Promotions For Black-Box Drugs Aren’t Specific Enforcement Targets, FDA Says

FDA advertising enforcement does not preference black-box drugs despite risk-based approach prioritizing products with significant risks; nor are drugs with small patient populations exempt from risk-based approach.

Promotion of a drug with a safety concern that warrants a boxed warning doesn’t necessarily receive any added attention from FDA’s Office of Prescription Drug Promotion.

Though products with significant risks are one of the agency’s risk-based criteria for prioritizing the review and enforcement of drug promotion regulations, the agency said boxed warning drugs aren’t a specific focus. Even so, 50% of OPDP letters issued from July to December 2013 covered products with boxed warnings.

“OPDP does not specifically target boxed warning drugs. We do have limited resources; we generally use a risk-based approach that is taken to identify the matters that need to be pursed for enforcement,” Robyn Tyler, OPDP regulatory counsel, said on FDA’s quarterly enforcement webinar Jan. 30. The webinar covered warning and “untitled” letters issued for promotional materials for the third and fourth quarters of 2013.

OPDP’s risk-based approached prioritizes the review and action of promotion for:

• Newly approved drugs and newly approved indications
• Products with significant risks
• Products cited in previous untitled letter and Warning Letters
• Products cited in complaints
• Promotion that is broadly disseminated

An analysis of the 282 OPDP letters issued from 2004 through mid-November 2013 found that products with boxed warnings were more likely to receive the more serious Warning Letters than products with regular labels, according to Mark Senak of the communications firm FleishmanHillard.

Forty of the 282 letters were for boxed warning products, with 45% of those being warning letters, Senak wrote in his Eye on the FDA blog. In comparison, of the 242 OPDP letters for regular products only 32% were warning letters.

Overall, products with boxed warnings made up only 14% of the OPDP letters while 34% of the 282 letters were Warning Letters.

OPDP also said on the call that a particular finding such as omission of risk information does not usually trigger whether a company receives a Warning Letter or an “untitled” letter for a promotion. The agency considers a number of factors – including the egregiousness of the violation, the need for corrective action and also repetitive behavior – and none are dispositive, Tyler said.

Orphan Products Not Exempt From Enforcement

FDA also doesn’t specifically target the promotion of orphan-designated drugs, but an advertisement shouldn’t expect to take cover from the OPDP’s watchful eye just because the promoted product is for a smaller patient population.

The agency was asked whether the July “untitled” letter issued to Spectrum Pharmaceuticals Inc.’s non-Hodgkin lymphoma treatment Zevalin (ibritumomab tiuxetan) shows an increased willingness to target orphan drugs for enforcement (Also see "Spectrum’s Zevalin Still Living In Rituxan’s Shadow, FDA Advertising Letter Shows" - Pink Sheet, 5 Aug, 2013.).

FDA does not specially target orphan drugs, Cynthia Ng, OPDP regulatory counsel said, again pointing to the risk-based priorities. “We do take a risk-based enforcement approach and so therefore we don’t target the specific designations.”

Disclaimers Can’t Mitigate Unsubstantiated Claims

OPDP also helped clarify a number of questions pertaining to the citations seen specific warning letters on the webinar.

For example, FDA was asked why Daiichi Sankyo Co. Ltd.'s hypertension treatments Benicar (olmesartan medoxomil) and Benicar HCT (olmesartan medoxomil/hydrochlorothiazide) were cited for unsubstantiated efficacy claims due to a bar graph that presented data from an open-label study since the company included a note that the blood pressure reduction seen in this study was greater than that seen in the drug’s pivotal placebo-controlled trials.

OPDP’s Tyler said the agency did review the information presented below the bar graph that discussed the results of the U.S. pivotal trial and that these results differed from the open label study. “However, this information did not mitigate the misleading implication,” she said.

The open-label trial does not constitute substantial evidence to support the efficacy claims, Tyler said. And she said the open-label study did not account for all the relevant subgroups to support the claims cited.

Facts Don’t Always Equal Clinical Benefit

OPDP was also asked why US WorldMeds LLC malignant hyperthermia treatment Revonto (dantrolene) was cited for saying the drug “puts time on your side” given that the drug can be reconstituted in 20 seconds as opposed to two to three minutes for other treatments. “Aren’t these claims self-evident?”

The agency disagreed on the self-evidentiary nature. OPDP’s Julie Chronis said that these reconstitution claims suggest that the faster time “makes for a better product with better clinical outcomes,” superiority claims that would need to be supported with well-controlled head-to-head clinical trials.

Kadmon Corp. LLC received similar criticism from FDA for its hepatitis C drug Ribasphere RibaPak (ribavirin). The company was cited for unsubstantiated efficacy claims due to statements about the adherence advantage because of the drug’s unique packaging.

FDA said in the letter to Kadmon that inferring that characteristics such as packaging, even if true on their own, may improve patient outcomes requires substantial evidence or substantial clinical experience (Also see "Rx Adherence Claims For Ribasphere RibaPak Sent Packing" - Pink Sheet, 10 Dec, 2013.).

“Adherence claims imply treatment benefit,” FDA said on the OPDP webinar, and benefit claims need to be supported by well-controlled trials.

Similarly, OPDP was asked why Spectrum was cited for omitting material facts when they made a claim about the median time to progression with Zevalin versus a comparator because they didn’t include the statistical significance of this claim. “Why is it necessary if the original claim is accurate?”

The statistical significance is key to the accurate interpretation of study results, FDA said, particularly in this case where the difference in time to progression was not statistically significant.