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Published on: February 6, 2015
Patient burden and clinical advances associated with postapproval monotherapy cancer drug trials: a retrospective
Benjamin Gregory Carlisle1, Adélaïde Doussau1, Jonathan Kimmelman2
1Biomedical Ethics, McGill University, Montreal, Quebec, Canada.
Objectives:
After regulatory approval, drug companies, public funding agencies and academic researchers often pursue trials aimed at extending the uses of a new drug by testing it in new non-approved indications. Patient burden and clinical impact of such research are not well understood.
Design And Setting:
We conducted a retrospective cohort study of postapproval clinical trials launched within 5 years after the drug's first approval, testing anticancer drugs in monotherapy in indications that were first pursued after a drug's first Food and Drug Administration (FDA) license, for all 12 anticancer drugs approved between 2005 and 2007. FDA, Medline and Embase search date 2019 February 12.
Primary And Secondary Outcome Measures:
Our primary objective was to measure burden and clinical impact for patients enrolling in these trials. Each trial was sorted into a 'trajectory' defined by the drug and cancer indication. The risk was operationalised by proportions of grade 3-4 severe adverse events and deaths. The clinical impact was measured by estimating the proportion of patients participating in trajectories that resulted in FDA approval, uptake into National Comprehensive Cancer Network (NCCN) clinical practice guidelines or advancement to randomised controlled trials within 8 years.
Results:
Our search captured 104 published trials exploring monotherapy, including 69 unique trajectories. In total, trials in our sample enrolled 4699 patients. Grade 3-4 adverse events were experienced by 19.6% of patients; grade 5 events were experienced by 2.8% of patients. None of the trajectories launched after initial drug approval received FDA approval. Five trajectories were recommended by the NCCN within 8 years of the first trial within that trajectory. Eleven trajectories were advanced to randomised controlled testing.
Conclusions:
The challenges associated with unlocking new applications for drugs that first received approval from 2005 to 2007 were similar to those for developing new drugs altogether. Our findings can help inform priority setting in research and provide a basis for calibrating expectations when considering enrolment in label-extending trials.
Insights
Clinical trials extending drug uses show significant patient risk with limited success. Post-approval cancer drug trials rarely led to new FDA approvals or guideline inclusion, highlighting challenges in label-extension research.
Area of Science:
- Oncology
- Clinical Pharmacology
- Health Services Research
Background:
- Post-regulatory approval, drug companies, public agencies, and researchers often initiate trials to explore new indications for approved drugs.
- The patient burden and clinical impact of these label-extension trials remain poorly understood, necessitating further investigation.
Purpose of the Study:
- To quantify the patient burden and clinical impact of post-approval clinical trials for anticancer drugs.
- To assess the success rate of extending drug indications through post-approval studies.
Main Methods:
- A retrospective cohort study analyzed 104 post-approval clinical trials for 12 anticancer drugs approved between 2005-2007.
- Trials were categorized by drug-indication trajectories, assessing severe adverse events (Grade 3-4), deaths, FDA approval, National Comprehensive Cancer Network (NCCN) guideline inclusion, and advancement to randomized controlled trials within 8 years.
Main Results:
- The study included 4699 patients across 69 unique trajectories. 19.6% experienced severe adverse events (Grade 3-4), and 2.8% died (Grade 5).
- None of the label-extension trajectories resulted in new FDA approvals. Five trajectories were incorporated into NCCN guidelines, and 11 advanced to randomized controlled trials.
Conclusions:
- The challenges in developing new applications for existing anticancer drugs are comparable to developing entirely new drugs.
- Findings can inform research priority-setting and manage expectations for patients considering enrollment in label-extending trials.
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