Josh Friedman , 2025-04-15 09:30:00
April 15, 2025
6 min read
Key takeaways:
- One in six participants in phase 2 cancer trials received a therapy that gained FDA approval.
- The results demonstrate phase 1 trials help filter out unsafe or ineffective drugs, investigators concluded.
Jonathan Kimmelman, PhD, has published multiple research papers and gotten into an inordinate number of debates about the clinical value of phase 1 trials.
“I’ve argued for a long time that for phase 1 trials, what justifies the risk [of patient participation] is not the prospect of getting a therapeutic drug, but rather the scientific value,” Kimmelman, James McGill Professor of Biomedical Ethics at McGill University in Montreal, told Healio.
Data derived from Ouimet C, et al. J Natl Cancer Inst. 2025;doi:10.1093/jnci/djaf013.
“When you design a phase 1 study, it’s really important that you have a good scientific rationale,” he added. “[It should be] designed and reported well so you’re getting as much scientific value as possible, because the patient is essentially getting a nontherapeutic drug. They’re being exposed to risk without the justification of the benefit.”
Kimmelman and colleagues previously found only 1.2% of patients who participate in phase 1 cancer trials receive a drug that eventually gains FDA approval.
Conversely, therapies that advance to phase 3 have already demonstrated the potential of clinical benefit.
The ultimate value of treatments evaluated in phase 2 trials, however, had been less clear.
Kimmelman and colleagues conducted a retrospective study to examine that issue. Results showed approximately one in six patients who participated in phase 2 cancer trials received a treatment that eventually garners FDA approval.
“It’s up to a patient to decide how they want to interpret those numbers,” Kimmelman said. “Some patients may say, ‘One-in-six odds of getting a drug that’s going to be approved for my indication is worth taking the risk [or] worth the extra burdens of participating in a trial.’ Others will say, ‘Why would I do this? There’s a five-in-six chance I’m going to get an unsafe and/or ineffective drug when I go into the trial. What’s more, if I’m in that lucky one in six, there’s still only a 25% or less chance that I’m actually going to have a therapeutic response.”
Background, methods
Several published studies have evaluated the risk-benefit balance of phase 1 cancer trials.
Research has shown objective response rates typically range from 3.8% to 13.2%, according to study background. Life-threatening adverse events occurred at rates between 10% and 19%.
“There hasn’t been very much that’s focused on what I call ‘the forgotten middle child’ of drug development, which are the phase 2 trials,” Kimmelman said. “There isn’t much data out there about risk and benefit. … It’s a gap that we’ve had for a really long time.”
Kimmelman and colleagues — including Charlotte Ouimet, MSc, PhD candidate in experimental medicine at McGill University — aimed to address that evidence gap.
They identified 1,154 eligible phase 1, phase 1/phase 2, or phase 2 trials initiated between Nov. 1, 2012, and Nov. 1, 2015. They then randomly sampled 400 of those trials, which included 25,002 participants and assessed 332 drugs.
The majority of trials were phase 2 (57%), included patients with solid tumors (77%) and evaluated combination therapies (57%). Less than half (43%) included dose escalation cohorts.
The researchers assessed whether the drug, dose and indication evaluated in each trial had been FDA approved within 7.5 years, whether it received an off-label recommendation based on National Comprehensive Cancer Network guidelines and whether it produced a substantial clinical benefit based on ESMO Magnitude of Clinical Benefit Scale (MCBS).
The number of participants in phase 2 trials to receive an FDA-approved treatment served as the primary endpoint.
Results
In all, 16.2% (95% CI, 10.3%-22.7%) of patients in the sample group received one of 71 treatment regimens that garnered FDA approval.
“We certainly expected to see the proportion improve [from phase 1 trials], but I did not expect this degree of improvement,” Kimmelman said. “I probably would have said maybe one in 10, or maybe one in 15. I would not have predicted one in six.”
Results showed 19.4% (95% CI, 14.1%-25.8%) of therapies evaluated received off-label recommendations based on NCCN guidelines, and 9.3% (95% CI, 4.7%-14.6%) produced substantial clinical benefit based on ESMO-MCBS.
Nearly one-third (32.5%; 95% CI, 26%-38.8%) of patients participated in a trial in which the treatment advanced to phase 3 testing.
Therapeutic response did not vary significantly by trial sponsorship, drug phase or trial characteristics.
Results showed patients who received immunotherapy or participated in trials that used biomarker enrichment had a higher likelihood of therapeutic benefit. However, the analysis did not have sufficient statistical power to rigorously test that association, Kimmelman said.
“We can’t really make conclusions from our data alone,” he said. “But if you see those trends alongside the literature, it reinforces the idea that if you’re a patient and you have a choice to go into a phase 2 study where you’ll be selected based on a biomarker vs. one where you’re not, go for the study with the biomarker testing.”
Researchers acknowledged study limitations, including use of historical phase 2 trials — which may not provide an accurate representation of current trials — as well as the inability to track which trial characteristics had a higher likelihood of approval and therapeutic benefit.
“I can’t really say whether one in six is good or not,” Kimmelman said. “What I think is encouraging is, if we really are going from one in 80 [for phase 1] to one in six [for phase 2], it suggests we have a really good filter set up. … There’s no reason to put patients in large trials of unsafe and ineffective drugs. You want to eliminate those drugs as early as possible, and it seems like we do a pretty good job of that.”
‘Ethically justify the risks’
The study data reinforced Kimmelman’s view that phase 2 studies benefit science more than patients.
“Just because you get a drug doesn’t mean you always benefit from it,” he said. “In many areas of medicine, including cancer, you often have to treat several patients with a drug for one patient to actually benefit. Some cancer immunotherapies have a number needed to treat of one in four. Some cancer drugs have a number needed to treat of one in 10. If you put that number of needed to treat next to our numbers, it still reinforces that the prospect of actually benefiting when you go into a phase 2 trial is pretty low.”
Kimmelman described clinical trials as “a human experiment.”
“The reason we do clinical trials is not to deliver treatment to patients,” he said. “There isn’t really good evidence that it’s a very effective way to deliver care to patients. The reason we do clinical trials is to answer a scientific question. We’re asking patients to do us a favor and help us answer a scientific question. We ought to have really good science backing the study, and the study ought to be very well designed and implemented from a scientific standpoint.”
Kimmelman has multiple ideas for expanding research into clinical trials so researchers could have more data to maximize overall benefit.
He and colleagues are evaluating the risk-benefit ratio of phase 2 trials based on tumor response and the chances of developing life-threatening toxicities. They added a phase 3 control with that investigation.
Additionally, Kimmelman has a significant interest in evaluating trial participants’ ultimate dream.
“When a lot of patients go into trials, they’re not thinking about the average response patients have when they go into trials like this,” he said. “What they’re thinking about is, ‘If I go into this trial, what’s the chance of my winning the lottery?’ … What’s the probability that if you go into a phase 1 trial that you’re to get access to a drug like imatinib that extends your survival by 20 years. That is such a crucial question to answer for phase 2 trials.”
Kimmelman also wants to know how much information trials derive per patient.
“It’s inconvenient to participate in a trial,” he said. “You have to make extra clinic visits. You may have to experience extra biopsies and whatnot. You’re giving patients a drug that’s not proven safe or effective. You really want to maximize how much information you get.”
Ultimately, these research ideas revolve around one question: “When you run a trial, how do you ethically justify the risks of giving a drug?” Kimmelman asked.
“I’ve always had the view that the best reason to participate in clinical trials is to create treatment opportunities for future patients,” he said. “I still believe that. What this paper suggests is there’s a five-in-six chance you’re going to get a drug that’s not [ultimately] approved. Some patients may think that those one-in-six odds of getting a drug that’s approved are still favorable enough to want to go into a phase 2 study. I’m not going to tell those patients how to think. Our task is to give patients all the information we can and to support them in making a good decision.”
References:
For more information:
Jonathan Kimmelman, PhD, can be reached at jonathan.kimmelman@mcgill.ca.