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Enforcement delays as critical as approval times


By Mari Serebrov
Regulatory Editor

When it comes to launching a new drug or medical device, time is money.

Thus, it's no surprise that the biopharma and med-tech industries center on FDA review and approval times when they negotiate user fee agreements with the agency. And when Congress looked to reduce the cost of new cures by streamlining R&D, it focused on clearing out obstacles in the agency's standard development and review practices.

What's been left out of the equation is how long it takes the FDA to address manufacturing problems noted in plant inspections. Its Center for Drug Evaluation and Research (CDER) and Center for Devices and Radiological Health (CDRH) won't approve new therapies if the facilities making them don't measure up, as lack of good manufacturing practice (GMP) compliance can affect the quality of a product.

Last year, GMP violations resulted in 14 complete response letters (CRL) for novel drugs, indefinitely delaying the launch of those products, said John Jenkins, the retiring director of CDER's Office of New Drugs. Many of those CRLs cited manufacturing issues as the primary deficiency. That's unusual, Jenkins said. CDER issued 47 CRLs for novel drugs from 2010 through 2015, but only four of those letters were due to GMP issues.

The CRLs should serve as a reminder to sponsors that all of their manufacturing facilities must comply with GMP regulations if they want to ensure approval of their applications, Jenkins said.


A CRL citing GMP concerns can catch sponsors unawares, especially since CDER is taking longer and longer to send out warning letters after a company has responded to inspection findings. "That is a problem," David Rosen, a partner at Foley & Lardner LLP and a former FDA official, told BioWorld Today. "This is a big issue."

In 2016, CDER sent 43 warning letters citing GMP violations. Even though the drug manufacturers responded to inspection concerns in a timely manner, 20 of the warning letters were sent at least a year after the inspection. One manufacturer in India received a warning letter 16 months after an inspection. The average time from inspection to CDER warning letter was seven months. (See GMP Warning Letters.)

CDRH seems to be doing a better job of notifying device companies of GMP violations. Of the 18 GMP warning letters it issued in 2016, one was sent out within eight months of the inspection, three within six months and the rest within four or five months. One of the 18 has been closed out already.

Getting timely feedback from the FDA on GMP compliance is crucial to sponsors, Rosen said, especially those developing new products. They need to know early on if their manufacturing plans for a new product are acceptable; otherwise, approval could be delayed and even a short delay can prove costly.

Recognizing that fact, Margaret Hamburg made the timely issuance of warning and closeout letters a priority soon after she came on board as FDA commissioner. She reduced the time companies had to respond to inspection observations to 15 days and said the agency would no longer indulge in a stream of back-and-forth correspondence before sending a warning letter.

That policy led to a shorter turnaround from inspection to warning letter – for a while. In 2011, after the policy was put in place, the average time between an inspection and warning letter for drug companies was 6.3 months. The time for device makers was two months shorter.


Slow FDA action on quality issues goes beyond approval delays; it also can impact the safety of drugs and devices already on the market. As a result of GMP issues, CDRH took steps to place products from 65 percent of the device makers receiving warning letters in 2016 on detention without physical examination (DPE).

Of the 43 drug manufacturers receiving a warning letter last year, 19 were placed on import alert. While CDER imposed the import alerts before sending the warning letters, it still took an average of 5.3 months to restrict the import of drugs that potentially had significant quality issues. In two instances, CDER waited nearly a year before imposing an import alert.

In another instance, CDER waited more than a year after inspecting Dongying Tiandong Pharmaceutical Co. Ltd.'s API plant in Shandong, China, to send it a warning letter spelling out the possibility that tainted heparin could have been used to manufacture API for the U.S. market. However, the company was not placed on import alert. (See BioWorld Today, Nov. 30, 2016.)

The letter was sent eight months after France's National Agency for Medicines and Health Products Safety (ANSM) cited similar problems and called on the EMA to revoke Dongying's good manufacturing practice certificate. The ANSM recalled the company's products in March and urged other EU members to do the same. (See BioWorld Today, March 9, 2016.)

When asked about the time it took to send Dongying the warning letter, a CDER spokesperson told BioWorld Today that agency "experts must review all available information regarding serious violations and evidence uncovered during the FDA inspection and any responses by the company to determine the appropriate and necessary next steps. This review can take time."

But such delays can undermine confidence in the FDA's ability to ensure the quality of drugs and devices on the U.S. market. "If a company isn't doing something right, I want the FDA to do its job," Rosen said. There has to be a minimum standard of quality drug and device companies must maintain to continue to market products in the U.S., and the FDA has to be tough on compliance – in a timely way, he added.