An FDA “Breakthrough” tag, which has been around since 2012, was once a highly coveted badge that in essence allows the regulator to help speed up development of new meds, and it was believed initially that these would be fairly rare occurrences held back for some truly innovative treatments.
Now, however, the FDA seems to be giving out these designations like candy, and not a month appears to go past without yet another experimental med gaining this label.
But just what does it really mean? Officially, a Breakthrough Therapy Designation (BTD) will only be given out when a med in development is:
“Intended alone or in combination with one or more other drugs to treat a serious or life threatening disease or condition, and ... preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.”
But this has led to some confusion, with a recent report suggesting that the public believed it carried a heavier meaning than implied.
In other studies, Dr. Steven Woloshin, professor of medicine at Dartmouth Institute and an author of two academic reports on the FDA’s expedited programs, has found that consumers and physicians mistakenly substitute the dictionary version of “breakthrough”:, meaning a sudden, dramatic and important discovery, when they hear about the FDA designation.
It doesn’t mean this in the FDA context, however, and a drug must simply show early clinical promise, with the caveat that this may not always be the case.
Back in April, the U.S. regulator appeared to acknowledge that this could be misleading.
Dr. Richard Moscicki, deputy director for science operations at the Center for Drug Evaluation and Research, said in a posted Q&A on BTD status: “Perhaps we should have used the term ‘potential breakthrough’ when the program was named to cut down on confusion, although I suspect it even then that the word 'breakthrough' would have appeared on its own in media stories.”
But its name has remained, and BTDs have now been given out to a swath of biopharmas, from the big boys at Roche, Pfizer and Merck, to Exelixis, Acadia and Gilead.
Many of these have been in cancer indications, but they have certainly not been limited to oncology, with BTDs also handed out for hep C, idiopathic pulmonary fibrosis, cystic fibrosis and a series of rare disorders.
Often, news of such a designation (which is requested by a company) will see a public biopharma’s shares tick up, notably for smaller biotechs, and it is often intrinsically seen as positive and has also even been a boost to a company’s IPO hopes.
But in reality, this tag has not always brought with it good luck in the longer term, and a number of these breakthroughs have over the past year broke down and failed to deliver in the lab.
Let’s take one of the more recent and, for the biotech, devastating: Seres Therapeutics. In the summer of 2015, it was riding high after getting a BTD for its lead microbiome treatment, SER-109, a Tylenol-sized capsule designed to treat recurrent Clostridium difficile infections by essentially changing the weather in the gut.
It was in midstage testing and, at the time of the BTD, was prepping for an IPO, which just weeks later it got off, raising $134 million. Fast forward to summer 2016, and the biotech posts miserable data showing SER-109 failed to outperform a placebo in terms of cutting the risk of infection. Its shares fell 70% premarket on the news.
Then there’s Aduro’s pancreatic cancer immunotherapy combo of CRS-207 and GVAX, which gained a BTD in the summer of 2014, with the biotech getting off a $119 million upsized IPO nearly a year later—to then see its therapy fail to hit its primary endpoint in May of this year.
And it’s a similar tale for Clovis Oncology and its lung cancer candidate rociletinib, which was given a BTD back in May 2014. Two years later, the biotech buried the drug after ending all ongoing studies, including the key pivotal trial, and cut a third of its staff after the FDA issued a direct message that it is prepping a formal rejection of the drug.
And just last month, Japanese pharma Daiichi Sankyo and its drug partner Plexxikon stopped taking on new patients in a late-stage trial of their BTD rare cancer candidate on the advice of the Data Monitoring Committee amid safety concerns. This isn’t a failure, and the trial may re-start soon, but it is still a setback for both co’s.
As of July 18 this year, the FDA had approved 46 BTD products, according to a database from Friends of Cancer Research, and lists that there have been 441 total requests for the designation, with 145 designations granted. The ones that have so far failed or stumbled are small in comparison, but it feels inherently wrong to find that a so-called breakthrough drug has flopped.
BTD is about promise, but the language around its use remains not vague, but all too clear about what it is: a medical breakthrough conjures up images of cures, remissions and a leap in innovation, but this is rarely the case with BTD assigned meds that have made it in the clinic, let alone those that have failed.
It's not an exact science, but BTD gives out extra hype (and biopharmas don’t need help in that department) for meds that have an innately precarious path to approval, especially when they are further back in that clinical development pathway.
As Dr. Moscicki explained himself: “In reality, new drug candidates described as 'breakthroughs' by the media, and sometimes even those given a Breakthrough Therapy designation by FDA, look really good in their early trials, but upon further study, unfortunately fail to deliver on the promise they had initially shown.
“What I’d like the public to understand is that the FDA tags drug candidates early in the development process with the ‘breakthrough’ designation because they have the potential to be true breakthroughs in the long run. Drugs that receive the breakthrough designation have given a signal during testing that encourages CDER to invest a major effort and make sure that they are evaluated as efficiently as possible.”
The FDA cannot foresee efficacy and/or safety issues in the future, as well as manufacturing glitches, which can and do regularly hit drug development. It can only go by its own limited criteria and data coming from a company, and the regulator cannot be held responsible for BTD meds that don’t make it.
Its intentions are to help, and alongside its priority reviews, fast track and orphan designations, it wants to incentivize innovation and speed—both of which are laudable aims. But it must remain careful not to overhype, as this can erode its very meaning and intentions, and put extra pressure on biopharma innovation, that can’t by its nature always deliver.