Only about 6% of cancer drugs tested in a phase 1 study in 2015 were ultimately approved by the US Food and Drug Administration (FDA) by 2021, a new analysis suggests.

The researchers also found that about 8% of approved agents were subsequently taken off the market.

“The 6% is not a big surprise to us since a few other studies using different methodologies and foci have estimated similar percentages,” Alyson Haslam, PhD, University of California San Francisco, told Medscape Medical News. “When you look at drug development, it makes sense that you have to test a lot of drugs to get one that works, but sometimes it is nice to quantify the actual percentage in order to fully appreciate the process.”

The fact that 8% were withdrawn, however, “elicits the question of how the approval process can be improved to avoid ineffective or harmful drugs from coming onto the market,” Haslam added.

The study was published online June 18 in the International Journal of Cancer.

More Desirable Features?

Monitoring trends over time helps oncologists assess whether more drugs are making it to market, and if certain factors make some drugs more likely to get approved.

Prior published estimates put the likelihood of approval between 6.7% and 13.4%, but these estimates were for drugs tested more than a decade ago.

To provide updated estimates, the researchers searched the literature for all oncology drugs tested in phase 1 studies during 2015 and evaluated their fate in subsequent phase 2/3 studies through FDA clearance.

Overall, the team found 803 phase 1 studies that met initial inclusion criteria; 48 trials that included only Japanese participants were excluded because these studies often evaluated drugs already approved in the US, leaving 755 studies for the 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 trials tested a drug as monotherapy; 43% were combination trials with one dose-escalated drug, and about 10% were combination trials with both drugs dose-escalated.

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 Four (7.8%) were subsequently withdrawn: nivolumab (Opdivo) and pembrolizumab (Keytruda) for small cell lung cancer, olaratumab (Lartruvo) for soft tissue sarcoma, and melflufen (Pepaxto) for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 overall number of approvals.

“We really wanted to look at the end fate of drugs (within a reasonable time frame), which is why we did not include the four drugs that were initially approved but later withdrawn, although this had little impact on the main finding,” Haslam explained.

The estimated probability of any drug or drug combination tested in a phase 1 trial published in 2015 and approved that year was 1.7% and reached 6.2% by the end of 2021, the researchers found.

Monoclonal antibodies had a higher probability of being approved (15.3%) compared with inhibitors (5.1%) and chemotherapy drugs (4.2%).

The FDA was also more apt to green-light drugs tested as monotherapy compared with drug combinations (odds ratio, 0.22). Drugs tested in monotherapy had a 9.4% probability of approval vs those tested in combination, which had a 5.6% probability of being approved when pairing a novel drug with one or more established agents as well as when combining two novel drugs. The probability of approval was <1% for trials testing two established drug combinations.

Other factors that boosted the odds of FDA approval include having a response rate over 40% in phase 1 testing, demonstrating an overall survival benefit in phase 3 testing, and having the trial sponsored by a top-20 drug company compared with a non-top-20 drug company.

Haslam found the last finding rather surprising, given the recent trend for bigger companies to invest in smaller companies who are developing promising drugs, rather than doing all of the development themselves. “In fact, a recent analysis found that only 25% of new drugs are sponsored by larger companies,” she noted.

Reached for comment, Jeff Allen, PhD, who wasn’t involved in the study, noted that “these types of landscape analyses are quite helpful in understanding the current state of oncology science and drug development.”

When looking at a 6.2% success rate for phase 1-tested oncology drugs, “it can be difficult holistically to determine all factors for which development didn’t continue,” said Allen, president and CEO of the nonprofit Friends of Cancer Research.

For instance, lack of approval may not signal the drug was a failure, “but rather an artifact of circumstances such as resource limitations or reprioritization,” Allen said.

Plus, he commented, “I don’t think that we should expect all these early studies to lead to eventual approvals, but it’s clear from the authors’ findings that continued efforts to improve the overall success rate in developing new cancer medicines are greatly needed.”

The study was funded by Arnold Ventures. Haslam and Allen ha ve no relevant disclosures. Study author Vinay Prasad, MD, MPH, receives royalties from Arnold Ventures.

Int J Cancer. Published online June 18, 2022. Abstract

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