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  1. News & Events for Human Drugs

FDA's Breakthrough Therapy Designation and Expedited Review Programs: Part I

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.

For more than two decades, CDER has employed expedited pathways aimed at speeding the drug development and review processes so that therapies that show early promise can reach patients faster. The popularity and value of these programs has grown so much during this time that over half of CDER’s 2015 novel drug approvals received some form of expedited review.

In this two part interview, Dr. Rich Moscicki takes a deep dive into FDA’s Breakthrough Therapy designation to help clarify common misunderstandings around this expedited program. Dr. Moscicki also breaks down each of CDER’s expedited pathways to help readers understand not only the lingo, but also the implications of expedited reviews and approvals.

PART I – FDA’s Breakthrough Therapy Designation

What conclusion do you think consumers reach when a new drug is described in the media as a “breakthrough?”

Well, no one can really know what all consumers think. But I have seen news reports and academic articles that indicate many consumers and health care providers are confused by FDA’s Breakthrough Therapy designation.

Many times the “breakthrough” designation is interpreted by the public in the traditional sense of term breakthrough – as though these drugs have already been conclusively shown to be a major game-changing advance. But in reality new drug candidates described as “breakthroughs” by the media, and sometimes even those given a Breakthrough Therapy designation by FDA, look really good in their early trials, but upon further study, unfortunately fail to deliver on the promise they had initially shown.

What I’d like the public to understand is that the FDA tags drug candidates early in the development process with the “breakthrough” designation because they have the potential to be true breakthroughs in the long run. Drugs that receive the breakthrough designation have given a signal during testing that encourages CDER to invest a major effort and make sure that they are evaluated as efficiently as possible.

So what does FDA mean when it uses the term ”breakthrough?”

When FDA uses the term Breakthrough Therapy, we’re speaking of the designation or expedited review program for drugs in development that have shown something truly exciting. Perhaps we should have used the term “potential breakthrough” when the program was named to cut down on confusion, although I suspect it even then that the word “breakthrough” would have appeared on its own in media stories.

Diving a little deeper into the term’s meaning at FDA, a drug candidate that receives a Breakthrough Therapy designation is one that, first, is intended to treat a serious condition and, second, also has preliminary clinical evidence to suggest it may be a substantial improvement over available therapies.

What types of exciting evidence or signals in early drug development might result in a breakthrough designation?

What we’re looking for is early patient data that tells us that the drug is likely to provide a substantial improvement over what is currently available to treat a serious disease or condition. Now, we have some flexibility in how we determine a “substantial improvement,” and it’s admittedly a judgment call that we make on a case-by-case basis. In each instance, we must consider the seriousness of the disease as a whole, including the usefulness of available therapies in addressing patient needs.

There are different ways that a company can show a substantial improvement. For instance, they can do a head-to-head comparison of their new drug to the current standard of care in an early clinical trial. A direct comparison can be a powerful way to establish whether there really is a meaningful basis for the breakthrough designation.

In some situations, we will consider early patient data where there isn't a direct comparison in the clinical study but we have other information – such as a solid understanding of the natural progression of the disease. For example, if we know that a form of cancer usually has an 80 percent progression rate within a twelve-month period, and a drug in early clinical studies shows only a 10 percent progression rate during that time, then we really don't need a head-to-head trial to say that is a substantial and exciting improvement.

There are four expedited review pathways at CDER. What sets the breakthrough designation apart?

I would say that what sets breakthrough apart from the other programs is our organizational commitment. Companies with a drug that has received a Breakthrough Therapy designation receive enhanced communication and input from CDER. After a Breakthrough Therapy designation is given, senior management becomes directly involved in the drug’s development to help guide and shape further clinical studies and make sure that the drug is being developed and reviewed as efficiently as possible.

There is also a cross-discipline project lead assigned to each Breakthrough Therapy development program. This person really helps to drive things forward and make sure that the review of the product’s data is efficient across all disciplines. We characterize it as “all hands on deck” to make sure the drug is properly evaluated as quickly as possible.

How successful is the program so far?

The Breakthrough Therapy program has been very popular since its 2012 start, and we’ve received very positive feedback from industry indicating they see a real value to the program. Indeed, by the end of March 31, 2016, CDER has received 342 requests from companies and has granted 111 breakthrough designations.

In cases where a request for a breakthrough designation wasn’t granted, the company often didn't quite understand exactly the type of evidence we were looking for. For example, there wasn’t patient data available, so we really couldn't determine whether there was a likely substantial improvement.

What’s next for the Breakthrough Therapy program?

As for what’s next, we’re now reviewing the program so we can truly assess its effectiveness. The early results look good. In fact, in the relatively short period of time since the program launched, 41 applications for breakthrough designated drugs have reached marketing approval. These numbers indicate that the program is working in terms of expediting development and review. But we want to make sure that we have the bar set at the right place in terms of judging what constitutes a “substantial improvement.”

By evaluating the program and fine-tuning our standards for a “substantial improvement,” we can make sure that the right new drug candidates are receiving the benefits of a breakthrough designation, so that they may ultimately become available to patients as soon as possible.

PART II - Review and comparison of CDER's expedited programs


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