FDA May Seek More Authority To Require Post-Marketing Safety Studies

FDA may consider asking for more authority to compel companies to undertake post-marketing drug safety studies after examining manufacturers' compliance with existing Phase IV commitments.

At a July 26 House Appropriations/FDA Subcommittee hearing, Ranking Member Rosa DeLauro (D-Conn.) asked FDA Commissioner Lester Crawford whether the agency wanted "the authority to get industry to conduct a safety study?"

FDA is "now examining how faithful these companies have been in doing these [post-marketing studies], when we ask for them," Crawford said. The hearing was Congress' first opportunity to question the newly confirmed commissioner regarding drug safety and FDA's operations.

"We found some difficulties with medical devices; we're now looking at the drugs. Pending that we may very well be in the position" to request more authority, Crawford said.

Rep. DeLauro noted that FDA's annual report on Phase IV commitment status found that "68% of agreed upon studies have not even been started. This is even worse than the report three years ago showing that 61% had not been started," she remarked

In the FDA report, 812 (68%) of 1,191 commitments for NDAs and ANDAs were classified as "pending"; when BLAs were included the figure was about 60%. Only 1% of NDAs/ANDAs were classified as delayed (¹ (Also see "Phase IV Status Report: Fewer Open Studies, But More Overdue Reports" - Pink Sheet, 28 Feb, 2005.), p. 17).

At a July 20 meeting of the Institute of Medicine Committee on Assessment of the U.S. Drug Safety System, Office of New Drugs Director John Jenkins acknowledged that in the past agency approval letters to companies often lacked a start or completion date for post-marketing commitments.

However, since the passage of the FDA Modernization Act, FDA writes the "letters such that there is a target for the date to start the study, a date to complete enrollment and a date for the final study report to be submitted," Jenkins said.

Congresswoman DeLauro pointed to a list of drugs four pages long for which FDA had issued safety warnings since January 1, 2005. "What is to be done in the post-marketing processes to shorten that list?" DeLauro asked Crawford.

Crawford replied that the evidence of the list meant that FDA was "on the job," adding "we hope to reduce the list." The FDA commissioner said, "we wish that all drugs had no risk, but sometimes we don't know about them until they go on the market."

Democratic legislators further pressed the new commissioner on whether FDA needed expanded authority to require industry to make changes to drug labeling.

"Do you want authority to make them change their labels?" DeLauro asked.

Crawford responded that while the agency was "open to discuss [the matter]...we don't have any administration position on that." He maintained that the current system, which depends on voluntary industry compliance to FDA's requests for label changes, "works like it is."

However, Rep. Maurice Hinchey (D-N.Y.) felt that the current system lacked teeth, noting that it took 14 months for Merck and FDA to agree to add cardiovascular risk information to Vioxx labeling.

"Vioxx...you have told us that you used all existing authority to make that label change happen. Is that right?" Hinchey asked.

"Yes, we used what we had," Crawford said.

"We're not proud of how long that took," Center for Drug Evaluation & Research Director Steven Galson interjected.

Galson sat behind Crawford at the hearing, along with Center for Biologics Evaluation & Research Director Jesse Goodman.

Merck added cardiovascular risk information to the Precautions section of Vioxx labeling in April 2002; The company withdrew the COX-2 inhibitor in September 2004 due to cardiovascular risk.

Since Vioxx' withdrawal, FDA has asked Pfizer to withdraw its COX-2 inhibitor Bextra , and it is requesting a "black box" warning in class labeling for all prescription non-steroidal anti-inflammatory drugs, including Pfizer's Celebrex (² (Also see "Bextra Withdrawn At FDA’s Request; Pfizer Holds Out Hope For Return" - Pink Sheet, 11 Apr, 2005.), p. 5).

If "you say you don't want additional authority, we can't assume that in any future case, when you ask for a label change, that anything different is going to take place," Hinchey told Crawford.

"Well, I've said that I am open to considering that but I can't commit to it now," Crawford replied.

Congressional efforts to expand FDA's regulatory authorities are not intended to "tie up industry, but to make an industry more productive, more focused on safety working in concert with us...in terms of getting this job done," DeLauro said.

Crawford said that FDA would look at legislation "and then develop a position on it. I assume you are going to develop a bill that we can look at," Crawford added.

"Yeah, we have a bill," Hinchey replied.

Currently, there are two bills in the Senate and the House aiming to increase FDA transparency and expand the agency's authority.

Hinchey has introduced the "FDA Improvement Act of 2005" (HR 2090) that would establish an independent "Center for Post-Market Drug Safety & Effectiveness" and increase agency's independence by severing its connection to industry through user-fee payments (³ (Also see "Drug Safety Bill Authorizes Fines On Industry, But Does Not Include User Fees" - Pink Sheet, 16 May, 2005.), p. 11).

The "^FDL-1 FDA Safety Act" (S 930), introduced April 27 by Senate Finance Committee Chairman Charles Grassley (R-Iowa) and Sen. Chris Dodd (D-Conn.), would create an independent drug safety center, funded by appropriations instead of user-fees, and increase authority to require post-marketing studies, change labeling, and pull drugs from the market (⁴ (Also see "FDA Safety Act Calls For “Expedited Procedures” For Drug Withdrawals" - Pink Sheet, 2 May, 2005.), p. 8).

Democratic lawmakers also criticized the lack of transparency within FDA's Drug Safety Oversight Board and questioned advisory committee members' conflict-of-interest with industry (see ⁵ ).

The July 26 House Appropriations/FDA Subcommittee hearing was held up for nearly six weeks awaiting Senate confirmation of Crawford's nomination.

Crawford was confirmed July 18 by a 78-16 Senate vote. Senate confirmation was delayed due to an impasse over Barr's emergency contraceptive Plan B and an HHS Office of the Inspector General investigation into allegations of misconduct (⁶ (Also see "Crawford’s First Business After Confirmation: Brief Senators On Mifeprex" - Pink Sheet, 25 Jul, 2005.), p. 4).

"You are in fact the first FDA commissioner not to be confirmed unanimously," DeLauro reminded Crawford. "I know you understand that you and the agency will remain under close scrutiny from this subcommittee."