Major pharmaceutical companies and a European Medicines Agency (EMA) committee are calling for changes to the US Food and Drug Administration’s (FDA) recent draft guidance on assessing the effects of food on drugs in investigational new drug (IND) applications and new drug applications (NDAs).
The 14-page draft guidance
was released for public comment in February and makes recommendations for conducting food-effect (FE) studies to measure whether food impacts systemic exposure to a drug; increases or decreases the variability of the systemic exposure; and if the effect is different based on the type of meal or fat/caloric content.
The results of these studies can impact the design of clinical trials and how a drug is labeled once approved.
In comments submitted to the public docket, EMA’s Pharmacokinetics Working Party (PKWP) requests that FDA revise its approach to studying food effects on drugs with a long half-life, arguing that the 24-hour threshold for half-life used in the guidance is too short for parallel design studies.
The PKWP also says it does not understand why FDA does not provide recommendations for drugs labeled for administration with special vehicles within the guidance and says that recommendations “similar to those for drugs administered with soft foods may be used.”
Additionally, the PKWP says the low-fat meal (400-500 kcal with 150 kcal from fat) described in the guidance is similar to the moderate-fat meal (400-500 kcal with 100-125 kcal from fat) defined by EMA.
“PKWP considers this too similar to be low and moderate and that this will be confusing for companies,” PKWP writes.
Both the PKWP and several of the drugmakers that commented on the guidance, including Roche, Janssen and AstraZeneca, focused on the lack of discussion of physiologically-based pharmacokinetic (PBPK) modeling.
While PKWP laments the lack of discussion of PBPK modeling in the guidance, the drugmakers that commented suggest that PBPK modeling could be used to avoid unnecessary FE studies or be used to assess changes in a drug’s formulation between early clinical trials and the “to-be-marketed” formulation.
“The agency should specify if PBPK modeling could be used to support FE study waivers for pivotal FE studies using the to-be-marketed formulation. Furthermore, inclusion of examples for which a FE study waiver would be granted should be incorporated into the guidance,” Janssen writes.
AstraZeneca also questions whether FE studies are necessary for fixed dose combinations if the individual drugs used in the combination have no known food effect.