If You’ve Got a Real Breakthrough, the FDA Wants To Talk

1/14/13Follow @xconomy

If you ever want to have an interesting chat with a healthcare journalist, ask about use of the word “breakthrough.” Like many reporters, I generally avoid it. The word may be good for generating eyeballs/pageviews/ratings, but it’s usually an exaggeration that serves the financial interest of drugmakers and gives patients false hope.

Sometimes, though, breakthroughs do occur. And now there’s a federal law on the books that’s encouraging companies to develop more groundbreaking, innovative therapies. From now on, you can expect to see drugmakers talk about getting official “Breakthrough Therapy Designation” from the FDA, and it won’t be just an empty, boastful phrase. It’s still early in the game, but I expect this new regulatory incentive structure will tilt the drug industry’s priorities toward difference-making therapies, and away from incremental advances that have prevailed for the past 20 years.

This past week, Cambridge, MA-based Vertex Pharmaceuticals (NASDAQ: VRTX) raised awareness of the new regulatory meaning for the word “breakthrough” when it said its cystic fibrosis treatments ivacaftor (Kalydeco) and VX-809 were granted the first two “Breakthrough Therapy Designations” by the FDA. The company was conservative in its statement, saying that the implications of the action “cannot be determined at this time.” Vertex CEO Jeff Leiden shared a little more with Bloomberg News, saying, “it’s an opportunity to have a different set of interactions and collaborative discussions” with regulators.

That might not sound like much, but there’s more. The FDA was instructed to prioritize reviews of such “breakthrough” therapies through the Food and Drug Administration Safety and Innovation Act (FDASIA) that was signed into law in July. For policy wonks, this is tied to the fifth extension of the Prescription Drug User Fee Act. Here’s a key section of the law (Section 902), regarding development of breakthrough drugs:

“The Secretary shall, at the request of the sponsor of a drug, expedite the development and review of such drug 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.”

What does that really mean? I asked a lot of biotech pros that question last week at the JP Morgan Healthcare Conference in San Francisco. I got more than a few shrugged shoulders. But one clear answer came from Tom Hughes, the CEO of Cambridge, MA-based Zafgen, a venture-backed startup working on a novel drug for severe obesity.

Tom Hughes, CEO of Zafgen

Hughes has been encouraged by public statements from Janet Woodcock, a top FDA official, and what he reads in the new law. Woodcock has made repeated comments in public about the need to encourage more “breakthrough” drugs.

Check this comment from Woodcock on an FDA blog last month:

 “The new law is designed to get “breakthrough” therapies developed as quickly and safely as possible so they can be available to treat the patients who need them. We’re excited about it! In fact, although the law is only a few months old, we’re already putting it to use. Recently we identified the first therapy to receive this special designation. And it likely won’t be long before we have more. Several other drug developers have already made inquiries and there is lots of interest in the pharmaceutical industry in taking advantage of this new development tool.”

Hughes, a former Novartis research leader, says he sees an opportunity for Zafgen’s beloranib to get one of these new designations. The company has shown that the injectable can help seriously obese people lose a lot of weight, quickly, in small clinical trials.

I’ll leave the value judgments to the FDA about whether Zafgen’s drug should count as a “breakthough therapy” in need of a shorter/faster clinical development path. But Hughes says he’s looking forward to submitting an application to be reviewed by the FDA’s Office of New Drugs, led by John Jenkins, one of the agency’s high-level officials.

If the agency decides within its 60-day review period to grant this designation, then Zafgen’s application would zoom up on the FDA’s priority list. Normally the company would wait weeks or months to hear feedback about a clinical trial plan from overextended FDA reviewers. Instead, the company could get a dedicated, cross-disciplinary project team at FDA charged with finding ways to shorten and shrink the clinical trials required to demonstrate that beloranib deserves a place on the U.S. market. The company would then be able to work closely, in collaboration with FDA reviewers and statisticians, to design trials that reflect the latest scientific understanding of the drug and the targeted patient population, Hughes says.

If approved under this streamlined pathway, it’s likely such a drug would come with a lot of strings attached. It would probably have to be limited to a narrow patient population, have a tightly controlled distribution network, and be prescribed under a “Risk Evaluation and Mitigation Strategy” while further studies continue to ask whether the drug’s benefits outweigh the risks.

Although such a drug would be off-limits to most obese people, the impact for a company like Zafgen could be “huge,” Hughes says. It could allow the company to run a series of clinical trials that cost $50 million in a small subset of morbidly obese patients, instead of a larger set of trials with thousands of obese patients that would take several more years and cost as much as $300 million, Hughes says. The FDA could always put the kibosh on the program at any time if new evidence emerges that says the drug’s risks outweigh the benefits.

Hughes, a data-driven scientific guy, was brimming with enthusiasm about the new possibilities last week.

“This could give us certainty in what we’re doing, as opposed to complete uncertainty. It makes our investors much more comfortable,” Hughes says. “For us, a small company with six people, to have a project team working with us at FDA—that is a huge, huge difference,” Hughes says. “It’s a real carrot.”

As with any new law or policy, the ultimate impact of the “breakthrough” designation will depend on how people execute on it in the real world. But early signs are encouraging. Jenkins is one of the FDA’s most senior and experienced officials. He is someone who can speak with authority about what applications warrant “breakthrough” designation to different divisions at the agency that review antibiotics, cancer drugs, antivirals, or more. Clearly, the agency picked a winner in ivacaftor (Kalydeco) for its first breakthrough designation. Anyone versed in the medical evidence would agree it’s a breakthrough for a subset of cystic fibrosis patients.

No doubt, there are reasons to tread cautiously down this new regulatory path. Any time you find ways to shorten and shrink clinical trials, there’s a risk a drug will prove unsafe when marketed to a wider population. The bar for this designation should remain high—a cancer drug that only offers a couple months of extra survival time shouldn’t qualify. FDA history suggests it’s constantly on a swinging pendulum, moving toward a cautious position when safety controversies flare up, and then toward a more permissive stance when it is accused of stalling important new innovations for patients. If the breakthrough therapy pathway is poorly administered, the whole thing could backfire on the FDA and the industry. The pendulum could easily swing back toward excessive risk-aversion.

There’s nothing new about the government working hard to create incentives for drug development. AIDS activists in the 1990s were successful in their efforts to create an “Accelerated Approval” pathway for potentially life-saving medicines that were bottled up in FDA reviews. In exchange for an earlier-than-usual drug approval on a slim body of evidence, companies were supposed to follow through on gathering more hard data on things like how long patients were living. That program worked pretty well, and was extended to cancer drugmakers over the years, with some mixed results.

Several investors I’ve spoken to are optimistic, or at least cautiously optimistic, about what will happen if the FDA truly follows through on this directive to advance breakthrough therapies.

“We as an industry have been going after lower-risk, more incremental products because the incentive structure was there,” says Bob More, a general partner with Frazier Healthcare Ventures. But the incentives are changing, and moving away from incrementalism. Insurers have gotten more aggressive in asking whether new drugs are really adding value to the healthcare system. The FDA’s new emphasis on breakthrough medicines is consistent with the kind of products that insurers have also been clamoring for, More says.

While I know some in the industry are cynical about whether the FDA means what it says, I think we’re seeing the FDA’s actions are speaking as loud, and maybe louder, than its words. Last year, the FDA approved the most new drugs in 15 years. Those actions, the new law, and what looks like a new attitude all appear to be fostering innovative new drug development. It’s good news for the industry, and patients.

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  • Rogan

    How long until only politically connected firms get “breakthrough” status? I could see a possible future where only drugs being bet on by Wall Street get a bump and everything else gets slowed down.