F.D.A. Posts Collection of Letters Outlining Concerns About New Drugs

F.D.A. Posts Collection of Letters Outlining Concerns About New Drugs
By: New York Times Health Posted On: July 10, 2025 View: 6

The Food and Drug Administration on Thursday published a database containing more than 200 letters to pharmaceutical companies detailing why the agency initially refused to approve their products, shedding light on an obscure and contentious aspect of drug development.

F.D.A. officials described the move as a form of “radical transparency.” But many of the documents were already available on the agency website, albeit often difficult to find and typically posted weeks after a drug’s approval.

The documents, referred to as “complete response letters,” are akin to rejection letters. Some outline problems with an experimental drug that cannot be remedied; those letters are never made public.

But the letters released on Thursday described the agency’s early concerns about drugs that were eventually approved.

In the past, some drug makers have informed investors that the agency has sent such a letter; that decision is often prompted by securities laws. But it has been left to the companies to explain what the F.D.A.’s worries were.

In a 2015 analysis, federal researchers discovered that the companies avoided publicly describing 85 percent of the agency’s concerns about safety and efficacy when a drug eventually gained approval.

F.D.A. officials said the database would help pharmaceutical companies understand what federal regulators need from them.

“For far too long, drug developers have been playing a guessing game when navigating the F.D.A.,” Dr. Marty Makary, the agency’s commissioner, said in a statement.

“Drug developers and capital markets alike want predictability,” Dr. Makary said. “So today we’re one step closer to delivering it to them, with an ultimate goal of bringing cures and meaningful treatments to patients faster.”

Andrew Nixon, a spokesman for the Department of Health and Human Services, acknowledged that many of the letters were public already, but said that this was the “first time a centralized, easy-to-access database” has been made available.

Mr. Nixon said the agency was also working to make more decision letters public.

Even if not “radical,” the move counts as “welcome transparency,” said Dr. Caleb Alexander, a professor of epidemiology and an expert in drug safety at Johns Hopkins University.

The database “is likely to be of high interest to drug developers and funders, as well as the general public,” Dr. Alexander said.

The real test, some agency experts said, will be whether the agency begins to release these letters as soon as they are issued, when a decision about a drug is in the news.

In past years, the agency has considered releasing much more information but ultimately never followed through, in part because of the administrative burden of having to redact company secrets.

Notably absent from the new database were rejection letters for drugs that never ended up winning approval.

Those letters would have revealed details about the agency’s reasons for rejecting drugs that may have been so serious that the manufacturer could not address them. Generally, neither the agency nor the companies tend to release those letters, as was the case with the high-profile rejection of a psychedelic drug last year.

Dr. Joseph Ross, a health policy researcher at Yale, said he hoped those kinds of letters would also be released, “as it would allow other sponsors and scientists to better understand what precluded drug approval — was it safety concerns or lack of efficacy — and ideally advance on that” to bring new drugs to market.

A review of the letters addressed to companies show that they often revolved around problems discovered in a manufacturing facility inspection, a routine step before a new drug is released to the public.

Others outlined concerns about safety or a drug’s effectiveness. Mr. Nixon, the spokesman for H.H.S., said the products in the letters were all eventually approved, “indicating that they remedied the deficiencies identified in the letter.”

One letter shows why the agency initially declined to approve the testosterone drug Jatenzo, then being developed by the now-defunct company Clarus Therapeutics.

The letter noted that the drug could increase blood pressure, raising the risk of major heart problems. The agency concluded that the drug’s risks outweighed its benefits.

Jatenzo was later approved with prominent warnings, which were toned down earlier this year. The change came after a study of the drug and similar formulas found similar cardiovascular risk among men with low testosterone using the gel compared to those using a placebo. (The company that now markets the drug, Tolmar, did not respond to a request for comment.)

In another case, the agency declined to authorize an estrogen suppository over concerns that it could increase a woman’s risk of endometrial cancer. Regulators also said that the company’s 12-week study was “inadequate to assess long-term” safety.

The F.D.A. eventually approved the suppository, Imvexxy, by TherapeuticsMD, a Florida company, with a prominent warning about the cancer risk. (TherapeuticsMD did not respond to a request for comment.)

Yet another letter describes the F.D.A.’s initial concerns about Mavenclad, a drug from EMD Serono, a U.S. subsidiary of Merck KGaA in Germany, used for relapsing symptoms of multiple sclerosis, an autoimmune disease.

Though the agency said the drug was effective, it deemed the number of cancer cases in people who took the drug “an unacceptable risk.”

In a review of all studies of people on the drug submitted to the agency, the F.D.A. said it found 33 cases of cancer, compared with two cases in those who took a placebo. It found an overall rate of eight cancer cases per 1,000 patients.

That drug, too, was eventually approved and also carries warnings about cancer risk. A company spokeswoman said the cancer rate had been followed carefully since approval in the United States and in other nations, and that the risk-benefit profile was positive.

Despite the troubled beginnings for some of the drugs, Dr. Ross said the move toward more transparency was a good one. “In general,” he said, “I think more information is better, and leads to greater trust.”

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