Guidance for Industry: Adverse Reactions Section of Labeling for Human Prescription Drug and Biological Products — Content and Format
Status of Guidance
Final
When was the Guidance released?
January 2006
Which organization released the guidance?
Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER)
Link to the Guidance
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM075057.pdf
Target audience
Sponsors preparing product labels for new or existing drugs and biologics, CDER and CBER reviewers
Laws and Regulations Referenced
21 CFR 201.56(a)(2): Drug labeling must be informative and accurate, never promotional or misleading. Labeling must be updated when new data makes the existing label incorrect.
21 CFR 201.57(c)(7): The adverse reaction profile of a drug must be described based on the entire safety database. Adverse reactions are defined as undesirable effects associated with the use of a drug.
21 CFR 201.57(c)(7)(i): Descriptions of adverse reactions must include enough background information (eg, frequency of adverse reaction in a clinical trial, nature of exposure to the drug) for healthcare providers to adequately interpret the data.
21 CFR 201.57(c)(7)(ii): Adverse reactions must be categorized by body system, by severity, in order of decreasing frequency, or some combination of these, as appropriate.
21 CFR 201.57(c)(7)(iii): Comparisons of adverse reactions between drugs must be supported with adequate and well-controlled clinical studies.
21 CFR 314.126: Adequate and well-controlled clinical studies are required to determine the effect of a drug.
Definitions
- Adverse event: Any undesirable medical event occurring during treatment that may or may not be related to use of a drug or biologic product.
- Adverse reaction: An undesirable effect (eg, symptom, change in laboratory parameters, or change in other measures of critical body function) caused by the use of a drug or biologic product. Commonly known as a “side effect.”
- Biologics: Products derived from living materials (eg, human, animal, or microorganism) that are meant to treat, prevent, or cure diseases in humans.
- Center for Biologics Evaluation and Research (CBER): The division of the FDA responsible for reviewing and approving applications from sponsors who wish to market biologics.
- Center for Drug Evaluation and Research (CDER): The division of the FDA responsible for reviewing and approving applications from sponsors who wish to market drugs.
- Drugs: Products derived from chemical compounds that are meant to treat, prevent, or cure diseases in humans.
- Postmarketing phase: Period after FDA marketing approval when a drug or biologic is available on the market.
- Sponsor: Company (usually pharmaceutical or biotechnology) that wishes to market and sell a drug or biologic.
Background
Regulation on product labels for pharmaceutical drugs and biologics was last published in 1979. In the intervening years, product labels became increasingly cluttered with unnecessary information making it difficult for healthcare providers to make consistently well-informed decisions about patient treatments. A 1995 Food and Drug Administration (FDA) telephone survey revealed that only 5% of office-based physicians consulted drug product labels when they needed drug information.
In December 2000, FDA proposed overhauling the structure of drug product labels to make them easier to use. The FDA solicited extensive feedback from physicians via surveys and focus groups to determine what information is most clinically useful. The resulting Physicians Label Rule (PLR) was published in January 2006.
“Adverse Reactions Section of Labeling for Human Prescription Drug and Biological Products — Content and Format” (“the Guidance”) was published in January 2006 as supporting documentation for the PLR. The goal of this Guidance is to help sponsors of pharmaceutical drugs and biologics create clearer, more useful drug labels.
Summary
The Adverse Reaction section of a drug label is critical in helping physicians determine whether the treatment is appropriate for a patient. It outlines which adverse reactions are associated with the drug, how severe those reactions may be, and who is affected. Inconsistencies in what information is included in the Adverse Reaction section and how the section is organized make it difficult for physicians to extract clinically useful information. The Guidance helps pharmaceutical and biotechnology companies write clear, easy-to-use Adverse Reaction section of drug labels.
Within the Guidance are 4 major sections addressing best practices: Adverse Reactions Section—Content and Format, General Principles for Selecting and Characterizing Data in the Adverse Reaction Section, General Principles for Presenting Adverse Reactions Data in a Table or List, and Updating the Adverse Reactions Section.
FDA recommends highlighting information that is useful in making clinical treatment decisions and eliminating irrelevant details. For example, the most common adverse reactions should be listed first and any adverse events that aren’t clearly associated with administration of the drug or biologic should be eliminated from the label.
FDA also provides suggestions as to how to present adverse reaction data in a clinically useful way, and reminds sponsors of the need to review and update labeling regularly.
While this Guidance was published in support of the mandatory changes to drug product labels described in the Physician Labeling Rule (PLR) of 2006, the Guidance itself is nonbinding. Sponsors may view the contents as recommendations and use their own judgement when creating drug labels so long as they satisfy all legal requirements.
Rationale
This Guidance is the product of extensive physician surveys and focus groups. Having solicited feedback from active practitioners, FDA believes the Guidance reflects the needs of healthcare providers.
Resulting Recommendations
Here are the major recommendations from each section of the Guidance:
Adverse Reactions Section—Content and Format
- Cross-reference serious or important adverse reactions that are discussed in other sections of the product label
- Highlight the most commonly occurring adverse reactions
- Make note of any adverse reactions that resulted in a significant rate of discontinuation or other clinical intervention in clinical trials
- Provide sufficient information about clinical trials conditions for healthcare providers to interpret adverse reaction data accurately
General Principles for Selecting and Characterizing Data in the Adverse Reaction Section
- Include an adverse reaction only if there is sufficient certainty about a causal relationship between administration of the drug and the adverse reaction
- Acknowledge any and all rare but serious adverse reactions associated with drug therapy, even if there is only a single event
- Calculate adverse reaction rates based on all reported reactions of that type, not a subset
- Use specific language to avoid misinterpretation
- Comparisons of the drug’s safety profile to that of another drug must be backed up with data from a well-controlled clinical study
General Principles for Presenting Adverse Reactions Data in a Table or List
- Use specific and clinically meaningful terms when describing adverse reactions
- Rank adverse reactions in the most appropriate order: frequency, severity, body system, or some combination of these
Updating the Adverse Reactions Section
- Sponsors should review the Adverse Reactions section for accuracy at least once per year
- If postmarketing data renders the existing Adverse Reactions section inaccurate, false, or misleading, the label must be updated accordingly
Impact
This Guidance makes the Adverse Reaction section of pharmaceutical drug and biologic drug labels easier to read and more useful for healthcare providers. This should help healthcare providers better understand the risks associated with a given treatment and decrease unanticipated adverse reactions.
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