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Break Through the Barriers: Breakthrough Therapy Designation for 505(b)(2)

Breakthrough therapy designation will speed the development and review of your 505(b)(2) product

Breakthrough therapy designation is the most recent addition to the suite of expedited programs offered by the FDA. Compared to fast track designation (discussed in a prior blog post), the qualifying criteria for breakthrough therapy designation are more stringent. However, if granted, breakthrough therapy designation 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 breakthrough therapy designation.

Breakthrough therapy designation history

The origins of the breakthrough therapy program date 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 treatment of metastatic melanoma. During Phase 1 studies of vemurafenib, more than 80 percent of patients experienced tumor reduction — a dramatic improvement compared to the standard of care at the time, which reduced tumor growth in only 10–20 percent 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 breakthrough therapy designation. 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 breakthrough therapy designation. Four 505(b)(2) products that received this designation have been approved by FDA as of October 2018: 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 breakthrough therapy designation are as follows:

Serious condition. The FDA considers a condition “serious” when it has a substantial impact on day-to-day functioning or survival, or if the condition, left untreated, will progress in severity. The drug under development must have an effect on the condition itself or on a serious aspect of the condition. See our previous blog post 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 breakthrough therapy designation 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 judgment, but the importance of the clinical effect and the magnitude of the effect are taken into consideration.

Some examples of a drug demonstrating substantial improvement include:

  • The drug shows a much greater or more important response to a clinically meaningful endpoint 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

Demonstration of an effect on a clinically significant endpoint is required for breakthrough therapy designation. 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 be findings that suggest an effect on IMM or serious symptoms and 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

Breakthrough therapy designation can be requested at the time the IND is opened or anytime thereafter, although ideally no later than the end-of-Phase 2 meeting. The FDA response time for breakthrough therapy designation is within 60 calendar days of receipt of the request.

Breakthrough therapy designation benefits

Breakthrough therapy designation carries substantial regulatory benefits. It 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 breakthrough therapy designation 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 2012-16 drug approvals found that the development time from IND application to FDA approval was, on average, more than three years (!) shorter for breakthrough therapies 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 that 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.


Angela Drew, PhD
Product Ideation Consultant