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FDA’s Breakthrough Therapy Designation and Expedited Review Programs: Part II

FDA’s Breakthrough Therapy Designation and Expedited Review Programs: Part II

CDERConversations 715pxRichard Moscicki, M.D.

A CDER Conversation with Richard Moscicki, M.D., Deputy Director for Science Operations, Center for Drug Evaluation and Research, FDA.

Continued from PART I – FDA's Breakthrough Therapy Designation.

PART II – Review and comparison of CDER’s expedited programs

Continuing the discussion of FDA's Breakthrough Therapy designation, Dr. Rich Moscicki breaks down each of CDER’s expedited pathways to help readers understand not only the lingo, but the implications of expedited reviews and approvals.

The breakthrough designation is one of several expedited review programs at CDER. What are the others?

There are four expedited review programs at CDER: Accelerated Approval, Priority Review, Fast Track and Breakthrough Therapy. All of these programs are aimed at serious diseases, many without adequate good treatment options. Expedited review pathways are for life-threatening diseases like cancer, not toenail fungus.

Will you break down Accelerated Approval for our readers?

Like the Breakthrough Therapy designation, an Accelerated Approval designation is for a drug candidate that addresses a serious condition and which we think may offer a meaningful advantage over available therapies. But the big distinction is that Accelerated Approval allows us to use a surrogate endpoint in the main clinical trial that we would use to approve the product. 

So what’s a surrogate endpoint?

Ok, let me back up a step to first define clinical endpoints – these are measurements of how a patient feels, functions, or survives after treatment with a drug. Clinical endpoints are the gold standards for approval via our traditional review pathway, but they often require a lot more patients and a very long time for companies to come up with a conclusive result. In some cases, we need to use something other than clinical endpoints to give us a quicker path to approval for serious, life-threatening diseases.

Surrogate endpoints are indicators of a change in the disease that we believe are likely to predict a clinical benefit. They serve as a stand-in for clinical endpoints and provide an estimate of how well a drug will treat a disease or condition. As a hypothetical example, we could use a decrease in tumor size over a five-month period as a surrogate endpoint or stand-in for measuring a cancer’s progression, and ultimately the patient’s survival, over a 12-month period.

Using surrogate endpoints gets a drug to the market more quickly, but, if approval is ultimately granted, an Accelerated Approval designation stipulates that the company still has to prove the clinical benefit. Continuing our hypothetical cancer example, the company will have to confirm the studies of their surrogate endpoint by performing additional, longer-term, larger clinical studies to show that patients taking the drug in fact do have improved survival or other clinical outcomes.

What about the Priority Review and Fast Track designations?

Priority Review is a little less complicated than Accelerated Approval. Again, this designation is for a very serious condition, but in this case the trials have been completed and we’ve seen that there is a significant improvement in safety, effectiveness or both. With a Priority Review designation, our review time is reduced from the more standard ten months down to six months.

The final expedited program for us to discuss is the Fast Track designation. Fast Track came into being back in 1997. It is designed for drug candidates intended to treat a serious condition and that demonstrated in non-clinical studies the potential to address an unmet medical need. 

With an expedited review are the safety or effectiveness standards compromised?

No, there's nothing about our reviews for the expedited programs that lowers our standards. I think this is a really important point for patients and health care professionals to know. So, even though we have some flexibility in how we review drugs that are a part of these expedited pathways, our standards for safety and effectiveness remain unchanged. All new drug candidates, whether they receive an expedited designation or not, still have to prove safety and effectiveness.

Does an expedited designation guarantee that the drug will be approved?

Well, some say that there are no guarantees in life, and that applies to our expedited programs as well. An expedited designation does not mean the product is automatically going to be approved. What it means is that we're going to give the drug candidate special attention and work with the company to develop, test and evaluate the drug’s safety and effectiveness as efficiently as we can.

Let’s recap. What are the primary similarities and differences in these expedited programs?

Let’s start with the differences. A Fast Track designation does not need clinical evidence and can be obtained very early in drug development based just on animal data. This requirement distinguishes Fast Track from the other expedited programs, which require evidence in human patients. Additionally, since the Accelerated Approval program relies on surrogate endpoints, companies will have to follow up by confirming the positive outcome of their surrogate studies with post-approval trials that assess clinical endpoints and confirm a clinical benefit.

Now to the similarities. All of these programs serve to speed up the development time and to a degree our review period. As I mentioned, Priority Reviews are shortened from the standard ten months down to six. Breakthrough Therapy and Fast Track reviews can be done on a rolling basis so that each part of the application is reviewed as it is received, rather than waiting for the final collection of all required data be filed before the review begins. The use of surrogate endpoints in the Accelerated Approval program can lead to shorter, more efficient trials that get drug products reviewed and to the public faster.

As you can see, there are areas of overlap in these programs and in fact, there are certain drug development programs that make use of three or four of these expedited review processes. So it's not unusual that a Breakthrough Therapy drug would also receive a Priority Review and receive an Accelerated Approval as part of its path to patients. And as I mentioned, all are aimed at serious diseases – like cancer and not toenail fungus.

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