The Biotechnology Industry Organization (BIO) thanks the Food and Drug Administration (FDA) for the opportunity to submit comments on the “Draft Guidance for Industry Drug Interaction Studies—Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations.”
BIO represents more than 1,100 biotechnology companies, academic institutions, state biotechnology centers and related organizations across the United States and in more than 30 other nations. BIO members are involved in the research and development of innovative healthcare, agricultural, industrial and environmental biotechnology products, thereby expanding the boundaries of science to benefit humanity by providing better healthcare, enhanced agriculture, and a cleaner and safer environment.
BIO applauds FDA for writing a Draft Guidance that is well thought through and written, and generally encompasses extensive detail that will be helpful to Sponsors. However, we find that the Draft Guidance lacks sufficient detail in certain respects, which could make it difficult for the Sponsor to make a go/no-go decision on the conduct of a clinical Drug-Drug Interaction (DDI) study, and potentially lead to non-uniform application of the guidance and a wide range of interpretation for some DDIs (please see our Specific Comments section, below, for more information). For example, we recommend that FDA provide guidance on certain cut-off values for clinical actions and the appropriate concentrations for DDI assessments. We also request more detail with respect to certain of the criteria in the Decision Tree (Draft Guidance, p. 16).
We note that due to the heterogeneity of cell systems or other in vitro evaluation tools, the cut off values of I/Ki, I2/Ki or R value can vary dramatically from lab to lab. We recommend that FDA add a footnote to clarify how this variation should be handled.
The Guidance regarding the threshold for metabolites of ≥25% of parent area under the concentration curve (AUC) should be revisited, in consideration of compounds that are extensively metabolized, in order to avoid overwhelming number of DDI studies on scores of metabolites. We suggest that for drugs that are extensively metabolized, a different threshold of ≥25% of total AUC be used.
In addition to the recommendations above, we suggest that this Draft Guidance document provide more clarity on how modeling and simulation data can be used in product labeling statements, and be harmonized with the similar European Union (EU) guidance document so that it will be more useful to the global pharmaceutical industry (e.g., the number of the main transporters listed in this FDA guidance document should be the same as those listed in EU guidance document).
It appears that several recommendations in the Draft Guidance (e.g., use of total Cmax versus unbound Cmax for organic anion-transporting polypeptides (OATPs) versus organic cation transporter/organic aniton transporters (OCTs/OATs), use of mRNA as endpoint for enzyme induction, and equations proposed for mechanistic models to assess investigational drug as inhibitor or inducer) are based on one or more publications from a single group or laboratory. Confidence in broad implementation of these recommendations would be strengthened by confirmation of original findings in single or limited publications by additional groups or labs. We recommend indicating potential limitations associated with recommendations based on single publication/laboratory as that field continues to evolve. Also, please provide literature reference when a recommendation is based on a single or limited number of references.
We note that this Draft Guidance only addresses the in vitro and in vivo DDI studies that are expected as part of NDA/BLA submissions in support of regulatory review and labeling. It would be useful to include guidance on DDI risk management during drug development. Especially in therapeutic areas such as oncology, clinical development is often initiated in patient populations where polypharmacy is common. The principles offered in this guidance for risk assessment from in vitro DDI data and application of physiological based pharmacokinetic (PB-PK) models of DDIs are equally applicable to guide inclusion/exclusion criteria with respect to concomitant medications and/or cautious use in patient studies when in vivo DDI information is not yet available. We suggest including risk management approaches for DDIs in clinical development prior to availability of in vivo clinical DDI results. For new molecular entities (NMEs) as substrates of interactions, the decision to exclude strong inhibitors/inducers of specific drug metabolizing enzymes or transporters versus allowing their cautious use may be determined based on the expected contribution of the particular enzyme/transporter to overall clearance. When the NME is expected to have clinically important toxicities or is a narrow therapeutic range (NTR) drug, a major contribution (e.g., 50% or higher) may indicate exclusion of strong and moderate inhibitors/inducers, whereas a smaller contribution (e.g., 25-50%) may only necessitate exclusion of strong inhibitors or inducers. For the NME as the interacting drug, in vitro-in vivo extrapolation using the approaches outlined in Figure 4 (using predicted human PK when clinical PK data are not available) may be used to estimate the level of DDI risk. If the predicted magnitude of interaction is not large, it may suffice to exclude concomitant use of NTR substrates only and recommend cautious use of non-NTR substrates. However, if the predicted interaction magnitude is large, it may be necessary to additionally exclude sensitive non-NTR substrates as well.
BIO appreciates this opportunity to comment on the “Draft Guidance for Industry Drug Interaction Studies—Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations.” Specific, detailed comments are included in the following chart. We would be pleased to provide further input or clarification of our comments, as needed.