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Pink Sheet – Breakthrough Therapy: 'A Lower Bar Of Evidence'?

Pink Sheet – Breakthrough Therapy: 'A Lower Bar Of Evidence'?

Executive Summary

MedPAC meeting elicits negative view of designation from one members and no one disagreed. Should US FDA reiterate what the special designation actually means?

It may be time for the US FDA to reiterate to the public the high standard for granting a “Breakthrough Therapy” designation to a promising therapy in development.


There has always been a gray area of what qualifies as a breakthrough and what does not. And that makes complete sense given the range of conditions, hard clinical endpoints and surrogate markers. FDA’s fact sheet on the subject offers two criteria for a drug to warrant breakthrough taken from the law. A breakthrough therapy is a drug:


  • 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.


Those criteria are fairly broad and give FDA maximum flexibility in making a determination. Nevertheless, it’s been over five years since the designation was enacted through (Section 902) of the FDA Safety & Innovation Act (FDASIA), and some clarity on what “breakthrough” actually means with regards to the importance of a given new medicine that received the designation to the public – and payors.


Case in point: A Jan. 11 MedPAC session on recommendations to bring down costs in Medicare Part D with the formal March report to Congress in mind included an odd digression from one of its well-known members.


MedPAC member Rita Redberg (University of California-San Francisco) painted a picture of the special expedited designation as wholly negative.


“There are a lot of really high-priced drugs coming on the market, and the FDA has clearly signaled this is going to increase in number in the next few years,” Redberg said, according to the transcript of the session. That of course references the 46 new molecular entity approvals in 2017 and the assumption that under the current administration, the numbers will only go up, not down.

‘Lower Bar For Evidence’?

Redberg then went further saying explicitly that “breakthrough” is leading to a lower evidentiary standard for approval.


“We have this new ‘Breakthrough’ status, which essentially means that drugs can get on the market with a lower bar for evidence, and there’s supposed to be more post-marketing,” Redberg said. “I think certainly beneficiaries, when they see ‘Breakthrough,’ don’t understand that that means the evidence bar was lowered. It looks actually like things are even better.”


Redberg’s claim may have been highly questionable but there was no apparent disagreement from the rest of the commission. Moreover, she is highly credible and is viewed as an authority on a number of health policy issues.


She is a prominent UCSF cardiologist, chair of CMS’ Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) – which makes recommendations on national coverage decisions for drugs, devices, and services – and editor of JAMA Internal Medicine. She also represents the ACC on the Institute for Clinical and Economic Review (ICER) Advisory Board.


The designation is supposed to mark therapies where efficacy is so dramatic that the goal is to streamline development and assure that all appropriate regulatory questions are answered as quickly as possible.


The most recent data for fiscal year 2018 from Oct. 1 through Dec. 31, 2017 shows a total of 37 “Breakthrough” requests, of which 10 were granted, 8 were denied, and 5 were withdrawn. (The rest are still pending.) In the agency’s biologics center, there have been 8 requests since Oct. 1, with 2 granted, 3 denied and the rest still pending.


Still, Redberg’s claim regarding “breakthrough” may sound familiar. Similar arguments have long been levied against Accelerated Approval. (Also see “Gottlieb Defends Accelerated Approval, Scorns Access Limits By Payors” – Pink Sheet, 23 Oct, 2017.) In that context, while FDA still argues that its standards for evidence are not lower, it is inarguable that FDA is accepting greater uncertainty in efficacy – either a surrogate endpoint or early clinical evidence that needs to be confirmed with post-marketing studies.

Will FDA Ever Set Guideposts?

It’s been more than three years since CDER Director Janet Woodcock for the first time truly put some guideposts around what qualifies for “breakthrough.”


In November 2014, Woodcock attempted to provide a reasonable marker for what constitutes a real breakthrough at the Friends of Cancer Research/Brookings annual conference on cancer clinical research: data showing more than a 50% improvement versus standard therapy on some important endpoint.


At the time, Woodcock noted that the wide range of conditions made it hard to set a bar. Woodcock said. She said that a 10% efficacy benefit fell well short of breakthrough.


On the other hand, Woodcock concluded that a risk reduction of over 50% when compared to an existing therapy on an endpoint like response rate or disease progression would qualify as a breakthrough.


That certainly doesn’t sound like the lower bar that Redberg alluded to at MedPAC.


In fairness, Woodcock did stress at the timethat “breakthrough” requests typically involve data from early stage trials, so in that sense, there are less data to go on. However, that is just to qualify for the designation. Once granted, it leads to the oft-repeated “all-hands-on-deck” approach to advising the sponsor on a drug development plan that will help show the efficacy is in fact real in a larger, well-designed trial of patients.


Interestingly, at the time of the Friends/Brookings meeting, Woodcock foresaw the potential criticism of using early data to designate a therapy and emphasized that “we don’t have to lower the bar to have a Breakthrough program.”


The prospect that “Breakthrough” designation will be translated into shorthand for a “lower bar” in payment policy discussions is a risk for manufacturers. In reality, FDA has set a high bar for “Breakthrough” status, with the vast majority of requests for designation turned down.


In 2014, Woodcock made it clear that FDA is not likely to set a clear threshold to qualify for a “Breakthrough” designation in the near term. It may be time now, however, to do just that before the “low bar” claim starts to stick.…