Skip links

“Breakthrough” the Barriers: Breakthrough Therapy Designation for 505(b)(2)

Breakthrough Therapy Designation Will Speed Up the Development and Review Time for Your 505(b)(2) Product

Breakthrough Therapy Designation (BTD) is the most recent addition to the suite of expedited programs offered by the FDA. In comparison to Fast Track Designation (discussed in a prior blog), the qualifying criteria for BTD are more stringent. However, if granted, BTD provides significant Agency commitment and guidance, leading to a more efficient development program and faster time to market. As described below, 505(b)(2) products can and have been approved with BTD.

Breakthrough Therapy Designation History

The origins of the Breakthrough Therapy program date back to 2001; sequencing of the human genome was complete, and the promise of molecularly targeted therapies was becoming a reality. One drug developed during this era was vemurafenib, for the treatment of metastatic melanoma. During Phase 1 studies of vemurafenib, over 80% of patients had tumor reduction – a dramatic improvement compared to the standard of care at the time, which reduced tumor growth in only 10–20% of patients. The Sponsor performed randomized, controlled clinical studies; however, ethical concerns arose about using a treatment shown to be clinically inferior. As more molecularly targeted products were developed, patient advocates urged the FDA to design regulatory approaches to speed the approval process for new products with early demonstration of substantially improved clinical efficacy. This ultimately led to the Breakthrough Therapy Designation program being added to the Food and Drug Administration Safety and Innovation Act of 2012.

Breakthrough Therapy Designation Criteria

As described in Section 506(a) of the FD&C Act, a product can be designated as a Breakthrough Therapy “if the drug is intended, alone or in combination with 1 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 1 or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.”

Similar to Fast Track Designation, 505(b)(1) and 505(b)(2) products are eligible for BTD. As long as the product is being developed for a serious condition and can meet the criteria for clinical evidence of improvement over existing therapies, it can be granted BTD. Four 505(b)(2) products that were granted BTD have been approved by FDA: Xuriden™ (uridine triacetate for treatment of hereditary orotic aciduria), Epclusa® (sofosbuvir and velpatasvir for treatment of adult patients with specific hepatitis C genotypes), Vyxeos™ (daunorubicin and cytarabine for treatment of adults with acute myeloid leukemia or acute myeloid leukemia with myelodysplasia), and Austedo®(deutetrabenazine for treatment of chorea associated with Huntington’s disease and tardive dyskinesia in adults).

The qualifying criteria for BTD are the following:

Serious Condition: The FDA considers a condition “serious” when it has a substantial impact on day to day functioning, survival, or if the condition (if left untreated) will progress in severity. The drug under development must have an effect on the condition itself or a serious aspect of the condition. See our previous blog on Fast Track Designation for more about the FDA’s definition of “serious condition.”

Preliminary Clinical Evidence: A key differentiator between Fast Track Designation and BTD is the requirement for preliminary (early phase) clinical data that show substantial improvement in a clinically significant endpoint over currently available treatments. Determination of “substantial” improvement is a matter of judgement, but the importance of the clinical effect and the magnitude of the effect are taken into consideration.

Some approaches to demonstrating substantial improvement include:

  • A much greater or more important response to a clinically meaningful endpoint of the new drug when compared with available therapy, a placebo, or a well-documented historical control
  • The new drug added to available therapy results in a much greater or more important clinical response compared to available therapy in a controlled study or to a well-documented historical control
  • The new drug can affect the underlying cause of the disease, or reverse or inhibit disease progression, in contrast to available therapies
  • The new drug has an important safety advantage that relates to serious adverse reactions compared with available therapies of similar efficacy.

For BTD, demonstration of an effect on a clinically significant endpoint is required. This type of endpoint is typically based on irreversible morbidity or mortality (IMM), or on symptoms that represent serious consequences of the disease. Other clinically significant endpoints can refer to findings that suggest an effect on IMM or serious symptoms can include:

  • An effect on a surrogate endpoint or on an intermediate clinical endpoint considered reasonably likely to predict a clinical benefit
  • An effect on a pharmacodynamic biomarker that strongly suggests the potential for a clinically meaningful effect on the underlying disease
  • A significantly improved safety profile compared to available therapy with evidence of similar efficacy

Breakthrough Therapy Designation Application Timeline

BTD can be requested at the time the IND is opened. BTD can also be requested anytime thereafter, although ideally no later than the End-of Phase 2 meeting.

The FDA response time for BTD is within 60 calendar days of receipt of the request.

Breakthrough Therapy Designation Benefits

BTD carries substantial regulatory benefits. BTD grants Sponsors all the benefits of Fast Track Designation, including expedited and rolling review, plus a significant commitment by the FDA to assist in making the development program as efficient as possible. Programs with BTD are eligible for the following:

  1. Intensive guidance on an efficient drug development program, beginning as early as Phase 1. This includes a commitment to timely advice and interactive communications from the Agency. With this increased support, the Sponsor and the Agency can discuss alternative clinical trial designs or interim data analysis. These approaches can reduce the size of trials and accelerate the overall development program.
  2. Organizational commitment involving senior managers. The FDA allocates senior managers, experienced reviewers and regulatory health project managers, and a cross-disciplinary project lead to the program. This promotes coordinated and timely internal interactions and communications with the Sponsor.

This additional regulatory support by the Agency can significantly streamline a development program. A recent analysis of 2012–2016 drug approvals found that the development time from IND application to FDA approval was, on average, over 3 years (!) shorter for BTD products than for products without this designation (Hwang, 2017).

Think your product may qualify for Breakthrough Therapy Designation? Contact Premier Consulting to discuss it with our regulatory team. Using innovative approaches, we have helped our clients qualify for these programs and ensure the regulatory benefits are used to their full potential. We can help you determine if your product meets the requirements for Breakthrough Therapy Designation and guide you through the application process. For more information, contact us.


Lisa Crose, PhD
Scientific and Regulatory Specialist

Angela Drew, PhD
Product Ideation Consultant