Pharma’s Cutting Edge

Pharma’s Cutting Edge Vol. 4 Number 2 - February 2006

FDA Guidance for Industry - Adverse Reactions Section of Label

Last month FDA published two final guidances on labeling: one on clinical studies and one on adverse reactions. These are the first-ever FDA guidance documents issued on these topics. Therefore, all prior labeling recommendations and decisions emanating from FDA were derived from varying intra-Agency interpretations of the governing federal statutes (21CFR201.57), providing a plethora of opportunities for label negotiations and a gradual weakening of the intended impact of the product label. FDA continues to lack important statutory authority to regulate label content and usage, discussed briefly here, but these guidances are an important step in the right direction.

In this month’s PCE, I discuss the adverse reactions guidance and some of its implications for sponsors and physicians. There was necessarily some choices to be made in the sections selected for commentary (bolded), but I tried to capture the guidance language that represented the greatest departure from historical practices.

Background
“Exhaustive lists of every reported adverse event, including those that are infrequent and minor, commonly observed in the absence of drug therapy or not plausibly related to drug therapy should be avoided….”

Implications
One reason that product labels are in need of re-vamping is that they have evolved into medico-legal documents that serve liability lawyers as much as doctors. This situation needs to change if doctors are to get and recognize the information they need to practice medicine wisely. Recognizing this, FDA starts off this guidance by denouncing a long-standing practice promoted by the industry of creating laundry lists of observed adverse events, regardless of frequency of occurrence or likelihood of causal relationship with therapy. By putting this issue up front, FDA makes it easy for reviewers to cite the policy and provides an externally driven check-and-balance mechanism between R&D and legal within pharma. The practice has been fading for at least the last 10 years, but this guidance should signal its death.

Use Best Available Data
“For example, if placebo-controlled data were available and sufficiently informative, there would usually be no need to present in a table active-controlled data, single-arm trial data, or the overall safety data, even if they are from larger databases.”

Implications
Sponsors had previously argued, with varying success, that active-comparator trials AE data indicating a higher frequency of events with the comparator compared with the test arm were appropriately included in the AE section. This guidance challenges that argument and probably nullifies it for future labels.

Adverse Reactions From Clinical Trials
“[T]he following statement, or an appropriate modification, should precede the presentation of adverse reactions from clinical trials: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.”

Implications
The above language is recommended as a preamble to the presentation of clinical trial-derived AEs. It seems like pretty obvious stuff, so why is FDA suggesting it? Labels serve as the basis for allowable promotional materials. If the label explicitly states the limitations of trial data, it limits how the drug may be promoted. While aggressive promotions that make comparisons to data outside the label were always subject to censure, this preamble will make DDMAC’s job that much easier.

Presentation of Less Common Adverse Reactions
“Serious, low-frequency adverse events generally will be listed when there is reason to suspect that the drug may have caused the event. Typical reasons to suspect causality for an event include (1) timing of onset or termination with respect to drug use, (2) plausibility in light of the drug’s known pharmacology, (3) occurrence at a frequency above that expected in the treated population, and (4) occurrence of an event typical of drug-induced adverse reactions (e.g., liver necrosis, agranulocytosis, Stevens-Johnson syndrome). For serious events that are typical of drug-induced adverse reactions, the occurrence of even a single event could be a basis for inclusion in the list. When none of these reasons exist, however, an event should be excluded from the list….Non-serious, low-frequency adverse events should be listed only when there is strong evidence that the drug caused the event. Such evidence may include, for example, positive challenge/dechallenge tests or rate of occurrence in a large controlled trial that, although low, is markedly imbalanced between drug and control arms.”

Implications
FDA leaves little room for negotiating which events make the list. This specificity will aid physicians enormously, who require a list containing only relevant events to guide prescribing of medication and reporting of adverse events. It’s a beautiful thing.

Avoiding Nonspecific Terms
“In characterizing overall adverse reaction experience, nonspecific terms that lack a commonly understood or precise meaning are discouraged, as use of such terms can be misleading.”

Marketers typically like non-specific terms for the same reason FDA does not—they are subject to varying interpretations. FDA specifically mentions well-tolerated as phrase that should be avoided. Promotions will need to refrain from using these non-specific clichés once labels have been cleansed of them.

Classifying Adverse Reactions
“Adverse reactions should be classified using meaningful and specific terms that best communicate the nature and significance of the reaction. There should ordinarily be a common classification scheme across all studies in the safety database. Events that are reported under different terms in the database, but that represent the same phenomenon (e.g., sedation, somnolence, drowsiness) should ordinarily be grouped together as a single adverse reaction to avoid diluting or obscuring the true effect.”

Implications
The above guidance makes more sense now that a majority of the industry has migrated to a common adverse reaction taxonomy and classification. There is not a universal reporting scheme quite yet, however, so there’s still going to be difficulty for physicians trying to draw inferences about relative frequency of AEs across labels. Nevertheless, lumping AEs together into categories whenever feasible solves the problem of AE dilution via classification.

Adverse Reaction Rates for Drug Less Than for Placebo
“Adverse reactions for which the placebo rate equals or exceeds the rate for the drug (after rounding) should not be included in the ADVERSE REACTIONS section unless there is some compelling factor (e.g., timing) that suggests that the event is caused by the drug. In that case, the adverse reaction should be discussed in the commentary following the table.”

Implications
A common sponsor ploy in the past that has been gradually phased out by FDA should finally be defunct with this document.

New or Outdated Information
“Applicants are urged to review at least annually the content of the ADVERSE
REACTIONS section to ensure that the information remains current.”

Implications
This remains a problem despite this guidance. FDA needs statutory authority to require sponsors to more frequently review AE information in labels and attest to its accuracy. They also should have the authority to require modifications to AE-related sections when sponsors resist. The availability of electronic forms of dissemination of information can help sponsors defray costs associated with more frequent paper-label changes. This issue goes beyond just the AE section and requires some wholesale changes in the ways that labels are published, disseminated and used.