medwireNews: Two studies published in the Journal of Clinical Oncology explore the process of drug approval and labeling in the USA, with one characterizing drugs that receive a breakthrough designation and the other examining post-approval modifications of drug labels.
The authors of the first study explain that the FDA’s breakthrough therapy program aims “to expedite the development and review of new medicines” that are “intended to treat a serious or life-threatening disease and, on the basis of preliminary clinical evidence, have the potential to offer substantial improvement over existing treatment options.”
And survey-based studies of both healthcare professionals and lay people have shown that the majority of respondents expect a drug designated as a breakthrough “to represent a major advance” and to be “more effective” than other drugs, say the researchers, who investigated whether this really is the case.
They identified 58 anti-cancer agents that were approved between January 2012 and December 2017, of which 43% received breakthrough therapy designation following the establishment of the program in July 2012.
Drugs designated as breakthrough therapies received approval quicker than other drugs, at a median of 5.2 versus 7.1 years, a significant difference.
But there was no significant difference between drugs with and without breakthrough designation in terms of improvement in progression-free survival, assessed either as the absolute gain or the relative reduction in risk, or response rates.
Breakthrough therapies were not more likely to have a novel mechanism of action, nor were they associated with a reduced incidence of serious adverse events or deaths not attributed to disease progression.
In conclusion, Aaron Kesselheim (Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA) and team say that “[c]ontinued follow-up, rigorous confirmatory studies, and more robust and transparent criteria for breakthrough designation are needed for patients and clinicians to distinguish true breakthroughs from those that are breakthroughs in name only.”
The second study – by Eitan Amir (Princess Margaret Cancer Centre, Toronto, Ontario, Canada) and colleagues – evaluated postmarketing label modifications with a view to assessing whether such changes were more likely for approvals that lacked a supporting randomized controlled trial (RCT).
Of 59 drugs approved for 109 solid tumor indications in the palliative setting during 2006–2016, 15.6% of the indications were not supported by evidence from an RCT.
Post-approval modifications in common adverse events were significantly more likely for indications without a supporting RCT, with modifications in 71% of labels versus 29% for indications with a supporting RCT (odds ratio=5.78).
The analysis also indicated a higher rate of major changes in warnings and precautions for indications approved on the basis of nonrandomized than randomized trials (88 vs 62%), but this was not statistically significant and was likely a false discovery, say the authors.
They add that the groups were comparable with regard to other types of changes, such as indication and usage, dosing and administration, boxed warnings, and contraindications.
“Health care professionals should be vigilant for unrecognized adverse effects when prescribing drugs approved without a supporting RCT,” conclude Amir et al.
They add: “[R]egulators should be aware of the potentially incomplete safety data when considering expedited approval of these drugs and should institute appropriate pharmacovigilance and risk management programs.”
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