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. Read the rest of this entry »