Cancer Drug Approvals Are Speedier, But at What Cost? Safety, benefits from accelerated reviews questioned
The FDA’s breakthrough therapy designation program has led to faster approval times for cancer drugs but not necessarily better or safer drugs, according to an analysis of recent approvals.
A review of cancer drugs approved from 2012 through 2017 showed that drugs receiving breakthrough therapy designation from the FDA reached the market 2 years faster than did drugs that did not get the designation. Drugs with and without breakthrough designation led to similar progression-free survival (PFS), objective response rate in solid tumors, death rates, and serious adverse events.
A separate analysis of drug approvals with solid-tumor indications showed that approvals without support from randomized, controlled trials (RCTs) were associated with higher rates of postapproval safety-related label modifications as compared with drugs and indications that had RCT evidence.
Authors of an editorial, which was published along with the two studies in the Journal of Clinical Oncology, said the analyses “challenge us to consider additional steps toward finding the right balance between enhanced drug access and patient safety.”
“A physician’s charge is to first, do no harm,” wrote Nicole M. Kuderer, MD, of Advanced Cancer Research Group, and Gary H. Lyman, MD, of Fred Hutchinson Cancer Research Center, both in Seattle. “Similarly, the FDA needs to first and foremost protect patients from serious adverse drug effects while it provides reasonable and timely access to promising new therapies for life-threatening conditions, especially those patients for which few remaining options exist.”
Congress established the breakthrough therapy program in 2012 to expedite development and review of new drugs. The program targets drugs for serious or life-threatening diseases and that have potential to offer substantial improvement over existing therapies, Aaron S. Kesselheim, MD, JD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, and co-authors said in the introduction to their analysis.
The program appears to have helped reduce drug development times, particularly with regard to cancer therapies, which accounted for more than half of all breakthrough-designation drugs approved since the program’s inception through the end of 2017, the authors continued. Beyond expedited review and approval, the impact of the program has remained unclear.
To understand the characteristics of cancer drugs approved through the breakthrough-therapy program, Kesselheim and coauthors evaluated the efficacy and safety of breakthrough drugs and compared findings with those associated with non-breakthrough drugs approved through 2017. Of the 58 new cancer drugs approved, 25 (43%) received the breakthrough-therapy designation. The analysis included about 7,000 patients treated with breakthrough therapies and about 12,000 patients treated with drugs that did not receive the designation.
Breakthrough status was associated with a median time to initial FDA approval of 5.2 years versus 7.1 years for the non-breakthrough drugs (P=0.01). Median PFS for breakthrough therapies was more than double that of non-breakthrough drugs, but the difference did not achieve statistical significance (8.6 versus 4.0 months, P=0.11). The median response rate for breakthrough drugs was 37% versus 39% for non-breakthrough drugs (P=0.74).
Breakthrough therapies were no more likely to represent a novel mechanism of action as compared with non-breakthrough drugs (36% versus 39%, P=1.00). Serious adverse events occurred in 38% of patients treated with breakthrough drugs and 36% of those treated with non-breakthrough drugs (P=0.93), and mortality unrelated to disease progressions in clinical trials was 6% with breakthrough drugs and 4% with non-breakthrough drugs (P=0.99).
“Although some therapies demonstrated clinically meaningful benefits, to date there is little evidence that breakthrough-designated cancer medicines offer substantially improved efficacy or safety or are more likely to act via a novel mechanism of action, as compared with non-breakthrough-designated drugs,” Kesselheim and coauthors concluded.
The second analysis focused on new indications for FDA-approved drugs used to treat solid tumors. The primary objective was to determine whether approval without supporting evidence from a RCT was associated with modifications to indications, dosing, or toxicity after FDA approval, as reported by Eitan Amir, MD, PhD, of Princess Margaret Hospital and the University of Toronto.
The review encompassed January 2006 through December 2016 and involved 59 drugs and 109 indications for solid tumors, as identified from the FDA website. Of 109 indications granted, 17 (15.6%) were not supported by a RCT. The authors’ analysis showed that indications without RCT support were more likely to:
- Require a companion diagnostic test (OR 3.90, P=0.02
- Have surrogate endpoints as primary outcomes (OR 7.88, P<0.001)
- Have breakthrough designation (OR 7.62, P=0.006) or accelerated approval (OR 17.67, P<0.001)
- Have post-approval major modifications of warnings and precautions (88% versus 62%, OR 4.61, P=0.05
Post-approval major modifications in indication, usage, dosing, administration, boxed warnings, and contraindications occurred in similar proportions of indications with and without RCT support.
“Cancer drugs approved by the FDA without supporting RCTs were associated with more postmarketing safety-related label modifications relating to adverse events,” Amir and coauthors concluded. “Healthcare professionals should be aware of this and should practice increased vigilance when using such drugs in the early post-approval setting.”
Hwang disclosed a relationship with Bain Capital. One or more co-authors disclosed relationships with Aetion, Chordata, Merck, PCORI, Vida Health, Roche, WntRx, and AstraZeneca.
Shepshelovich reported having no relevant disclosures with industry. Coauthor Eitan Amir disclosed a relationships with Apobiologix.
Kuderer disclosed relationships with Generex Biotechnology, Janssen, Coherus Biosciences, Halozyme, G1 Therapeutics. Myriad Genetics, Mylan, Celldex, and Amgen. Lyman disclosed relationships with Generex Biotechnology, Halozyme, G1 Therapeutics, Coherus Biosciences, and Amgen.
Journal of Clinical Oncology
Source Reference: Hwang TJ, et al “Efficacy, safety, and regulatory approval of Food and Drug Admnistration-designated breakthrough and nonbreakthrough cancer medicines” J Clin Oncol 2018; 36:1805-1812.
Journal of Clinical Oncology
Source Reference: Shepshelovich D, et al “Postmarketing modifications of drug labels for cancer drugs approved by the US Food and Drug Administration between 2006 and 2016 with and without supporting randomized controlled trials” J Clin Oncol 2018; 36:1798-1804.
Journal of Clinical Oncology
Source Reference: Kuderer NM, Lyman GH “Evolving landscape of US Food and Drug Administration drug approval in te era of precision oncology: Finding the right balance between access and safety” J Clin Oncol 2018; 36:1773-1776.
Originally published on medpagetoday.com