The Breakthrough Designation Program: Four Factors for Long Term Success

This month Rita Numerof assesses the successes that the FDA’s Breakthrough Therapy Designation has enjoyed to date and explains what this fledgling submission process means for pharmaceutical market access.

The FDA’s Breakthrough Therapy Designation - created when the FDA Safety and Innovation Act was signed on 9 July 2012 - is entering its second year after a successful start.  Enacted to provide another mechanism to accelerate the path of critical therapeutics to market, the statute has exceeded expectations. The regulatory agency has granted the designation a total of 31 times as of October 25, 2013, compared to initial estimates that only 3 or 4 drugs per year would earn the title - and the advantages that follow.


So what does the FDA consider a “breakthrough”? These therapies must both treat a serious or life threatening condition and demonstrate a substantial improvement over one or more clinical endpoints.  The program is intended for early-stage development, as early as Phase 1 and ideally no later than Phase 2.  For the designees, it will mean an early and intense commitment from the FDA to provide guidance on drug development, as well as eligibility for all the benefits of the FDA Fast Track program, such as Accelerated Approval and Priority Review. 

With this accelerated pathway and increased communication with regulators in place, a designee could potentially gain approval nearly three years faster than a product without the designation.  The industry hope is that this regulatory pathway will provide an avenue to get much-needed drugs to patients earlier - in fact, the majority of the current designees are oncology drugs, with others treating severe conditions for which early intervention can extend lives, such as Cystic Fibrosis and Hepatitis C. 

If the first year of the Breakthrough Designation program was characterized by unanticipated demand, the next few years will give us our first sense of results - how the designation translates to getting these drugs to patients who need them.  The longer term success and impact of the program will depend on four questions that will soon be answered:

  1. What is the true volume of applications and designees over time, and does the FDA have the capacity to manage it? 
  2. Can pharmaceutical companies successfully adjust their commercialization planning processes to account for shorter timeframes?
  3. Will Real World Evidence reveal weaknesses about these products that were not evident during the accelerated development and approval process?
  4. Will other activities become a bottleneck to accelerated product launch?

Sustainability of the Initial Pace of Designations

The FDA promises to its Breakthrough designees that they will provide augmented regulatory guidance, product development support, and an accelerated path to approval.  With an estimated time to approval of 53 months (from initiation of Phase 1 through regulatory approval), we may start to see the first designees approved in the next couple of years.  Whether this happens or not will be the first indication of the effectiveness of the program and the commitment of the FDA to the goal of getting crucial drugs out sooner.  

The longer term impact of the legislation will also depend on the rate at which products apply for and receive the designation.  Is the high number of designees in the first year of the program an exception caused by pent up demand, or a true reflection of the current state of innovation caused by the industry’s efforts in recent years to reinvigorate its R&D pipelines?  If it is the latter, the FDA will need to respond to ensure it has the capacity and resources to support this higher than anticipated volume of designees – without compromising its ability to carry out its other duties.

Impact on Commercialization Strategies

Gaining Breakthrough designation will require pharma companies to initiate their market access strategy earlier.

While the FDA has committed to working closely with companies that achieve the Breakthrough designation throughout the development process, the goal is focused only on gaining regulatory approval.  The task of developing a value proposition and market access strategy will be left up to the designees and if all goes according to plan,  assuming they gain early approval, they will have less time to get their strategy in place before launch. 

The current reimbursement environment is already driving manufacturers to provide compelling economic and clinical value that defines and differentiates their product in order to secure optimal reimbursement, yet the very nature of the breakthrough program emphasizes needing less data to get to launch faster. 

Gaining Breakthrough designation will require pharma companies to initiate their market access strategy earlier. Likewise, companies will not have the same opportunity to refine their commercialization strategy as additional data becomes available during late stage (Phase 3) clinical trials.  The shorter timeframe to registration will be a challenge, but the designation should confer some benefit as payers and media critics will have a hard time being negative towards a product whose clinical value has been designated as a “Breakthrough” by the FDA. 

Companies should leverage the designation to create goodwill and anticipation among patients, physicians and payers.  If they can get geared up to collect the right data to present a solid value proposition, manufacturers can ensure that their product retains a competitive edge beyond the early approval process.

The Impact of RWE on Breakthrough Products

The accelerated timeline for approval of breakthrough therapies may leave gaps in clinical safety and efficacy data that is normally collected in later stages of development.  Some problems only become evident as the population increases and the drug is used for longer periods of time. To manage the risk of unforeseen events once the drugs reach large populations, we may see a more extensive use of post marketing surveillance requirements imposed by regulators at the time of approval.

On the one hand, breakthrough therapies entering the market early will have a leg up on their potential competitors in collecting real world evidence to support their value proposition.  Payers are increasingly demanding real world data that demonstrates safety and effectiveness in high-risk patients, reduced risk of complications and side effects, and simplicity of treatments.  The fact that breakthrough therapies are being given the green light early in the game means that they can start collecting this data sooner! 

On the other hand, that same early real world evidence may reveal weaknesses in efficacy, safety, or both.  A critical part of product development for breakthrough therapies is going to have to include a robust strategy for collecting and presenting real world evidence and recognition that pharmacovigilance needs to be incorporated into commercialization activities.

Complementary Activities to Support Breakthrough Products

In addition to the market access and commercialization planning activities described above, other areas of development may also become rate limiting factors that constrain the ability to achieve the reduced time to market that the Breakthrough designation is designed to enable.  Manufacturing requirements and the need for companion diagnostics are two of the most likely bottlenecks. 

The FDA is taking internal steps to overhaul drug manufacturing similar to the Pharmaceutical cGMPs for the 21st Century initiative of a decade ago.  Pharmaceutical companies can also address their own manufacturing limitations to minimize delays.  This may be a more intractable issue for biologics.  It will be interesting to see if manufacturing of large molecules – which have not yet received Breakthrough designation – can be accelerated to the same degree as that of small molecules. 

Many of the therapies that can benefit from Breakthrough designation do so in part because they are able to demonstrate superior efficacy and safety in a targeted patient population.  These targeted therapies often rely on a companion diagnostic to identify the right patients at the right time.  The development and approval processes for these companion diagnostics will need to be similarly expedited to enable the Breakthrough program to achieve its desired goals of getting much needed drugs to waiting patients. 

What’s next?

As the answers to these four questions emerge over the next few years they will reveal whether the expedited approach to regulatory approval provided by the Breakthrough program is sustainable without compromising safety.  If the program is going to be successful, it will require not only a new regulatory approach from the FDA (and hopefully foreign regulators in due course), but also a new approach to commercialization planning on the part of drug manufacturers, who must deal with a reduced timeframe in which to gather and communicate the evidence supporting their products’ value.

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