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A new Alzheimer’s drug shows why the FDA’s speedy approval process is broken

Too often, pharma companies fail to hold up their end of the bargain by running solid tests to confirm the drugs’ effectiveness

A sign for the biotechnology company Biogen, maker of a new drug to treat Alzheimer's, is seen March 18, 2017. (Dominick Reuter/AFP)
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Whether it’s covid or cancer, when you’re a patient facing a life-threatening disease without good treatment options, your risk tolerance is bound to be pretty high. You would probably prefer to try something now that might work rather than wait for solid proof, especially if chances are high you’ll be dead by the time that proof comes around.

The Food and Drug Administration’s “accelerated approval” pathway is intended to address this challenge by allowing conditional approval of treatments that appear promising while requiring drugmakers to continue to study them to prove their benefit. But after three decades, problems with the program are evident, as highlighted by the FDA’s accelerated approval of aducanumab (under the brand name Aduhelm) for Alzheimer’s disease in June. The drug got the green light despite weak evidence, substantial risks and a price tag that remains exceedingly high, even after its maker, Biogen, slashed the price in half, to $28,200 annually for the average patient.

We think accelerated approval is a policy worth saving, but fixes are needed to make sure companies quickly follow through on rigorous confirmatory studies of these drugs. Too often, drugmakers are failing to keep their end of the deal.

FDA approval requires — in addition to a determination that a drug is safe for its intended use — “substantial evidence” of a drug’s effectiveness. That’s usually demonstrated through data showing that there’s a clinical benefit in how patients feel, function or survive. Do they live longer, can they walk or breathe better, is their cognitive decline slowed? These are things that really matter, but that kind of evidence can take a long time to generate.

As an alternative to waiting for such clear-cut findings to emerge, the FDA can grant accelerated approval based on outcomes deemed only “reasonably likely to predict clinical benefit.” These are placeholders for what patients care about — surrogate markers such as tumor shrinkage in the case of a cancer drug or, for Aduhelm, a reduction in the amyloid plaques sometimes found in the brains of patients with Alzheimer’s. These proxy outcomes aren’t always reliable gauges of efficacy, but they can be studied quickly, allowing the FDA to approve promising drugs more expeditiously, and patients to try them more swiftly. In return for this speed, companies are required to conduct additional clinical trials to confirm predicted benefits. If those trials aren’t completed or don’t confirm a benefit, the FDA can withdraw approval.

The pathway has had some big successes. Most notably, it got the lifesaving drug imatinib (Gleevec) to leukemia patients years sooner. But it has also left questionable or ineffective drugs on the market for years. For example, an expensive muscular dystrophy drug, eteplirsen (Exondys 51), received accelerated approval in 2016, but the confirmatory trial isn’t slated to end till 2026. The FDA often sets unreasonably distant deadlines for companies to report confirmatory trial results and more than 1 in 10 accelerated approvals predating 2016 still haven’t produced evidence to support transition either to traditional approval or withdrawal.

Even when they are completed, confirmatory trials are often poorly designed, failing to produce strong evidence that a drug improves patient health. This is in part because companies know that once drugs are on the market, the FDA can be hesitant to pull them off, especially when patients lack other approved options. In fact, the FDA sometimes allows accelerated approvals to stand even when companies fail to meet deadlines, or when post-approval studies fail to confirm a benefit.

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Drugs that are approved but don’t work have costs beyond siphoning financial resources from patients and others paying the bills. Side effects that impair patients’ health aren’t justifiable if a drug doesn’t do what it’s supposed to do. And even if a drug is very safe, time spent taking an ineffective drug is time not spent pursuing other options, including trials of other products. Also troubling is that after the FDA accepts a surrogate outcome, other companies will seek accelerated approval on the same basis — putting more drugs and more patients in a precarious position if those outcomes fail to actually produce a benefit. Overall, this approach can delay the development of better alternatives.

Part of the problem is that after accelerated approval — once they can sell their drugs and generate revenue — companies have little reason to pursue fast, high-quality confirmatory trials. To change that, policymakers should add an expiration date to accelerated approvals, perhaps two to five years depending on how rare the disease is and how quickly it progresses. And they should make clear that withdrawal will be automatic when standards aren’t met. Creating a default expectation that accelerated approval drugs will be withdrawn absent clear evidence of a clinical benefit, rather than allowed to linger on the market, would nudge companies toward conducting better, faster trials.

Another part of the problem may stem from patients rather than companies. Sometimes, confirmatory trials can be hard for companies to conduct because patients have too little incentive to participate once they can access desired treatments without enrolling. It might be possible to make trial participation after drug approval more attractive by making it more convenient, by offering incentives, or by making clearer to patients the extent of uncertainty around accelerated approval drugs. Drugmakers might also — as Biogen recently announced in the case of Aduhelm — move confirmatory trials to foreign locales where the drug hasn’t yet been approved, to attract more eager participants (although that could possibly affect generalizability of the findings).

Another useful policy intervention would be for insurers to pay less (or nothing) for accelerated approval drugs until they are proved to work. Historically, public and private insurers have reimbursed low-quality products and services and then inflated premiums or taxes to cover them. But given the extremes of Aduhelm’s cost and lack of proof, many insurers have refused coverage without stronger evidence of a benefit, creating pressure that prompted Biogen to announce plans to have confirmatory results ready several years before the FDA’s deadline. An objection to this approach, of course, is that it means only patients who can afford to pay out of pocket can then have access, while everyone else has to wait.

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Medicare is a special case. Although it spends $9.1 billion annually for unproven accelerated approval drugs, Congress has not given the program flexibility to “negotiate” drug prices, which includes paying less than full price when there are questions about efficacy. Instead, Medicare must make binary cover-or-not determinations; this month it will make a preliminary decision about whether to cover Aduhelm. What Medicare can do, however, is choose to pay only in the context of a clinical study. We agree with two expert advisers to Medicare who recently suggested that Aduhelm coverage be limited to beneficiaries who volunteer to participate in a new randomized, placebo-controlled trial of the drug. Although this approach would limit access compared with typical payment models, it gets accelerated approval closer to a reasonable compromise between access and evidence.

In the early days of accelerated approval, some advocates for HIV patients warned that weakened standards of proof might leave patients with an armload of drugs and no way to know which were worthwhile. In some cases, and across a range of diseases, these fears have come true. Accelerated approval has been a popular pathway for drugs for cancer and for some rare conditions — and after Aduhelm, we’re likely to see an onslaught of drugmakers seeking similar approval for other Alzheimer’s drugs. Some of these may prove to be boons. But others will be duds. The system needs to change so that patients not only have treatment options, but options they can be confident work.