Use of Bridging Justifications to Support the Safety of Excipients in Generic Drug Products

Transcription

1 Use of Bridging Justifications to Support the Safety of Excipients in Generic Drug Products Sruthi King, Ph.D. Pharmacology/Toxicology Team Leader Division of Clinical Review, Office of Generic Drugs Center for Drug Evaluation Research U. S. Food and Drug Administration May 23, 2017

2 Disclaimer: The opinions expressed in this presentation are those of the speaker and may not reflect the position of the U. S. Food and Drug Administration. 2

3 Outline Excipient Safety Reviews in Generic Drugs Bridging Justifications: What, When, Why Case Studies Summary 3

4 Excipients in Drug Products An excipient is any component other than an active ingredient that is added during the manufacturing process and is present in the final ( to-bemarketed ) drug product (21CFR210.3) Colorings, flavorings, emulsifiers, lubricants, preservatives, solvents Pre-IND Phase 1, 2, 3 clinical trials IND mtg, EOP2 mtg/pre-nda mtg NDA Approval Clinical, Chemistry, Pharm/Tox, Clin Pharm Pre-IND mtg IND 4

5 Safety Review of Excipients in Drug Clinical and nonclinical data may be needed to qualify excipients with no previous history of use in an approved product. Support the route of administration and duration of exposure in the intended patient population. Nonclinical studies can address endpoints (carci, histo, repro, etc.) that are not feasible in clinical trials. Products FDA Guidance for Industry: Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients (May 2005) 5

6 Excipients in Generic Drug Products Generic Drugs must demonstrate bioequivalence to the reference listed drug (RLD), 21 CFR (a)(9) Similarities: active ingredient(s), dosage form, strength, route of administration, conditions of use, manufacturing standards Differences: Excipients Q1/Q2: Products for parenteral, ophthalmic or otic use Exceptions: buffers, antioxidants, and preservatives if information is provided to support their safety We recommend the applicant identify and characterize the differences in excipients and provide information demonstrating that the differences do not affect the safety of the proposed drug product. - Excipient s Guidance 6

7 Safety Review of Excipients in ANDAs Pre-ANDA ANDA Chemistry, Bioequivalence, Labeling, Inspections Approval Controlled Correspondence Safety consult: Pharm/Tox, Clinical Review Cycles New listing on IID 7

8 Inactive Ingredient Database The IID lists the maximum potency of each excipient in an approved product. The maximum potency is the highest level of excipient per unit dose in each dosage form (e.g. oral, topical, etc.). The IID is used by the innovator and future generics. A listing on the IID represents a prior finding of safety for a specific route of administration. 8

9 Safety Review of Excipients in Generics Excipients may impart toxicities and are therefore evaluated for safety from clinical and nonclinical perspectives, on a consult basis. The goal of excipient review within the Division of Clinical Review/Office of Generic Drugs (DCR/OGD) is to ensure that the safety profile of the generic is the same as that of the innovator drug. Clinical (Medical Officers) and Nonclinical (Pharm/Tox) reviewers Our finding of safety of a proposed level of excipient contributes to the Inactive Ingredient Database (IID) Context of use and duration of exposure are a review issue Appropriate justification is needed to make a safety call high quality generics 9

10 Safety Review of Generics: Excipients Guidance Regulatory considerations include: Is there prior evidence of safe use for the proposed dose in an approved product? Has the context of use (route of administration, duration of exposure, target population) been addressed? Will the excipient exacerbate disease state and worsen safety profile of drug product? Are relevant toxicology information available? IF, after review, a gap in safety data remains that warrants additional studies (clinical and nonclinical), THEN, applicant will be advised to Reformulate or pursue a 505(b)(2) pathway. Carcinogenicity studies needed Clinical context of use not justified with nonclinical data alone (e.g., no safety data for the proposed route or patient population) Contact RLD division in Office of New Drugs for further guidance 10

11 Pharm/Tox Review in OGD: Distribution of Work Consult review discipline Assess safety of Impurities, Residual Solvents, Extractables & Leachables, Elemental Impurities, Excipients Apply ICH and FDA guidances to safety review Bridging Justifications are a subset of Excipient Safety Reviews conducted by OGD Pharm/Tox Excipients Bridging justifications Impurities Residual Solvents, E&L Elemental Impurities 11

12 Bridging Justifications: What, When, Why Justifications built on available safety data for one or more compounds for a different compound Use a weight-of-evidence approach to extrapolate the safety of an excipient based on what is known about related compounds Used in NDA and ANDA setting Used when there is a lack of safety information on the excipient of interest 12

13 Bridging Justifications in FDA s Excipient Guidance Large polymers that differ from previously characterized excipients only in molecular weight (chain length) can be adequately characterized in an abbreviated manner using less safety data, provided that the new excipient and the previously studied excipient are sufficiently similar with regard to physical state, pharmacokinetics, and levels of unreacted monomers and other impurities. We will consider such excipients on a case-by-case basis 13 13

14 Use all available data to fully inform safety Can inform target organs, safety signals, tolerability Applicant s justification is essential for review by OGD Data and justification are a pivotal for our review Essential for meeting review timelines Important to understanding the excipient class Reduce animal usage Why Bridging Justifications? 14

15 Bridging and OGD Pharm/Tox: Review Considerations What is the excipient family/class? Has it been reviewed before? What do we know about this grade? What do we know about how this excipient is used? How does the proposed grade differ from other grades with available safety data: Physicochemical characteristics, Function, Manufacturing Process Have we reviewed this specific grade? If yes, in what context? Has the proposed grade been used before in an approved product for the same route of administration? 15

16 OGD Pharm/Tox Review Considerations How does the proposed grade differ from what has been used previously in approved products? What is in the RLD? Were any toxicology data submitted? Can toxicology profile be extrapolated to this grade based on what is known about other grades? Is a bridging justification appropriate for this grade? Where are the gaps in data about this grade? Dose, Duration of Exposure, Patient Population, Route of Administration Apply principles of the Excipients Guidance 16

17 OGD P/T: Bridging Justification Experience OGD Pharm/Tox has reviewed several dozen ANDAs that involved bridging justifications (2014-Present) On occasion, we send an Easily Correctable Deficiency (ECD) to request further information for the bridging justification during our review P/T Team is reviewing bridging justifications within ANDAs without a disproportionate amount of deficiencies 17 17

18 Case Studies Bridge Different Grade Bridge Higher Amount of a Different Grade Bridge Grade and Route of Administration Bridge Grade and Patient Population 18

19 Case 1: Different Grade Rectal suppository formulation for chronic inflammatory bowel disease Proposed maximum daily intake of Excipient A is 500 mg Excipient A is composed of glyceride chains 19

20 Case 1: Applicant s Justification Justification based on available toxicology information on related grades and uses of these grades in pharmaceuticals ADME, local tolerance, systemic toxicity, genotoxicity, carcinogenicity High level description of similarities and differences in chemical properties and manufacturing processes between grades extrapolate to proposed grade Listing on IID and compendial limits of various grades used in products for various routes of administration (oral, vaginal, rectal), GRAS status 20

21 Case 1: OGD Pharm/Tox Safety What Do We Know? Similarities in chemical composition, but specifics not known No known FDA-approved products with proposed grade for the rectal route RLD contains a different grade at similar amount Submitted toxicology data may support systemic and local safety of proposed MDI, if bridge can be made Review Where s the Gap? How does the proposed grade relate to the grades with known safety data? How did we resolve it? ECD requesting more specific information regarding the differences between the proposed grade and grades with known safety information (molecular weight, chain length, viscosity, etc.) Confirmed similarities between proposed grade to grades with known safety information Extrapolated available safety data to proposed MDI for Excipient A Acceptable 21

22 Case 2: Higher Amount of Different Grade Chronically used oral tablet to treat hypertension in adults Excipient B proposed at an MDI higher than approved levels for oral route Other grades of this excipient family are approved at levels higher than proposed MDI of Excipient B 22

23 Case 2: Applicant s Justification IID listing of approved grades with higher MDIs for oral route 23

24 Case 2: OGD Pharm/Tox Safety What Do We Know? Excipient B is used in chronically used oral products of similar context at 50% of proposed MDI RLD contains similar grade Literature review for tox assessment of: Subchronic oral repeated dose toxicology data in one species; chronic toxicology in one species Not genotoxic or carcinogenic Review Where s the Gap? Minimal Data Gaps: (two species chronic tox missing) Recommendation Comparative analysis of grades supports extrapolation of available safety data to proposed grade Prior evidence of safe use in an approved product of similar context + animal tox data with sufficient margins of exposure Totality of evidence supports proposed MDI of Excipient B for chronic oral use in adults Acceptable 24

25 Case 3: Different Route Atypical antipsychotic for use in adults and pediatric patients 10 years and older Two proposed excipients for sublingual route of administration exceed previously approved levels One of the excipients (Flavor C) is a different grade than what is used in currently approved products Other excipient is a Polymer D 25

26 Case 3: Applicant s Justification Minimal justification provided IID citation of excipient family 26

27 Case 3: OGD Safety Review What Do We Know? Grade of flavor different from what is used in RLD Comparative risk assessment proposed polymer grade with what was previously approved in products with similar context of use Physicochemical properties (potential for absorption from oral cavity, molecular weight, etc.) Where s the Gap? Flavor composition Prior evidence of use of proposed flavor Evidence of local and systemic safety How did we resolve it? Sent ECD to obtain flavor composition Conducted literature review: Identified safety data with the proposed grade and approved grades of the excipient 27

28 Case 3: Recommendations Component approach for Flavor C: CFR citation of certain components Considered safety of flavor components after oral and mucosal exposure: Prior evidence of use in approved product with similar route of administration and available toxicology data Polymer grade D: Correlated degree of absorption in oral cavity to molecular weight of polymer Low degree of exposure through oral mucosa Low evidence of local irritation, sensitization Considered oral safety (systemic safety) Weight of evidence approach: Proposed MDIs of Flavor C and Polymer grade D Acceptable 28

29 Case 4: Different Grade and Patient Population Excipient E proposed in an oral suspension product for use in adults and children (2-16 years of age) as an antiepileptic Excipient E is a member of a family of polymers which vary in molecular weight and viscosity Proposed MDI of Excipient E varies with maximum daily dose for each indicated population (MDI range: mg, depending on clinical population) 29

30 Case 4: Applicant s Justification JECFA/WHO summary evaluations on the polymer family Summaries of nonclinical information on higher molecular weight polymer family members (acute, parenteral, acute and chronic exposure, reproductive toxicity, carcinogenicity, genetic toxicology) Two toxicology studies with Excipient E: local tolerance and reproductive toxicity 30

31 Case 4 OGD Safety Review: What Do We Know Proposed MDI is 20-fold higher than approved use of Excipient E for the oral route No approved products with Excipient E for chronic oral use in pediatric patients Approved use of Excipient E limited to drugs with very different context of use Larger fraction of Excipient E likely to be absorbed after oral administration as compared to higher molecular weight polymers: Systemic toxicity in relevant patient population is a concern Submitted available toxicology data with higher molecular weight grades, where absorption after oral administration is less of a concern: Acute and repeat-dose toxicology, genotoxicity data No genotoxicity or chronic toxicology data with Excipient E Submitted reprotox data with Excipient E not complete; not directly applicable 31

32 Case 4: OGD Safety Review Where s the Gap? Absorption and systemic exposure after oral administration Safety of chronic exposure to Excipient C in pediatric patients aged 2 years and up Genotoxicity Reproductive toxicology data or juvenile animal data (bridge if possible to repeat-dose studies in adult animals) Recommendation Bridging justification based on higher molecular weight polymers not acceptable Physicochemical properties of proposed grade of polymer significantly different Proposed MDI Not Acceptable Provide safety information for Excipient E to support use in pediatric patients 2+ years (clinical and/or nonclinical) 32

33 Summary OGD Pharm/Tox reviews Bridging Justifications in the context of ANDAs using the principles described in the Excipients Guidance, similar to the Office of New Drugs Pharm/Tox Bridging Justifications can be useful to: Fill known data gaps regarding context of use Use available data effectively to meet review timelines Reduce animal use by extrapolating known safety data Acceptability of a bridging justification is based on: Similarities and differences between the proposed grade and grades with known safety information Prior evidence of safe use in an approved product of similar context The role of Pharm/Tox in safety review of excipients is to complement available clinical data and inform where there are gaps: Dose, Duration of Use, Patient Population, Route of Administration 33

34 Summary (cont.) Ultimately, our goal is to ensure that a proposed generic does not impose greater risk for potential toxicities and adverse events, as compared to the RLD. 34

35 Acknowledgements DCR Pharm/Tox Team DCR Clinical Consult Team DCR Management 35

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