The Rx safety oversight system outlined in the legislation passed out of the Senate Health Committee April 18 has a greater focus on active surveillance systems than the bill originally introduced by Sens. Edward Kennedy, D-Mass., and Michael Enzi, R-Wyo.

The "FDA Revitalization Act" now calls for the creation of a public/private partnership to develop an active surveillance system for Rx safety that would screen databases of medical records to detect adverse event patterns.

Such a program has been endorsed by industry as an effective approach to assessing postmarket safety issues (¹ Also see "Public/Private Partnership Is Best Vehicle For Active Rx Surveillance System" - Pink Sheet, 2 April, 2007., p. 28).

The effort would be funded through an additional $30 million in appropriations that would be authorized under the bill. The bill also adds $50 million in user fees to pay for FDA's review of the Risk Evaluation and Mitigation Strategies which sponsors would be required to develop when the agency felt a product warranted additional safety attention.

The chairman's mark had originally included $70 million in additional safety-related user fees and did not authorize additional money for surveillance (² Also see "PDUFA Draft Bill Adds $70 Mil. For Rx Safety To User Fee Totals; Mark-Up Looms" - Pink Sheet, 16 April, 2007., p. 14).

The original Kennedy/Enzi bill, unveiled last session and reintroduced with tweaks in February, called for all new products to include a REMS, although the minimum components were limited. The bill expands FDA's authority to require labeling changes and post-marketing studies, and gives the agency the ability to fine companies for non-compliance.

Under the revised bill passed by the committee, FDA may ask for a REMS when it feels that safety information necessitates such an action.

Despite the changes, the bill is still opposed by the administration. In a ³ letter to Kennedy, HHS Secretary Michael Leavitt said, "Many of these bill provisions seem fixed on process changes and structural changes in government programs, and not on making fundamental improvements in the science of drug safety."

"Some changes prescribe specific agency action when the science of drug safety may not require such intervention, such as the requirements to present all new molecular entities to advisory committees for discussion."

During the mark-up, Sen. Judd Gregg, R-N.H., offered an amendment that would have further limited the use of REMS by requiring that they be employed only after a safety signal has been detected through the active surveillance system and vetted by outside bodies.

Sen. Tom Coburn, R-Okla., said, "As a practicing physician, I don't think REMS will stop the next Vioxx the way it's set up" because it focuses on FDA activities after a safety signal has been detected, not on creating a system to detect signals.

Gregg's amendment was defeated 9-12, with Enzi joining the Democrats in opposition.

In addition to the safety powers, the legislation also boosts the number of trials that need to be reported to public databases, and tasks FDA with reducing conflicts of interest by advisory committee members and integrating staff from the drug safety office into the review of new drugs.

The legislation, which also reauthorizes FDA's drug user fee program, will continue to be tweaked before appearing on the Senate floor, possibly in June.

Kennedy and Enzi pledged to work with several members who symbolically introduced and withdrew amendments on issues ranging from patents to pediatrics.

The bill cleared the committee 15-5, with Republican senators Enzi, Lamar Alexander (Tennessee), Pat Roberts (Kansas), and Orrin Hatch (Utah) joining the Democrats. After passage, Enzi called the bill "by no means a finished product."

The mark-up saw one revision related to FDA's safety powers. An amendment from Sen. Richard Burr, R-N.C., would establish a more definitive time for consideration of labeling changes by FDA.

Kennedy endorsed the changes after Burr said they were additions, not replacements, to the language in the bill. In addition to reauthorizing the user fee program, the bill gives FDA additional authority to oversee drug safety and reauthorizes the pediatric exclusivity program.

Two amendments related to FDA's safety authorities garnered the support of Enzi, suggesting those issues may have more weight as the bill is discussed on and off the Senate floor.

Enzi backed an amendment from Roberts that would have scaled back FDA's powers to restrict direct-to-consumer advertising and replaced them with the ability to fine companies for false and misleading advertising (see ⁴ Also see "DTC Limits May Land In Court After Opponents Fail To Strip FDA Powers From Bill" - Pink Sheet, 23 April, 2007.).

The advertising oversight powers could be seen as indicative of what critics of the legislation call its overly bureaucratic approach. While the bill would allow FDA to block DTC ads for up to two years, it does not appear to give FDA the authority to fine companies for false advertising outside the context of a REMS.

Enzi also endorsed an amendment from Sen. Wayne Allard, R-Colo., that would have restored six months of pediatric exclusivity for blockbuster drugs; the amendment fell 10-11.

The reauthorization of the Best Pharmaceuticals for Children Act included in the bill caps the exclusivity at three months for products with over $1 billion in sales.

The pediatric provisions have been adjusted since the initial chairman's mark, including reviving the sunset provision for FDA's authority to require pediatric studies. Sen. Hillary Clinton, D-N.Y., offered and then withdrew an amendment that would have made the powers permanent.

An amendment from Gregg exempting bioterror drugs from the new safety requirements, and from Coburn eliminating the power to limit prescribing to certain kinds of doctors, went down to defeat without Enzi's support. Enzi shares Coburn's concerns, though, and his staff is working on provisions that ensure patients in rural areas have access to restricted medicines.

Enzi's choices of which amendments to support suggest the ranking member is firmly committed to the measure's expansion of authority in the labeling and distribution arena, though perhaps not marketing.

Among the other elements that may be included in the bill on the floor is a pathway for generic biologics.

- M. Nielsen Hobbs (n.hobbs@elsevier.com) & Cathy Dombrowski (c.dombrowski@elsevier.com)

Rx Safety Bill Produces Restless REMS; Core Of “KEnzi” Is Narrowed But Intact

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