Breakthrough therapy designation: FDA’s newest mechanism for accelerating approval for promising pipeline therapies

In July of 2012, a provision in the newly ratified FDA Safety and Innovation Act (FDASIA), paved the way for FDA to further assist drug manufacturers in expediting the development and introduction of new drugs demonstrating early signs of advancement in the treatment of key conditions. Known as the “breakthrough therapy” designation, this new tool is seen by many as yet another positive sign that FDA is committed to ensuring that innovative drug products are brought to market even more quickly for the millions of patients with serious medical conditions, desperately in need of new therapeutic options.

Section 506(a) of the FD&C Act, as amended by FDASIA, provides for the designation of a drug 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.”

While FDA has introduced various programs since 1988 to speed market accessibility of drugs for serious conditions, concerns have lingered that such pathways have still not been sufficient enough in propelling market availability of important pipeline therapies for those most in need. These programs have included "fast-track designation," "accelerated approval," and "priority review" and have been employed in the review of both traditional and biologic drug products regulated by FDA’s Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER).

The following is an overview of these various programs that have been available to date:

1) Fast-track designation

· Established in 1988, this designation was designed to facilitate and expedite review of new drugs designed to address unmet need in the treatment of serious  disease.

· Fast-track designation can be requested at any time, and if granted, would allow for earlier and more frequent communication with FDA during clinical development

· Also permits "rolling submission" of data, whereby manufacturers can submit portions of a marketing application before submitting the complete application

· A standard review (10 months) of that data would still take place after last data is submitted

2) Accelerated approval

· Introduced in 1992, this program allows for a more expedient development and approval of a drug that has demonstrated an effect on a surrogate end point likely to predict positive clinical benefit

· Also can be employed for a drug demonstrating benefit on a clinical end point that can be measured earlier on in treatment, but likely to predict a positive benefit on irreversible morbidity or mortality long-term.

· Most often used in settings where disease course is long and extended time frame is required to measure true clinical benefit of a drug

· Conditional approval can be granted using surrogate endpoints from phase 2 trials or interim data from phase 3.

· A standard review (10 months) of that phase 2 and interim phase 3 data would still take place after last data is submitted

· Often requires post-marketing trials to verify drug’s clinical benefit and safety.

3) Priority review

· Also introduced in 1992 under the Prescription Drug User Fee Act (PDUFA),  priority review shortens the review time to a goal of 6 months versus the standard review time of 10 months

· Status determined at the time of Biologics License Application (BLA) or New Drug Application (NDA) submission

So how is it that this new breakthrough therapy designation is differentiated from these various other means of expedited drug review and development? The primary difference lies in what needs to be demonstrated to qualify for these programs. With the breakthrough therapy program, not only does the drug need to be targeted to treat a serious or life-threatening condition, its manufacturer must also provide preliminary clinical evidence demonstrating unprecedented improvement on a clinically significant endpoint over other available therapies. In contrast, the fast-track designation can be assigned to a drug based upon clinical or nonclinical data to address unmet medical need.

To assist manufacturers, on June 25 FDA released a draft guidance entitled “Expedited Programs for Serious Conditions-Drugs and Biologics,” as well as a related Manual of Policies and Procedures entitled “Review Designation Policy: Priority (P) and Standard (S).” The draft guidance provides extended detail into FDA’s breakthrough therapy designation program as well as key reference info on FDA’s other expedited review programs listed above. The draft guidance also describes the conditions under which a breakthrough therapy can lose its designation.

To date, FDA has already received 62 requests from drug manufacturers for breakthrough therapy designation since program inception and has granted breakthrough designation to 20 potential innovative new drugs that have shown encouraging early clinical results. How significant this designation will be in terms of impact on the timing and influence in health system formulary decision-making remains to be determined.