Only about 6% of cancer drugs tested in a phase 1 study in 2015 will have been finally approved by the US Food and Drug Administration (FDA) by 2021, a new analysis shows.
The researchers also found that about 8 percent of the approved agents were subsequently withdrawn from the market.
“The 6 percent is not a huge surprise to us, as several other studies using different methodologies and focuses have calculated similar rates,” said Alison Haslam, Ph.D., of the University of California, San Francisco. Medscape Medical News. “When you look at drug development, it makes sense to test a lot of drugs to get one that works, but sometimes it’s nice to quantify the actual rate to fully appreciate the process.”
The fact that 8% were withdrawn, however, “raises the question of how the approval process can be improved to avoid ineffective or harmful drugs entering the market,” Haslam added.
The study was published online June 18 in International Journal of Cancer.
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Observing trends over time helps oncologists gauge whether more drugs are coming to market and whether certain factors make certain drugs more likely to be approved.
Previous published estimates put the likelihood of approval between 6.7 percent and 13.4 percent, but those estimates were for drugs tested more than a decade ago.
To provide updated estimates, researchers searched the literature for all oncology drugs tested in phase 1 trials in 2015 and assessed their fate in subsequent phase 2/3 trials through FDA clearance.
Overall, the team found 803 phase 1 studies that met the initial inclusion criteria; 48 studies involving only Japanese participants were excluded because these studies often evaluated drugs already approved in the US, leaving 755 studies for analysis.
The most common tumor types were solid/multiple tumors (24.2%), leukemias (12.8%), and lung cancer (8.5%). Just under half (47%) of the studies tested a drug as monotherapy; 43% were combination trials with one drug at an increased dose and about 10% were combination trials with both drugs at an increased dose.
The FDA approved 51 drugs during the study period. Four (7.8%) were subsequently withdrawn: nivolumab (Opdivo) and pembrolizumab (Keytruda) for small cell lung cancer, olaratumab (Lartruvo) for soft tissue sarcoma, and melflufen (Pepaxto) for multiple myeloma. These four were not counted in the total number of approvals.
“We really wanted to look at the ultimate fate of the drugs (within a reasonable time frame), so we didn’t include the four drugs that were initially approved but later withdrawn, even though this had little impact on the main finding,” Haslam explained .
The predicted probability for any drug or combination of drugs tested in a phase 1 study published in 2015 and approved that year is 1.7%, and it reaches 6.2% by the end of 2021, the researchers found.
Monoclonal antibodies were more likely to be approved (15.3%) than inhibitors (5.1%) and chemotherapy drugs (4.2%).
The FDA was also more likely to green-light drugs tested as monotherapy compared with drug combinations (odds ratio, 0.22). Drugs tested as monotherapy have a 9.4% probability of approval compared to those tested in combination, which have a 5.6% probability of approval when a new drug is combined with one or more established agents, as well as when two new drugs are combined medicines. The probability of approval is <1% for studies testing two established drug combinations.
Other factors that increased the chances of FDA approval included a response rate greater than 40% in phase 1 testing, demonstration of an overall survival benefit in phase 3 testing, and trial sponsorship by top 20 pharmaceutical companies compared to non-top -20 pharmaceutical company.
Haslam found the latter finding quite surprising, given the recent trend for large companies to invest in smaller companies developing promising drugs rather than doing all the development themselves. “In fact, a recent analysis found that only 25 percent of new drugs are sponsored by larger companies,” she noted.
Reached for comment, Dr. Jeff Allen, who was not involved in the study, noted that “these types of landscape analyzes are quite useful for understanding the current state of oncology science and drug development.”
When looking at a 6.2 percent success rate for phase 1 cancer drugs, “it can be difficult to holistically determine all the factors that didn’t continue,” said Allen, the nonprofit’s president and CEO. Friends of Cancer Research.
For example, the lack of approval may not signal that the drug was a failure, “but rather an artifact of circumstances such as resource constraints or shifting priorities,” Allen said.
He further commented, “I don’t think we should expect all of these early studies to lead to eventual approvals, but it is clear from the authors’ findings that continued efforts are very much needed to improve the overall success rate of developing new drugs for crab .”
The study was funded by Arnold Ventures. Haslam and Allen ha ve no relevant disclosures. Study author Vinay Prasad, MD, MPH, receives honoraria from Arnold Ventures.
Int J Cancer. Published online June 18, 2022. Abstract
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