcomes in real-world clinical settings, has increased significantly over the past several years. Pragmatic trials offer the ability to test treatment options on realistic patient populations with fewer exclusions for common conditions that could affect outcomes in practice. The resulting data can be used for standalone analysis or as part of the RCT. For example, real-world data sources were used in a recent study to analyze the treatment patterns and duration of palbociclib (PAL; Ibrance), an oral inhibitor of cyclin-dependent kinase 4/6 inhibitor, with endocrine therapy (ET; aromatase inhibitor or fulvestrant) versus ET in men with metastatic breast cancer (mBC). The study used a retrospective analyses of pharmacy, medical claims, and other data and arrived at the conclusion that men with mBC derived clinical benefit from the addition of PAL to ET.² According to investigators, given the challenges of conducting RCTs involving men with mBC, RWE data appear to be useful for assessing the benefit of novel therapies in this setting.

Synthetic control

Synthetic control cohorts must be embraced to support drug development and regulatory approval of breakthrough medicines designed to improve patient care. According to the FDA, synthetic control arms could help augment new clinical data by allowing biopharma company sponsors to reduce the number of patients assigned to the control arm in randomized trials or to conduct smaller randomized trials. The 2017 approval of avelumab (Bavencio) for Merkel cell carcinoma (MCC) marked the first-ever use of RWE for FDA approval. The approval was based on a phase II trial with only an active agent arm and a real-world retrospective analysis of patients with MCC treated with chemotherapy. The rarity of the disease made it impractical to conduct an RCT.³

Standard of care as control group

Wide Spectrum of Potential Uses of RWD/RWE in Clinical Studies (Click to Enlarge)

Formalize a 2-Step Regulatory Approval Process

Under the FDA’s expanded access program, patients with an immediately life-threatening condition or serious disease may gain access to investigational drugs for treatment outside of clinical trials when no alternative therapy options are available. For patients who have exhausted approved options for treatment, participating in the expanded access program may be worth the risk of using an unapproved drug.

Although RWE is an extremely important tool to help address unmet patient needs, it is not a well-established regulatory pathway. The FDA has predicted that greater use of RWE will result in safety and efficacy information becoming available sooner and will help to further inform regulatory decisions.⁴ This is an opportunity to consider formalizing expanded access through the implementation of a 2-step approval process, similar to that used in Europe.

The European Medicines Agency (EMA) uses conditional marketing authoriza-tions (CMA) to speed up access to medicines for patients with unmet medical needs. Between 2006 and 2016, CMAs were granted for 30 medicines that target such conditions as HIV infection, cancer, severe epilepsy in infants, and multidrug-resistant tuberculosis. Of these CMAs, 11 have been converted into full marketing authorizations, 2 have been withdrawn for commercial reasons, and the remainder remain valid CMAs.⁵ Companies that receive CMAs are required to conduct further studies to obtain complete data or meet other postauthorization requirements. According to the EMA, it takes an average of 4 years to generate the additional data needed to receive full marketing authorization.

In the United States, biopharma companies could receive conditional approval from the FDA on the basis of early-phase RCT data, such as a completed phase II trial data or initial data from a phase III trial. Once conditional approval is granted, the sponsor would be required to complete more comprehensive trials for final approval of a new drug application (NDA) or supplemental NDA.

RWE can be analyzed and compared with outcomes expected under an RCT by using a pragmatic trial and monitoring patients longitudinally for 12 to 18 months. The FDA has signaled openness to this approach in its recent RWE framework and in the expansion of its RCT DUPLICATE demonstration project, designed to use RWE to attempt to replicate the results of 30 RCTs. The goal of this project is to help inform the FDA’s standards for using RWE in regulatory decision-making and to identify when and where RWE can provide estimates of treatment safety and efficacy.

Rethinking RCT Eligibility

Clinical trial recruitment is sometimes challenging, and cancer trials can be closed prematurely because of poor accrual. Additionally, significant disparities exist in RCT participation. Clinical trial populations tend to encompass younger, healthier patient populations than are found in the real world, with limited ethnic and gender diversity. Although RCTs remain the gold standard for the assessment of safety and efficacy, clinical trials alone will not be sufficient to accelerate desperately needed advances in cancer care. RWE will continue to play an important role in drug development and testing by providing critical information about how new treatments perform in real clinical settings. As the FDA finalizes its guidelines for how and when industry can use RWE to support regulatory decisions, we must also work in parallel to expand RCT eligibility to include real-world patient populations. This will improve our ability to recruit patients and complete RCTs as well as bring new oncology drugs to market sooner.

According to the National Cancer Institute, standard of care is defined as treatment that experts agree is appropriate, accepted, and widely used. If a study is comparing new treatment options with a standard treatment that has not changed for years, why not use historic RWE as the control? If multiple biopharma companies are developing new drugs for the treatment of renal cell carcinoma, and each is conducting trials with nearly identical control groups, the possibility exists for all to draw data from the same control group. This may present some risk to the biopharma companies but could be a major boost for patients in the form of faster access to promising new therapies.