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

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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.

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Outline

• Excipient Safety Reviews in Generic Drugs

• Bridging Justifications: What, When, Why

• Case Studies

• Summary

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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-be-marketed”) drug product (21CFR210.3)

– Colorings, flavorings, emulsifiers, lubricants, preservatives, solvents

Pre-IND

IND

NDA Approval

Clinical, Chemistry, Pharm/Tox, Clin Pharm

Pre-IND mtg

Phase 1, 2, 3 clinical trials IND mtg, EOP2 mtg/pre-NDA

mtg

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Safety Review of Excipients in Drug Products

“FDA Guidance for Industry: Nonclinical Studies for the Safety Evaluation of Pharmaceutical

Excipients” (May 2005)

• 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.

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Excipients in Generic Drug Products

• Generic Drugs must demonstrate bioequivalence to the reference listed drug (RLD), 21 CFR 314.94(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

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Safety Review of Excipients in ANDAs

ANDA

Review Cycles

Approval

Pre-ANDA Chemistry, Bioequivalence,

Labeling, Inspections

Safety consult: Pharm/Tox,

Clinical

Controlled Correspondence

New listing on IID

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• 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.

– http://www.accessdata.fda.gov/scripts/cder/iig/index.Cfm

• A listing on the IID represents a prior finding of safety for a specific route of administration.

Inactive Ingredient Database

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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

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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

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Impurities

Residual Solvents,

E&L

Elemental Impurities

Excipients Bridging justifications

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

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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

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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”

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• 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?

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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?

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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

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• 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

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OGD P/T: Bridging Justification Experience

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Case Studies

• Bridge Different Grade

• Bridge Higher Amount of a Different Grade

• Bridge Grade and Route of Administration

• Bridge Grade and Patient Population

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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

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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

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Case 1: OGD Pharm/Tox Safety Review

• 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

How does the proposed

grade relate to the grades

with known safety data?

• 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

What Do We Know?

Where’s the Gap?

How did we resolve it?

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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

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Case 2: Applicant’s Justification

• IID listing of approved grades with higher MDIs for oral route

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Case 2: OGD Pharm/Tox Safety Review

• 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

Minimal Data Gaps: (two

species chronic tox missing)

• 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

What Do We Know?

Where’s the Gap?

Recommendation

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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

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Case 3: Applicant’s Justification

• Minimal justification provided

• IID citation of excipient family

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Case 3: OGD Safety Review

• Sent ECD to obtain flavor composition

• Conducted literature review: Identified safety data with the proposed grade and approved grades of the excipient

• 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.)

What Do We Know?

Where’s the Gap?

How did we resolve it?

• Flavor composition • Prior evidence of use of

proposed flavor • Evidence of local and

systemic safety

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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

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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: 960-480 mg, depending on clinical population)

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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

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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

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Case 4: OGD Safety Review

• 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)

• 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)

Where’s the Gap? Recommendation

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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

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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.

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Acknowledgements

DCR Pharm/Tox Team

DCR Clinical Consult Team

DCR Management