FDA offers insights on blood pressure studies, immunogenicity labeling

The US Food and Drug Administration (FDA) issued a pair of draft guidance documents last week with recommendations about the premarketing assessment of a drug’s effect on blood pressure and labeling advice for immunogenicity data.

Pressor guidance

The draft guidance on the pressor effects of drugs has been revised since it was originally issued in May 2018. The updated guidance provides greater detail on study design, including statistical powering recommendations. It also makes recommendations on how to incorporate blood pressure information into the drug’s prescribing information. (RELATED: FDA drafts guidance to help address blood pressure effects in drug development, Regulatory Focus 30 May 2018; Roche, Novo Nordisk and Merck Weigh in on FDA draft guidance on assessment of pressor effects, Regulatory Focus 24 August 2018)

“Although nearly every drug development program has some assessment of the drug’s blood pressure effects, the methods used for assessing blood pressure are not consistent and not always adequate. As a result, small increases in blood pressure that could be relevant to the risks of a drug may not be reliably detected in some drug development programs,” FDA wrote in the draft guidance.

For drugs intended for chronic use, FDA recommended the use of ambulatory blood pressure monitoring (ABPM). Studies to assess blood pressure should generally be powered to exclude a 3-mmHg increase in 24-hour average systolic blood pressure using an upper bound of the two-sided 95% confidence interval, assuming the true effect is 0 mmHg, according to the guidance. FDA recommends that blood pressure be measured at least twice an hour over 24 hours using ABPM at baseline and on-treatment to assess the overall effect, and that ABPM trials be of at least 4 weeks’ duration.

In terms of labeling, FDA recommends that the ABPM study results are summarized in the Pharmacodynamics subsection of the Clinical Pharmacology section of the label. Regardless of whether a drug is shown to increase blood pressure, the ABPM study design and population should be included in the label. If the drug is associated with an increase in blood pressure, the Pharmacodynamics subsection should include the following:

Effects on systolic and/or diastolic blood pressure with the doses studied
Distribution of blood pressure effect sizes
Dose or exposure response
Time course of the blood pressure effect
Key subgroup differences in blood pressure response (e.g., demographics, concomitant illness, concomitant treatments)

Any adverse reactions from an increase in blood pressure should be included in the Adverse Reactions section and a “clinically significant” increase in blood pressure should be included in the Warnings and Precautions section and possibly as part of a Boxed Warning or Contraindications, according to the draft guidance.

Immunogenicity labeling

FDA also issued draft guidance on incorporating immunogenicity information into labeling for biologic products and certain drugs. The guidance does not apply to vaccines or allergenic products, which are intended to induce a specific immune response.

Historically, immunogenicity information has been included in the Adverse Reactions section of the labeling, but FDA is recommending that the information be located in a dedicated Immunogenicity subsection of the Clinical Pharmacology section.

“Presenting immunogenicity information in a consistent manner will enable health care practitioners to more easily identify and differentiate products associated with clinically significant anti-drug antibodies from products whose anti-drug antibodies are not associated with clinically significant effects on pharmacokinetics, pharmacodynamics, safety, or effectiveness,” FDA wrote in the draft guidance.

The Immunogenicity subsection should include the incidence of anti-drug antibodies and the known effect on pharmacokinetics and pharmacodynamics. The subsection should also include the duration of exposure to the drug and time period during which anti-drug antibody sampling was conducted. Any clinically significant anti-drug antibody effects should be cross referenced in the labeling to the Warnings and Precautions sections of the labeling. Any adverse reactions associated with anti-drug antibodies, such as hypersensitivity or anaphylaxis, should be summarized in the Adverse Reactions section.

The draft guidance also recommends a standard labeling statement to be included in the Immunogenicity section if the data is inadequate for providing an assessment of the incidence of anti-drug antibodies. In cases where the uncertain effect poses a potential safety concern, that information should be included in the Adverse Reactions section.

Draft guidance: Assessment of Pressor Effects of Drugs

Draft guidance: Immunogenicity Information in Human Prescription Therapeutic Protein and Select Drug Product Labeling

FDA offers insights on blood pressure studies, immunogenicity labeling

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