Industry seeks changes to FDA’s enteral tube-administered drugs guidance

Drugmakers and industry groups are calling for changes to the US Food and Drug Administration’s (FDA) recently issued draft guidance on testing oral drug products’ suitability for enteral feeding tube administration.

The guidance, released for comment in June, outlines recommendations for “consistent in vitro testing of oral drug products to demonstrate their suitability to be administered via enteral tube.” The guidance specifically excludes oral solutions from its recommendations. (RELATED: FDA provides draft guidance for enteral tube-administered drugs, Regulatory Focus 2 June 2021)

FDA said that guidance is needed in this area because in vitro testing of oral drugs that might be administered via enteral feeding tube is “not sufficiently widespread or consistent,” and labeling statements often vary in both content and format.

The agency received nine comments from several drugmakers, the generic drug industry group the Association for Accessible Medicines (AAM) and two healthcare professionals.

In its comments, AAM asked FDA for additional details on the comparative analyses that are required to be performed by generic drug sponsors to establish therapeutic equivalence. “It is not clear what standards the generic sponsor should apply to identify formulations at highest risk especially in cases where, based on the differences in the design of the [reference listed drug] RLD and the generic, the risk level of a dose strength may vary between the two. The guidance has not provided any clarity as to the conditions for which a comparative study(ies) may need to be performed for multiple strengths of the proposed generic product,” AAM wrote.

Mark Klang, chair of the Drug-Nutrient Interaction Section of the American Society for Parenteral and Enteral Nutrition, pushed for several changes to the guidance, but praised FDA for making strides in this area.

“The administration of drugs through a feeding tube is a complicated process as it must compete with nutrition support administered by the same route. Most drugs have not been evaluated for the feeding tube route. Crushing medications and/or extemporaneous compounding can lead to changes in drug absorption and result in both toxicity and sub-therapeutic delivery depending on the formulation. It is indeed admirable that the FDA developed guidance for oral drug manufacturers to conduct appropriate testing to ensure safe delivery by the feeding tube route,” he wrote.

However, Klang suggested that FDA expand the guidance to address oral solutions, which can present their own challenges when administered via enteral tube and noted that “oral and catheter type syringes are no longer the standard for feeding tube administration. All feeding tubes are being converted to En-Fit type connections, and tests conducted to evaluate potential clogging should be done on the devices most used.”

Several drugmakers had specific comments on the guidance.

Boehringer Ingelheim asked why the guidance does not address oral solutions and whether the agency is considering a draft guidance to address such products. The company also asked for clarification about the dissolution profiles referenced in the guidance. “What should be the reference dissolution profile for this test? Is it the dissolution profile of the freshly prepared drug product dispersion or the dissolution profile of the undispersed drug product?” Boehringer Ingelheim asked.

Apotex, in its comments, asked for FDA to clarify the number of units of test and reference product that should be assessed for each tube being tested. “If all the representative selection of the tube is subjected to comparative in vitro study with n=12 of tests and reference products, the applicant will need to acquire a very large volume of reference product and tubing which can be extremely challenging to obtain and will lead to a delay in the submission/approval of a generic.” The company suggests FDA recommend “at least 3 units of test product and 3 units of reference product [for] each selected tube.”

Viatris raised two concerns with the guidance as written. First, the company said the guidance is silent on generic drugs that are Q1/Q2 (qualitatively and quantitatively equivalent) to the RLD. “When ANDA drug products are Q1/Q2, it may not be scientifically justified to require the same in vitro enteral tube testing as the RLD,” Viatris wrote. The company also sought guidance from FDA for situations where an ANDA applicant discovers that an RLD is extremely difficult to administer via an enteral tube.

In addition to the recommendations in the draft guidance, Merck asked that FDA also allow for the use of a case-by-case risk-based assessment, “considering properties and interactions of the drug product, the enteral tube(s), medium, and other factors, as a basis upon which to inform specific recommendations on in vitro testing.”

Regulations.gov

Industry seeks changes to FDA’s enteral tube-administered drugs guidance

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