Linaclotide Guidance Leaves BE Study with Clinical Endpoints as One Option but Also Provides for In Vitro Option as Well

Linaclotide capsules are “minimally absorbed with negligible systemic availability following oral administration.  Concentrations of linaclotide and its active metabolite in plasma are below the limit of quantitation after oral doses of 145 mcg or 290 mcg were administered.  Therefore, standard pharmacokinetic parameters such as area under the curve (AUC), maximum concentration (Cmax), and half-life (t½) cannot be calculated.”  Its site of action is locally in the bowel and intestines.  “It is a guanylate cyclase-C agonist indicated in adults for treatment of: irritable bowel syndrome with constipation and chronic idiopathic constipation.”

Looking back a decade or more, such a product (that is, a product with minimal systemic absorption and local action in the intestines) would almost certainly require a biostudy with clinical endpoints to support a showing of bioequivalence.  A petition was submitted in 2016 requesting that ANDA applicants seeking approval for a generic version of this product be required to perform a BE study with clinical endpoints.  That petition was apparently just answered (although the FDA response does not yet appear on the regulations.gov web page).  We can only speculate that the partial government shutdown has delayed its posting.  However, the Federal Register Notice announcing both the posting of the petition response and the draft BE guidance can be found here.  The original Citizen Petition can be found here, and the draft guidance was located on the FDA webpage and can be found here.

The guidance falls in line with other BE guidances for non-systemically absorbed oral drug products and is part of the new wave of products for which in vitro studies can provide evidence of bioequivalence if the test product is formulated both qualitatively and quantitatively the same as the innovator.  Failure to formulate the product in this manner will default the BE requirements to a BE study with clinical endpoints.  In addition, the FDA has very specific recommendations for the sameness of the API:

Sameness of synthetic linaclotide can be established based on comparative physico-chemical and biological characterizations.  The characterizations should include the following categories in order to support API sameness:

  1. Primary peptide sequence and related molecular properties such as molecular formula, specific optical rotation, and spectroscopic properties
  2. Configuration of the three disulfide bonds
  3. In vitro biological activity (e.g., binding, functional assays)

This trend for using in vitro testing and highly specific physicochemical characterization of the active ingredient provide generic applicants a shorter development and reduced bioequivalence testing burden.  Given recent Agency actions, the guidance that the FDA has issued appears to be the new standard for such products.

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