In 2023, expect more sponsors to think outside the box when it comes to designing clinical trials. As pharma increasingly develops drugs for specific patient populations, a one-size-fits-all approach to clinical trial design is beginning to fall out of favor. Instead, studies built for precision medicine will lead the charge in 2023—driven by Phase 0 and master protocol trials.
According to GlobalData’s clinical trials database, the most common nontraditional study designs are all on the rise, setting the stage for a likely surge in innovation in 2023. Experts say Phase 0 trials, which identify patient-specific drug activity prior to Phase I studies, and master protocol studies—which use the same protocol for multiple drugs or studies—could see the biggest uptake. Meanwhile, nontraditional N-of-1 trials, basket trials, and umbrellas trials are similarly on the rise. GlobalData is the parent company of Clinical Trials Arena.
Experts say most nontraditional trial innovation will take place in oncology, which is at the forefront of personalized medicine approaches. Still, the pharma industry has a long way to go before these innovative trial designs go mainstream.
“The biggest barrier to new trial designs is companies stepping out of their current conventional approach to drug development and trying something new,” explains Richard Klinghoffer, CEO of Presage Biosciences. “We need more innovation and more players to step up.”
New technology to drive Phase 0 trials in oncology
In oncology, trial sponsors often struggle to pair the right patients with the right drugs, leading to inefficient studies where only a small subset of patients respond. An uptick in Phase 0 trials, bolstered by new imaging technology, could give oncology drug development a much needed boost in 2023.
In a Phase 0 oncology trial, individual patients receive a microdose of an experimental drug to see whether the treatment penetrates the tumour environment, Klinghoffer explains. Recent advances in spatial molecular imaging, which reveal drug activity on the scale of individual cells, will allow sponsors to see whether a new drug can become active in a specific patient’s tumour, prior to initiating a full-scale drug development program, he notes.
“In high detail, spatial molecular imaging allows us to elucidate the complex responses induced by different drugs in a non-invasive way,” Klinghoffer notes. “In the next five years, we’re going to benefit greatly from the emergence of spatial biology.”
Overall, the oncology space has seen a sizeable uptick in Phase 0 studies over the past decade, according to GlobalData’s database. Phase 0 studies accounted for only 1.1% of all oncology drug trials initiated in 2014, before peaking at 7.3% of oncology trials initiated in 2020. Based on planned trials documented in GlobalData’s database of publicly available information, Phase 0 trials are set to account for 9.15% of all oncology drug trials in 2023.
Among Phase 0 oncology trials in the past five years, gastrointestinal tract cancer and blood cancers have been the most common indications, according to GlobalData’s database. But looking ahead, experts say glioblastoma multiforme (GBM) could be a key area of growth in Phase 0 trials. In particular, Phase 0 “window of opportunity” trials allow clinicians to determine whether experimental drugs cross the blood brain barrier.
Adaptive trial designs gaining foothold
As clinical trials narrow their focus to specific patient populations with precision medicine, master protocols will become more common to reduce regulatory inefficiencies. Master protocol designs, including platform trials, allow sponsors to start multiple different studies under the same protocol, including asynchronously. As a result, sponsors running multiple similar trials do not need to repeatedly undergo a lengthy approval process for each initiation.
Over the past five years, master protocol designs have quickly become more prevalent, according to GlobalData’s database. Master protocol designs accounted for 0.18% of all drug trials initiated in 2022—up from less than 0.01% of all trials initiated in 2018. The biggest share of master protocol trials initiated have been Phase II studies, followed by Phase III trials.
While master protocols are seeing increased use across many study types, they will likely carve out a niche in two specific nontraditional designs: Phase 0 studies and N-of-1 trials. Presage Biosciences has approval for a Phase 0 master protocol design (NCT04541108), which Klinghoffer says eliminates the need to gain FDA approval for each new study. Instead, he explains, new Phase 0 trials are inserted as sub-studies under the master protocol. “Master protocols are a business efficiency and a regulatory efficiency, and they shave off about three months from the evaluation process,” he notes.
Meanwhile, researchers are building master protocol designs for N-of-1 trials, which test an individualized treatment for a single patient with an ultra-rare disease. Specifically, researchers are building a master protocol to test custom-made antisense oligonucleotides (ASOs), which target single-gene alterations. With a master protocol design, sponsors can develop an ASO based on a specific patient’s gene alteration and test the drug under a master protocol, without developing a new trial from scratch for each now ASO tested.
Will trial innovation decline in a post-pandemic world?
In the height of the Covid-19 pandemic, many trial sponsors became ambitious with innovative new study designs—led by a surge in decentralised clinical trials (DCTs). Miruna Sasu, CEO of healthcare data company COTA, says she has seen a “backslide” in 2022 with respect to major advances in drug development that took place during the Covid-19 pandemic. “It’s like we’ve taken our foot off the gas when it comes to new [healthcare] approaches that spiked during the pandemic,” she says.
But to keep drug development progress moving forward in 2023, Klinghoffer says companies need to keep the same spirit of innovation, particularly in oncology. “Translational oncology needs innovation because what we are currently doing isn’t working,” he says. “If you want to really walk the walk instead of talking the talk in terms of innovation, then try something new.”
- As oncology trials increasingly focus on specific genetic biomarkers, Phase 0 trials will become more prevalent as a tool for testing patient-level drug activity earlier in the drug development process.
- Master protocol trials will become more common as a tool for increasing regulatory efficiencies, particularly for Phase 0 and N-of-1 studies that focus on precision medicine.
- To avoid backslides in innovation in a post-pandemic era, clinical trial sponsors must continue in the spirit of trying new study design strategies.