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To speed regulatory approval of drugs for unmet medical needs, the US House passed a bill earlier this year to jump start the process. Supporters say the 21st Century Cures Act is long overdue and will help ensure that treatments reach patients faster. The Senate is considering a similar version.

But critics say the bill may lower standards by allowing the Food and Drug Administration to approve added uses for drugs without relying on randomized controlled trials. These are the gold standard for determining whether a drug actually offers a benefit or poses a safety risk. Instead, the FDA would be able to rely on shorter, midstage trials and on surrogate markers, rather than specific outcomes.

To test the notion, a group of researchers at the National Center for Health Research, a think tank in Washington, D.C., examined three Alzheimer’s drugs that, over the past five years, failed in late-stage, or Phase 3, trials. Their goal was to gauge what might have happened had the medicines been approved based on the midstage, or Phase 2 studies. Their results are disconcerting.


They noted that all three drugs — semagacestat, bapineuzumab, and latrepirdine — had shown promise during Phase 2 trials and generated considerable excitement, particularly on Wall Street. But subsequent late-stage trials revealed a lack of effectiveness and potential for patient harm, according to their paper, which was published in BMJ. As a result, the drugs never made it to market.

Inside a healthy brain, proteins called beta amyloids are destroyed; in the brains of people with Alzheimer's disease, they are not and accumulate to form sticky plaques. Dom Smith/STAT

Under the bill, the FDA would have been permitted to approve the drugs. Yet the researchers write that the shortcomings would not have been known until larger studies were carried out, which typically take about four years to complete. And this would have come at a great price, given that there are an estimated 5 million Americans with Alzheimer’s, including 1.3 million who are currently being treated.


The researchers calculated that about 234,000 patients would have been treated on just one drug, which would have cost about $7 billion while waiting four years for late-stage study results. (They reached this conclusion by noting the Lipitor cholesterol drug grabbed 18 percent of the US market during its first year of sales, also based on a surrogate marker).

Under such a scenario, the 21st Century Cures Act “could to lead to patients taking ineffective and potentially harmful drugs and waste billions of healthcare dollars,” the researchers wrote.

Of course, not everyone agrees. One former FDA official, who now consults for drug makers, believes the legislation is a necessary compromise toward getting more needed drugs to market sooner.

“If we want more investment in difficult and complicated science, then the FDA is going to have to be both a partner and regulator in developing 21st century cures,” said Peter Pitts, a former FDA associate commissioner for external affairs, who now does policy consulting for the pharmaceutical industry.

However, Pitts concedes that tracking Phase 3 data will be important to prevent the sort of outcomes seen with the Alzheimer’s medicines. “Using early data for approvals will save significant clinical trial costs, but with less evidence, these products will also need more robust postmarketing surveillance,” he said. “Value will ultimately be measured by outcomes.”

As for the Alzheimer’s medications that were examined, semagacest targeted amyloid plaques, sticky buildups outside nerve cells that some believe are responsible for causing the disease. A Phase 2 trial showed a significant drop in plaques, but a Phase 3 trial ended early when some patients began developing skin cancers.

Similarly, midstage trials for bapineuzumab, which was overseen by Johnson & Johnson and Pfizer, showed promising results in decreasing plaques, but late-stage trials did not demonstrate any cognitive improvement. In Phase 2 trials for latrepirdine, the drug seemed to improve cognition, but a Phase 3 trial did not do so. Both drugs also were tested to combat amyloid plaques.