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Alzheimer’s Drug Discord puts FDA’s fast-track system under fire

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(Bloomberg) – A US drug rush approval program that has been around for nearly three decades is under fire for criteria used by regulators to decide which therapies should be approved and for letting ineffective treatments remain on the market.

The Food and Drug Administration’s expedited process has been hailed for quickly addressing unmet medical needs with novel treatments. But critics say changes are needed to make it more transparent, to better measure efficacy and to quickly halt sales of drugs that fail confirmatory trials.

The approval of the Alzheimer’s disease drug Aduhelm has accelerated debate about the program. Rather than being approved based on its effectiveness, Aduhelm gained approval by showing that it can reduce amyloid plaques in the brain, a physical biomarker or surrogate related to disease. Meanwhile, the drug’s maker, Biogen Inc., has nine years to complete a trial of its efficacy.

“We are still in a situation where we don’t know if Aduhelm really helps patients,” said David Whitrap, vice president of communications for the Institute for Clinical and Economic Review. “If approval had been denied and the company had been asked to conduct a third trial to provide more information on whether the drug works, that trial surely could have been done long before 2030.”


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Overall, there were 41 cancer approvals through the accelerated program last year, most since the program began. Still, it’s unclear how well they work, and about half that number are yet to report their confirmatory trials.

While there have been many successes in the expedited approval program, there are issues that need to be addressed, Whitrap said in a telephone interview.

“We need more transparency,” he said. “We need more consistency around evidentiary standards, we need incentives for companies to go ahead and complete confirmatory trials within a reasonable time.”

Domino effect

The approval of Aduhelm, which is priced at $ 56,000 a year and expected to be taken by millions of patients, could have a ripple effect for other potential Alzheimer’s drugs in the works, Whitrap said, adding that it could make patients they are less willing to enroll in trials of other promising therapies.


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Allison Parks, a spokeswoman for Biogen, said in an email that the company is “working urgently and putting resources and plans in place towards the goal of completing the confirmatory test by the nine-year deadline, with a focus on high-quality data. . “

He referred to the fast-track program as “a well-established regulatory pathway that can lead to tremendous innovation.”

Bishal Gyawali, an oncologist and associate professor at Queen’s University in Canada, is concerned that the use of disease surrogates for approvals could act as a disincentive for other drug manufacturers in the future to use survival as an endpoint.

Surrogates are a laboratory measurement or physical sign that is used in trials as a surrogate for a significant clinical outcome where it can take a long time to see an effect in the treatment of a particular disease.


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“If this trend continues,” Gyawali said, “then I think a big threat that I can see going forward is that none of these drugs will use overall survival as an endpoint.”

Missed deadlines

Surrogate-based approvals are just one area of ​​concern. Drug makers also miss the follow-up trial deadlines required by the program, the researchers say. And in some cases, the FDA may not withdraw approval of a drug for years after a negative study result.

Roche Holding AG’s Tecentriq, for example, gained accelerated approval in patients with metastatic urothelial carcinoma in May 2016. It failed its confirmatory trials the following year, but its approval for that purpose was not withdrawn until this year, a delay of four years. .


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Tecentriq continues to be approved for the treatment of other cancer indications, Nathalie Meetz, a Roche spokeswoman, said in an email.

A 2019 study found that only about 20% of 93 cancer drugs received accelerated approval as of December. February 11, 1992, and May 31, 2017 showed improvements in overall survival, generally considered the most important standard for determining whether a cancer treatment is effective.

Avastin, another drug made by Roche, is a good example. It was granted expedited approval in 2009 based on a delayed tumor response to glioblastoma, one of the most common and aggressive forms of brain cancer. While confirmatory trials did not show that the drug improved quality of life or survival, the FDA approved it eight years later to confirm a surrogate measure called progression-free survival.


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The FDA is aware of concerns about the program and has been taking a closer look at how it works, said Chanapa Tantibanchai, a spokesman.

During the first months of 2021, several pharmaceutical giants, including AstraZeneca Plc and Merck & Co., voluntarily withdrew cancer drug indications after failing to meet their post-marketing requirements. In all cases, the companies said the decisions were made in consultation with the FDA, as part of the agency’s industry review of expedited approvals.

Prevention committee

As part of its review, the FDA’s Cancer Drugs Advisory Committee held a three-day meeting in April to vote on whether to keep six recent cancer immunotherapy approvals despite failing their confirmatory studies.


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The panel agreed to keep four of the six indications, although the final decision on whether to keep all six indications will be made by FDA career officials at the Center of Excellence for Oncology.

The FDA is also considering the recommendations of a white paper issued by Friends of Cancer Research in November 2020. The report urges the agency to consider ways in which the path could be streamlined, making comparisons with similar programs in Europe and Canada that require an annual evaluation. Post-market requirements update to ensure commitments are met in a timely manner.

The agency will continue to evaluate expedited approval programs and their confirmatory trials to determine if there is still a benefit to the patient, the FDA’s Tantibanchai said, and “may continue to periodically convene advisory committee meetings to discuss expedited approvals.”


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Good example

Lilly’s Lartruvo, a drug intended to treat advanced soft tissue sarcoma, is a good example of how the expedited approval process should work, according to Gyawali of Queen’s University.

Lartruvo received expedited approval in 2016, but confirmatory trials provided no evidence that it extended patients’ lives and within three years it was off the market.

The company made more than $ 500 million in sales from the treatment, according to Tracy Henrikson, a spokesperson for Lilly. “We do not have a development cost estimate to provide,” he added, “but we can say that Lartruvo’s development costs exceeded total revenues.”

Meanwhile, Gyawali called the $ 500 million a small price to pay in the pursuit of life-saving drugs. If Lartruvo’s clinical trials were not conducted in a timely manner, it could have cost billions of US dollars, he said.


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And if they had used a surrogate measure instead of overall survival as an endpoint, Gyawali added, we would probably never know the drug didn’t work.

Substitute use

However, C. Michael White, head of the Department of Pharmaceutical Practice at the University of Connecticut, said that the use of a surrogate in Biogen’s approval could be helpful.

If Biogen’s confirmatory trial shows benefit, the agency is likely to be even more comfortable with the surrogate endpoint of beta amyloid plaque. And if not, the FDA will be less willing to allow it in the future.

“The FDA has a list of surrogate endpoints that they are comfortable with,” White said. “They expanded it to include beta amyloid plaques, but have shown that they are reluctant to add additional substitutes without stronger support for the links between the substitute and the end health outcome.”

White said he “personally is not as sure as the FDA that this bet will be settled by blocking beta amyloid, but it could. The net result would be earlier access to effective therapy rather than long delays and possibly forgoing the drug, and never doing the study to find out if it works. “

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