AIDS Drugs Were the Start. Let’s See More FDA Accelerated Approvals

3/12/12Follow @xconomy

There’s been a lot of talk in biotech lately about the need for reforms at the FDA, to make it run faster and more predictably. One idea is taking shape in a bill starting to move through Congress. And at least at first glance, it looks like it’s based on good common sense.

The idea is to make it possible for experimental drugs for rare, life-threatening diseases get to the market faster, by expanding the FDA’s “Accelerated Approval” pathway. A bill called “FAST” that seeks to make this happen was introduced last week and discussed at a public hearing held by the House Energy & Commerce Committee’s Subcommittee on Health.

Here’s the background. Twenty years have gone by since AIDS activists scored a historic victory by getting the FDA to allow for “Accelerated Approval” of experimental drugs that might save lives. That deal enabled patients who were dying of AIDS to get faster access to drugs that otherwise would have been bottled up for years in clinical trials, as researchers tried to gather proof that they helped people live longer than placebos. In backing away from that demanding stance for medical evidence, the FDA agreed to accept certain “surrogate endpoints.” Those measurements—things like viral suppression in AIDS patients—might suggest at an earlier stage of development whether a drug is working and worth delivering to more patients.

In exchange for an earlier-than-usual drug approval on a thinner body of evidence, companies were supposed to follow through on gathering more hard data on things like how long patients were living. And if later evidence emerged that suggested the early indicators were misleading, and the new drug wasn’t actually as safe or effective as first believed, then the FDA would have the right to revoke the “accelerated approval.” For many years since, this same regulatory path has helped make it possible to bring cancer drugs to the market faster than they otherwise would. (There have been problems with this approach, but more on that in a minute.)

The key idea in this FAST bill is that this same regulatory template should be extended to many more “serious or life-threatening” diseases. The logic here is sound: If we can use surrogate endpoints to measure the effectiveness of HIV and cancer drugs, the same idea can be applied to rare diseases like beta-thalassemia or Huntington’s disease. Boosters of the legislation like to claim that as understanding of biology advances, and we learn more about biomarkers in the blood that are leading indicators of disease, we ought to take advantage of them to speed up drug development.

John Maraganore, CEO of Alnylam Pharmaceuticals

“Why just limit it to HIV and cancer?” says John Maraganore, the CEO of Cambridge, MA-based Alnylam Pharmaceuticals (NASDAQ: ALNY), who testified before the House committee last week. “I think it’s important to get medicines to patients faster while retaining the safety and efficacy standards we rely on.”

Of course, Maraganore acknowledges his company “has a dog in this hunt.” Alnylam is developing treatments for rare diseases like TTR amyloidosis, Huntington’s, and hemophilia that could all end up benefitting from a faster regulatory approach. It’s hard to quantify the difference this bill could make for Alnylam, or any other company competing in those fields, because every disease, and its surrogate endpoint of progress, is going to be a different. But speaking generally, if investors have a choice of investing in a clinical trial program that will take seven years and $50 million to get the data needed for FDA approval, or one for the same drug that requires three years and $20 million of investment, which clinical trial plan do you think they’d rather back?

The investment concern is a real one. Without a more aggressive push for accelerated approvals, the overall pipeline of drug candidates could dry up in a hurry. As Maraganore pointed out in his testimony, a survey by the National Venture Capital Association last fall said that 39 percent of VCs plan to decrease their investments in cancer drugs over the next three years. That’s in large part, he said, because “there appears to be a fundamental re-evaluation” of cancer drug approval standards, which has injected a lot of uncertainty into how much time, money, and data it will take to win an FDA approval.

There are potentially negative consequences if accelerated approval goes too far. There are going to be questions about how “serious or life-threatening” diseases get defined. Is diabetes in this category, in need of shorter regulatory pathways? I think most people would say diabetes is a serious disease, but what about enlarged prostate?

Companies, once they get accelerated approvals, tend to lose the laser-focused motivation they once had to complete clinical trials which might end up reflecting badly on their cash cows. The FDA hasn’t often exercised authority to revoke accelerated approvals. But commissioner Margaret Hamburg did make one of those tough calls last November when Roche’s bevacizumab (Avastin) lost its clearance as a breast cancer treatment.

Essentially, there’s a risk here that the FDA could end up letting a lot of sketchy drugs onto the market, forcing it to later make painful and embarrassing recalls when the evidence becomes more clear-cut. And while enthusiasts of new biomarkers may be right about their value some of the time, there are bound to cases where some supposedly compelling biomarker turns out to mean little. Researchers have seen plenty of cases, for example, of cancer drugs that appear to shrink tumors which don’t end up helping people live longer.

The bill, known as House Bill 4132, which I took time to read in all its boring glory, doesn’t include any specifics about what kinds of data will be necessary to satisfy “accelerated approval” standards at the FDA. That’s wise, because those decisions will have to be made on a case-by-case basis, by the FDA, companies, and researchers—not Congress. If this bill is passed, the details—and the details are really all that matter—will be hashed out in a million little decisions made between the FDA and companies over the years to come.

Still, Maraganore says passage of the bill would make a big difference in one key respect—it would boost the confidence of investors in biotech. And he says the FDA has been willing to work on a variety of reform proposals, including this one. “They have gone a long way to work with industry to think about the proposals that are now in front of Congress,” Maraganore says. “There is a solid working relationship between industry and the FDA on thinking about what’s the right thing for patients.”

There are a number of smallish ideas tucked into the bill that also make some sense. In the Senate version of the FDA reform bill, known as TREAT, there’s language that would call for the FDA to hire a “chief innovation officer” who would be charged with identifying “promising new scientific and regulatory approaches” to help speed up drug development and regulatory reviews.

Every year, lots of bills get introduced that go nowhere, but this year there’s an incentive to get things done, as the Prescription Drug User Fee Act (PDUFA) V—a key piece of legislation that provides the FDA with industry user fees it needs to function—expires at the end of September. It’s entirely possible that the ideas contained in the FAST and TREAT bills could get rolled into the broader PDUFA reauthorization bill, which has to pass to essentially keep the FDA operating.

I’ve already gone on my soapbox with “Five Things Industry Can Do to Support True FDA Reform and Restore Public Confidence.” I don’t think these bills are going to come close to solving all that ails the drug development industrial complex, but they are reasonable. I’d love to hear your thoughts about what kind of impact this legislation could have.

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  • Steven Walker

    The TREAT and FAST bills are a start. If passed, we will likely see a modest shift in the way FDA regulates development and approval of some of the most needed new medicines. However, if Congress fails to actively oversee FDA’s performance in implementing the new law, and make adjustments with new legislation on an annnual basis, we will see little change. Broad use of Accelerated Approval was supposed to happen after passage of the Food and Drug Administration Modernization Act of 1997. It was used extensively in HIV/AIDS, and has been used occasionally in cancer (although often in name only for oncology drugs), and not much in any other disease area. FDA will neutralize these bills as well, which some FDA review division directors will do automatically, unless Congress makes it clear that its direction is to be followed.

  • Luke Timmerman

    Steve–I’m not so sure the FDA will neutralize these bills, it sounds more and more to me like the FDA is willing to embrace some new ideas for improving its processes. In theory, Congress could do some good by passing these bills and holding the FDA feet to the fire to make sure it happens, but I’m not optimistic Congress will continue to pay close attention. It’s always been easier for members of Congress to say to the voters, ‘Look at that cozy regulator approving dangerous drugs’ when something clearly goes wrong than to say ‘Look at that overly cautious regulator that’s delaying lifesaving drugs from reaching the market because of process technicalities.’ Sadly, I don’t see anyone in Congress taking on this issue and popularizing it.

  • CMCguy

    FAST/Treat sound good conceptually yet wonder if will do much in the end if are passed. Since inception “Accelerated Approval” most inside industry viewed has offered a feasible path to gain quicker access to new drugs through use of surrogate markers. FDA probably has been “guilty” of neutralizing this an option for many things however see has more been lack of resources with recruiting and retaining qualified staff (amount of info to review remains huge and complex but time to look at compressed) and mission focus and responsibilities growth that diverts efforts. Not sure FDA alone totally at fault as I see those as a more result of Congress (general) that has not always provided sufficient and consistent budgets plus Congress (as individuals) either adding increased mandates or getting caught up in hot-topic issues (hearings). So as you state Luke when Congress focuses elsewhere will the FDA lose momentum (or have to deal with immediacy of Congress target interest).