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Breakthrough Therapy Designation-Not Necessarily a Slam Dunk

Accelerating your CMC Timeline


Breakthrough therapy (BT) designations have been receiving much attention since the Advancing Breakthrough Therapies for Patients Act was approved in 2012. A drug candidate may receive BT designation if it treats a serious or life-threatening disease, and preliminary clinical data suggests that the drug provides a substantial improvement over existing therapies.

BTT status can significantly shorten product and process development as well as launch timelines. However, the FDA has stressed that BT designation does not mean sponsors can do less development; rather they need to start sooner with certain activities. This may necessitate committing development resources while the overall program is still considered high-risk. For example, process development and scale-up may need to start before definitive proof-of-concept (POC) data is available and risk analysis is complete. Postponing risk analysis activities until after POC is achieved will require allocation of additional resources in order to generate the necessary regulatory filing data for an accelerated approval. The bottom line is that BT designation does not change the fundamental FDA expectations. However, the designation will likely change the timing of when certain activities must be completed. FDA has been open to discussions with companies about how best to plan for the completion of certain activities.

At BPTC, we recommend that companies conduct an early risk-benefit assessment to determine what activities to start earlier and identify where there will be a need to deploy more resources later. The tradeoff is between the risk of having less robust quality and CMC information available at the time of license application versus patient benefit by getting the product on the market faster. The associated accelerated clinical timelines will necessitate new approaches to product and process development, commercial readiness, launch and regulatory filings. This can be accomplished by focusing on reliable product supply of appropriate quality at launch, and not worrying as much about process optimization.

When short pivotal trials (< 2 years) are involved, process characterization and validation activities will be on the critical path for inclusion in a license application. The decision to accelerate these activities can require a significant increase in resources. For example,

  • front-loading process characterization studies by using a Quality by Design development strategy before seeking BT designation, or
  • front-loading analytical studies to offset the limited process understanding and to support future comparability analysis, or
  • testing qualification lots before assay validation is completed.

Each of the above options has its own unique associated risks that need to be carefully evaluated as part of the overall risk-benefit assessment.

These risk trade-offs shift the focus on the reliability of the Phase 1 cell line, process and formulation. If a front-loading strategy is followed, only critical CMC issues are likely to be addressed before filing and many post-approval process changes may be needed. This approach may be acceptable for well-characterized products such as monoclonal antibodies, but can lead to significant risk for complex products such as cell therapy products.

Additional acceleration approaches to consider can include leveraging supportive platform process data where applicable rather than generating de novo data. Stability data from representative pilot scale lots with the same formulation can be used as lead-in supportive data if a shorter timeframe, such as 6 or 12 months, of real time stability of commercial lots is submitted. A commitment to provide real time confirmatory data during review and post approval is expected. The sponsor should request flexibility to modify the control strategy, specifications, or Critical Process Parameters post-launch with additional manufacturing experience if they file with more tests initially and provide justification to eliminate some test post-launch.

It is important to understand what CMC/cGMP requirements can be deferred post-approval without compromising patient safety. The sponsor should identify potential patient safety related activities and classify them into three categories:

  • must comply fully to address patient safety
  • may be delayed post filing but completed prior to launch
  • can be deferred until post-approval

Submitting a Post-Approval Lifecycle Management Plan with the license application to support completion of deferred activities post-launch will communicate to the FDA the commitment to follow-through on certain activities. The options described above need to be negotiated with the FDA prior to an application submission. However, once you have successfully negotiated a filing and approval strategy with the FDA, that strategy is very likely to be further complicated by expectations for simultaneous submissions in other markets (EU, Japan, Emerging Markets).

Since its inception, FDA has received approximately 283 requests for BT designations, but fewer than half (103) of the requests have been granted. As of the end of September 2015 (most recent data available), 27 BT commercial approvals have been granted. The actual number of products approved as BTs is lower since this number includes approvals of multiple supplements for the same product. The ratio of requests to grants of BT designation has been relatively steady at approximately 60-65%, but the rate of commercial approvals has declined between 2014 to 2105 (14 versus 10, respectively) This drop may reflect the need to devote significant additional resources to the rapid development of a product with this designation. The BT designation is an extremely useful designation to accelerate your product through the clinic, but may not necessarily accelerate your product approval.


Blog article by: Patti Seymour