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FDA Increasingly Halting Human Trials as Companies Pursue Risky, Cutting-Edge Drugs

FDA Increasingly Halting Human Trials as Companies Pursue Risky, Cutting-Edge Drugs

The Food and Drug Administration is pressing pause on drug-company testing of experimental medicines more often, a side effect of the industry’s move into promising but less-proven technologies.

The agency, which must sign off before companies can begin testing an experimental drug in people, has long used its authority to place holds on studies due to safety concerns. As biotechs pursue more cutting-edge cell and gene therapies, the FDA has been issuing more suspensions than it had, according to a Wall Street Journal review of FDA data on clinical holds, some of which was obtained through a Freedom of Information Act request.

The agency halted clinical trials for experimental drugs an average of 664 times each year from 2017 to 2021, up from 557 each of the previous five years, according to the review of agency data. Through mid-December last year, the FDA had placed 747 of the holds.

“The barometer has changed from go as fast as you can to let’s be cautious,” because the technologies are newer, said Jefferies Financial Group analyst Michael Yee.

New technologies promise breakthroughs against challenging diseases such as hemophilia and muscular dystrophy, but their development presents risks. Testing of gene therapies, which replace defective genes, has been shadowed by the deaths of some young study subjects and other safety scares. The new technologies also require more time and effort from regulators to keep up with complicated advances.

Among the closely watched drugs whose studies were temporarily stopped in recent months were a sickle-cell gene therapy from Bluebird Bio Inc., after a teenage subject developed anemia. Testing of a Vertex Pharmaceuticals Inc. diabetes cell therapy was halted after the FDA said it needed more information on doses. Both trials have restarted.

The holds can damage shares, especially at small companies without approved products generating sales, according to analysts and lawyers.

The day after Entrada Therapeutics Inc. said last month that testing of an experimental muscular-dystrophy therapy had been paused, its stock fell 20%. Entrada said it was disappointed but is working to address the FDA’s concerns.

At issue in the suspensions is a pillar of the pharmaceutical industry: the hundreds of new studies that companies sponsor each year to evaluate whether a drug candidate works safely.

The FDA reviews study results when deciding whether to approve a drug. Under federal regulations, it can halt clinical trials for reasons including to protect study volunteers from unreasonable risk of illness or injury or because a study’s design is deficient.

The stop-order can prevent a study from starting or new subjects from joining, or it can require taking volunteers off study drugs.

The FDA doesn’t disclose clinical holds publicly at the time it issues the orders, nor does it require companies to reveal them. Sometimes they choose to do so, however.

A clinical hold “can be very damaging to not only what the medical community might think of the program, but also what investors might think of the company’s approach,” said Julie Tibbets, a lawyer at Goodwin Procter LLP who advises companies facing clinical holds. “It casts a bit of a dark cloud that then the company has to find its way out from.”

The suspensions don’t necessarily hinder a drug’s eventual approval and may result in better medicines, industry researchers who analyzed 39 cancer-drug trial holds wrote in a study posted on the medRxiv preprint server in June.

“However, such events can cause a significant drop in investor interest, particularly for small biotechnology companies,” the researchers wrote.

Some holds have triggered shareholder lawsuits alleging that companies withheld information about a hold or delayed sharing information about a hold. Some investors have criticized certain companies for misrepresenting why the FDA requested a hold, after the reasons emerged in public documents.

An FDA task force on transparency called on the agency, in 2010, to disclose holds and their removals, but its recommendations haven’t been implemented.

“For every trial, there are people who are watching with bated breath,” said Joshua Sharfstein, who led the 2010 effort while FDA deputy commissioner and who is now a professor and vice dean at Johns Hopkins School of Public Health. “It helps patients, providers, the companies, investors, everyone to know the truth.”

Both the FDA division that approves new drugs and the division that approves new biological products, such as vaccines, have been issuing more study holds in recent years, according to the Journal analysis of agency data.

The increase in holds by the Center for Biologics Evaluation and Research, the FDA division that reviews big-molecule drugs, is likely due to more new clinical trials for cell and gene therapies, an agency spokeswoman said. She said trends in holds from the FDA’s small-molecule drugs division would be harder to identify without a review of individual decisions.

“The FDA continues to work with medical product developers and researchers to facilitate the development of new potential treatments,” the agency said. “This includes ensuring that study participants will not be subjected to unreasonable risks in early clinical testing and that study designs address their objectives.”

The uptick in pauses may also be in part due to an increase in the number of new trials overall in recent years, analysts said.

“The big bull market led to an unprecedented expansion of the sector in terms of the number of programs and companies,” said Brian Skorney, an industry analyst with Robert W. Baird & Co. Many of the companies had trouble hiring seasoned teams, he said. “So you have a dynamic of a lot of programs being managed by relatively inexperienced groups.”

The FDA saw a 43% increase in the number of requests for permission to conduct clinical trials using experimental drugs from 2014 to 2021, according to the analysis of agency data. It saw a 66% increase in clinical holds during that time.

In December 2021, the FDA told Bluebird Bio that it had to pause trials of its sickle-cell treatment for patients under 18 years old while the company investigated the case of a teenager who developed anemia after treatment with the company’s drug, the company said. The company said last month that the agency had lifted the hold.

“We are very pleased to have addressed the FDA’s questions and resolved the partial clinical hold,” said Richard Colvin, the company’s chief medical officer. “We are working closely with study investigators and clinical-trial sites to resume enrollment and treatment.”

The FDA in May put a hold on the clinical trial for Vertex’s diabetes therapy after three patients had received doses but no serious adverse events had occurred, the company said. It said the agency said there was insufficient information to support giving higher doses to study volunteers. The company also said it was surprised by the hold.

The agency lifted the hold two months later.

Entrada said Dec. 19 it would share more information about the hold on its muscular-dystrophy drug once the FDA sends a letter, which it has 30 days to do. The drug uses a cutting-edge gene-based technology known as an oligonucleotide.

Shares in the company dropped 20% the day after it disclosed the hold. It had dropped another 11% as of the close on Jan. 6.

Write to Liz Essley Whyte at