SPECIFIC COMMENTS ON TEXT

Transcription

1 1500 K Street, NW Suite 1100 Washington, DC Telephone: info@iqconsortium.org Website: IQ CONSORTIUM COMMENTS ON Draft Guidance for Industry Clinical Drug Interaction Studies Study Design, Data Analysis, and Clinical Implications 19-Jan-2018 We are pleased to offer the following comments, developed by the Clinical Pharmacology Leadership Group (CPLG) and Drug Metabolism Leadership Group (DMLG) of the International Consortium for Innovation and Quality in Pharmaceutical Development ( The IQ Consortium is a not-for-profit organization of pharmaceutical and biotechnology companies with a mission of advancing science and technology to augment the capability of member companies to develop transformational solutions that benefit patients, regulators and the broader research and development community. Both of the Leadership Groups, and in particular their Regulatory Guidance Review/Commenting Groups appreciate the opportunity to review the draft guidance and to share detailed feedback, below. First, specific comments on the current draft guidance s text are presented. In conclusion, several general comments are listed regarding topics that are not addressed in the current draft but might be appropriate to consider for inclusion. I. INTRODUCTION SPECIFIC COMMENTS ON TEXT Subsection Comment and Rationale Proposed change (if applicable) Line 19 Introduction highlights that guidance does not refer to therapeutic proteins. It does not highlight that it focuses on PK interactions and not PD interactions. This should be added.

2 Lines Noteworthy exclusions to the evaluations of the DDI potentiation pertain to: therapeutic proteins, reference to UGTs, contraceptive steroids and transporter-independent DDI mechanisms that may impact absorption of investigational or concomitantly administered drugs (e.g. ph, solubility or complexation). Previously, the 2012 Guidance (lines ) and harmonized with the EMA (2012) Guidance, stipulated that if a potential teratogen is intended for use in fertile women, an in vivo study for effects on contraceptive steroids is expected, regardless of the in vitro induction study results,. Further, the 2012 Guidance (lines ) referenced conduct of clinical studies of oral contraceptives evaluating possible CYP3A perpetrator effects. Given the potential for complex drug interactions especially in the setting of combination regimens for the treatment of HCV/HIV together with an anticipated publication of a draft guidance related to contraceptive steroids, it should be planned that an additional footnote on page 1 will be included, similar to that for therapeutic proteins (3), to alert Sponsors to further DDI topics with a link to the relevant guidance, as appropriate, in in order that all guidelines be considered in the clinical development program. Given the addition of footnote (3), it assumed that topics previously reviewed within that related to therapeutic proteins (e.g. lines ; lines ) are planned to be incorporated into a separate, focused guidance, with a link to the relevant guidance, as appropriate, in order that all guidelines be considered in the clinical development program. Previously, the 2012 Guidance (lines , ; ) summarized the important role of UGTs in drug metabolism and disposition with decision tree (Figure Guidance) for evaluation of investigation drugs as UGT substrates, noting polymorphic variants that may be used to inform the DDI potential or further characterize the pharmacokinetics of UGT substrates. Given the omission of this content from the present (2017) Guidance, the Agency is requested to address these assessments in the present guidance as their omission may suggest that the 2

3 absence of clinically relevant contributions of UGTs to drug disposition. It would be beneficial to include a reference that the guidance does not pertain to PK-based DDI mechanisms unrelated to drug metabolizing enzymes or transporters and where additional guidance on this topic may be addressed. II. SPECIFIC COMMENTS ON TEXT TIMING OF CLINICAL DDI STUDIES Subsection Comment and Rationale Proposed change (if applicable) Lines Lines Recommend softening the language since many times the Clinical DDI evaluation may not be complete prior to dosing in patients (such as in Oncology studies where patients are enrolled in Phase 1) and the DDI is managed using protocol inclusion/exclusion criteria for concomitant meds.. In practical terms, conducting clinical DDI studies prior to proof-of-concept may unnecessarily expose patients to a drug whose development may not advance beyond that stage. Although the document has broad language here (e.g. any clinical study), the concluding statement about the indicated patient population suggests that this is mainly a problem with Phase 3 trials. Change Should to Should consider if possible on line 65 Insert the words pivotal or registrational between the words any and clinical on line 68 3

4 III. SPECIFIC COMMENTS ON TEXT DESIGN AND CONDUCT OF CLINICAL TRIALS Subsection Comment and Rationale Proposed change (if applicable) Line 87 Lines Lines 97-99: Lines and Line 142 Lines It is recognized that throughout this document that reference to metabolic pathway also may infer transporter pathways ; however, for clarity and consistency through the document, reference to transporter should also be considered in the cited sentence. Terms Index Perpetrators and later also Index Substrate are used which is a change from the previous guidance where probe substrate or probe inhibitors were used. The EMA guidance also uses the word probe Recommend altered wording for Retrospective evaluation to Consistent with the content presented in Section V.B.3 (Lines ), it is agreed that there is no standardized classification for transporter and phase II metabolizing enzyme inducers or inhibitors The term moderate sensitive index substrates is confusing. Either the substrate is moderate or sensitive. Index perpetrators ae drugs that inhibit or induce a given metabolic or transporter pathway by a defined magnitude when administered with a sensitive substrate and are commonly used in prospective studies. Recommend to keep the term probe instead of using a new term index for consistency and to limit any confusion when working with clinical teams and health authorities Data used from trials not specifically designed for DDI assessment must include adequate precision and sufficient statistical power to adequately assess the potential for a DDI (see section ). Reference to strong index perpetrators in association with drug transporters should be omitted. Alternatively, the content of Section V.B.3 (Lines ) should be included in this section with additional clarifying statements incorporated that strong or similar descriptions are currently only applicable to CYP inhibitors or inducers as reviewed in Section V.B.3. Change the term moderate sensitive index substrates to moderate index substrates. Propose to change the term moderate sensitive index substrates to moderately sensitive index substrates. 4

5 Lines Line 158 Line 160 Lines Consistent with that reported by Bodin et al (2001) and Dicsfalusy et al (2011), it is acknowledged that the Agency does not recommend using an endogenous substrate for index studies owing to the absence of consistent results. However, based upon these data it should also be considered that information related to effects on CYP3A mediated metabolism differentiates strong from weak induction effects only. Regarding use of internal probe to assess CYP3A induction (4B-OH Cholesterol) Oral contraceptives are the most commonly concomitant meds that are used along with different therapies. There are approaches suggested in past to conduct single dose or multiple dose DDI or multiple dose with three cycles to evaluate PK and PD effects. A small description of the approach that should be taken with OC interaction would help in decision to conduct this study It would be helpful to provide more information around considerations for assessment of nonindex (concomitant use) drugs. Are there expectations around the source of data for determining the likelihood of co-administration (e.g., claims data), or threshold for frequency of co-administration (e.g., 5% of patients taking the Evaluating the effect of an investigational drug on an endogenous substrate (e.g. 4β-hydroxycholesterol) can provide information about differentiating strong from weak effects on a metabolic pathway (e.g. induction of cytochrome P450 3A- (CYP3A-) mediated metabolism. The use of 4B-OH cholesterol for induction is scientifically shown to be a sensitive method to detect induction following multiple dose studies (i.e., at least 2 weeks of continuous dosing). Therefore, propose to add that a negative induction with 4B-OH cholesterol may be used to replace an induction study as a perpetrator of CYP3A induction. Please add. Expand on process and criteria for evaluating non-index (conmed) victims and perpetrators as part of DDI package. 5

6 Line 173 Lines conmed)? How does availability of other agents within a class relate to the risk-based approach? Consider softening the language around sponsor obligation to identify concomitant medications from Sponsor should evaluate the concomitant to Sponsor should evaluate concomitant. The former seems to generate an implied obligation for the sponsor to identify and de-risk all possible concomitant meds but the remedy is to use a risk-based approach based upon understanding underlying mechanisms of the sponsor drug interaction which {properly} places the sponsor responsibility on clearly understanding the mechanisms of its therapy s interactions. It also does not exclude responsibility to directly test for any potential interactions of specific concern. Consider illustrative example(s) of scenarios or reference to scientific publications/approvals whereby based upon qualification of a model for a moderate inhibitor/inducer, an in silico approach could be considered to predict interactions with strong index perpetrators. Alternatively, introduce some flexibility that would permit Sponsors to apply in silico methods to predict the effects of enzyme modulators in both directions (e.g. predict strong from weak/moderate, vice versa ) providing the models can describe available data on DDIs with other inhibitors or inducers of the same pathway. Line 205 replace CDER, FDA, issues related with CDER, FDA, opportunities and considerations related Lines Lines and Lines What caps the dose consideration for the perpetrator? It sounds like the highest tox dose or the limit of the physical chemical properties as written It is assumed that reference to linear pharmacokinetics pertains to linear systemic (e.g. CL and V) pharmacokinetics rather than doseproportionality related to exposure (e.g. AUC and Cmax). We suggest a consideration consistent with that for victim drugs which is based in the therapeutic dose range like maximizing the possibility of identifying a clinical DDI.. This should take into account the potential for a duplicated dose but should it have to identify worst case for an overdose situation? The assumptions related to linearity compared to doseproportionality should be clarified to avoid confusion or misunderstanding. 6

7 Line Lines Line 262 Lines Also, there should be consideration for dose interval relative to drug exposure for all such studies. While there may be a maximally achieved DDI after repeat dosing that sustains a drug level, which may be completely inconsistent with its intended dose frequency. The draft guidance suggests that PK of the index inhibitor may need to be assessed if administered as a single dose to demonstrate near maximal inhibition at single dose exposures. Would this also be the case if published data support near maximal inhibition at a single dose? If not, the sponsors recommend adding a statement that that PK of the index inhibitor may not need to be assessed if evidence supports near maximal inhibition at single dose exposures. The sponsor can administer concomitant drugs evaluated as inhibitors as a single dose if clinically relevant concentrations of the concomitant drug are achieved Theoretically, the degree of inhibition will change with any change in concentration for any competitive inhibitor. Thus, consider replacing and the degree of inhibition does not change over the dosing interval with and the degree of inhibition is similar over the time course studied for the substrate. The idea here is 2-fold, Wording to reflect the exposure under conditions of intended use? Possibly a specific exception for potential drugs of abuse as identified per schedule? Add a statement that that PK of the index inhibitor may not need to be assessed if evidence supports near maximal inhibition at single dose exposures. Suggest to add the inhibiting metabolite to the sentence, i.e. The sponsor can administer concomitant drugs evaluated as inhibitors as a single dose if clinically relevant concentrations of the concomitant drug and its inhibiting metabolite are achieved,. An example of the justification for the suggested change: CYP3A inhibitor itraconazole (listed in Line 405 on Page 11 of this guidance) has a potently inhibiting metabolite that takes multiple doses to reach steady state! Itraconazole would be dosed to a patient for quite a long time as an antifungal drug. Replace and the degree of inhibition does not change over the dosing interval with and the degree of inhibition is similar over the time course studied for the substrate. 7

8 Line 264 Line Lines one suggesting similarity rather than not changing AND that the dosing interval is not clear with single doses. The time of concern is the assessment of the DDI after single doses of both. (assuming that the substrate is a single dose as well), not the typical dosing interval., and the degree of inhibition does not change over the dosing interval. This statement could be interpreted multiple ways. Is this referring to the degree of inhibition not changing relative to multiple dose? I.e., related to accumulation only or are there other factors? Is it acceptable to increase the dose as a single-dose to achieve similar or greater concentrations as multiple-dose to achieve the same degree of inhibition or maximal inhibition? Rather, does this statement refer to [I]/IC50 not changing over the dosing interval? This would be drug-dependent and does not seem to be universally relevant. It is not clear what is meant by degree of inhibition does not change over the dosing interval.? Is this established to be between 80 and 125% like bioequivalence? The available data may be insufficient to confirm the criteria that clinically relevant concentrations are achieved and the degree of inhibition does not change over the dosing interval if the investigational drug is the interacting (perpetrator) drug. However, if the investigational drug is evaluated as a substrate with an index perpetrator utilized in the clinical Clarify expectation. Suggest if inhibitor shows the same effect after single dose or multiple doses, then single dose is sufficient. Otherwise, multiple dose is needed. This concept is already present in Lines Please clarify. Further clarification concerning under which conditions would collection and analysis of plasma samples of a perpetrator drug be necessary to support interpretation of clinical DDI results is requested. 8

9 Lines Line Line Line study (at standard or recommended doses), the pharmacokinetic profile of the known inhibitor/inducer is well-established and extensively published such that there is no further need to collect and analyze plasma samples in this setting. Sufficient dosing to ensure maximal induction is referenced. Based upon experience, clinically relevant induction may be characterized as that achieving 80% induction with marginal differences in index substrate pharmacokinetics achieved with 90% or greater induction.; See left for proposed change; if the substrate shows time-nonlinear PK, data after single dosing could be less informative. And, to be consistent within the document. Recommend that this paragraph be the first paragraph in Section 3: Single or Multiple Doses. For substrates that display PK non-linearity with respect to dose, if the extent of accumulation at steady-state is predicted by single-dose data (i.e., half-life) across the dose/exposure range (e.g., based on MAD study), then a single dose as a victim in a DDI study should be acceptable, as long as the change in exposure is within the previously observed range where it was The Agency is requested to clarify maximal induction in the context of a clinically relevant effect (e.g., 80%, but not 100%) rather than maximal without further qualification this cannot be consistently interpreted. Single-dose administration of the substrate is acceptable if the substrate displays dose- proportional exposure. should be changed to Single-dose administration of the substrate is acceptable if the substrate displays dose-proportional and timeinvariant exposure. Lead with the incomplete idea expressed in sentence #2 (currently Line 276-7). A single dose should be acceptable if single-dose studies can be extrapolated to steady-state conditions. This should start with the concept that if there is no accumulation at steady-state, single-dose studies are acceptable. Then get into linear vs. nonlinear PK. Revise text to suggest that in some cases, it may be acceptable to perform a DDI study with single-dose administration of a substrate with dose-dependent nonlinearity, if previous data (e.g., MAD study) demonstrates that the extent of accumulation at steady-state is predicted by single-dose data (i.e., half-life) across a dose/exposure range that encompasses that observed in the DDI study. 9

10 Line 289 Lines 289 to 302 Lines 291 to 292 Lines established that single-dose data predicts accumulation at steady-state. Steady state exposure can be predicted from single dose data for drugs that exhibit dose-linear PK, not just dose-proportional PK. In parallel vs cross over studies, the agency appears to have made an inadvertent omission that allows for use of single sequence cross over studies when the half life of the agent under study is very long In many cases (very long half-life drugs) a fixed sequential design is used. It does not require large sample size or longer time compare to cross over design. A fixed sequence design is simpler than a 2 sequence randomized crossover; in which we could expect less carryover effect. A fixed sequence design is also advantageous in terms of reduced inter-subjective variability compared to parallel design. Text as written seem to limit crossover design to the two-way crossover even though the section might be intended to convey crossover designs are preferred over parallel designs. Both randomized and fixed sequence designs have been commonly implemented to rigorously interrogate a DDI potential and therefore, both could reflect preferred methods. As this subsection relates to the justification of parallel versus cross-over studies, it is recommended that Single dose administration of a substrate should be adequate if the substrate displays dose-proportional/linear exposure. In addition, this applies if no accumulation is observed in drug exposure after multiple dose using clinically relevant dosing regimen. Please consider adding a statement similar to Line 1088 from 2012 draft guidance on DDI: A study can use a randomized crossover (e.g., S followed by S+I, S+I followed by S), one-sequence crossover (e.g., S followed by S+I), or a parallel (S in one group of subjects and S+I in another group) design, and there may be reason to have another period when the I is removed to assess effect duration Propose adding text about utility of a fixed sequence design (ie., victim only followed by victim with perpetuator). Consider adding: Single sequence cross over studies can also be used to avoid carryover effects of enzyme induction/inhibition. Two-way crossover studies are preferred over parallel study designs due to reduced inter-subject variability. 10

11 Lines Line 321 Lines and Lines Lines reference to randomized be omitted, with any additional guidance in the setting in which this would be an expectation provided. While indeed the duration of the washout period should consider the pharmacokinetics of the substrate and perpetrator, this interval should also consider the duration necessary for enzyme activity to return to baseline/normal or potential pharmacodynamic effects to return to pretreatment levels. Baseline condition did not indicate what the section is about For some medicinal products, including many antibacterials, antivirals and drugs requiring concentration monitoring, Cmin may be an important and clinically relevant pharmacokinetic parameter and therefore, should be evaluated as part as a comprehensive DDI study. However, this parameter may not be clinically relevant for all investigational drugs in clinical development and therefore, rather than this prescriptive criteria, parameters in addition to AUC and Cmax should be provided as illustrative examples with final selection based upon their relevance from a pharmacological profile and may include partial AUCs or others. The guidance on PD is vague and may not provide sufficient guidance. Pharmacodynamic interactions are common (ex : alcohol and CNS drugs like benzo ),. Their investigation is part of the evaluation of a Recommend additional clarification related to considerations other than those solely based upon pharmacokinetics to inform the duration of the washout period. Replace Baseline Condition Drug Use with Extrinsic factors influencing DDI Pharmacokinetic sampling times should be sufficient to characterize the AUC0-INF (for single-dose studies), the AUC0-TAU (for multiple-dose studies), the maximum concentration and (Cmax) of the substrate drug administered alone and under conditions of the anticipated interaction. Sponsors should collect data on additional pharmacokinetic parameters based upon the pharmacokinetic and/or pharmacological relevance (e.g. Cmin, partial AUC, Tmax). Please clarify. 11

12 Lines Line 387 Line 387 Lines Line , Line Lines 453 footnote 16 Line Line compound, especially when it comes to frequently co-prescribed drugs. These type of interaction, at the receptor level for example, are even not mentioned in the section B.9 on page 9 about PD endpoints. Unclear what FDA expects regarding measurement of PD endpoints in a clinical DDI Link to the non-clinical guidance here as there is for section IV E when it comes to transporterbased DDIs Consider adding back a section on Phase II enzymes as was included in the previous version of the guidance Add reference to Section IV.G.1 as was included on line 563 in Section IV.E.1 In IV.G.1. Line , a specific criterion, i.e. fm>80% was required for such gene-drug study to substitute for a prospective DDI study, whereas here the word "significant" was used to describe the contribution of polymorphic enzyme in the metabolism of the investigational drug. It is not clear whether a quantitative criterion should be used under such circumstance. Bupropion hydroxylation is a specific CYP2B6 clinically mediated metabolic pathway The statement about intestinal absorption being a major cause of variability in drug response to justify a P-gp and BCRP mediated DDI, may be limiting and subject to misinterpretation. The recommendation to consider a DDI study if hepatic elimination is a significant clearance pathway for the investigational drug which is an 12 Please clarify. Please add. Please consider adding. Add reference to Section IV.G.1 Provide clarification and be consistent throughout the guidance document. Examples of clinical relevance of any specific criteria would be helpful. For the latter instance (Currently Lines ), cross-reference section IV.D.1. for consideration of additional drug-specific factors besides fm, such as alternate elimination pathways (Line 420). Please consider bupropion as a CYP2B6 specific substrate. Consider change to When changes in intestinal absorption has the potential to significantly alter the exposure and impact activity and/or safety in a clinically meaningful way. Would suggest, given the large number of compounds eliminated by hepatic pathway, to provide some suggested criteria, beyond

13 Line 521 Line 555 Line 575 Line 578 Line 580 Line 617 OATP1B1/3 substrate appears overly broad. Clarification on whether hepatic elimination refers to unchanged parent drug or includes metabolites (though not sure how/when you would know this)? It is very challenging to identify selective index inhibitors for transporter related DDI studies, and therefore, rifampin (SD) and probenecid can be used as index perpetrators for OATP1B or OAT1 and OAT3 related DDI studies, respectively. However, based upon current scientific literature, a single oral dose of rifampin is not a selective inhibitor of OATP1B as it also is a relatively potent inhibitor of BCRP and a weak inhibitor of P-gp based on in vitro and clinical DDI evaluation (Prueksaritanont et al., 2014, 2017). Likewise, probenecid can also inhibit other organic anion transporters, such as MRP2, in addition to OAT1 and OAT3. Is there any reference information of BCRP inhibition by cyclosporine in clinical studies? Is there any reference information of OCT2 inhibition by cimetidine or pyrimethamine in clinical studies? Based upon current scientific literature, ganciclovir has been identified as a selective substrate for OAT2 rather than OAT1 (Cheng et al., 2012, PMID: ; Mathialagan et al 2017, PMID: ). just being an OATP1B1/3 substrate to necessitate a DDI study. Please clarify. Remove selective inhibitor for both rifampin and probenecid to avoid potential misinterpretation of clinical DDI data, and indicate that they can also inhibit other transporters. Please provide this information in a footnote if available. To ensure consistency, please refer to as OATP1B1/1B3. Please provide this information in a footnote if available. Please change MATE1/2K. to MATE1/2-K Consider removing ganciclovir as an example of an OAT1 index substrate from both the guidance and the companion FDA website of drug development and drug interactions: table of substrates, inhibitors and inducers. Lines Lines repeat lines Please delete or clarify the difference. 13

14 Lines G.1. Line 668 Both negative and positive results are referenced; however there are no criteria to classify results from a cocktail study as such. Given that these studies may be conducted early in the clinical development program and largely informing initial inclusion and exclusion criteria and prior to any preliminary or final assignment of no effect boundaries, criteria for conclusions of negative or positive results should be considered to provide guidance to Sponsors during the continuum of clinical development through labeling expectations. It would be useful if the guidance can specify which CYP enzymes and/or transporters that are considered polymorphic where assessment between poor metabolizers/lack of transporter activity vs extensive metabolizers/high transporter activity has the potential to replace a formal DDI study with a probe substrate. Conclusions from this paper should be taken into consideration for the content of this section of the guidance There appears to be no guidance information on if a drug is substrate for 2 polymorphic enzymes (eg, CYP3A5 and 2D6) Add list of all polymorphic CYP enzymes and/or transporters Please clarify. 14

15 IV. REPORTING AND INTERPRETING STUDY RESULTS Subsection Comment and Rationale Proposed change (if applicable) Lines Lines A truncated AUC (eg AUC(0-72 or 96)) is generally used in case of drugs with long half-life(>200 hrs). A general statement regarding long half life drugs and ways to evaluate its DDI potential should be mentioned Please clarify the following sentence: Sponsors should also report measures of the observed variability of the interaction. Please consider adding. Please clarify. Lines Lines Lines Line 746 Is it referring to summary statistics of exposure (each of AUC and Cmax) ratio? This could not be obtained if parallel study was selected where data w and w/o perpetuator respectively comes from different subjects. It would be helpful if examples of continuous and non-continuous PD endpoints could be given (as in the 2012 guidance) e.g. blood biomarker measured at same times as PK? Outliers can be difficult to define if the study is conducted early in development. There should be some latitude on the prespecification of the outlier criteria. Unclear whether the primary analysis should include these subjects (would assume that it should), or if a secondary analysis is required similar to their outlier request. in addition to the primary pharmacokinetic parameters might be referring to those as output of poppk modeling results but since it s stated after a list of PK exposure parameters more relevant in DDI 15 Please consider adding. Insert the words when possible at the beginning of the paragraph starting on line 723. Clarify what is meant by Sponsors should highlight subjects with more than 20 percent AUC0-inf extrapolated. Does this mean that subjects that fit this description should just be mentioned, or is the Agency requesting analyses with and without these subjects, similar to the request with the outlier data Suggest moving parameters in parenthesis in Line 749 to after primary PK parameters in Line 746

16 Lines Lines Lines Lines assessment, it will help to specify what is meant by primary PK parameters. The guidance states that in some cases NCA may not be adequate and that Pop PK method should be utilized. Recommend softening the language to state that poppk analyses could potentially be used. The stated preferred response is frequently not possible because DDI studies may be conducted prior to administration of drug to patients. This also feels somewhat inconsistent with their earlier request that patients should not be excluded from any clinical study for DDI reasons. Approach 1 (Preferred) No-effect boundaries can be based on concentration-response relationships derived from pharmacokinetic and pharmacodynamic analyses. The agency considers no-effect boundaries based on concentrationresponse relationships preferable to conservative % goal post-based boundaries. This seems to be in conflict with the recommendation for Timing of Clinical DDI Studies to be early where E/R relationships are not likely to be well-characterized. Please clarify the statements on no-effect boundaries in the context of the recommended study timing Sponsor should seek agency agreement on explicit no-effect boundaries in advance of study completion for clarification. Replace should with could potentially at the beginning of Line 755 Insert the words when possible right before No Effect boundaries on line 772 Please clarify. Line 829 Typo CYP substrate Lines Currently, there is no standardized classification system for transporter and phase II metabolizing enzyme inducers or inhibitors. Add a recommendation for expectations of a sponsor when For most studies, these should be relatively straightforward and requiring a milestone meeting to agree seems overly bureaucratic Please add. 16

17 significant UGT-mediated metabolism is expected based on in vitro or clinical metabolite data. Alternatively, is this guidance not applicable to those investigational drugs VI1 ABBREVIATIONS SPECIFIC COMMENTS ON TEXT Subsection Comment and Rationale Proposed change (if applicable) Line 1055 Add MATE - Multidrug and toxin extrusion (transporter) Add PLR as abbreviation> GENERAL COMMENTS: A A section on Organ Impairment & Pediatrics & Geriatrics is not present in this draft as it is in the 2012 draft guidance. B C D E In the In Vitro DDI Study draft guidance document, there is statement on prioritization of in vivo DDI studies when inhibition of multiple CYP enzymes is observed based on in vitro study results. It will be helpful to include the same language in this document or at least refer to the In Vitro DDI Study draft guidance on timing/prioritization of in vivo DDI studies when drug candidates show CYP inhibition potential on multiple enzymes There is a lack of discussion on physiochemical based DDIs (e.g. gastric ph and binding in the gut) No guidance on non-cyp based DDI like other phase 1 enzymes (MAO, FMO, XO ) or UGT even though these are mentioned in the in vitro doc The selection of transporter substrates is not fully transparent. One could interpret the guideline in two ways. Either: as selective transporter substrates do not exist, relevant co-medications which are substrates of the respective transporter should be used in the clinical DDI studies. Suggest adding text on these populations back into the 2017 draft guidance Or : If specific transporter substrates are available, it is recommended to use those, to allow 17

18 F G translation to other substrates in the label. In case no specific transporter substrate exists, it is recommended to use co-medications which are substrates of the respective transporter in the clinical DDI studies Some links did not work. Not sure if the problem is with the link or the website/internet connection. Consider inclusion of decisions trees that were included in the previous version of the guidance H Aldehyde oxidase is missing Add suggestions regarding the approach to AO 18