Extending FDA-approved cancer drug indications requires high patient numbers, study finds

In a recent article published in Scientific Reports, researchers estimated the number of patient participants needed for label-extension efforts (to obtain secondary approval) of a new cancer drug that received its first United States Food and Drug Administration (US-FDA) approval.

Study: Large numbers of patients are needed to obtain additional approvals for new cancer drugs: A retrospective cohort study. Image Credit: Image Point Fr/Shutterstock.comStudy: Large numbers of patients are needed to obtain additional approvals for new cancer drugs: A retrospective cohort study. Image Credit: Image Point Fr/Shutterstock.com


During the label extension of a drug, researchers add more indications to an FDA label based on its post-approval 'trajectory,' i.e., a series of clinical trials testing unique drug-indication pairing.

The study estimated the patient participants needed to achieve an off-label recommendation and secondary approvals with substantial clinical benefits per the National Comprehensive Cancer Network clinical practice guidelines (NCCN-CPG) and the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS), respectively.

The former is more permissive, while the latter is a more stringent drug development milestone.


The number of patients required in label extension research, a narrow version of drug repurposing, is a key metric of drug development efficiency. It determines whether an approved new drug will eventually reach the end user. 

Clinical trials, especially for cancer drugs, have high failure rates and lengthy timelines; also, nearly one-third aim at extending the label of approved drugs.

While label-extension efforts involve less uncertainty concerning the safety of drugs under testing, several factors diminish their efficiencies relative to pre-approval research.

In pre-approval stages, drug companies test drugs in populations most likely to respond to a drug, e.g., people having appropriate biomarkers, which minimizes the time and costs of drug testing. However, in the post-approval settings, companies' diminished incentives to maximize efficiencies erode gains in efficiency.

Even though pharmaceutical companies bear most of the risks and expenses associated with clinical trials, patient-participants also endure trial-related risks and costs. They make clinic visits, undergo invasive procedures (e.g., repeated biopsies), and cope with the side effects of study interventions.  

Thus, it is crucial to better understand the most efficient drug development aspects from a patient's point of view to help policymakers and academic researchers balance their approach toward these efforts.

In this way, patients and patient advocates could also maximize the value of their participation in clinical research.

About the study

In the present study, researchers extensively searched Drugs@FDA to identify all cancer drugs receiving approval between January 1, 2012, and December 31, 2015.

This search criterion allowed follow-up of secondary drug approvals of new cancer drugs for up to six years. Next, they classified these novel cancer drugs as intended for cytotoxic, targeted, immunotherapy, or others.

Further, the researchers searched ClinicalTrials.gov to capture all clinical trials initiated after the drugs' initial FDA approval. In addition, they ensured that every drug in the sample had an equivalent amount of time to reach a milestone.

Regarding milestone attainment, they obtained several secondary approvals stemming from post-approval trajectories. Secondly, they determined whether trajectories led to an FDA approval per ESMO-MCBS or a recommendation in NCCN CPG.

The team performed a descriptive analysis of all the outcomes. The primary outcome was the number of patients enrolled in all post-approval trajectories divided by the number of secondary FDA approvals.

Additionally, they evaluated the number of patients needed per approval for industry-initiated vs. non-industry-initiated trajectories.

Furthermore, the team performed a post-hoc analysis evaluating the proportion of approved drug indications for a rare cancer (having an incidence of less than six per 100,000).


For label extension of a prior FDA-approved drug, 9,253 patient participants were needed, whereas obtaining a clinically beneficial secondary approval per ESMO-MCBS criterion required 32,387 patient participants.

However, obtaining an NCCN recommendation for a secondary FDA approval required only 4627 patient participants. Industry vs. non-industry-initiated drug label extension efforts needed a comparable number of patient participants.

Note that industry-initiated trajectories comprise only 18% of all 'trajectories'; however, they are more successful than non-industry-initiated trajectories, fetching 50% of secondary FDA approvals.

Regarding pre- vs. post-approval drug development efficiencies, the study results suggested that the patient participants needed to obtain the first secondary approval was comparable to the number of patient participants required for the first FDA licensure.

Simply put, post-approval development was not very efficient on a per-patient basis compared to the first pre-approval drug discovery (5.4% vs. 19%). 

Further, the authors noted that the proportion of drug development trajectories employing biomarker enrichment was the same for pre- and post-development license trials, suggesting that biomarker use might not be the reason for the decline in the number of post-approval drug development trials getting new FDA approvals.

Consistent with these findings, another study found that cancer drugs approved between 2005 and 2007 received no new FDA approvals despite 69 disease-indication pairings launched into these trials.

Moreover, only 15% of these secondary approvals occurred within six years of first licensure for these cancer drugs.

Perhaps label extension efforts are less clinically impactful than the original drug approval based on the effect sizes of approved indications.

The researchers could not conclude whether lower investments in post-approval trials lower the number of post-approval drug development trials ending up in new FDA approvals or it simply reflects a poor probability of scientific hypotheses tested after approval being relevant.


Overall, the study remarkably demonstrated that label extension of an FDA-approved cancer drug required the enrollment of many patient participants (~129,548) in a post-approval clinical trial.

These trials are more likely to advance treatment options for rare cancers. Moreover, they validate cancer drugs' effectiveness, pharmacology, and safety profile.

Future studies should investigate the reasons for higher failure rates of post-approval drug development efforts than pre-approval efforts.

Resolution of this issue could help improve the success rates of post-approval clinical trials, which are crucial for advancing cancer research and improving patient care.

Journal reference:
Neha Mathur

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.


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