The Food & Drug Administration’s implementation of the new “breakthrough” therapy designation has had a pretty impressive start.

As of July 26, FDA has issued breakthrough designations to 25 drug and biologic marketing applications. That alone is notable: breakthrough products must be intended to treat serious or life-threatening conditions and have clinical data demonstrating a substantial improvement over existing therapies. The fact that there are two dozen such products in development (and as many as 29 additional applications under review) says something pretty significant about the current state of drug R&D.

It’s even more impressive when you consider that FDA was expecting to designate two, three, maybe four breakthrough products a year – not the 30 or 40 that the agency appears to be on track to issue by the program’s one-year anniversary on October 1. Whether that’s an initial wave that will eventually subside or a sign of a new era of drug development remains to be seen. But either way, it’s an unexpected success story.

And when it comes to what drug developers are actually getting from the breakthrough therapy designation, early reports are nothing but positive. Sponsors say the most important difference between a breakthrough and FDA’s other expedited programs (like the fast track designation, for example), is the quality and frequency of the communication with FDA officials about a development program – and who’s at the table.

“It’s a different kind of conversation,” Vertex Pharmaceuticals Inc. President and CEO Jeffrey Leiden said during a Friends of Cancer Research panel discussion on Capitol Hill July 24. “It’s iterative. It’s continuous. It’s ‘pick up the phone if you have a problem.’” (Vertex received the first two designations for its cystic fibrosis program, and thus has been working with FDA on breakthrough the longest.)

But that “all hands on deck” approach has one serious downside: it’s really resource-intensive for FDA.

FDA is certainly used to making do with tight budgets; the agency has been underfunded by Congress for years, and has only partially made up the difference with increased user fees from industry. But the agency has been stretched further under the Congressional budget sequester, preventing it from accessing $209 million in FY 2013 funding, including $82 million in user fees used to fund drug reviews. ([A#14130301008])

That’s led some sponsors to question whether FDA can afford to implement the breakthrough program under the budget sequester – especially since it is being used at a significantly higher rate than anyone ever expected. And if FDA is making breakthrough products a priority, what does that mean for all the other applications that might not have qualified, but still may be important new treatments?

FDA’s Center for Drug Evaluation & Research Director Janet Woodcock acknowledged those challenges. The agency is clearly spending more on applications with breakthrough designations, she said, but added that the process should be inherently more efficient overall: If the “big question” of whether a drug is effective is taken off the table, FDA should be able to complete those reviews more quickly, Woodcock argued.

Industry should hope she’s right. The new breakthrough designations should speed more targeted and efficacious treatments to patients faster. But Woodcock hopes the program will go a step further and improve the entire drug development process by encouraging industry to upgrade manufacturing facilities and design more efficient clinical trials to meet the needs of a greatly accelerated review.

The question is whether FDA has the resources to see it through.

“A Different Way of Interacting”

When the breakthrough therapy designation was first conceived and later passed by Congress in the FDA Safety & Innovation Act of 2012, there were a lot of questions about how it would be any different than FDA’s other expedited programs – the fast track designation, particularly, but also the priority review and accelerated approval pathways.

And that’s understandable: not much was known about breakthrough when FDA started granting designations. Agency officials weren’t able to say too much about the parameters of the program while the details were worked out internally, and FDA took nearly nine months to issue a draft guidance outlining the breakthrough designation, and how it compares to the other expedited programs. ([A#14130625001])

Even with the guidance document, substantial confusion remains about the basics. During an FDA informational webinar on the draft guidance on August 5, officials took almost 50 questions from stakeholders and still didn’t get to everyone in the queue. And based on the questions asked, it is clear many are still fuzzy on how the agency is implementing the breakthrough designation.

And then there’s the biggest question of all: What is the value in receiving a breakthrough designation? Also see "What’s Breakthrough Status Worth? Analysts Ask, But Companies Don’t Have Answers" - Pink Sheet, 13 May, 2013. The significance of a priority review, for example, is straightforward: A faster review, and, in most cases, a faster time to approval. (Last year, 70% of priority reviews were approved in the first cycle.)

But the value of a breakthrough designation is a bit less clear: For sponsors with qualified products, it’s a commitment from FDA to fully engage everyone at the agency to expedite the development and review. But what is that really worth?

As it turns out, quite a bit.

Working under a breakthrough designation is a “different way of interacting with the FDA,” Vertex’ Leiden said at the Hill briefing. Instead of a “ping-pong process” where a company sends FDA a document and waits for a response, “we pick up the phone and talk with the division in real time. And that makes the…progression of the development immeasurably smoother.”

That communication is not a one-way street, Johnson & Johnson Global Regulatory Affairs Head Jay Siegel added. “They’ll call us and say ‘here’s a way you might do this faster,’ or ‘have you thought about this problem? Let’s think together about how to address it.’” And with one or two exceptions, he said, “all the relevant people are at the table,” which “allows the critical assessment of all aspects of all those rate-limiting steps of the process.”

“We call it an all-hands-on-deck mentality,” FDA’s Woodcock said. After a breakthrough designation has been made, she said, senior FDA drug officials give “marching orders” to everyone involved in the review – from the statistics team to manufacturing – to find the most efficient development path for that product.

Vertex received the first two breakthrough designations from FDA for two cystic fibrosis treatments; the first applies to Kalydeco (ivacaftor) for an expanded use in cystic fibrosis beyond the current indication of patients ages 6 and older who have the G551D mutation in the CFTR gene. The second is for the investigational combination therapy VX-809. Also see "Breaking Down the First “Breakthrough”" - Pink Sheet, 9 January, 2013. (See Exhibit 1.)

Exhibit 1

Breakthrough Designations Announced by Sponsors

Drug Name	Manufacturer	Indication	Date Announced
ivacaftor monotherapy	Vertex Pharmaceuticals	Potential indications beyond the currently approved use for cystic fibrosis patients ages 6 and older who have the G551D mutation	January 6, 2013
ivacaftor/VX-809 combination use	Vertex Pharmaceuticals	Treatment of cystic fibrosis in patients with two copies of the most common CF mutation (F508del)	January 6, 2013
ibrutinib monotherapy	Janssen/Pharmacyclics	Relapsed or refractory mantle cell lymphoma (MCL) in patients who have received prior therapy	February 12, 2013
ibrutinib monotherapy	Janssen/Pharmacyclics	Waldenstrom's macroglobulinemia	February 13, 2013
LDK378	Novartis	Second-line therapy for patients with ALK+ metastatic non-small cell lung cancer who had progressed during treatment with, or were intolerant to, Pfizer’s Xalkori (crizotinib)	March 15, 2013
ibrutinib monotherapy	Janssen/Pharmacyclics	Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) patients with deletion of the short arm of chromosome 17 (deletion 17p)	April 8, 2013
palbociclib (PD-0332991)	Pfizer	First-line treatment for post-menopausal patients with ER+, HER2- locally advanced or metastatic breast cancer	April 10, 2013
lambrolizumab (MK-3475)	Merck	Advanced melanoma	April 24, 2013
daclatisvir, in combination with asunaprevir and BMS-791325	Bristol-Myers Squibb	Hepatitis C in treatment-naïve, genotype 1 patients	April 25, 2013
SD-101	ScioDerm	Inherited epidermolysis bullosa	April 29, 2013
daratumumab	Genmab/Johnson & Johnson	Patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who are double refractory to such drugs	May 1, 2013
Antiviral combination of the protease inhibitor ABT-450 boosted with ritonavir, NS5A inhibitor ABT-267 and non-nucleoside polymerase inhibitor ABT-333	AbbVie	genotype 1 hepatitis C	May 6, 2013
GA101 (obinutuzumab)	Genentech (Roche)	Chronic lymphocytic leukemia	May 15, 2013
sebelipase alfa	Synageva	Early onset lysosomal acid lipase deficiency (LAL deficiency), also known as Wolman disease	May 20, 2013
asfotase alfa	Alexion	Treatment of patients with the ultra-rare metabolic disease hypophosphatasia	May 28, 2013
serelaxin (RLX030)	Novartis	Acute heart failure	June 21, 2013
drisapersen (formerly GSK2402968/PRO051)	GlaxoSmithKline/Prosensa	Duchenne muscular dystrophy in boys with dystrophin gene mutations amenable to an exon 51 skip	June 27, 2013

Pharmaceutical Approvals Monthly

The breakthrough designation has also had an “enormous impact” on J&J’s development of daratumumab and ibrutinib, Siegel said. FDA has issued four designations for the two oncology products: three for ibrutinib (mantle cell lymphoma, Waldenstrom’s macroglobulinemia and chronic lymphocytic leukemia or small lymphocytic lymphoma) and one for daratumumab (multiple myeloma).

The bottom line should be a faster route to approval. Breakthrough isn’t a review pathway, so there’s no official commitment on the part of FDA to complete a review in less time. But the intense guidance from top officials all but guarantees an expedited process. In the case of ibrutinib, for example, J&J expects the drug to be approved two years earlier under the breakthrough designation. ([A#14130710003])

Time will tell whether J&J’s prediction bears out. But for critics still questioning what a breakthrough designation is worth, there’s one clear answer.

Can FDA Get it All Done?

So it is clear there is a lot to like about breakthrough – at least according to the sponsors that have already received a designation.

FDA is also quite taken with the program, having issued far more designations than ever imagined when the program was first conceived. And in the drugs center, approximately half of all requests are being granted, although some requests have been withdrawn by the sponsor. The results have been far less compelling at the center for biologics, where clearly management has seen less convincing early data; of the eight requests to CBER, seven have been denied. (See Exhibit 2.)

Of the CDER denials, at least one has been made public: Ariad Pharmaceuticals Inc. told analysts on August 7 that FDA had denied breakthrough status for its non-small cell lung cancer treatment candidate AP26113; the company had earlier told investors that it had requested the designation from FDA.

[Sidebar#2013500100]

The Ariad denial is just one example of the challenges that sponsors face in communicating with investors about breakthrough designations. Also see "PDUFA V and Investor Communications" - Pink Sheet, 21 March, 2013.

Exhibit 2

Breakdown of the “Breakthrough” Requests

FDA Center	Requests Received	Requests Granted	Requests Denied	FDA Performance (action taken within 60 days)
Center for Drug Evaluation & Research	73	25	22	98.63%
Center for Biologics Evaluation & Research	8	0	7	100%

Note: CDER data as of July 26; CBER data as of July 31

Food & Drug Administration

Only time will tell whether all those designations stick. FDA can rescind a breakthrough designation if the early clinical data do not hold up – or another product is fully approved for the same indication, and the sponsor of the pending product cannot demonstrate substantial improvement over the newly approved treatment. As CDER Deputy Director for Clinical Science Robert Temple put it during the FDA/CMS Summit last year, “breakthrough can go away.” Also see "A Regulator’s Perspective For 2013: FDA’s Temple Discusses FDASIA, Caronia, and Breakthrough Development" - Pink Sheet, 22 January, 2013.

But another question both inside and outside the agency is one of resources. A breakthrough designation, by design, consumes a lot of FDA’s time. The agency has prioritized certain “breakthrough” applications before the official designation – the initial approval of Vertex’ Kalydeco is a case in point – but to have so many hyper-priority products at FDA at one time would appear to be unprecedented.

FDA is used to tackling heavy caseloads with limited budgets. But the agency is also operating with fewer resources than normal under the Congressional budget sequester, making funding even more scarce than before. Given those resource challenges – and a 10-fold increase in designations compared to initial expectations – some stakeholders are questioning how FDA will be able to handle the extra workload.

Friends of Cancer Research Executive Director Ellen Sigal voiced that concern during her organization’s Capitol Hill briefing, calling the additional strain a “huge issue.”

Vertex’ Leiden agreed: “Ecosystems are delicate, and when you mess with them and disrupt them, they can die, and they don’t come back overnight,” he said. “My big concern is that when you begin to slash funding from multiple quarters – the NIH, FDA…we run the risk of strangling this ecosystem that we’ve created here, which has led the world in biomedical innovation.”

FDA’s Woodcock acknowledged that challenge: “We’re always short of resources, and that is an issue,” she said. “We are constantly pulled and stretched....But we have a body of work we have to do….It’s a portfolio we have to manage…so we’re just going to have to figure it out the best we can.”

Fewer Big Questions for Breakthrough

While the breakthrough products are certainly time-consuming for FDA, Woodcock hopes that the frequent communication with the sponsor – coupled with the fact that a breakthrough product should have a clear-cut safety and efficacy profile – will make those reviews much more streamlined than a traditional review. And in the end, she says, they’ll be more time-efficient.

“What do we spend most of our time agonizing over? It’s one question: does it work?” Woodcock said. Much of a review “is agonizing and having long discussions in advisory committees and internally about whether these drugs work.” With a breakthrough product, she said, “that question is off the table.” As a result, “some of the activities that we have done in the past will not be the ones we do in the future.”

J&J’s Siegel was open to that argument. “It’s clear that the agency is spending more resources on these products at the present time. Those are precious resources. But I’m inclined to think that maybe the overall amount of resources spent will not be that much more. Often that type of close partnership will lead to a more efficient resolution of processes and problems than trial and error, or communicating back and forth by email over a year.”

But he added that while the central part of the review may not be “an agonizing question about whether the drug works,” there are always “ancillary questions” that can weigh down a review: “‘What’s the right dose? What’s the right combination? What’s the right outcome? What do we need to know before we get it to patients? And how do we learn the rest of it after we get it to patients?’ Those aren’t easy questions.”

Siegel also wondered whether there may be potential spillover effect to the rest of the drug review system. “Given a time when FDA resources are constrained, especially under the sequester, to what extent will this program pull resources from other drugs?”

“The breakthrough drugs aren’t the only important drugs. There are a lot of important new drugs out there that may be great…but you cannot tell that as easily from the early data,” Siegel said. “And so it really is important that for all innovative drugs we retain the appropriate resources to ensure that there is an expeditious approval process.”

There is one recent change that may help preserve resources: FDA has more time to complete the review of all new product applications. The fifth Prescription Drug User Fee Act tacked on a two-month “filing period” to the beginning of each review, giving FDA 12 months to complete the review of a standard new drug or biologic application (versus 10 months), and eight months to complete the review of a priority application (versus six months). Also see "Time for Transparency: PDUFA V’s Big “Experiment”" - Pink Sheet, 19 January, 2012.

But that extended timeline also requires FDA to hold more meetings with sponsors, which are – you guessed it – time-consuming and resource-intensive. And let’s not forget what happened the last time FDA felt overwhelmed with additional work: The agency started missing user fee deadlines while it managed the implementation of the FDA Amendments Act and the “Safety First” initiative. Also see "Running Late: FDA Review Timelines Lengthen For New Product Applications" - Pink Sheet, 1 September, 2008.

No one at FDA has suggested that will be an issue this time around. But it’s clear what can happen when the agency has too much on its plate and not enough funding: A stressed drug review program.

One Rate-Limiting Step: Manufacturing

Manufacturing has always been a potential roadblock that can delay an approval or product launch. But breakthrough is a different story altogether. When the development and review of a treatment is as condensed as it is expected to be for a breakthrough product, the question is whether all the work on the manufacturing side – from scale-up to final inspections – can be completed within that timeframe.

Ibrutinib, which J&J is developing with Pharmacyclics Inc., is a case in point. “Inspections has been one of those issues that have been a little bit tricky…especially scheduling foreign inspections under the PDUFA process,” Siegel said. “That’s an issue that we’re still looking at. I’m sure there will be other issues that we just need to figure out how to deal with because every time you accelerate one thing, something else becomes the rate-limiting step.”

J&J has seen a good deal of flexibility on FDA’s part in making other parts of the process more efficient.

For example, Sigel said, a sponsor would normally validate all tests before producing final product batches. Under breakthrough, FDA is allowing J&J to use those early batches before the testing mechanisms have been fully validated. “The fact that we’ve already started making the batches doesn’t still mean that we can’t now define what will be the validation criteria,” Siegel said. “Not surprisingly, given the way breakthrough is headed, we found great flexibility at the agency to take that out of order.”

Siegel thinks some of the initial challenges with implementing the breakthrough program may eventually work themselves out.

“Some of the challenges we are seeing are because the breakthrough designation is coming later in the process for some drugs because of a backlog. Hopefully, we can think creatively with newer products from an earlier point in development and how to keep manufacturing from being a rate-limiting step. Although, I don’t know we’ll have all of the answers, or that they will be the same for every product.”

And Vertex’ Leiden is hopeful that the breakthrough designation will go one step further, and encourage drug companies to invest in manufacturing upgrades. The breakthrough era is an opportunity to rethink “how we do manufacturing differently so it’s not quite as cumbersome, so it is easier to inspect,” he said. “While I do see it as a challenge, sometimes those challenges become opportunities to streamline the process.”

Woodcock agrees. “It may well be that breakthrough is an opportunity that will motivate folks to put the effort in” to upgrade manufacturing facilities, she said.

On manufacturing, FDA is meeting sponsors halfway: The agency has been working internally for five or six months to restart its “21^st Century” manufacturing initiative. The previous 21st Century initiative, which ran from 2002-2004, revamped FDA’s review and inspection policies based on state-of-the-art pharmaceutical science and encouraged industry to adopt new technological advances.

Woodcock hopes to repeat that success. “Ten years ago, the companies that adopted it decreased a lot of waste, they did transfer and scale-up much more effectively without all the problems,” she said. “But there is another level we can get to” and “ways to do this that other industries have adopted,” Woodcock added. “What we do now is not really high-tech.”

Overall, Woodcock is enthusiastic about the targeted, effective treatments she is seeing in the pipeline for undertreated diseases. And FDA is emphasizing its expedited pathways to reflect the way that science has changed.

“In the 1990s, we might have designated two products as breakthroughs,” she said. “We didn't see these therapies in Phase I looking totally different, or Phase II trials where you said 'bingo,' you've got a likely winner.’”

If the breakthrough model works, “we will gradually develop a new pathway for development that is more efficient,” Woodcock said. “The hope and belief is that this probably reflects the investment in science that has been made over the past 40 years.”

Now FDA just needs the resources to implement it.

FDA’s “Breakthrough” Exceeds Expectations; Will It Break The Bank?

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