Six years ago, the US Food and Drug Administration (FDA) created a new approval process to speed up the development of drugs intended to treat serious and life-threatening conditions. Known as Breakthrough Therapy designation, the process was designed to get drugs and medications that weren’t previously approved reviewed quicker so they could treat patients with serious health conditions.
A new analysis by the Yale University School of Medicine, published in the Journal of the American Medical Association, found that trials supporting the drugs commonly had small sample sizes and lacked randomisation and control groups. As such, researchers believe both patients and doctors may have been misled by the strength of evidence and that the FDA may need to conduct further research to verify the safety and benefit of the drug beyond the original approval.
Using the FDA database, researchers identified all new drugs approved from January 2012 through to December 2017. For each therapeutic indication granted the Breakthrough Therapy designation, researchers analysed FDA-determined regulatory, therapeutic characteristics and postmarking requirements. Some drugs granted Breakthrough Therapy designation also qualify for other review programs.
Next, researchers identified all trials that supported each drug’s approval and determined the use of randomisation, blinding, comparator group, primary end point and number of patients.
Read more: Why you could be misusing medication without even knowing it
In total, the FDA approved 46 therapeutics with Breakthrough Therapy designation, based on 89 pivotal trials. Cancer treatment was the most common therapeutic with 25 Breakthrough Therapy designations, followed by eight infectious disease treatments and five genetic or therapeutic treatments. While all were granted priority review, 65.2 per cent also qualified for Fast Track review, while 39.1 per cent were granted Accelerated Approval.
It was discovered the median number of patients enrolled among all pivotal trails was 222, with 27 (58.7 per cent) using randomisation, 21 (45.7 per cent) using double-bind allocation, 25 (54.3 per cent) using a placebo comparator group, while 10 (21.7 per cent) used a clinical primary end point. Researchers also found the pivotal trials used to support breakthrough approvals with Accelerated Approval status weren’t as likely as trials without Accelerated Approval to be randomised or include a control group.
“This study of all FDA approvals granted Breakthrough Therapy designation from 2012 through 2017 suggests that pivotal trials supporting these approvals commonly lacked randomisation, double-binding, and control groups, used surrogate markers as primary end points, and enrolled small numbers of patients,” researchers said. “Furthermore, more than half were based on a single pivotal trial.”
Read more: Expert answers: How safe is it to use expired medication?
Researchers concluded that patients and physicians may have misconceptions about the strength of evidence of breakthrough trials and concluded that further researcher by the FDA is “critical” to confirm the safety and benefit of newly-approved therapies and medications.
While Australia doesn’t have specific Breakthrough Therapy pathways, the Therapeutic Goods Administration (TGA) implemented the ‘Priority Review’ and ‘Provisional Approval’ pathways for the registration of certain promising prescription medicines which meet specific eligibility criteria, from 1 July 2017. These were in line with the Australian Government’s response to the Review of Medicines and Medical Devices Regulation.
“The TGA was aware of the criticisms of the US pathways when developing the Australian pathways and have built in additional safeguards to avoid similar concerns,” a spokesperson told Starts at 60. “The key objective of these pathways is to facilitate earlier access to medicines that address unmet clinical needs for Australian patients, without compromising the TGA’s standards for safety, efficacy and quality.”
The Provisional Approval pathway provides earlier access to certain promising new medicines that do not yet have a full dossier of data. This is the most similar to the FDA’s Breakthrough Therapy pathway. Meanwhile, Provisional Approval is open to all promising medicines that comply with the proposed data.