The US Food and Drug Administration (FDA) is highlighting efforts to promote innovative trial design that will accelerate the typically time-consuming and expensive process of developing and testing drugs for cancer patients. New trial designs, often referred to as seamless clinical trials, merge the traditional, sequential Phase I, II and III path into fewer protocols that expand or shift based on interim data checks. The idea is to more rapidly move oncology treatments through the regulatory process to market. One large continuous trial can shave off years from the development program and millions of dollars in cost, while also reducing the need to enroll scores of patients. Moreover, FDA commissioner Scott Gottlieb has emphasized these new trial designs are also “highly consistent with the goals of the 21st Century Cures Act and the FDA Reauthorization Act.”
In a seamless trial, oncology sponsors can progress from a first-in-human (FIH), single-arm trial and add expansion cohorts if they detect strong responses during the early stages of development, even going straight to registration if the efficacy signal is strong enough. A notable example is Merck’s FIH trial of Keytruda® (pembrolizumab), an immune checkpoint inhibitor targeting programmed cell death receptor-1 (PD-1). The study began in 2011 as a FIH dose-finding Phase I trial focused on safety and tolerability, and investigators were ultimately able to add 20 more cohorts to the study (bringing the grand total of enrolled patients to above 1,200) when early results showed positive responses in patients with metastatic melanoma or non-small cell lung cancer*. That opened the trial to further evaluation of efficacy, alternative dosing, and a potential predictive biomarker. In 2014, the FDA approved Keytruda as the first anti-PD-1 therapy, based on results from a single-arm cohort of 173 patients with melanoma. By Q4 2014, data collected from this seamless trial with expansion cohorts in NSCLC were used to obtain breakthrough therapy designation and support the accelerated approval of Keytruda in NSCLC in 2015.
Seamless clinical trials are becoming increasingly popular with oncology sponsors. In 2016, the FDA received more than 40 active commercial investigational new drug (IND) applications for large FIH oncology trials using such design strategies**. This may come as no surprise in light of statistics illustrating how seamless design may increase the likelihood of approval - 16 percent of investigational agents in seamless trials received accelerated approval, a markedly higher number than the 5 percent of oncology therapies that ultimately receive FDA approval. Although any conclusion from these data should be tempered by the potential selection bias for therapies that are developed using adaptive or seamless trials, as these therapies often receive breakthrough designation status and display better efficacy than available therapies.
In a white paper that dives into alternate trial routes to faster approval, we break down key aspects oncology sponsors must consider when pursuing a seamless trial design. Here is a brief overview of some of these aspects:
- Protocols: Expansion protocols in seamless trials must show the criteria and scientific basis for using this approach, including the statistical justification of how the quantity and size of cohorts will address objectives of each group and the overarching trial. The FDA suggests maintaining certain traditional trial design features that will provide greater attention to 1) the statistical rationale and analysis plan for additional cohorts, 2) set up of oversight committees, and 3) communication between all parties involved.
- Endpoints and imaging: Single-arm studies should use an objective response to determine the primary outcome, instead of a clinical endpoint such as progression-free or overall survival (PFS, OS) that may take many years to realize. This objective response (or surrogate endpoint), typically tumor shrinkage, is the first efficacy signal. Sponsors exploring immuno-oncology therapies should note the limitations of regulatory-accepted Response Evaluation Criteria In Solid Tumors (RECIST 1.1) and consider the current landscape around newer evaluation criteria such as iRECIST.
- Companion diagnostics: Many targeted oncology investigational agents are approved in tandem with companion diagnostics (CDx). Protocol planning discussions with regulatory agencies should address the nature of the diagnostics used to meet approval criteria and occur early in program development, often with CDx trials running in parallel with the therapeutic agent.
- Safety: The FDA proposes that sponsors leverage ‘Breakthrough Therapy Designation’ to determine if an investigational agent exhibits the early evidence of efficacy that warrants a seamless development program. Sponsors are then recommended to use an independent data and safety monitoring committee to evaluate safety and efficacy data from cohorts at planned intervals, and to counsel on adding, pausing or closing cohorts.
- Budget and resourcing: Scaling up to more cohorts will require increases in staff, resources and time. Additional treatments later in the trial (such as supportive care) can also hike up costs. Sponsors can plan for this from the get-go or begin with a small proof-of-concept trial and amend it based on results or a shift in direction. For those planning to manage their own expansion, a partnership with the right CRO can make a difference.
- Payers: Approval from payers has become a significant hurdle to marketing oncology drugs. For global access, superiority of outcomes data may be needed. Comparator cohorts can provide efficacy and safety data, but sponsors should also collect quality-of-life data to aid in creating a robust profile for their investigational agents.
For more information on considerations relevant to seamless trial design, please read our whitepaper, “Embracing Innovative Designs in Early Phase Oncology Studies: A Different Route to Faster Approvals.”