FDA appears to have a relatively smooth task ahead of itself as it works to finalize its proposed rule delineating when firms can change product labels without prior agency approval since the comments supporting the proposal contain few suggested changes.

Whether the rule would be implemented, however, remains in question, given the amount of congressional pressure on FDA to withdraw it. The administration appears committed to finalizing the proposal, but must race against the clock to finish because if it is issued late in the year, the next president may have the power to suspend it due to the 60-day latency period for most new rules.

When the Bush administration came into office, it issued a "regulation freeze" that stopped work on several FDA projects - including post-marketing surveillance and opioid jurisdiction - while they were reviewed by newly appointed officials (¹ Also see "FDA Adverse Event Rule Halted At OMB By Administration Regulation Freeze" - Pink Sheet, 29 January, 2001., p. 10).

As the administration works on a slew of projects in its waning days, it aims to avoid a similar fate for its rule on "Supplemental Applications for Proposing Labeling Changes for Approved Drugs," which would considerably strengthen sponsors' pre-emption defense in product liability suits.

The proposed rule on "changes being effected" supplements, issued in January, would define a narrow window of opportunity for companies to revise product labeling without prior agency approval; it states that only newly emerging safety information would warrant such changes. In addition, companies may strengthen contraindications and warnings "only if there is sufficient evidence of a causal association with the drug, biologic, or device" (² Also see "FDA Preemption: Agency’s Proposed Labeling Rule Riles Plaintiffs’ Bar" - Pink Sheet, 21 January, 2008., p. 21).

PhRMA Suggests More Limits On CBEs

The liability ramifications seem to be why the proposal has drawn strong praise from industry groups and strong objections from consumer groups and some congressmen.

The comments from Pharmaceutical Research and Manufacturers of America are typical for industry in that they endorse the proposed rule (footnote 4 is singled out for particular praise) and contain relatively minor suggestions for modification.

PhRMA asked FDA for additional clarification emphasizing that CBE supplements are not appropriate for modifications to three elements: risk evaluation and mitigation strategies, the "highlights" section of labeling and medication guides.

The Biotechnology Industry Organization asked the agency for specifics regarding the length of time FDA would consider information "newly acquired."

"A process for formally notifying the sponsor after FDA completes its review of previously submitted safety information may help draw the distinction between newly acquired safety information and previously reviewed data," BIO states.

Congress Wants To Crunch The Numbers

Congressional commentators questioned the rationale for the proposed rule and called on FDA to withdraw it.

"We are concerned that the intent of this proposal is to protect companies in the pharmaceutical and device industry from being held liable for marketing products they know are unsafe," states a Jan. 23 letter signed by Reps. Henry Waxman, D-Calif., John Dingell, D-Mich., Rosa DeLauro, D-Conn., and Sen. Edward Kennedy, D-Mass., among others. "Such a policy change comes at the expense of consumers and violates the mission of the FDA."

Congress could of course take legislative action to block the rule, but any major push on the Hill related to pre-emption will likely await a decision by the Supreme Court in the Wyeth v. Levine case, which is expected to be decided in the fall term (³ Also see "FDA Preemption Deadlocks Supreme Court; Congress Pushes To Resolve Issue" - Pink Sheet, 10 March, 2008., p. 16).

In the agency's response to the members' comments, FDA said that the rule, if finalized, would not alter existing practices "with respect to accepting or rejecting labeling changes proposed by a [changes being effected] supplement."

Additionally, the rule "would not inhibit appropriate and timely submissions of new safety information, or the agency's ability to review supplements in a prompt manner."

In what appears to be an effort to make a case that the new rule is unnecessary, members of Congress asked the agency to describe any cases in which a manufacturer used the CBE procedure in a harmful way to explain why revising the regulations is now a "public health priority."

FDA identified 19 cases of "not approvable" CBE supplements among the 1,826 received since 2004. Four were relevant to the congressional request; the remaining 15 involved cases where "the CBE supplement was not used to add or strengthen a contraindication, warning, precaution, or adverse reaction."

"Three supplements for one product were not approved because FDA determined it was necessary to have stronger warnings than were proposed by the applicant," the agency states.

"In the case of one CBE supplement, FDA did not approve it because the applicant's causality assessment was inadequate to support the labeling change," the agency states. FDA informed J&J on Dec. 6, 2005 that the CBE supplement submitted Feb. 4, 2005 for the antipsychotic Risperdal (risperidone) did not adequately demonstrate the link between concomitant use with furosemide and risk of death.

"Subsequently, the applicant resubmitted the CBE supplement with additional data and the risk information was approved," FDA said.

The agency also noted that it began working on the proposed rule in "mid-May 2007," around the time Congress began debating the pre-emption issue as it drafted the expanded safety powers contained in the FDA Amendments Act (⁴ Also see "Federal Preemption Defense Against Product Liability Weakened In House Bill" - Pink Sheet, 11 June, 2007., p. 7).

Philosophical Objections To Pre-emption

The Conference of Chief Justices, which represents the "highest judicial official in each of the 50 states," raised philosophical and legal objections to the pre-emption claims made by FDA.

"What raises a concern for members of the CCJ is FDA's assertion that the proposed rule pre-empts state law under the principle of implied consent," the comments state. Citing Executive Order 13132, the group says that agencies should construe federal law to pre-empt state law "only where the statute contains an express pre-emption provision or there is some clear evidence that Congress intended the pre-emption."

- Carlene Olsen (c.olsen@elsevier.com)

FDA’s Labeling Rule Should Be Tweaked, Firms Say; Dems Want It Squashed

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