Benefit, burden, and impact for a cohort of post-approval cancer combination trials
Benjamin Gregory Carlisle1, Adélaïde Doussau1, Jonathan Kimmelman1
1Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, Montreal, QC, Canada.
Background:
After approval, drug developers often pursue trials aimed at extending the uses of a new drug by combining it with other drugs. Little is known about the risk and benefits associated with such research.
Methods:
To establish a historic benchmark of risk and benefit, we searched Medline and Embase for clinical trials testing anti-cancer drugs in combination within 5 years of approval by the Food and Drug Administration of 12 anti-cancer "index" drugs first licensed 2005-2007 inclusive. Risk was assessed based on grade 3 or above drug-related adverse events; benefit was assessed based on efficacy outcomes and advancement of combinations into clinical practice guidelines or approval by the Food and Drug Administration.
Results:
We captured 323 published post-approval trials exploring combinations, including 266 unique combination-indication pairings and enrolling 29,835 patients. The pooled risk ratios for treatment-related grade 3-4 severe adverse events and deaths attributed to the study drugs for trials randomized between a combination arm and a comparator were 1.54 (1.33-1.79) and 1.51 (1.16-1.97), respectively. The pooled hazard ratios for overall survival and progression-free survival were 0.99 (0.92-1.05) and 0.85 (0.79-0.93), respectively. None of the combination-indication pairings launched after initial drug approval received approval by the Food and Drug Administration, and 13 pairings (4.9%) were recommended by the National Comprehensive Cancer Network within 5 years of the first trial within that pairing. The proportion of patients in our sample who participated in trials leading to an approval by the Food and Drug Administration or a National Comprehensive Cancer Network guideline recommendation was 12.7% with 5 years of follow-up, and 22.3% among pairings for which there were 8 years of follow-up.
Conclusion:
Patients were just as likely to benefit in the treatment arm as the control arm in terms of overall survival, but they were more likely to experience a treatment-related severe adverse event in post-approval trials of combination therapy.
Insights
Post-approval combination cancer drug trials show increased severe adverse events without improving overall survival. While some combinations gain guideline recommendations, FDA approval is rare, highlighting risks in extending drug uses.
Area of Science:
- Oncology
- Clinical Pharmacology
- Drug Development
Background:
- Post-approval studies frequently investigate combining new drugs with existing therapies.
- Limited data exists on the risks and benefits of these combination trials.
Purpose of the Study:
- To establish a benchmark for risk and benefit in post-approval combination cancer drug trials.
- To analyze trials conducted within five years of index drug approval.
Main Methods:
- Searched Medline and Embase for clinical trials of anti-cancer drug combinations.
- Included trials within 5 years of FDA approval for 12 index drugs (2005-2007).
- Assessed risk via severe adverse events (Grade 3+) and benefit via efficacy and guideline/FDA approval.
Main Results:
- 323 trials (266 unique pairings, 29,835 patients) were analyzed.
- Pooled risk ratio for severe adverse events (Grade 3-4) was 1.54; for deaths, 1.51.
- Pooled hazard ratios: Overall Survival 0.99, Progression-Free Survival 0.85.
- No combination-indication pairings received FDA approval post-launch; 4.9% were NCCN recommended within 5 years.
Conclusions:
- Patients in combination arms faced higher severe adverse event rates.
- Overall survival benefit was similar to control arms in post-approval combination trials.
- Limited clinical practice guideline advancement suggests modest benefit realization.
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