Earlier this month, the Food and Drug Administration announced the creation of Project Facilitate. This pilot program facilitates access to innovative treatments for cancer that have not yet been approved by individuals who aren’t able to enroll in clinical trials. This move suggests that the FDA finds the approval process for cancer drugs to be too slow.
At the same time, some experts want the FDA to slow down the approval process for cancer treatments. A recent article in JAMA Internal Medicine argued that cancer drugs are receiving accelerated approval without sufficient evidence proving they are safe and effective. More specifically, the article raised concerns over the widespread use of surrogate outcomes to measure treatment efficacy.
Surrogate outcomes, such as progression-free survival and treatment response rate, are imperfectly correlated with overall survival. The authors suggest that the FDA is approving cancer drugs too quickly, as these surrogate endpoints may not provide sufficient evidence of improved long-term survival.
Is the FDA correct in its approach? Research I have done with various colleagues argues that if you believe in patient-centered care, the FDA is indeed doing the right thing.
Taylor Schwartz, Tony Okoro, John Romley, and I looked at whether cancer patients and physicians had similar preferences regarding the risks of treatment. We surveyed patients with advanced melanoma and physicians who treat the disease, asking them to choose between two hypothetical cancer therapies: Therapy A provided certain survival of exactly four years, no more and no less. Therapy B had the same average survival as Therapy A, but was riskier. Specifically, half of individuals who received Therapy B lived for less than a year, but 1 in 5 lived for more than seven years.
While only 30% of physicians preferred the riskier Therapy B, 63% of melanoma patients preferred it. In fact, patients were willing to give up one year of certain survival on average in order to have a chance to get Therapy B.
We got similar results when we repeated this survey in patients with lung cancer and physicians who treat it.
The phenomenon that individuals with terminal illnesses prefer riskier therapies is known as the value of hope, something that has been confirmed in other studies. Cancer patients — or more generally people with terminal illnesses — have a strong preference for therapies that provide some chance of long-term, durable survival even if they are riskier.
While our study described patients’ preferences when the survival outcome is known, in most cases the odds of survival are uncertain because many clinical trials use surrogate endpoints. Other research I’ve conducted shows that many surrogate outcomes are often good — albeit imperfect — predictors of real-world survival.
In a study published in Value in Health, my colleagues and I used data from clinical trials and real-world evidence to determine how well surrogate endpoints predicted real-world overall survival. The study followed a three-step process. First we examined 21 trials that reported both a surrogate and an overall survival endpoint and looked at reported treatment effectiveness using both. Next we used real-world data to measure the effectiveness of these treatments on overall survival. Finally we measured the ratio of treatment efficacy assessed in the clinical trial with that measured using real-world survival data.
Our study found that treatments were 16% less effective in the real world than predicted in the trial based on surrogate endpoints. The percentage varied depending on tumor type, the number of patients enrolled in the clinical trial, line of therapy, and a number of other factors. Overall, we found that while a discount should be applied to evidence from clinical trials using surrogate endpoints, these endpoints are useful predictors of real-world effectiveness.
A final item to consider when weighing whether to speed up or slow down access to cancer treatments is the cost of delays. These costs occur along two dimensions: money and health.
The FDA could require longer clinical trials or additional confirmatory trials. These trials would clearly be useful for providing additional high-quality evidence, but doing so comes with additional financial costs. If clinical trial requirements become stricter, it is likely that drug manufacturers’ research and development costs will rise. In response, they may raise prices to offset higher R&D costs. Or, if prices are held constant, there is likely to be less innovation.
In addition to the monetary cost, any FDA push for more detailed evidence requirements would likely delay access to treatment and have an adverse impact on patient health. Research I conducted with other colleagues found that faster access to novel cancer therapies dramatically improves outcomes. Specifically, we found that cancer patients who lived in regions with the most rapid access to novel cancer therapies survived 10 months longer than individuals who lived in regions with the slowest access.
Thus, while increased evidence requirements may improve health outcomes by ensuring that cancer drugs are safe and effective, it’s important to consider that the delays they cause may cost lives if patients who need treatment can’t receive it.
The argument I’m making is not that we don’t need robust evidence on the safety and efficacy of cancer drugs. We do. Rather, when making decisions about the required level of evidence to approve cancer drugs, the FDA should continue taking a more patient-centered approach and weigh more carefully the costs of delayed access to novel cancer treatments.
Jason Shafrin, Ph.D., is the senior director of policy and economics at Precision Xtract, a consultancy to the pharmaceutical and life sciences industries, and the founder and editor of the Healthcare Economist blog.
Thought this quote was particularly illuminating: “patients were willing to give up one year of certain survival on average in order to have a chance to get Therapy B.” Super powerful statistical analysis!
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