Rx Label Format Changes Should Be Phased In Without "Highlights" - PhRMA

FDA's prescription drug labeling initiative should proceed in areas where there is consensus between the agency and the pharmaceutical industry, the Pharmaceutical Research & Manufacturers of America said in comments on the proposed rule.

"As a first step, FDA should require only those aspects of the proposed rule on which there is a consensus, such as the reorganization of the comprehensive prescribing information," PhRMA said in its June 13 comments on FDA's proposal to change the format and content of drug labeling.

While drug manufacturers support the reordering of information, they do not support all of FDA's proposed changes to the main body of labeling, such as the change to the definition of adverse reactions (¹ (Also see "FDA Labeling Proposal Should Allow "Flexible" Warnings, Merck Tells Agency" - Pink Sheet, 16 Apr, 2001.)).

"These agreed changes should be required only for new applications and effectiveness supplements," the comments suggest.

The proposed implementation plan would require applications submitted on or after the effective date of the final rule to follow the revised format and content requirements; applications pending at the effective date and products approved up to one year prior would have three years to conform. The rule includes a staggered implementation schedule for older marketed products (² (Also see "In Vitro Data Not Relevant To Clinical Use Should Be Cleared From Label - FDA" - Pink Sheet, 1 Jan, 2001.)).

Among the "considerable benefits to this more cautious approach," PhRMA said, is that it "would focus the resources of sponsors and the agency on the most important labeling to revise, and would provide additional experience with the new labeling rules before broader changes are required."

Among the proposed changes where FDA needs more study before implementation, PhRMA said, is the "Highlights" summary section. PhRMA suggested FDA conduct studies to determine if reordering the comprehensive labeling information alone could change the way labeling is used, thus obviating the need for the Highlights.

"At a minimum, PhRMA urges that any aspects of the proposed rule that have not yet been field tested be subjected to further scrutiny on a pilot basis before adoption," the comments say.

"Further market research should probe whether there is a real need for a new 'Highlights' section in light of the other proposed changes to the labeling, and whether the new labeling will result in desired behavioral changes by health care practitioners in the way they use approved prescribing information," PhRMA added.

The potential for the Highlights to increase manufacturers' product liability, by giving emphasis to only selected information about product safety and efficacy, remains a concern for industry.

"Every pharmaceutical product liability case involves allegations regarding the adequacy of the information disclosed about the product," PhRMA pointed out, "including allegations that important information is missing or that risk or other information disclosed was not sufficiently prominent."

"The only way to resolve these liability risks would be for FDA to mandate the precise content of the 'Highlights' section for a particular product," PhRMA maintained.

Agency-mandated content in the Highlights would also be necessary to address concerns that products in the same drug class could have inconsistent labeling, PhRMA said.

To further shield manufacturers from product liability arising from the labeling changes, PhRMA suggested the agency incorporate into the rule "a statement that FDA approval of labels and labeling preempts conflicting or contrary state law, regulations or decisions of a court of law for purposes of product liability litigation."

Although Aventis also opposes inclusion of Highlights in labeling, the company suggested that, if adopted, it could be used to replace the brief summary in advertising.

Noting that "the proposed rule does not delineate the form the brief summary would need to have to be consistent with the new labeling requirements," Aventis said "perhaps the FDA would entertain the idea that, if adopted, the 'Highlights of Prescribing Information' could serve as an alternative brief summary."

Because FDA is proposing that Highlights include the most important risk information and a bolded disclaimer reminding prescribers the section is not intended to stand alone, "this would alert practitioners to the fact that they still need to consult the full labeling, which is how they should already be using the brief summary in its current form," Aventis said.

Industry expects the redesign to significantly lengthen the label, up to 70% in some cases. The length would then necessitate "new trade packaging for some products to accommodate the added text," PhRMA said.

FDA has underestimated the implementation costs of the rule, PhRMA added. The agency's estimate of $94.53 mil. "is based on an incorrect assumption about how much longer package inserts would become...and does not reflect the full attendant costs for retooling packaging lines," the comments explain.

Merck has projected that for its 50 packaging lines the total capital costs would reach $40 mil. (³ (Also see "Rx Label "Highlights" Under FDA Rule Could Yield Inconsistencies - Merck" - Pink Sheet, 16 Apr, 2001.)).

Further, the cost estimates "do not reflect the indirect costs that will be incurred as the result of the agency resources that would be diverted to process the flood of labeling supplements and waiver requests that would be triggered."

Because of the large number of products that would require new labeling in the first year after the rule takes effect, PhRMA suggested FDA's attention to the initiative could distract it from reviewing new drugs.

"Approximately 1,838 products would require relabeling the first year after the rule becomes effective," the association said. "Implementing the rule as proposed will increase the number of supplements requiring review and thus impose a significant burden on the agency."

"Given this burden, PhRMA is concerned that this initiative might compromise the agency's attention to the drug review and drug approval process."

The Highlights summary would also need to be longer than the proposed half-page. FDA based the half-page limit on practitioner input from agency focus groups.

"We cannot fit the necessary information in the proposed space allocated for this purpose, and practitioners do not want to increase the length of the section," Lilly said. PhRMA described the disagreement over length as "irreconcilable."

"Drugs have varying levels of complexity and a 'one size fits all' approach is not appropriate," Immunex said. "If manufacturers will be required to choose which information is most important for practitioners, they must be permitted the flexibility to include all of the information that they deem appropriate."

"Companies have tried in good faith to create mock-ups of 'Highlights' section for actual products and have been unable to satisfy the half-page limitation," PhRMA stated.

Several companies objected to the proposed use of an inverted black triangle to denote a newly marketed product for which the safety profile has not yet been fully established.

While the symbol is currently used in the U.K., it is unfamiliar in the U.S. and would necessitate an extensive education campaign, companies indicated. "Without specific explanation, the symbol adds little value and would likely cause confusion," Pharmacia said.

"In principle, use of a symbol creates a two-tiered catalog of prescription drugs ('new' versus 'old'), absent any legal or regulatory basis for FDA to make such a distinction," GlaxoSmithKline maintained.

Should the symbol be used, Aventis recommended "very objective" criteria for its use; "i.e., related only to time on the market, not to patient exposure or to potential safety concerns the agency may have with the product."

Other proposed criteria - such as an indication for a new population, a new route of administration, or a new drug delivery system - would cause a product to carry the symbol "throughout its marketed life, while the safety profile may have been well established years before," Aventis' comments explain.

Companies also rejected FDA's proposal that boxed warnings exceeding 20 lines be summarized in the Highlights. Such a summary "risks paring down the information to the point that it looses its usefulness," Immunex maintained.

"The proposal would force a reduction of what should already be irreducibly brief," GSK stated.

FDA is preparing a series of guidances on individual sections of Rx labeling to clarify implementation of the redesign (⁴ (Also see "Confidence Intervals Favored Over P-Values In FDA Clinical Studies Guidance" - Pink Sheet, 9 Jul, 2001.)).