Just a 20-minute walk from the Leiden University Medical Center, in Leiden, the Netherlands, is a two-story mural by the American poet e.e. cummings. A fragment reads: “the city sleeps with death upon her mouth having a song in her eyes.”
The poem, included in Leiden’s wall poems project, unwittingly pays tribute to one of the city’s more obscure claims to fame. Leiden was the birthplace of a key research question in cancer: How does a person with cancer choose between length of life and quality of life (QoL)?
In 1994, a team at Leiden University’s Department of Clinical Oncology, headed by psychologist Gwendoline M. Kiebert, PhD, was the first to attempt to quantify how patients with cancer weigh these choices.
Kiebert and colleagues found that patients did not necessarily value survival to the exclusion of everything else. In their article, published in the newly created journal Quality of Life Research, they called for further examination of “the impact of treatment on dimensions of QoL” ― and, in particular, how such data should feed into health-technology assessments.
Thirty years later, it seems that cancer research still struggles with this.
Since the publication of Kiebert’s and colleagues’ article, hundreds of new cancer drugs have been approved, but there is little in the way of QoL data to help physicians and patients weigh treatment options, according to a new article by Canadian researchers.
The team found that just 14% of 214 oncology drug indications that were approved by the US Food and Drug Administration (FDA) from 2006 to 2017 were backed up by QoL data. For indications that were approved by the European Medicines Agency (EMA) during that period, the percentage was 26%.
The researchers focused on approvals by the FDA and the EMA because these agencies tend to drive drug-approval decisions for the rest of the world, commented lead author Kelvin Chan, MD, PhD, a medical oncologist at the Sunnybrook Odette Cancer Center, the University of Toronto, Toronto, Canada.
The study was published online February 1 in JAMA Network Open.
The wafer-thin QoL evidence was all the more remarkable because the cancer indications that were approved were for use in noncurative settings, Chan commented.
“We’ve often heard from patients that they value not only the time they gain from treatments but the quality of the time ― how well they can live during the time that they have,” Chan told Medscape Medical News.
“There’s a mismatch between what the patient wants from anticancer treatments vs the way we have set up our system to develop these drugs, to evaluate these drugs, and to approve these drugs,” he added.
Chan and colleagues’ systematic review included 214 FDA-approved and 170 EMA-approved indications in noncurative settings that were granted from January 2006 to December 2017. The researchers also used QoL data from registration trials published after the drugs’ approvals; the cutoff date was October 2019.
At the time of approval, QoL evidence was available for only 14% of the FDA indications and 26% of the EMA’s indications. By the cutoff date, almost 2 years later, this had increased to 40% and 58% of the FDA- and EMA-approved indications, respectively.
The researchers also assessed minimal clinically important difference values, a standard method of interpreting and contextualizing QoL changes.
They found that at the time an indication got a green light from the FDA in these noncurative settings, only 3% (7/214) of the indications were supported by clinically meaningful improvements in QoL. This increased to just 6% (13/214) by the cutoff date.
This is not the first time such discouraging findings have been reported. In 2017, a British team delved into EMA oncology-drug approvals for the period 2009–2013. Across 68 new indications for 48 cancer drugs in both curative and noncurative settings, the researchers found significant improvements in QoL for only 10% of the indications.
“Ten percent is frighteningly low,” said senior author Ajay Aggarwal, MD, PhD, consultant clinical oncologist and associate professor at the London School of Hygiene and Tropical Medicine, London, the United Kingdom.
Aggarwal told Medscape Medical News: “People want to know that you’re going to either try and prolong length of life or improve quality of life. And if you can give them some surety of that, people are sensible enough. We just need to treat patients as humans who understand ― because they live with the disease ― and give them the evidence they need.”
This lack of data on QoL, as well as a lack of data on overall survival, for newly approved cancer drugs has been repeatedly highlighted by Vinay Prasad, MD, a hematologist-oncologist at the University of California, San Francisco (and a former regular contributor to Medscape). He elaborates in detail on these points in his 2020 book, Malignant: How Bad Policy and Bad Evidence Harm People With Cancer.
Prasad highlighted the issue once again in February 2021 in an invited commentary in JAMA Internal Medicine, in which he and his coauthor, Myung S. Kim, MD, argued that surrogate endpoints such as progression-free survival “are not optimized to ensure that the drug can improve the length or quality of life….
“It is hard to not view the entire global cancer drug ecosystem as broken,” Prasad and Kim concluded.
Prasad and Chan point out that companies that develop new drugs are under no legal pressure to include QoL data in regulatory submissions to the FDA or the EMA.
Speaking for the FDA, Vishal Bhatnagar, MD, associate director for patient outcomes at the FDA’s Oncology Center of Excellence, confirmed the agency’s position in an email.
“The vast majority of submissions in oncology do include this type of information,” Bhatnagar said, “There is no legal mandate that sponsors must collect or submit patient experience data in marketing applications.”
“That’s exactly the issue,” said Chan. “There’s no incentive for manufacturers to do the research and assess whether quality of life is improved or not, no specific levers to mandate the generation of that evidence.”
How has the FDA responded to calls for change?
Almost 10 years ago, the FDA endeavored to rework its framework in what it called “patient-focused drug development.” These efforts took tangible shape following passage of the 21st Century Cures Act in 2016. The plan was to develop eight guidance documents by 2021 on how data regarding the patient’s experience should be generated and used by the FDA.
The FDA Patient-Focused Drug Development Guidance Series will comprise four documents. One is complete.
The most relevant FDA guidance for companies seeking to have drugs approved is Guidance 4: Incorporating Clinical Outcome Assessments Into Endpoints for Regulatory Decision Making. Work on this document kicked off on December 6, 2019, with a 1-day public consultation. The draft guidance is not yet available.
Even when this project is completed, drug developers will not be required to submit QoL data for drug approvals. That would require a change in the law, according to Nick Manetto and colleagues of the US Food and Drug Law Institute. In an article published on December 3, 2020, Manetto and colleagues recommended that “Congress should consider building upon existing law to require that patient experience information be incorporated into product labeling.”
Andrew Bottomley, PhD, is assistant director of the European Organization for Research and Treatment of Cancer (EORTC). He leads EORTC’s Quality-of-life Department from Belgium.
Bottomley told Medscape Medical News, “Of course [patients] want…better survival, but they don’t just want to survive. They want to survive with a good quality of life.”
Bottomley believes that drug developers should be able to outline clearly to patients how they will feel when taking their products. “It’s very important that they can explain [to] the patient, ‘You may live an extra 2 years, but you may feel a bit sick during the first 6 months when you’re under this active therapy. But afterwards, you’re going to be great.'”
Regulatory agencies are not solely to blame for the current situation, he commented. He noted that QoL data that are submitted to them are frequently of poor quality. “Sometimes…the drug companies’ submissions may not have been ― how do I say this? ― the most optimal,” he said. “So, for example, if there’s a lot of missing data, how can an agency draw a conclusion?”
For the past 2 years, Bottomley has led the SISAQOL consortium, which was initiated in partnership with the FDA and the EMA, along with approximately 40 other organizations worldwide. SISAQOL recently published international standards for the analysis of QoL and patient-reported outcome (PRO) data from cancer trials.
Now funded by a 4-year EU grant of €5 million ($5.9 million), SISAQOL is continuing to work with the regulators to “fill in the gaps,” said Bottomley, in order to build a complete guide to standardized QoL and PRO research in cancer.
The ultimate goal, Bottomley said, is “a full program of international guidance to harmonize and standardize all the work in quality of life” that will be officially endorsed by regulators. This will allow sponsors to submit already-compliant, high-quality QoL data that are in conformity with the new rules.
Aggarwal acknowledged the complexity of this issue. He recommends a commonsense approach: “So if you [told] a patient, ‘We can’t tell you in 90% of these drugs whether there’s going to be any improvement in your quality of life,’ you’ve got to ask, are we giving patients the right information before they consent and [to] payers before they pay for those therapies?
“No one’s trying to be controversial; we just have to put the patient at the heart of this,” concluded Aggarwal.
The Canadian Center for Applied Research in Cancer Control is funded by the Canadian Cancer Society Research Institute grant. Chan is on the pan-Canadian Oncology Drug Review Expert Review Committee. Aggarwal and Bottomley have disclosed no relevant financial relationships.
JAMA Netw Open. Published online February 11, 2021. Full text
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