John Carroll

The FDA has several regulatory avenues mapped out for the most promising new drugs in the pipeline. A favored therapy can be put on the agency’s fast track, offered an abbreviated priority review, and occasionally provided an accelerated approval. But it’s the agency’s new “breakthrough drug” (BTD)designation that’s all the rage these days in drug development circles.

Congress included the breakthrough drug designation in the 2012 Food and Drug Administration Safety and Innovation Act, an olive branch for an industry that was required under the Affordable Care Act to offer discounts for drugs used by Medicare and was charged hundreds of millions of dollars in added fees.

The rule of thumb in biopharma, spelled out in studies undertaken by the Tufts Center for the Study of Drug Development, is that it takes 10 years and a billion dollars to get a new therapy through all stages of drug development.

That’s a controversial bottom line — debated endlessly among industry critics and supporters. But an uncontested drought of new drug approvals between 2000 and 2010 prompted lawmakers to demand that the FDA commit itself to an open-door policy for the leading experimental drugs that offer a pioneering approach that could transform the treatment of serious diseases.

Breakthrough drug programs will require a “different communication structure,” FDA oncology chief Richard Pazdur promised a large group of cancer researchers recently, “with much more of a continuous dialogue with sponsors.”

While it’s still early in the game, the FDA’s initial moves have clearly signaled that the rules have changed for these drugs. The intention is to significantly shorten the development time line for some drugs, with a goal of cutting years out of the R&D process and restructuring marketing time lines for pharma managers at health insurers who will now need to red-flag fast moving therapies in the clinic.

Carving out Phase III

Under the new regulations, agency officials are vowing to provide monthly internal reviews to help guide companies, offering pointers on adapting clinical trial designs, perhaps, to hammer out a more efficient path to endpoint data. Developers should also find ready help qualifying a drug’s manufacturing process or even coming up with an acceptable commercial name.

But the single biggest opportunity for drug developers is getting a green light to potentially land a new drug approval at the FDA ahead of the big, long Phase III study that has dominated drug development efforts for decades. Under this new scenario, a drug could gather enough data in a relatively small study using surrogate endpoints — perhaps a biomarker that can be substituted for a traditional clinical endpoint like overall survival rates — for an approval, with the long-term Phase III conducted after the therapy arrives on the market.

In a matter of months, the FDA has handed out 17 publicly discussed breakthrough designations, almost all within the 60-day period the law allows for a decision. It’s still the early days in the process. As of the end of July, no BTD had won marketing approval, but the first wave of these drugs says a lot about which treatments are likely to get green-lighted for the regulatory short cut.

All but one of these first-year drugs are either entirely owned by a big pharma company or a large biotech organization. Small developers flying solo have largely been excluded from this first round, though the agency says there is no bias based on company size. And the biggest initial effect is likely to be felt in the oncology market, while diseases like diabetes, where the FDA has insisted on very high safety standards and huge Phase III studies, are not covered.

Impressive survival data

Almost half of these breakthrough drugs are for cancer. One of them, ibrutinib from Pharmacyclics and Johnson & Johnson, has won a record three BTD designations. The drug is designed to inhibit the enzyme Bruton tyrosine kinase, and has produced some impressive survival data for patients with B-cell malignancies. In early July it was submitted to the FDA for chronic lymphocytic leukemia/small lymphocytic lymphoma as well as previously treated mantle cell lymphoma.

The breakthrough drug designation “allowed us to focus and optimize the use of Phase II data for registration,” says Urte Gayko, PhD, Pharmacyclics’ senior vice president for regulation and a 16-year veteran in the field. That has helped shorten the new drug application process by seven to nine months.

The scientific understanding of how many of these new targeted cancer drugs work — both through improved safety profiles as well as enhanced survival times — has clearly benefited a whole wave of cancer therapeutics which stand to benefit from the new classification.

Carving a few months — or a few years — out of the development time line is a big deal in the industry. Ibrutinib helps illustrate just how big a deal it is.

After it bought Celera, Quest Diagnostics wound up with a mid- to high-single-digit royalty interest in the drug. It just sold that royalty stream for $485 million, more than it paid for Celera, leaving some analysts to speculate the deal was based on expected peak sales of $6 billion to $7 billion a year. At the high end, a single extra month’s revenue would be worth about $600 million.

“Not all of these breakthrough drug designations are at the same stage,” says John Jenkins, director of the FDA’s Office of New Drugs. “Some are pretty much done,” leaving the agency only limited opportunities to find a shortcut to an approval.

Others, such as Merck’s early-stage cancer immunotherapy lambrolizumab, are still in Phase I and Phase II, and there the agency promises to make a real impact.

Not only can the FDA provide developers some clear ideas about smaller trials or surrogate endpoints that could pave the way to a fast approval, but there’s also the prospect of a shortcut on the manufacturing path.

Typically, the FDA requires drug developers to prove that they have a full-fledged manufacturing process in place ahead of marketing approval, with approved facilities ready to produce commercial quantities. A breakthrough drug, though, could find ways to an inside track that would rely on a developer’s proven ability to produce clinical trial drug quantities, with the more burdensome hurdle held in abeyance.

“We need to try to expedite,” says Jenkins, “see if there are places where we can be more open to approve something other than commercial manufacturing. That can come later,” provided that the FDA “thinks that process can assure the integrity and quality” of the therapy. But he emphasizes that this aspect of the breakthrough process is still being hammered out.

Jenkins says the agency is disease-agnostic when it comes to handing out these designations, but adds that the FDA already has plenty of experience at speeding up approvals for oncology therapies, where single-arm (without a control group) trials may be more welcome than in disease fields that require large numbers of patients for testing.

How good are the data?

The FDA’s primary concern is how good the data are, he adds, not the size of the company. And these drugs promise to quickly dominate the disease niche they’re targeted at — even without some of the advanced pharmacoeconomic studies that payers are demanding more and more often.

“In many areas, breakthrough drugs have implied superiority,” says Jenkins. The law specifies this field is reserved for drugs that offer patients a substantial clinical improvement over what’s available. For cancer drugs, a standard hurdle is proving that a drug works for refractory disease after one or more standard therapies have failed.

There’s an implied if not actual superiority, he adds, “and that goes a long way to assessing whether benefits outweigh risks.”

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