Legislation to reauthorize FDA's user fee program and expand the agency's oversight powers on drug safety has cleared the Senate with much stronger fines than originally envisioned by the sponsors, thanks to an amendment by Sen. Charles Grassley, R-Iowa.

The bill, managed by Health Committee Chairman Edward Kennedy, D-Mass., is similar to the one introduced by Ranking Member Michael Enzi, R-Wyo., when he led the committee last session. However, the new legislation has undergone several modifications in the weeks leading up to its passage.

Changes include limiting the range of drugs that would be required to develop Risk Evaluation and Mitigation Strategies and eliminating FDA's authority to ban consumer advertising (¹ Also see "Rx Safety Triggers Tighten As Senate Continues Work On FDA Revitalization Act" - Pink Sheet, 7 May, 2007., p. 3). The bill passed 93-1, with Bernie Sanders, I-Vt., the lone vote against.

Grassley's amendment, which was adopted 64-30, sets fines for failing to comply with a REMS at $250,000 for the first 30 days, with the amount then doubling every 30 days until it reaches a total of $2 million.

Larger Fines Are In The House

Under Kennedy and Enzi's bill, companies would have been "subject to a civil money penalty of not less than $15,000 and not more than $250,000 per violation, and not to exceed $1,000,000 for all such violations adjudicated in a single proceeding."

Kennedy and Enzi had urged rejection of the amendment, with Enzi arguing their fine structure matched the penalties for device firms, and Kennedy suggesting that the matter would be best addressed after the House takes up the legislation.

"We are going to have to look at this in conference, and it's clear that the House is going to raise the fines," Kennedy said.

Even with the increased fines in the Senate bill, the issue may become a discussion point between the two chambers. On the House side, Rep. Henry Waxman, D-Calif., has introduced a version of the bill which would impose fines of at least $50,000 and at most 10 percent of a product's annual U.S. sales (² 'The Pink Sheet' March 26, 2007, p. 5).

The House is expected to take up the FDA bill in earnest after the Memorial Day recess, following a series of hearings by the Energy and Commerce Subcommittee on Health.

Another Grassley amendment would have given FDA's Office of Surveillance and Epidemiology joint sign-off authority with the Office of New Drugs on post- marketing activities, but was narrowly defeated, 46-47.

Finance vs. Health, The Finale

Grassley's amendments - among the last potential modifications to the bill considered by the Senate - provide a fitting conclusion to the drug safety debate that began in the chamber following the withdrawal of Merck's COX-2 inhibitor Vioxx .

The discussions have included territorial as well as policy disagreements, with Grassley pushing to give FDA safety officers more authority through an independent postmarketing center, holding hearings on the issue when he chaired the Finance Committee.

Enzi acceded to the external deliberation on the drug safety issue, but emphasized that authority of the Health committee would not be usurped.

"Other committees held hearings on the FDA, even though the FDA is under the jurisdiction of our committee, and we have no problem with that," Enzi said on the floor April 30 during the opening day of debate on the bill.

Another attempt to change agency policy was an amendment from Sen. Richard Durbin, D-Ill., that would have allowed FDA only one conflict of interest waiver per advisory committee.

The measure was defeated, 47-47, as Kennedy and Enzi argued that FDA is addressing the issue with guidance development (³ [A#00690130008], p. 16).

The chairman's mark of the bill includes several measures designed to address concerns about FDA's operational transparency at the behest of Health committee member Sen. Barbara Mikulski, D-Md., who was a supporter of Grassley's concept of a independent safety center within FDA.

Mikulski's changes include requiring FDA to report on the progress of integrating safety personnel into new drug reviews (⁴ [A#00690070010], p. 17).

The bill also calls for the creation of an Office of Chief Scientist at the commissioner level. The administration has expressed concern with the proposed position because of its potential to reduce the agency's flexibility and its conflict with the newly created position of chief medical officer (⁵ Also see "Janet Woodcock’s Mission: Predict Adverse Events, ID Them After They Happen" - Pink Sheet, 5 February, 2007., p. 6).

In addition to safety reforms, the bill promises large changes to the generic drug approval process, including decoupling citizen petition review (⁶ Also see "Follow-On Biologics Face Negotiation Slalom After Scaling Mount PDUFA" - Pink Sheet, 7 May, 2007., p. 5) and the potential for a pathway to approval of follow-on biologics (⁷ [A#00690190002], p. 4).

The citizen petition reforms are accompanied by exclusivity enhancements for brand antibiotics and enantiomers sponsored by Sen. Orrin Hatch, R-Utah.

Hatch noted in a May 7 floor speech that "in order to address the potential for abuse, the revised provision limits five-year exclusivity [for enantiomers] to approvals in a new therapeutic class."

In addition to the modifications to the FDA provisions, floor debate also produced several additional provisions related to topics from food safety to pet turtles (see chart: " ⁸ Putting The 'Pet' In Pet Projects "). The bill provided a convenient vehicle for senators to express their concerns about FDA oversight of food safety, but the amendments highlight the competing priorities that agency leaders and congressional appropriators will face as they try to set the direction of FDA.

While the changes to FDA's drug oversight authority were not as profound as originally envisioned in the Senate bill, they are still momentous, according to former FDA and CMS chief Mark McClellan.

McClellan said at a May 8 Health Affairs briefing on improving drug safety that the legislative debate is part of a "pendulum process."

"There will be times when the emphasis is on access and removing regulatory barriers and other times -like the times that we live in right now - where it's a very high level public concern about whether we may have gone too far in providing easier access to treatments with the result of safety risks and other problems for treatments on the market," he said.

The Biggest Swing Since 1962

"This is going to be the biggest set of changes in post market drug regulation since at least 1962," when FDA began requiring efficacy in addition to safety testing for drugs, McClellan said. "FDA will be doing no less than entering a new era of postmarket drug regulation when this happens."

McClellan, a visiting senior fellow at the AEI-Brookings Joint Center for Regulatory Studies, foresees the potential burden of increased postmarket activity as a catalyst to swing the debate back towards promoting access to drug treatment.

Additionally, McClellan expects new drug safety legislation will create new interactions between FDA, Medicare and private payers regarding drug utilization.

Highlighting prior authorization requirements and tiered benefit designs, McClellan emphasized that health care payment and reimbursement systems will increasingly influence the practice of medicine regardless of FDA regulations.

"How we pay has a big impact on how medicine is practiced," McClellan said.

"Just because the FDA doesn't impose some regulatory requirements along with [a] label doesn't mean there aren't other influences on the practice of medicine coming in. ... Some of those may be good, and some of those may be bad. We need to do a careful job of studying their impact, but they are definitely going to be an increasingly important part of the practice of medicine."

- M. Nielsen Hobbs (n.hobbs@elsevier.com) & Daniel Poppy (d.poppy@elsevier.com)

FDA Reform Bill Leaves Senate With Reduced Safety Powers But Stiffer Fines

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